Reviews

INTRODUCTION

Hodgkin lymphoma, previously known as Hodgkin’s disease, is a B-cell malignancy with unique pathological and epidemiological features for which highly effective therapies exist. The disease is characterized by the presence of mononuclear and multinucleate giant cells called Hodgkin and Reed-Sternberg (HRS) cells.¹

Hodgkin lymphoma is unique compared to other B-cell lymphomas because of the scarcity of the malignant cells in the tumor tissue. The HRS cells usually account for only 0.1% to 10% of the cells in the affected tissues, and the HRS cells induce accumulation of nonmalignant lymphocytes, macrophages, granulocytes, eosinophils, plasma cells, and histiocytes, which constitute more than 90% of tumor cellularity.² Although the disease was first described by Sir Thomas Hodgkin in 1832, in part because of this unique histopathology, not until 1991 was it conclusively demonstrated that HRS cells are in fact monoclonal germinal center–derived B-cells. This article reviews management and frontline treatment options for limited-stage classical Hodgkin lymphoma and nodular lymphocyte predominant Hodgkin lymphoma. Treatment of advanced stage and relapsed/refractory Hodgkin lymphoma will be discussed in a separate article.

EPIDEMIOLOGY

Hodgkin lymphoma accounts for 0.5% of all malignancies and 11.7% of all lymphomas among adults in the United States.³ The incidence of Hodgkin lymphoma has been steadily increasing over the past 4 decades and was estimated to be 8260 cases in the United States in 2017, with a slight male predominance. Hodgkin lymphoma is expected to cause 1070 deaths in 2017, accounting for 0.2% of all cancer deaths.³ First-degree relatives of patients with Hodgkin lymphoma have a 3- to 9-fold increased risk of having the disease compared to the general population,⁴ and monozygotic twin siblings of Hodgkin lymphoma patients have a greatly increased risk for developing the disease—up to 100-fold—compared to normal cohorts.⁵ The incidence is highest among Caucasians, African Americans, and Hispanics, and lower in Asians and American Indians.³ Hodgkin lymphoma incidence shows a bimodal peak distribution, with 1 peak between the ages of 15 and 44 years, and another peak after age 65 years.⁶

ETIOLOGY/PATHOGENESIS

The cause of Hodgkin lymphoma is unknown. Epstein-Barr virus (EBV) infection is present in up to 40% of Hodgkin lymphoma cases, suggesting a role of this virus in the pathogenesis of some cases. The risk of EBV-positive Hodgkin lymphoma was found to be higher following an episode of infectious mononucleosis, while the risk of EBV-negative Hodgkin lymphoma remained unchanged.⁷ The incidence of Hodgkin lymphoma is 5 to 14 times higher in HIV-infected patients than in noninfected patients.⁸ It is not considered an AIDS-defining illness, but has become more frequent with the growth and aging of the HIV-positive population.^9,10 Hodgkin lymphoma patients with HIV typically have CD4 lymphocyte counts greater than 200 cells/μL,¹¹ with the incidence of Hodgkin lymphoma actually declining with lower CD4 lymphocyte counts.¹² HIV-related Hodgkin lymphoma tends to have an aggressive course, with high rates of EBV positivity.¹³ The incidence of Hodgkin lymphoma is 1.8 times higher among smokers, and the risk appears to increase with duration of smoking.^14,15

The cell of origin of Hodgkin lymphoma, while long suspected to be the HRS cell, remained unproven until the 1990s when micro-dissection and single-cell polymerase chain reaction techniques allowed for confirmation that the HRS cell was in fact a monoclonal germinal center derived B cell.^16,17 These HRS cells lack immunoglobulin due to defective transcription regulation and not due to crippling mutations.^18,19 The cellular infiltrate in Hodgkin lymphoma appears to play a decisive role in allowing the HRS cells to survive by providing an environment that suppresses cytotoxic immune responses as well as by providing cellular interactions and cytokines that support their growth and survival. The extensive inflammatory infiltrate in classical Hodgkin lymphoma is comprised of T helper 2 (Th2) and regulatory T cells and lacks T helper 1 (Th1) cells, CD8 cytotoxic T cells, and natural killer cells.²⁰ The HRS cells escape apoptosis by several mechanisms which include latent EBV infection and constitutive nuclear factor (NF)-kB pathways, as well as other deregulated signaling pathways that promote survival, such as EBV nuclear antigen 1 (EBNA1) protein, EBV latent infection membrane protein 1 (LMP1), and LMP2.^21,22

Genetic alterations in the 9p24 locus which encodes PD-L1/PD-L2 are nearly universally present in classical Hodgkin lymphoma and are now considered a disease-defining feature.²³

According to the 2008 World Health Organization (WHO) classification, Hodgkin lymphoma has 2 clearly defined entities: classical Hodgkin lymphoma (cHL), which accounts for approximately 95% cases, and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), which accounts for the remaining cases.²⁴ These 2 entities differ in their clinical, pathological, and biological features, which in turn affect prognosis and treatment options. Classical Hodgkin lymphoma is characterized by a paucity of HRS cells surrounded by a background of mixed inflammatory infiltrate comprised of histiocytes, small lymphocytes, eosinophils, neutrophils, plasma cells, fibroblasts, and collagen. Depending on the particular combinations of these elements and the specific features of the neoplastic cells, cases can be subclassified into several cHL subtypes: the nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted types.²⁵

The diagnosis of cHL is made based on a combination of morphology of HRS cells and the other cells infiltrating the tissue, combined with immunohistochemical staining. Because of the rare nature of the malignant (clonal) cell in Hodgkin lymphoma specimens, flow cytometry is generally of little value. The HRS cells in cHL are CD30-positive and CD45 negative in virtually all cases, and CD15-positive in 85% of cases.²⁶ B-cell antigens are typically negative except for CD20, which is positive in about 20% cases.²⁷

Nodular sclerosis Hodgkin lymphoma (NSHL) is the most common subtype of cHL, accounting for 65% to 75% of cases. It is common among young adults and tends to involve the mediastinal, supraclavicular, and cervical lymph nodes. NSHL is characterized by the presence of collagen bands that divide the lymphoid tissue into circumscribed nodules. This subtype usually presents as stage I or II disease, typically with neck and/or mediastinal disease, and evidence of EBV infection is present in approximately 10% to 40% of North American cases.⁷ Patients diagnosed with NSHL generally have a very good prognosis.

Mixed cellularity Hodgkin lymphoma (MCHL) constitutes about 20% to 25% of cHL cases. It affects a somewhat older population, with a median age at diagnosis of 38 years. The typical bimodal age distribution is not seen with MCHL. MCHL has a male predominance (70%), and is more frequent in HIV-infected patients (70% of whom also have EBV infection). Lymphoid tissues have classic HRS cells and significant inflammatory infiltrates. Approximately 50% of patients with MCHL present as stage III or IV with abdominal lymphadenopathy or splenic involvement, and B symptoms are frequent.²⁴

Lymphocyte-rich Hodgkin lymphoma (LRHL) is uncommon, accounting for only 3% to 5% of cases of cHL.²⁸ The disease usually presents at an older age and has a 2:1 male predominance. HRS cells are commonly seen and a large number of reactive lymphocytes are also present. Although on the basis of morphology and immunohistochemistry LRHL belongs to the cHL group, clinically it more closely resembles LPHL. Patients usually present at early stage and rarely have B symptoms. LRHL carries an excellent prognosis, with a greater than 90% PFS after 5 years.^23,29

Lymphocyte-depleted Hodgkin lymphoma (LDHL) is the least common form of cHL, accounting for less than 5% of cases. Many cases previously placed in this category are now recognized as diffuse large B-cell lymphoma (DLBCL), anaplastic large-cell lymphoma (ALCL), or NSHL with lymphocyte depletion.³⁰ HRS cells are frequently seen, but reactive inflammatory cells are relatively sparse. EBV infection is seen in up to 90% of cases, commonly associated with HIV-infected individuals. Advanced-stage and symptomatic disease are more common. Prognosis is slightly worse compared to other categories.

NLPHL accounts for approximately 5% of cases of Hodgkin lymphoma. It has a unimodal age distribution, with the peak incidence in the fourth decade, and male predilection of 3:1.²⁸ NLPHL is characterized by large primary lymphoid follicles, with polytypic small B lymphocytes and extensive meshworks of follicular dendritic cells. The lymphocytic/histiocytic (L and H), or “popcorn,” cells scattered within the nodules differ from classic HRS cells, both in their morphology and in their biochemical profile, being frequently negative for CD15, CD30 and for the EBV genome, and usually positive for B-cell antigens such as CD20, suggesting that L and H cells may be immunoglobulin-synthesizing monoclonal B cells. CD45 is also typically positive in NLPHL, in distinction from cHL. NLPHL has an indolent course compared to cHL, and long-term survival is common.^19,31 NLPHL commonly presents with limited-stage disease. NLPHL may eventually transform into a more aggressive lymphoma, such as diffuse large B-cell lymphoma (including centroblastic, immunoblastic, or T-cell/histiocyte–rich subtypes), at a rate of 4% to 12%. This can occur even 15 to 20 years after the initial diagnosis of NLPHL.^32,33 In a recent large retrospective study of 222 patients with NLPHL, the rate of transformation to DLBCL was 7.6%, with a median time to transformation of 35 months. Overall survival was not adversely affected in patients undergoing transformation compared to those without transformation.³⁴

PRESENTATION

Classical Hodgkin lymphoma usually presents with asymptomatic mediastinal or cervical lymphadenopathy. Half of patients present with stage I or stage II disease.³⁵ A mediastinal mass is seen in most patients with NSHL, at times with bulky disease, with “bulky” defined as a mediastinal mass measuring one-third or more of the maximal thoracic diameter on chest x-ray, or 10 cm on computed tomography (CT) scan. Systemic symptoms, or "B" symptoms—fevers (> 38°C), drenching night sweats, and unexplained weight loss (> 10% of baseline body weight over the preceding 6 months or less)—are detected in approximately 25% of patients. Between 10% and 15% will have extranodal disease, most commonly involving lung, bone, and liver. NLPHL usually presents with limited-stage disease without B symptoms; it typically has a more indolent presentation and clinical course than cHL.

The initial workup includes a complete blood count (CBC), erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH), and chemistry studies to evaluate renal function and liver function. Fine-needle aspiration will usually fail to identify the infrequent HRS cells, and instead only reveal the reactive background of inflammatory cells. Generous (large gauge) core needle biopsies may provide diagnosis effectively in some cases, but in general, an excisional lymph node biopsy is preferred to ensure an accurate diagnosis and avoid the need for repeated biopsy procedures. In cases where an excisional biopsy would be difficult or risky, a core needle biopsy procedure is a reasonable first step, with the understanding that a subsequent surgical procedure may still be necessary.

Baseline imaging includes CT scans of the neck, chest, abdomen, and pelvis. Use of positron emission tomography (PET) scanning is now standard in the initial evaluation and assessment of treatment response in Hodgkin lymphoma.³⁶ Due to the increased sensitivity of PET or PET/CT scan, additional lesions may be identified that were not seen on conventional CT scans. This will alter the staging, and potentially the treatment plan, in up to 25% to 30% of patients.^37,38 PET/CT scan performed during initial evaluation also facilitates optimal interpretation of post-therapy PET/CT scans and is therefore strongly encouraged as a part of the initial staging evaluation.³⁹

Recent studies have shown that bone marrow biopsy is not routinely needed in the initial staging of cHL. A study of 454 patients concluded that bone marrow biopsy would not have altered the stage in any stage I or II patients. It was further concluded that overall treatment strategy would not have been altered for any of the patients.⁴⁰ Based on this study and others, it is now clear that FDG-PET has a high sensitivity, and when PET scan is negative (in the bone marrow and skeleton), a bone marrow biopsy provides little additional value. For patients with significant cytopenias, a bone marrow biopsy is reasonable. Such patients may benefit from a bilateral biopsy, which increases the probability of demonstrating bone marrow involvement by 16% to 33%.^41,42 Techniques such as staging laparotomy and lymphangiography are now considered obsolete.

Hodgkin lymphoma is staged according to the Ann Arbor staging system (Table 1). The original Ann Arbor staging was published in 1971,⁴³ and in 1989 the “Cotswold modifications” extended the definitions of stage IV disease and the suffix “X” was added to denote bulky disease.⁴⁴ Both systems were developed for the staging of Hodgkin lymphoma, but are now used for staging non-Hodgkin lymphoma as well.

PROGNOSTIC FACTORS

For the purposes of prognosis and selection of treatment, Hodgkin lymphoma is commonly classified into early-stage favorable, early-stage unfavorable, and advanced stage. Early-stage Hodgkin lymphoma refers to patients with Ann Arbor stage I or stage II disease. With early-stage Hodgkin lymphoma, the prognosis varies significantly based on factors such as the presence of B symptoms, elevated erythrocyte sedimentation rate ([ESR] > 50 mm/hr), number of nodal sites involved, older age, and a large mediastinal mass. For this reason, most clinical trials to evaluate treatment strategies for early-stage Hodgkin lymphoma are based on various combinations of these risk factors. The definition of early-stage unfavorable Hodgkin lymphoma varies across different clinical trial study groups, and it is important to understand the definition in interpreting the results of these trials (Table 2).^45,46

In the German Hodgkin Study Group (GHSG) trials, early-stage Hodgkin lymphoma is stratified into a high risk (“unfavorable”) group defined by any of the following: a large mediastinal mass (one third of maximum thoracic diameter), extra-nodal disease, 3 or more nodal areas, and an ESR of > 50 mm/hr in asymptomatic patients or > 30 mm/hr in patients with B symptoms. Low-risk (“favorable”) patients lack all of these factors.⁴⁷ The European Organization for Research and Treatment of Cancer (EORTC) defines the unfavorable prognostic group as older than 50 years of age, large mediastinal adenopathy (maximum width on a chest radiograph of at least one third of the internal transverse diameter of the thorax at the level of T5 through T6 or any mass of ≥ 10 cm in the largest dimension), an ESR of 50 mm/hr and no B symptoms, or with an ESR of 30 mm/hr in those who have B symptoms, and/or 4 or more regions of involvement.⁴⁸ The National Cancer Institute of Canada (NCIC) Clinical Trials Group and the Eastern Cooperative Oncology Group (ECOG) define high-risk groups as presence of B symptoms, bulky disease with a mediastinal mass width of at least one third of the maximum chest wall diameter, or any mass greater than 10 cm, and patients with intra-abdominal disease.^49,50

Gene-expression profiling in Hodgkin lymphoma has identified a gene signature of tumor-associated macrophages that was able to identify patients with a higher risk for primary treatment failure. In an independent cohort of patients, an increased number of CD68-positive macrophages was correlated with inferior outcomes.^51,52 Studies such as these underscore the importance of the tumor “microenvironment” (ie, the nonmalignant cells within a tumor) in determining the overall clinical behavior of a malignancy. While quantification of CD68-positive macrophages has potential to be applied to routine clinical practice, prospective data using CD68 as a tool for risk-adapted therapy is lacking.

Genetic alterations and amplifications in the 9p24.1 locus have recently been found to be a defining genetic feature of cHL. Amplification of 9p24.1 has been associated with unfavorable outcomes. Amplification of 9p24.1 (which includes the loci encoding the PD-L1 and PD-L2 genes) is more common in patients with advanced stage disease and is associated with shorter PFS.²³

A recent study attempted to integrate several different prognostic factors in cHL patients who were treated with ABVD (adriamycin [doxorubicin], bleomycin, vinblastine, and dacarbazine) and underwent an interim PET (iPET) scan after 2 cycles of ABVD. Focusing on those with a negative iPET scan, it was found that expression of CD68 and PD-1 in microenvironment cells, and STAT1 negativity in HRS cells identified a subset of PET-2 negative patients with a 3-year PFS significantly lower than that of the remaining PET-2 negative population (64% versus 95%). The algorithm correctly predicted the response to treatment in more than half of the patients who had relapse or disease progression despite a negative PET-2 scan. It therefore appears feasible, using tissue biomarkers at diagnosis, to identify patients at increased risk for poor outcome, even if the iPET scan is negative.⁵³

ROLE OF PET/CT IN ASSESSMENT OF RESPONSE TO THERAPY

PET/CT has been increasingly used for response assessment at various stages in lymphoma in recent years. Almost all types of lymphomas are fluorodeoxyglucose (FDG) avid; however, Hodgkin lymphoma is FDG avid in 97% to 100% of cases. In 2009, a 5-point scale was developed to score PET images with regard to treatment response, either partway through treatment (iPET) or at the end of therapy.⁵⁴ It was recommended as the standard reporting tool at the First International Workshop on PET in Lymphoma in Deauville, France, in 2009, and is thus now referred to as the Deauville score. A score of 1 is given if there is no uptake, 2 if the uptake ≤ mediastinum, 3 if > mediastinum but ≤ liver, 4 if uptake moderately higher than liver, 5 if uptake is markedly higher than liver and/or new lesions. X designates new areas of uptake unlikely to be related to lymphoma. In most trials, a score of 1 or 2 is considered a complete response and a score of 4 or 5 is considered a treatment failure. A score of 3 is sometimes considered a complete response, depending on the study. The Deauville criteria have been widely used in newer clinical trials utilizing response-adapted treatment as defined by PET response. PET/CT is recommended for staging and restaging at the end of therapy, in clinical practice, and clinical trials. Interim PET/CT scan, while commonly performed in clinical practice, is only recommended if the results will alter therapy (eg, if that information will result in the clinician omitting radiation therapy [RT] or altering the chemotherapy plan).

Early studies of iPET showed that achieving PET negativity early in the course of treatment was strongly associated with PFS and overall survival.⁵⁵ Subsequent studies confirmed the importance of achieving a negative iPET. As a result, considerable efforts have been put into designing response-adapted treatment approaches using iPET (see Treatment section), with some of these approaches now being listed in the National Comprehensive Cancer Network (NCCN) guidelines and being used in standard practice.

TREATMENT

EVOLUTION OF TREATMENT

The treatment of Hodgkin lymphoma has evolved over the past century, starting with the discovery of RT as effective treatment in the early 20th century. Long-term survival of patients with Hodgkin lymphoma treated with involved-field radiation therapy (IFRT) was first reported in the 1960s.^56,57 Outcomes improved further with the introduction of combined modality treatment (CMT) using chemotherapy and RT, with the overall 5-year relative survival for patients with Hodgkin lymphoma (all stages) treated in 2006–2012 being 85.4% to 87.3%.³ Since the majority of patients are now cured with modern therapy, treatment-related complications have become an important competing cause of mortality. Recent studies have therefore focused on maintaining efficacy while reducing toxicities, and refining the process of selecting patients who might benefit from more aggressive therapy. While RT was the first treatment modality shown to be curative for Hodgkin lymphoma,^56,57 multiple subsequent studies showed that CMT is superior to RT alone in terms of relapse-free survival.^58–63 In the GHSG H8-F trial, the estimated 5-year event-free survival and overall survival rates were significantly higher after 3 cycles of MOPP-ABV (mechlorethamine, vincristine, procarbazine, and prednisone combined with doxorubicin, bleomycin, and vinblastine) plus IFRT than after subtotal nodal radiotherapy alone. The 10-year overall survival estimates were 97% and 92%, respectively (P = 0.001).⁶⁴ As a result, CMT replaced RT alone as the standard of care for limited-stage Hodgkin lymphoma. However, for elderly or infirm patients, or those with other comorbidities making them poor chemotherapy candidates, RT alone may be a very reasonable option.⁶⁵ More recently, an increasing body of evidence has accumulated to support the use of chemotherapy alone in early stage cHL. This literature has consistently shown that omission of RT is associated with a modest increase in relapse, without a clear compromise in long-term overall survival. For some patients, the trade-off in terms of avoiding radiation (and the associated late effects) may be worth the small increase in relapse risk, since long-term survival does not appear to be substantially worse with chemo-therapy alone. Table 3 and Table 4 provide a summary of recent key studies which have defined treatment options for early-stage cHL.^48,66–71

NLPHL usually presents with limited-stage disease without B symptoms and has an indolent course with a slightly better prognosis compared to cHL.⁷² Due to the rarity of the disease, treatment guidelines are mostly based on retrospective analyses from single or multi-institution studies or subgroup analyses, often with relatively short follow-up. These studies must be interpreted with caution because of the possibility of inaccuracies in the pathologic diagnosis, small sample sizes, and selection bias. Treatment options for limited-stage NLPHL include observation, single-agent rituximab, IFRT (or involved-site radiation therapy [ISRT]) alone, or CMT.⁴⁶

Historically, patients with limited-stage NLPHL have been treated with RT alone, with 80% to 85% PFS and 85% to 95% overall survival rates.^73–75 Patients who relapse or progress after RT in general can successfully undergo salvage therapy.⁷⁴ In one study, rates of PFS and overall survival were similar among patients who had limited-field, regional-field, or extended-field RT,⁷⁵ indicating that IFRT is preferred. Studies comparing RT alone and CMT are limited. The GHSG HD7 trial included a subset of NLPHL patients, with a trend towards improved freedom from treatment failure (96% versus 83%) favoring CMT. This, however, did not translate into improved overall survival.⁴⁷ A retrospective analysis of the British Columbia Cancer Agency database compared patients with limited-stage NLPHL treated with RT alone to patients who received 2 cycles of ABVD followed by RT. A significant improvement in PFS (91% versus 65%) and overall survival (93% versus 84%) was seen, favoring CMT.⁷⁶

Chemotherapy alone is not recommended for limited-stage NLPHL since studies evaluating chemotherapy alone are quite limited and indicate relatively high rates of treatment failure. Given that the malignant cells in NLPHL are CD20-positive, single-agent rituximab has also been studied in this disease, including a study as frontline therapy in limited-stage patients. In this phase 2 trial in newly diagnosed patients with stage IA disease, an overall response rate (ORR) of 100% was seen, with an 85% complete response (CR) rate.⁷⁷ At 3 years, overall survival was 100% and PFS was 81%, indicating that the responses with single-agent rituximab are less durable than those with RT.

Advani et al evaluated rituximab followed by observation versus rituximab (R) followed by maintenance rituximab (MR) for 2 years in 39 new or previously treated patients. At 4 weeks the ORR was 100% (with CR in 67%, and partial response in 33%). At a median follow up of 9.8 years for R alone, and 5 years for R+MR, median PFS was 3 and 5.6 years, respectively (P = 0.26). Estimated 5-yr PFS and overall survival in patients treated with R versus R+MR were 39.1% and 95.7% versus 58.9% and 85.7%, with Pvalues of 0.26 (PFS) and 0.38 (overall), respectively. Maintenance rituximab therefore appears to prolong remission, although the results did not quite reach statistical significance.⁷⁸ Even though rituximab does not appear to be curative in NLPHL, it is a reasonable option for patients with early-stage NLPHL who are not good candidates for definitive RT. Whether combining rituximab with RT or CMT might further improve outcomes in early-stage NLPHL has not yet been determined.

In children, surgery alone may lead to long-term remission or possibly cure of limited-stage NLPHL. In a European multicenter retrospective study, 58 patients underwent surgery for limited-stage NLPHL. Among the 51 patients who achieved complete remission following surgery, 67% remained progression-free and 100% were alive at a median follow up of 43 months.⁷⁹ In adults, there is no data to support surgical treatment alone for NLPHL. Finally, observation may be a reasonable option in elderly or infirm patients for whom NLPHL is unlikely to affect life expectancy. For younger patients, given the excellent outcome with modern therapy and the long-term risk of transformation of NLPHL into an aggressive non-Hodgkin lymphoma, observation is generally not recommended.

The NCCN recommends RT (ISRT or IFRT, 30–36 Gy) as the preferred treatment for stage IA and IIA non-bulky NLPHL. In patients with stage IA disease with complete excision of solitary nodule, observation may be appropriate. A course of chemotherapy with ISRT with or without rituximab is recommended for patients with stage IB or IIB disease, or patients with stage IA or IIA bulky disease.

FIRST-LINE TREATMENT OF LIMITED-STAGE CHL

Early-Stage Favorable cHL

There is lack of consensus regarding the ideal treatment approach for patients with early-stage favorable cHL. However, there are several excellent options available, with overall survival rates exceeding 90%. Most of these regimens involve CMT, although some chemotherapy-alone approaches have been evaluated as well. Concurrent with the demonstration of excellent long-term remission rates with CMT, it became apparent that the long-term survival and quality of life of these patients is determined in large part by the risk of serious (and potentially fatal) treatment-related toxicities. Such toxicities consist primarily of secondary malignancies and cardiovascular events, and can continue to cause significant morbidity and mortality even 2 to 3 decades after treatment.^80–82 As a result, treatment decisions for these patients are complicated and require balancing efficacy against risk of late complications.

In the United States, until recently, CMT was generally considered the standard of care, with robust long-term data regarding efficacy. The most commonly used regimen has been ABVD for 2 to 4 cycles followed by IFRT. In some German studies, escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) has been used, but this is not a general standard of care in the United States for early-stage patients.

More recent data suggests that the rate of serious late complications in Hodgkin lymphoma patients is decreasing, likely due to less extensive radiation fields, lower radiation doses, and a movement away from the MOPP regimen to ABVD.^83,84 For patients who meet the “favorable” criteria set forth in the GHSG HD10 trial (see Table 2), 2 cycles of ABVD followed by 20 Gy of IFRT is an attractive option, with efficacy preserved and a low anticipated rate of late effects.⁶⁶ With this approach, and with long-term (10 years) follow up, all 4 arms had similar PFS (87%) and overall survival (94%), whether 2 or 4 cycles of ABVD were given. When the effects of 20-Gy and 30-Gy doses of RT were compared, there were also no significant differences in freedom from treatment failure or overall survival. Adverse events and acute toxic effects of treatment were most common in the patients who received 4 cycles of ABVD and 30 Gy of RT.^66,71

In recent years, in an attempt to reduce late effects further, regimens consisting of chemotherapy alone have been investigated. In a study by Meyer et al, at 12 years the rate of overall survival was 94% among those receiving ABVD alone, as compared with 87% among those receiving subtotal nodal RT; the rates of freedom from disease progression were 87% and 92% in the 2 groups; and the rates of event-free survival were 85% and 80%, respectively.⁵⁰ However, it is important to note that this study did not include a CMT arm for the early favorable patients, and did not utilize modern RT techniques. Nevertheless, this early study and others⁶⁰ suggested that chemotherapy alone may be a reasonable option for some early-stage cHL patients, particularly for patients who are felt to be at increased risk for late toxicities from RT. As a result, additional studies have been conducted evaluating CMT versus chemotherapy alone for early-stage cHL. Many of these studies have incorporated interim PET/CT scan to develop a response-adapted approach to decide which patients are least likely to benefit from RT.

The HD-13 study was a follow-up study for HD-10, looking at deletion of bleomycin, dacarbazine, or both from the ABVD backbone. The ABD arm was closed early, because of an excess rate of treatment failure. Among the 1243 patents assigned to either the ABVD or AVD arm at 5 years of follow-up, there was 4.3% difference in PFS. This study was not able to demonstrate that 2 cycles of AVD was noninferior to 2 cycles of ABVD, each followed by 30 Gy IFRT, even though there was no difference in all 4 groups. It confirmed 2 cycles of ABVD as the preferred regimen in early favorable Hodgkin lymphoma, when CMT is the plan of care. However, for patients over age 60 to 65 years, or those with underlying cardiac or pulmonary comorbidities, bleomycin has significant risk of toxicity. In that setting, AVD is a safer option, with only a very modest decrease in 5-year PFS.

Based on the observation that iPET scan is highly predictive of outcome in Hodgkin lymphoma,^55,85 several trials have employed the use of an iPET scan to guide therapy. It is hoped that such studies will lead to new PET-directed treatment algorithms in which patients who require more aggressive therapy (eg, with CMT, or escalated BEACOPP) can be identified, and the remaining patients can be safely treated less aggressively (eg, with chemotherapy alone).

In the EORTC H10 trial, performed to evaluate treatment adaptation on the basis of iPET scan results in stage I and II Hodgkin lymphoma, a control arm received standard combined modality treatment (3 or 4 cycles of ABVD with INRT) irrespective of PET scan results. In the experimental arm, patients with a negative PET scan after 2 cycles of ABVD continued with 1 or 2 cycles of ABVD and did not receive RT. The iPET-positive patients received either standard treatment with ABVD plus INRT or escalated BEACOPP plus INRT. The iPET-negative patients received either ABVD only or ABVD plus INRT. The final results of this study, published recently, showed that in the iPET-positive patients the 5-year PFS was improved from 77.4% with standard ABVD plus INRT to 90.6% with escalated BEACOPP plus INRT (P = 0.002). In iPET-negative patients, 5-year PFS in the favorable group was 99% versus 87.1% in favor of ABVD plus INRT. The H10 study suggested that PET results after 2 cycles of ABVD can be integrated into treatment planning, In iPET-negative patients, the study was technically not able to demonstrate the noninferiority of the ABVD only regimen, owing to a higher risk of relapse if INRT is omitted, particularly in the favorable group.⁴⁸ However, this study does show that excellent outcomes can be obtained with omission of RT in patients with a negative iPET scan. This study provides a cautionary lesson though, in that the increase in relapse rate associated with omission of RT was more substantial (12%) for favorable versus unfavorable early-stage patients (2.5%), and this difference was only apparent after longer (5 years) follow-up. Despite this, chemotherapy alone is considered a reasonable treatment option, especially for patients felt to be at increased risk for late toxicities of RT or for patients who wish to avoid the risks of RT, with over 99% of patients alive at 5 years.

Similar results were shown in the RAPID trial, in which patients with limited-stage cHL underwent 3 cycles of ABVD followed by PET assessment.⁶⁷ Patients with a negative PET (n = 426) were then randomized to RT (n = 209) versus no further therapy (n = 211). At a median of 60 months of follow-up, 3-year PFS was 94.6% in the RT group and 90.8% in the chemotherapy alone group. Similar to the H10 trial, it was concluded that chemotherapy alone was statistically inferior to CMT in terms of PFS. However, also similar to the H10 trial, the RAPID trial demonstrated that excellent results can be obtained in early-stage cHL patients with omission of RT, if iPET scan is negative after 3 cycles of ABVD, as there was no survival difference. These findings indicate that, when relapses occur as a result of omission of RT, such patients can be effectively treated later.

In the ongoing GHSG HD16 trial, patients with early-stage favorable cHL will be randomly assigned to a standard approach (ABVD × 2 cycles followed by 20-Gy IFRT) versus an experimental approach in which they receive ABVD for 2 cycles and then undergo PET scan. If the PET remains positive, they will receive 20-Gy IFRT. If the PET is negative, they will receive no further therapy. This trial could ultimately define ABVD for 2 cycles as a treatment option.

It is clear from these studies that omission of RT results in a somewhat higher rate of relapse but can be considered in selected patients. However, taking a less aggressive frontline approach may also be justified by the fact that, for those who do relapse, successful salvage therapies are available. Aggressive salvage therapy with autologous stem cell transplantation historically can cure approximately 50% of relapsed patients. With new and emerging therapies for relapsed disease, such as brentuximab vedotin and the PD-1 inhibitors (eg, nivolumab and pembrolizumab), the ability to cure relapsed patients may improve even more, further calling into question the practice of applying CMT uniformly for early-stage patients undergoing first-line therapy. Unfortunately, there is insufficient data from large randomized studies with long-term follow-up to fully address this issue currently, and there remains some controversy around this issue. NCCN recommends restaging PET/CT after 3 cycles of ABVD if a chemotherapy alone treatment modality is chosen. If the Deauville score is 1 or 2, either observation or 1 additional cycle of ABVD is recommended.⁴⁶

Early-Stage Unfavorable cHL

In the United States, historically early-stage unfavorable Hodgkin lymphoma has been treated with CMT, most commonly 4 to 6 cycles of ABVD followed by consolidative RT. With this approach one can expect a 5-year PFS of approximately 80% to 85%.^58,64,86 The GHSG HD8 trial showed that RT volume size reduction from extended-field to involved-field after COPP + ABVD chemotherapy for 2 cycles produced similar results and less toxicity in patients with early-stage unfavorable cHL.⁸⁶ The GHSG trial HD11 established ABVD for 4 cycles plus 30-Gy IFRT as a standard for early unfavorable Hodgkin lymphoma. The freedom from treatment failure at 5 years was 85.0%, and overall survival was 94.5%.⁶⁸

In the HD14 study by the GHSG, patients with early unfavorable cHL were treated with 2 cycles of escalated BEACOPP followed by 2 cycles of ABVD, versus 4 cycles of ABVD. All patients then received 30 Gy of consolidative IFRT. A 5-year PFS of 95% was seen in the experimental arm, compared with 89% in the standard (ABVD) arm. As expected, this regimen was associated with more acute hematologic toxicity, and there was no difference between the 2 regimens with respect to overall survival or fertility.⁶⁹ Given the lack of improved survival and increased toxicity, ABVD has remained the standard chemotherapy regimen for early unfavorable cHL in the United States. NCCN recommends a restaging PET scan after 2 cycles of ABVD and to continue with 2 to 4 cycles of ABVD or escalated BEACOPP with or without ISRT based on Deauville scores.

Another viable treatment option is the Stanford V regimen, a condensed, 12-week regimen that includes mechlorethamine, doxorubicin, vinblastine, prednisone, vincristine, etoposide, and bleomycin, followed by IFRT.⁸⁷ In a randomized phase 3 trial conducted by ECOG (E2496), patients with stage I/II Hodgkin lymphoma with bulky mediastinal disease or advanced-stage disease were randomized to ABVD × 6 to 8 cycles versus Stanford V. RT was given (36 Gy) for those with bulky mediastinal disease or to sites of disease greater than 5 cm in the Stanford V arm. In a subset analysis focusing only on those with stage I/II bulky mediastinal disease, the 5-year failure free survival was 85% versus 79% and the 5-year overall survival was 96% versus 92% for the ABVD versus Stanford V arms, respectively. These differences were not statistically significant.⁷⁰ While the Stanford V regimen has the advantages of a 12-week treatment duration and a lower cumulative amount of bleomycin and doxorubicin, the Stanford V arm had higher rates of grade 3 lymphopenia and grade 3 to 4 peripheral neuropathies. In addition, Stanford V requires that most patients undergo RT (to original sites of disease measuring 5 cm or more plus contiguous areas). As a result, the investigators concluded that ABVD × 4 cycles plus IFRT remains the standard of care for patients with early unfavorable Hodgkin lymphoma with bulky mediastinal disease.

Other regimens have been studied in hopes of reducing toxicity, including the EVE regimen (epirubicin, vinblastine, and etoposide). This regimen was compared to ABVD in early unfavorable Hodgkin lymphoma patients, with all patients undergoing the same RT program. No differences were observed between the ABVD and EVE arms in terms of complete remission rate and overall survival. However, patients who received EVE had a significantly worse outcome than those who received ABVD in terms of relapse-free survival and failure-free survival.⁸⁸ EBVP (epirubicin, bleomycin, vinblastine, and prednisone) followed by IFRT was less efficacious compared with MOPP/ABV–type therapy.⁵⁸

An area of active investigation is whether RT can be safely omitted in patients with early- stage unfavorable cHL. The EORTC H10 study showed that, for patients with a negative iPET scan (after 2 cycles), the 5-year PFS rates were 92.1% versus 89.6% for ABVD plus INRT versus ABVD alone, respectively. While this technically did not meet criteria for noninferiority of ABVD alone, this study demonstrated that, for those with negative iPET, ABVD × 6 cycles (without radiation) can result in long-term remission in a high proportion (89%) of patients. For iPET-positive patients, 2 cycles of escalated BEACOPP were given followed by 30 Gy of IFRT on the experimental arm. This resulted in a 5-year PFS of 90.6% versus 77.4%, suggesting this may be a preferred approach for early-stage unfavorable patients with a positive iPET.⁴⁸ Even though the noninferiority of ABVD alone could not be established based on the statistical design of the study, the current NCCN guidelines recommend restaging after 2 cycles of ABVD for stage I or II unfavorable cHL and using that iPET as a guide, based on Deauville scores. For scores 1–3, ABVD × 2 cycles (total 4 cycles) plus ISRT or AVD × 4 (total 6) with or without ISRT is recommended. For a Deauville score of 4, escalated BEACOPP × 2 cycles or ABVD × 2 cycles (total 4) followed by ISRT is recommended. If the Deauville score is 5, further treatment decisions should be made based on repeat biopsy results. A follow up PET/CT is recommended for Deauville scores of 4 and 5 to confirm complete response.⁴⁶

LATE EFFECTS AND THE EVOLUTION OF RADIATION THERAPY

The RT given in Hodgkin lymphoma has evolved considerably over the years, from extended field or subtotal nodal fields developed in the 1960s, to the more focused involved-field or even involved-site radiation commonly given now. This approach reduces radiation volumes, and it already is becoming evident that the relative risk of breast cancer among young females receiving mediastinal RT for Hodgkin lymphoma is declining.⁸⁹ Cardiac dose is reduced significantly with IFRT compared to older radiation techniques as well. The extent of radiation may be reduced even further with involved-nodal/involved site or intensity-modulated approaches.⁹⁰

With new RT techniques allowing for more focused therapy and lower doses of radiation, models predict that the rate of long-term complications will decline further.^91,92 Furthermore, response-adapted (ie, PET-directed) approaches, as discussed in detail earlier in the article, are expected to increasingly allow for identification of patients who can safely avoid radiation entirely, which will hopefully lead to an even lower rate of late complications of therapy.

MONITORING FOR RELAPSE

A number of recent studies have shown that, for patients who achieve complete remission with first-line therapy, performing repeated scheduled surveillance imaging does not improve outcomes. In fact, most relapses are detected by the patient (due to symptoms or recurrence of lymph node enlargement). It is rare that a relapse would be detected by surveillance imaging alone. Furthermore, surveillance that includes routine imaging has not been associated with improved survival.⁹³ As a result, it is now recommended that patients undergo regular follow-up with symptom review, physical exam, and basic laboratory studies. Imaging studies should be obtained as needed for patients who develop signs, symptoms, exam findings, or laboratory values concerning for relapse.

More important than scheduled surveillance imaging for relapse is monitoring for late effects of therapy. These fall into several broad categories such as cardiovascular disease (coronary disease, congestive heart failure, valvular disease, carotid artery disease), pulmonary disease, hypothyroidism, and secondary malignancies. Aggressive surveillance for breast cancer is especially warranted in female patients who underwent chest radiation.⁴⁶

CONCLUSION

Hodgkin lymphoma is characterized pathologically by the presence of HRS cells accompanied by a polymorphous cellular infiltrate. It is a disease with a bimodal age distribution, several pathologic subtypes, and numerous treatment options. Overall, the prognosis for patients with early-stage disease is excellent, and although a majority of patients can now be cured, further studies are needed to optimize treatment such that short- and long-term treatment-related toxicities are minimized, without compromising disease control and cure.

INTRODUCTION

Hodgkin lymphoma, previously known as Hodgkin’s disease, is a B-cell malignancy with unique pathological and epidemiological features for which highly effective therapies exist. The disease is characterized by the presence of mononuclear and multinucleate giant cells called Hodgkin and Reed-Sternberg (HRS) cells.¹

Hodgkin lymphoma is unique compared to other B-cell lymphomas because of the scarcity of the malignant cells in the tumor tissue. The HRS cells usually account for only 0.1% to 10% of the cells in the affected tissues, and the HRS cells induce accumulation of nonmalignant lymphocytes, macrophages, granulocytes, eosinophils, plasma cells, and histiocytes, which constitute more than 90% of tumor cellularity.² Although the disease was first described by Sir Thomas Hodgkin in 1832, in part because of this unique histopathology, not until 1991 was it conclusively demonstrated that HRS cells are in fact monoclonal germinal center–derived B-cells. This article reviews management and frontline treatment options for limited-stage classical Hodgkin lymphoma and nodular lymphocyte predominant Hodgkin lymphoma. Treatment of advanced stage and relapsed/refractory Hodgkin lymphoma will be discussed in a separate article.

EPIDEMIOLOGY

Hodgkin lymphoma accounts for 0.5% of all malignancies and 11.7% of all lymphomas among adults in the United States.³ The incidence of Hodgkin lymphoma has been steadily increasing over the past 4 decades and was estimated to be 8260 cases in the United States in 2017, with a slight male predominance. Hodgkin lymphoma is expected to cause 1070 deaths in 2017, accounting for 0.2% of all cancer deaths.³ First-degree relatives of patients with Hodgkin lymphoma have a 3- to 9-fold increased risk of having the disease compared to the general population,⁴ and monozygotic twin siblings of Hodgkin lymphoma patients have a greatly increased risk for developing the disease—up to 100-fold—compared to normal cohorts.⁵ The incidence is highest among Caucasians, African Americans, and Hispanics, and lower in Asians and American Indians.³ Hodgkin lymphoma incidence shows a bimodal peak distribution, with 1 peak between the ages of 15 and 44 years, and another peak after age 65 years.⁶

ETIOLOGY/PATHOGENESIS

The cause of Hodgkin lymphoma is unknown. Epstein-Barr virus (EBV) infection is present in up to 40% of Hodgkin lymphoma cases, suggesting a role of this virus in the pathogenesis of some cases. The risk of EBV-positive Hodgkin lymphoma was found to be higher following an episode of infectious mononucleosis, while the risk of EBV-negative Hodgkin lymphoma remained unchanged.⁷ The incidence of Hodgkin lymphoma is 5 to 14 times higher in HIV-infected patients than in noninfected patients.⁸ It is not considered an AIDS-defining illness, but has become more frequent with the growth and aging of the HIV-positive population.^9,10 Hodgkin lymphoma patients with HIV typically have CD4 lymphocyte counts greater than 200 cells/μL,¹¹ with the incidence of Hodgkin lymphoma actually declining with lower CD4 lymphocyte counts.¹² HIV-related Hodgkin lymphoma tends to have an aggressive course, with high rates of EBV positivity.¹³ The incidence of Hodgkin lymphoma is 1.8 times higher among smokers, and the risk appears to increase with duration of smoking.^14,15

The cell of origin of Hodgkin lymphoma, while long suspected to be the HRS cell, remained unproven until the 1990s when micro-dissection and single-cell polymerase chain reaction techniques allowed for confirmation that the HRS cell was in fact a monoclonal germinal center derived B cell.^16,17 These HRS cells lack immunoglobulin due to defective transcription regulation and not due to crippling mutations.^18,19 The cellular infiltrate in Hodgkin lymphoma appears to play a decisive role in allowing the HRS cells to survive by providing an environment that suppresses cytotoxic immune responses as well as by providing cellular interactions and cytokines that support their growth and survival. The extensive inflammatory infiltrate in classical Hodgkin lymphoma is comprised of T helper 2 (Th2) and regulatory T cells and lacks T helper 1 (Th1) cells, CD8 cytotoxic T cells, and natural killer cells.²⁰ The HRS cells escape apoptosis by several mechanisms which include latent EBV infection and constitutive nuclear factor (NF)-kB pathways, as well as other deregulated signaling pathways that promote survival, such as EBV nuclear antigen 1 (EBNA1) protein, EBV latent infection membrane protein 1 (LMP1), and LMP2.^21,22

Genetic alterations in the 9p24 locus which encodes PD-L1/PD-L2 are nearly universally present in classical Hodgkin lymphoma and are now considered a disease-defining feature.²³

According to the 2008 World Health Organization (WHO) classification, Hodgkin lymphoma has 2 clearly defined entities: classical Hodgkin lymphoma (cHL), which accounts for approximately 95% cases, and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), which accounts for the remaining cases.²⁴ These 2 entities differ in their clinical, pathological, and biological features, which in turn affect prognosis and treatment options. Classical Hodgkin lymphoma is characterized by a paucity of HRS cells surrounded by a background of mixed inflammatory infiltrate comprised of histiocytes, small lymphocytes, eosinophils, neutrophils, plasma cells, fibroblasts, and collagen. Depending on the particular combinations of these elements and the specific features of the neoplastic cells, cases can be subclassified into several cHL subtypes: the nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted types.²⁵

The diagnosis of cHL is made based on a combination of morphology of HRS cells and the other cells infiltrating the tissue, combined with immunohistochemical staining. Because of the rare nature of the malignant (clonal) cell in Hodgkin lymphoma specimens, flow cytometry is generally of little value. The HRS cells in cHL are CD30-positive and CD45 negative in virtually all cases, and CD15-positive in 85% of cases.²⁶ B-cell antigens are typically negative except for CD20, which is positive in about 20% cases.²⁷

Nodular sclerosis Hodgkin lymphoma (NSHL) is the most common subtype of cHL, accounting for 65% to 75% of cases. It is common among young adults and tends to involve the mediastinal, supraclavicular, and cervical lymph nodes. NSHL is characterized by the presence of collagen bands that divide the lymphoid tissue into circumscribed nodules. This subtype usually presents as stage I or II disease, typically with neck and/or mediastinal disease, and evidence of EBV infection is present in approximately 10% to 40% of North American cases.⁷ Patients diagnosed with NSHL generally have a very good prognosis.

Mixed cellularity Hodgkin lymphoma (MCHL) constitutes about 20% to 25% of cHL cases. It affects a somewhat older population, with a median age at diagnosis of 38 years. The typical bimodal age distribution is not seen with MCHL. MCHL has a male predominance (70%), and is more frequent in HIV-infected patients (70% of whom also have EBV infection). Lymphoid tissues have classic HRS cells and significant inflammatory infiltrates. Approximately 50% of patients with MCHL present as stage III or IV with abdominal lymphadenopathy or splenic involvement, and B symptoms are frequent.²⁴

Lymphocyte-rich Hodgkin lymphoma (LRHL) is uncommon, accounting for only 3% to 5% of cases of cHL.²⁸ The disease usually presents at an older age and has a 2:1 male predominance. HRS cells are commonly seen and a large number of reactive lymphocytes are also present. Although on the basis of morphology and immunohistochemistry LRHL belongs to the cHL group, clinically it more closely resembles LPHL. Patients usually present at early stage and rarely have B symptoms. LRHL carries an excellent prognosis, with a greater than 90% PFS after 5 years.^23,29

Lymphocyte-depleted Hodgkin lymphoma (LDHL) is the least common form of cHL, accounting for less than 5% of cases. Many cases previously placed in this category are now recognized as diffuse large B-cell lymphoma (DLBCL), anaplastic large-cell lymphoma (ALCL), or NSHL with lymphocyte depletion.³⁰ HRS cells are frequently seen, but reactive inflammatory cells are relatively sparse. EBV infection is seen in up to 90% of cases, commonly associated with HIV-infected individuals. Advanced-stage and symptomatic disease are more common. Prognosis is slightly worse compared to other categories.

NLPHL accounts for approximately 5% of cases of Hodgkin lymphoma. It has a unimodal age distribution, with the peak incidence in the fourth decade, and male predilection of 3:1.²⁸ NLPHL is characterized by large primary lymphoid follicles, with polytypic small B lymphocytes and extensive meshworks of follicular dendritic cells. The lymphocytic/histiocytic (L and H), or “popcorn,” cells scattered within the nodules differ from classic HRS cells, both in their morphology and in their biochemical profile, being frequently negative for CD15, CD30 and for the EBV genome, and usually positive for B-cell antigens such as CD20, suggesting that L and H cells may be immunoglobulin-synthesizing monoclonal B cells. CD45 is also typically positive in NLPHL, in distinction from cHL. NLPHL has an indolent course compared to cHL, and long-term survival is common.^19,31 NLPHL commonly presents with limited-stage disease. NLPHL may eventually transform into a more aggressive lymphoma, such as diffuse large B-cell lymphoma (including centroblastic, immunoblastic, or T-cell/histiocyte–rich subtypes), at a rate of 4% to 12%. This can occur even 15 to 20 years after the initial diagnosis of NLPHL.^32,33 In a recent large retrospective study of 222 patients with NLPHL, the rate of transformation to DLBCL was 7.6%, with a median time to transformation of 35 months. Overall survival was not adversely affected in patients undergoing transformation compared to those without transformation.³⁴

PRESENTATION

Classical Hodgkin lymphoma usually presents with asymptomatic mediastinal or cervical lymphadenopathy. Half of patients present with stage I or stage II disease.³⁵ A mediastinal mass is seen in most patients with NSHL, at times with bulky disease, with “bulky” defined as a mediastinal mass measuring one-third or more of the maximal thoracic diameter on chest x-ray, or 10 cm on computed tomography (CT) scan. Systemic symptoms, or "B" symptoms—fevers (> 38°C), drenching night sweats, and unexplained weight loss (> 10% of baseline body weight over the preceding 6 months or less)—are detected in approximately 25% of patients. Between 10% and 15% will have extranodal disease, most commonly involving lung, bone, and liver. NLPHL usually presents with limited-stage disease without B symptoms; it typically has a more indolent presentation and clinical course than cHL.

The initial workup includes a complete blood count (CBC), erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH), and chemistry studies to evaluate renal function and liver function. Fine-needle aspiration will usually fail to identify the infrequent HRS cells, and instead only reveal the reactive background of inflammatory cells. Generous (large gauge) core needle biopsies may provide diagnosis effectively in some cases, but in general, an excisional lymph node biopsy is preferred to ensure an accurate diagnosis and avoid the need for repeated biopsy procedures. In cases where an excisional biopsy would be difficult or risky, a core needle biopsy procedure is a reasonable first step, with the understanding that a subsequent surgical procedure may still be necessary.

Baseline imaging includes CT scans of the neck, chest, abdomen, and pelvis. Use of positron emission tomography (PET) scanning is now standard in the initial evaluation and assessment of treatment response in Hodgkin lymphoma.³⁶ Due to the increased sensitivity of PET or PET/CT scan, additional lesions may be identified that were not seen on conventional CT scans. This will alter the staging, and potentially the treatment plan, in up to 25% to 30% of patients.^37,38 PET/CT scan performed during initial evaluation also facilitates optimal interpretation of post-therapy PET/CT scans and is therefore strongly encouraged as a part of the initial staging evaluation.³⁹

Recent studies have shown that bone marrow biopsy is not routinely needed in the initial staging of cHL. A study of 454 patients concluded that bone marrow biopsy would not have altered the stage in any stage I or II patients. It was further concluded that overall treatment strategy would not have been altered for any of the patients.⁴⁰ Based on this study and others, it is now clear that FDG-PET has a high sensitivity, and when PET scan is negative (in the bone marrow and skeleton), a bone marrow biopsy provides little additional value. For patients with significant cytopenias, a bone marrow biopsy is reasonable. Such patients may benefit from a bilateral biopsy, which increases the probability of demonstrating bone marrow involvement by 16% to 33%.^41,42 Techniques such as staging laparotomy and lymphangiography are now considered obsolete.

Hodgkin lymphoma is staged according to the Ann Arbor staging system (Table 1). The original Ann Arbor staging was published in 1971,⁴³ and in 1989 the “Cotswold modifications” extended the definitions of stage IV disease and the suffix “X” was added to denote bulky disease.⁴⁴ Both systems were developed for the staging of Hodgkin lymphoma, but are now used for staging non-Hodgkin lymphoma as well.

PROGNOSTIC FACTORS

For the purposes of prognosis and selection of treatment, Hodgkin lymphoma is commonly classified into early-stage favorable, early-stage unfavorable, and advanced stage. Early-stage Hodgkin lymphoma refers to patients with Ann Arbor stage I or stage II disease. With early-stage Hodgkin lymphoma, the prognosis varies significantly based on factors such as the presence of B symptoms, elevated erythrocyte sedimentation rate ([ESR] > 50 mm/hr), number of nodal sites involved, older age, and a large mediastinal mass. For this reason, most clinical trials to evaluate treatment strategies for early-stage Hodgkin lymphoma are based on various combinations of these risk factors. The definition of early-stage unfavorable Hodgkin lymphoma varies across different clinical trial study groups, and it is important to understand the definition in interpreting the results of these trials (Table 2).^45,46

In the German Hodgkin Study Group (GHSG) trials, early-stage Hodgkin lymphoma is stratified into a high risk (“unfavorable”) group defined by any of the following: a large mediastinal mass (one third of maximum thoracic diameter), extra-nodal disease, 3 or more nodal areas, and an ESR of > 50 mm/hr in asymptomatic patients or > 30 mm/hr in patients with B symptoms. Low-risk (“favorable”) patients lack all of these factors.⁴⁷ The European Organization for Research and Treatment of Cancer (EORTC) defines the unfavorable prognostic group as older than 50 years of age, large mediastinal adenopathy (maximum width on a chest radiograph of at least one third of the internal transverse diameter of the thorax at the level of T5 through T6 or any mass of ≥ 10 cm in the largest dimension), an ESR of 50 mm/hr and no B symptoms, or with an ESR of 30 mm/hr in those who have B symptoms, and/or 4 or more regions of involvement.⁴⁸ The National Cancer Institute of Canada (NCIC) Clinical Trials Group and the Eastern Cooperative Oncology Group (ECOG) define high-risk groups as presence of B symptoms, bulky disease with a mediastinal mass width of at least one third of the maximum chest wall diameter, or any mass greater than 10 cm, and patients with intra-abdominal disease.^49,50

Gene-expression profiling in Hodgkin lymphoma has identified a gene signature of tumor-associated macrophages that was able to identify patients with a higher risk for primary treatment failure. In an independent cohort of patients, an increased number of CD68-positive macrophages was correlated with inferior outcomes.^51,52 Studies such as these underscore the importance of the tumor “microenvironment” (ie, the nonmalignant cells within a tumor) in determining the overall clinical behavior of a malignancy. While quantification of CD68-positive macrophages has potential to be applied to routine clinical practice, prospective data using CD68 as a tool for risk-adapted therapy is lacking.

Genetic alterations and amplifications in the 9p24.1 locus have recently been found to be a defining genetic feature of cHL. Amplification of 9p24.1 has been associated with unfavorable outcomes. Amplification of 9p24.1 (which includes the loci encoding the PD-L1 and PD-L2 genes) is more common in patients with advanced stage disease and is associated with shorter PFS.²³

A recent study attempted to integrate several different prognostic factors in cHL patients who were treated with ABVD (adriamycin [doxorubicin], bleomycin, vinblastine, and dacarbazine) and underwent an interim PET (iPET) scan after 2 cycles of ABVD. Focusing on those with a negative iPET scan, it was found that expression of CD68 and PD-1 in microenvironment cells, and STAT1 negativity in HRS cells identified a subset of PET-2 negative patients with a 3-year PFS significantly lower than that of the remaining PET-2 negative population (64% versus 95%). The algorithm correctly predicted the response to treatment in more than half of the patients who had relapse or disease progression despite a negative PET-2 scan. It therefore appears feasible, using tissue biomarkers at diagnosis, to identify patients at increased risk for poor outcome, even if the iPET scan is negative.⁵³

ROLE OF PET/CT IN ASSESSMENT OF RESPONSE TO THERAPY

PET/CT has been increasingly used for response assessment at various stages in lymphoma in recent years. Almost all types of lymphomas are fluorodeoxyglucose (FDG) avid; however, Hodgkin lymphoma is FDG avid in 97% to 100% of cases. In 2009, a 5-point scale was developed to score PET images with regard to treatment response, either partway through treatment (iPET) or at the end of therapy.⁵⁴ It was recommended as the standard reporting tool at the First International Workshop on PET in Lymphoma in Deauville, France, in 2009, and is thus now referred to as the Deauville score. A score of 1 is given if there is no uptake, 2 if the uptake ≤ mediastinum, 3 if > mediastinum but ≤ liver, 4 if uptake moderately higher than liver, 5 if uptake is markedly higher than liver and/or new lesions. X designates new areas of uptake unlikely to be related to lymphoma. In most trials, a score of 1 or 2 is considered a complete response and a score of 4 or 5 is considered a treatment failure. A score of 3 is sometimes considered a complete response, depending on the study. The Deauville criteria have been widely used in newer clinical trials utilizing response-adapted treatment as defined by PET response. PET/CT is recommended for staging and restaging at the end of therapy, in clinical practice, and clinical trials. Interim PET/CT scan, while commonly performed in clinical practice, is only recommended if the results will alter therapy (eg, if that information will result in the clinician omitting radiation therapy [RT] or altering the chemotherapy plan).

Early studies of iPET showed that achieving PET negativity early in the course of treatment was strongly associated with PFS and overall survival.⁵⁵ Subsequent studies confirmed the importance of achieving a negative iPET. As a result, considerable efforts have been put into designing response-adapted treatment approaches using iPET (see Treatment section), with some of these approaches now being listed in the National Comprehensive Cancer Network (NCCN) guidelines and being used in standard practice.

TREATMENT

EVOLUTION OF TREATMENT

The treatment of Hodgkin lymphoma has evolved over the past century, starting with the discovery of RT as effective treatment in the early 20th century. Long-term survival of patients with Hodgkin lymphoma treated with involved-field radiation therapy (IFRT) was first reported in the 1960s.^56,57 Outcomes improved further with the introduction of combined modality treatment (CMT) using chemotherapy and RT, with the overall 5-year relative survival for patients with Hodgkin lymphoma (all stages) treated in 2006–2012 being 85.4% to 87.3%.³ Since the majority of patients are now cured with modern therapy, treatment-related complications have become an important competing cause of mortality. Recent studies have therefore focused on maintaining efficacy while reducing toxicities, and refining the process of selecting patients who might benefit from more aggressive therapy. While RT was the first treatment modality shown to be curative for Hodgkin lymphoma,^56,57 multiple subsequent studies showed that CMT is superior to RT alone in terms of relapse-free survival.^58–63 In the GHSG H8-F trial, the estimated 5-year event-free survival and overall survival rates were significantly higher after 3 cycles of MOPP-ABV (mechlorethamine, vincristine, procarbazine, and prednisone combined with doxorubicin, bleomycin, and vinblastine) plus IFRT than after subtotal nodal radiotherapy alone. The 10-year overall survival estimates were 97% and 92%, respectively (P = 0.001).⁶⁴ As a result, CMT replaced RT alone as the standard of care for limited-stage Hodgkin lymphoma. However, for elderly or infirm patients, or those with other comorbidities making them poor chemotherapy candidates, RT alone may be a very reasonable option.⁶⁵ More recently, an increasing body of evidence has accumulated to support the use of chemotherapy alone in early stage cHL. This literature has consistently shown that omission of RT is associated with a modest increase in relapse, without a clear compromise in long-term overall survival. For some patients, the trade-off in terms of avoiding radiation (and the associated late effects) may be worth the small increase in relapse risk, since long-term survival does not appear to be substantially worse with chemo-therapy alone. Table 3 and Table 4 provide a summary of recent key studies which have defined treatment options for early-stage cHL.^48,66–71

NLPHL usually presents with limited-stage disease without B symptoms and has an indolent course with a slightly better prognosis compared to cHL.⁷² Due to the rarity of the disease, treatment guidelines are mostly based on retrospective analyses from single or multi-institution studies or subgroup analyses, often with relatively short follow-up. These studies must be interpreted with caution because of the possibility of inaccuracies in the pathologic diagnosis, small sample sizes, and selection bias. Treatment options for limited-stage NLPHL include observation, single-agent rituximab, IFRT (or involved-site radiation therapy [ISRT]) alone, or CMT.⁴⁶

Historically, patients with limited-stage NLPHL have been treated with RT alone, with 80% to 85% PFS and 85% to 95% overall survival rates.^73–75 Patients who relapse or progress after RT in general can successfully undergo salvage therapy.⁷⁴ In one study, rates of PFS and overall survival were similar among patients who had limited-field, regional-field, or extended-field RT,⁷⁵ indicating that IFRT is preferred. Studies comparing RT alone and CMT are limited. The GHSG HD7 trial included a subset of NLPHL patients, with a trend towards improved freedom from treatment failure (96% versus 83%) favoring CMT. This, however, did not translate into improved overall survival.⁴⁷ A retrospective analysis of the British Columbia Cancer Agency database compared patients with limited-stage NLPHL treated with RT alone to patients who received 2 cycles of ABVD followed by RT. A significant improvement in PFS (91% versus 65%) and overall survival (93% versus 84%) was seen, favoring CMT.⁷⁶

Chemotherapy alone is not recommended for limited-stage NLPHL since studies evaluating chemotherapy alone are quite limited and indicate relatively high rates of treatment failure. Given that the malignant cells in NLPHL are CD20-positive, single-agent rituximab has also been studied in this disease, including a study as frontline therapy in limited-stage patients. In this phase 2 trial in newly diagnosed patients with stage IA disease, an overall response rate (ORR) of 100% was seen, with an 85% complete response (CR) rate.⁷⁷ At 3 years, overall survival was 100% and PFS was 81%, indicating that the responses with single-agent rituximab are less durable than those with RT.

Advani et al evaluated rituximab followed by observation versus rituximab (R) followed by maintenance rituximab (MR) for 2 years in 39 new or previously treated patients. At 4 weeks the ORR was 100% (with CR in 67%, and partial response in 33%). At a median follow up of 9.8 years for R alone, and 5 years for R+MR, median PFS was 3 and 5.6 years, respectively (P = 0.26). Estimated 5-yr PFS and overall survival in patients treated with R versus R+MR were 39.1% and 95.7% versus 58.9% and 85.7%, with Pvalues of 0.26 (PFS) and 0.38 (overall), respectively. Maintenance rituximab therefore appears to prolong remission, although the results did not quite reach statistical significance.⁷⁸ Even though rituximab does not appear to be curative in NLPHL, it is a reasonable option for patients with early-stage NLPHL who are not good candidates for definitive RT. Whether combining rituximab with RT or CMT might further improve outcomes in early-stage NLPHL has not yet been determined.

In children, surgery alone may lead to long-term remission or possibly cure of limited-stage NLPHL. In a European multicenter retrospective study, 58 patients underwent surgery for limited-stage NLPHL. Among the 51 patients who achieved complete remission following surgery, 67% remained progression-free and 100% were alive at a median follow up of 43 months.⁷⁹ In adults, there is no data to support surgical treatment alone for NLPHL. Finally, observation may be a reasonable option in elderly or infirm patients for whom NLPHL is unlikely to affect life expectancy. For younger patients, given the excellent outcome with modern therapy and the long-term risk of transformation of NLPHL into an aggressive non-Hodgkin lymphoma, observation is generally not recommended.

The NCCN recommends RT (ISRT or IFRT, 30–36 Gy) as the preferred treatment for stage IA and IIA non-bulky NLPHL. In patients with stage IA disease with complete excision of solitary nodule, observation may be appropriate. A course of chemotherapy with ISRT with or without rituximab is recommended for patients with stage IB or IIB disease, or patients with stage IA or IIA bulky disease.

FIRST-LINE TREATMENT OF LIMITED-STAGE CHL

Early-Stage Favorable cHL

There is lack of consensus regarding the ideal treatment approach for patients with early-stage favorable cHL. However, there are several excellent options available, with overall survival rates exceeding 90%. Most of these regimens involve CMT, although some chemotherapy-alone approaches have been evaluated as well. Concurrent with the demonstration of excellent long-term remission rates with CMT, it became apparent that the long-term survival and quality of life of these patients is determined in large part by the risk of serious (and potentially fatal) treatment-related toxicities. Such toxicities consist primarily of secondary malignancies and cardiovascular events, and can continue to cause significant morbidity and mortality even 2 to 3 decades after treatment.^80–82 As a result, treatment decisions for these patients are complicated and require balancing efficacy against risk of late complications.

In the United States, until recently, CMT was generally considered the standard of care, with robust long-term data regarding efficacy. The most commonly used regimen has been ABVD for 2 to 4 cycles followed by IFRT. In some German studies, escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) has been used, but this is not a general standard of care in the United States for early-stage patients.

More recent data suggests that the rate of serious late complications in Hodgkin lymphoma patients is decreasing, likely due to less extensive radiation fields, lower radiation doses, and a movement away from the MOPP regimen to ABVD.^83,84 For patients who meet the “favorable” criteria set forth in the GHSG HD10 trial (see Table 2), 2 cycles of ABVD followed by 20 Gy of IFRT is an attractive option, with efficacy preserved and a low anticipated rate of late effects.⁶⁶ With this approach, and with long-term (10 years) follow up, all 4 arms had similar PFS (87%) and overall survival (94%), whether 2 or 4 cycles of ABVD were given. When the effects of 20-Gy and 30-Gy doses of RT were compared, there were also no significant differences in freedom from treatment failure or overall survival. Adverse events and acute toxic effects of treatment were most common in the patients who received 4 cycles of ABVD and 30 Gy of RT.^66,71

In recent years, in an attempt to reduce late effects further, regimens consisting of chemotherapy alone have been investigated. In a study by Meyer et al, at 12 years the rate of overall survival was 94% among those receiving ABVD alone, as compared with 87% among those receiving subtotal nodal RT; the rates of freedom from disease progression were 87% and 92% in the 2 groups; and the rates of event-free survival were 85% and 80%, respectively.⁵⁰ However, it is important to note that this study did not include a CMT arm for the early favorable patients, and did not utilize modern RT techniques. Nevertheless, this early study and others⁶⁰ suggested that chemotherapy alone may be a reasonable option for some early-stage cHL patients, particularly for patients who are felt to be at increased risk for late toxicities from RT. As a result, additional studies have been conducted evaluating CMT versus chemotherapy alone for early-stage cHL. Many of these studies have incorporated interim PET/CT scan to develop a response-adapted approach to decide which patients are least likely to benefit from RT.

The HD-13 study was a follow-up study for HD-10, looking at deletion of bleomycin, dacarbazine, or both from the ABVD backbone. The ABD arm was closed early, because of an excess rate of treatment failure. Among the 1243 patents assigned to either the ABVD or AVD arm at 5 years of follow-up, there was 4.3% difference in PFS. This study was not able to demonstrate that 2 cycles of AVD was noninferior to 2 cycles of ABVD, each followed by 30 Gy IFRT, even though there was no difference in all 4 groups. It confirmed 2 cycles of ABVD as the preferred regimen in early favorable Hodgkin lymphoma, when CMT is the plan of care. However, for patients over age 60 to 65 years, or those with underlying cardiac or pulmonary comorbidities, bleomycin has significant risk of toxicity. In that setting, AVD is a safer option, with only a very modest decrease in 5-year PFS.

Based on the observation that iPET scan is highly predictive of outcome in Hodgkin lymphoma,^55,85 several trials have employed the use of an iPET scan to guide therapy. It is hoped that such studies will lead to new PET-directed treatment algorithms in which patients who require more aggressive therapy (eg, with CMT, or escalated BEACOPP) can be identified, and the remaining patients can be safely treated less aggressively (eg, with chemotherapy alone).

In the EORTC H10 trial, performed to evaluate treatment adaptation on the basis of iPET scan results in stage I and II Hodgkin lymphoma, a control arm received standard combined modality treatment (3 or 4 cycles of ABVD with INRT) irrespective of PET scan results. In the experimental arm, patients with a negative PET scan after 2 cycles of ABVD continued with 1 or 2 cycles of ABVD and did not receive RT. The iPET-positive patients received either standard treatment with ABVD plus INRT or escalated BEACOPP plus INRT. The iPET-negative patients received either ABVD only or ABVD plus INRT. The final results of this study, published recently, showed that in the iPET-positive patients the 5-year PFS was improved from 77.4% with standard ABVD plus INRT to 90.6% with escalated BEACOPP plus INRT (P = 0.002). In iPET-negative patients, 5-year PFS in the favorable group was 99% versus 87.1% in favor of ABVD plus INRT. The H10 study suggested that PET results after 2 cycles of ABVD can be integrated into treatment planning, In iPET-negative patients, the study was technically not able to demonstrate the noninferiority of the ABVD only regimen, owing to a higher risk of relapse if INRT is omitted, particularly in the favorable group.⁴⁸ However, this study does show that excellent outcomes can be obtained with omission of RT in patients with a negative iPET scan. This study provides a cautionary lesson though, in that the increase in relapse rate associated with omission of RT was more substantial (12%) for favorable versus unfavorable early-stage patients (2.5%), and this difference was only apparent after longer (5 years) follow-up. Despite this, chemotherapy alone is considered a reasonable treatment option, especially for patients felt to be at increased risk for late toxicities of RT or for patients who wish to avoid the risks of RT, with over 99% of patients alive at 5 years.

Similar results were shown in the RAPID trial, in which patients with limited-stage cHL underwent 3 cycles of ABVD followed by PET assessment.⁶⁷ Patients with a negative PET (n = 426) were then randomized to RT (n = 209) versus no further therapy (n = 211). At a median of 60 months of follow-up, 3-year PFS was 94.6% in the RT group and 90.8% in the chemotherapy alone group. Similar to the H10 trial, it was concluded that chemotherapy alone was statistically inferior to CMT in terms of PFS. However, also similar to the H10 trial, the RAPID trial demonstrated that excellent results can be obtained in early-stage cHL patients with omission of RT, if iPET scan is negative after 3 cycles of ABVD, as there was no survival difference. These findings indicate that, when relapses occur as a result of omission of RT, such patients can be effectively treated later.

In the ongoing GHSG HD16 trial, patients with early-stage favorable cHL will be randomly assigned to a standard approach (ABVD × 2 cycles followed by 20-Gy IFRT) versus an experimental approach in which they receive ABVD for 2 cycles and then undergo PET scan. If the PET remains positive, they will receive 20-Gy IFRT. If the PET is negative, they will receive no further therapy. This trial could ultimately define ABVD for 2 cycles as a treatment option.

It is clear from these studies that omission of RT results in a somewhat higher rate of relapse but can be considered in selected patients. However, taking a less aggressive frontline approach may also be justified by the fact that, for those who do relapse, successful salvage therapies are available. Aggressive salvage therapy with autologous stem cell transplantation historically can cure approximately 50% of relapsed patients. With new and emerging therapies for relapsed disease, such as brentuximab vedotin and the PD-1 inhibitors (eg, nivolumab and pembrolizumab), the ability to cure relapsed patients may improve even more, further calling into question the practice of applying CMT uniformly for early-stage patients undergoing first-line therapy. Unfortunately, there is insufficient data from large randomized studies with long-term follow-up to fully address this issue currently, and there remains some controversy around this issue. NCCN recommends restaging PET/CT after 3 cycles of ABVD if a chemotherapy alone treatment modality is chosen. If the Deauville score is 1 or 2, either observation or 1 additional cycle of ABVD is recommended.⁴⁶

Early-Stage Unfavorable cHL

In the United States, historically early-stage unfavorable Hodgkin lymphoma has been treated with CMT, most commonly 4 to 6 cycles of ABVD followed by consolidative RT. With this approach one can expect a 5-year PFS of approximately 80% to 85%.^58,64,86 The GHSG HD8 trial showed that RT volume size reduction from extended-field to involved-field after COPP + ABVD chemotherapy for 2 cycles produced similar results and less toxicity in patients with early-stage unfavorable cHL.⁸⁶ The GHSG trial HD11 established ABVD for 4 cycles plus 30-Gy IFRT as a standard for early unfavorable Hodgkin lymphoma. The freedom from treatment failure at 5 years was 85.0%, and overall survival was 94.5%.⁶⁸

In the HD14 study by the GHSG, patients with early unfavorable cHL were treated with 2 cycles of escalated BEACOPP followed by 2 cycles of ABVD, versus 4 cycles of ABVD. All patients then received 30 Gy of consolidative IFRT. A 5-year PFS of 95% was seen in the experimental arm, compared with 89% in the standard (ABVD) arm. As expected, this regimen was associated with more acute hematologic toxicity, and there was no difference between the 2 regimens with respect to overall survival or fertility.⁶⁹ Given the lack of improved survival and increased toxicity, ABVD has remained the standard chemotherapy regimen for early unfavorable cHL in the United States. NCCN recommends a restaging PET scan after 2 cycles of ABVD and to continue with 2 to 4 cycles of ABVD or escalated BEACOPP with or without ISRT based on Deauville scores.

Another viable treatment option is the Stanford V regimen, a condensed, 12-week regimen that includes mechlorethamine, doxorubicin, vinblastine, prednisone, vincristine, etoposide, and bleomycin, followed by IFRT.⁸⁷ In a randomized phase 3 trial conducted by ECOG (E2496), patients with stage I/II Hodgkin lymphoma with bulky mediastinal disease or advanced-stage disease were randomized to ABVD × 6 to 8 cycles versus Stanford V. RT was given (36 Gy) for those with bulky mediastinal disease or to sites of disease greater than 5 cm in the Stanford V arm. In a subset analysis focusing only on those with stage I/II bulky mediastinal disease, the 5-year failure free survival was 85% versus 79% and the 5-year overall survival was 96% versus 92% for the ABVD versus Stanford V arms, respectively. These differences were not statistically significant.⁷⁰ While the Stanford V regimen has the advantages of a 12-week treatment duration and a lower cumulative amount of bleomycin and doxorubicin, the Stanford V arm had higher rates of grade 3 lymphopenia and grade 3 to 4 peripheral neuropathies. In addition, Stanford V requires that most patients undergo RT (to original sites of disease measuring 5 cm or more plus contiguous areas). As a result, the investigators concluded that ABVD × 4 cycles plus IFRT remains the standard of care for patients with early unfavorable Hodgkin lymphoma with bulky mediastinal disease.

Other regimens have been studied in hopes of reducing toxicity, including the EVE regimen (epirubicin, vinblastine, and etoposide). This regimen was compared to ABVD in early unfavorable Hodgkin lymphoma patients, with all patients undergoing the same RT program. No differences were observed between the ABVD and EVE arms in terms of complete remission rate and overall survival. However, patients who received EVE had a significantly worse outcome than those who received ABVD in terms of relapse-free survival and failure-free survival.⁸⁸ EBVP (epirubicin, bleomycin, vinblastine, and prednisone) followed by IFRT was less efficacious compared with MOPP/ABV–type therapy.⁵⁸

An area of active investigation is whether RT can be safely omitted in patients with early- stage unfavorable cHL. The EORTC H10 study showed that, for patients with a negative iPET scan (after 2 cycles), the 5-year PFS rates were 92.1% versus 89.6% for ABVD plus INRT versus ABVD alone, respectively. While this technically did not meet criteria for noninferiority of ABVD alone, this study demonstrated that, for those with negative iPET, ABVD × 6 cycles (without radiation) can result in long-term remission in a high proportion (89%) of patients. For iPET-positive patients, 2 cycles of escalated BEACOPP were given followed by 30 Gy of IFRT on the experimental arm. This resulted in a 5-year PFS of 90.6% versus 77.4%, suggesting this may be a preferred approach for early-stage unfavorable patients with a positive iPET.⁴⁸ Even though the noninferiority of ABVD alone could not be established based on the statistical design of the study, the current NCCN guidelines recommend restaging after 2 cycles of ABVD for stage I or II unfavorable cHL and using that iPET as a guide, based on Deauville scores. For scores 1–3, ABVD × 2 cycles (total 4 cycles) plus ISRT or AVD × 4 (total 6) with or without ISRT is recommended. For a Deauville score of 4, escalated BEACOPP × 2 cycles or ABVD × 2 cycles (total 4) followed by ISRT is recommended. If the Deauville score is 5, further treatment decisions should be made based on repeat biopsy results. A follow up PET/CT is recommended for Deauville scores of 4 and 5 to confirm complete response.⁴⁶

LATE EFFECTS AND THE EVOLUTION OF RADIATION THERAPY

The RT given in Hodgkin lymphoma has evolved considerably over the years, from extended field or subtotal nodal fields developed in the 1960s, to the more focused involved-field or even involved-site radiation commonly given now. This approach reduces radiation volumes, and it already is becoming evident that the relative risk of breast cancer among young females receiving mediastinal RT for Hodgkin lymphoma is declining.⁸⁹ Cardiac dose is reduced significantly with IFRT compared to older radiation techniques as well. The extent of radiation may be reduced even further with involved-nodal/involved site or intensity-modulated approaches.⁹⁰

With new RT techniques allowing for more focused therapy and lower doses of radiation, models predict that the rate of long-term complications will decline further.^91,92 Furthermore, response-adapted (ie, PET-directed) approaches, as discussed in detail earlier in the article, are expected to increasingly allow for identification of patients who can safely avoid radiation entirely, which will hopefully lead to an even lower rate of late complications of therapy.

MONITORING FOR RELAPSE

A number of recent studies have shown that, for patients who achieve complete remission with first-line therapy, performing repeated scheduled surveillance imaging does not improve outcomes. In fact, most relapses are detected by the patient (due to symptoms or recurrence of lymph node enlargement). It is rare that a relapse would be detected by surveillance imaging alone. Furthermore, surveillance that includes routine imaging has not been associated with improved survival.⁹³ As a result, it is now recommended that patients undergo regular follow-up with symptom review, physical exam, and basic laboratory studies. Imaging studies should be obtained as needed for patients who develop signs, symptoms, exam findings, or laboratory values concerning for relapse.

More important than scheduled surveillance imaging for relapse is monitoring for late effects of therapy. These fall into several broad categories such as cardiovascular disease (coronary disease, congestive heart failure, valvular disease, carotid artery disease), pulmonary disease, hypothyroidism, and secondary malignancies. Aggressive surveillance for breast cancer is especially warranted in female patients who underwent chest radiation.⁴⁶

CONCLUSION

Hodgkin lymphoma is characterized pathologically by the presence of HRS cells accompanied by a polymorphous cellular infiltrate. It is a disease with a bimodal age distribution, several pathologic subtypes, and numerous treatment options. Overall, the prognosis for patients with early-stage disease is excellent, and although a majority of patients can now be cured, further studies are needed to optimize treatment such that short- and long-term treatment-related toxicities are minimized, without compromising disease control and cure.

INTRODUCTION

Hodgkin lymphoma, previously known as Hodgkin’s disease, is a B-cell malignancy with unique pathological and epidemiological features for which highly effective therapies exist. The disease is characterized by the presence of mononuclear and multinucleate giant cells called Hodgkin and Reed-Sternberg (HRS) cells.¹

Hodgkin lymphoma is unique compared to other B-cell lymphomas because of the scarcity of the malignant cells in the tumor tissue. The HRS cells usually account for only 0.1% to 10% of the cells in the affected tissues, and the HRS cells induce accumulation of nonmalignant lymphocytes, macrophages, granulocytes, eosinophils, plasma cells, and histiocytes, which constitute more than 90% of tumor cellularity.² Although the disease was first described by Sir Thomas Hodgkin in 1832, in part because of this unique histopathology, not until 1991 was it conclusively demonstrated that HRS cells are in fact monoclonal germinal center–derived B-cells. This article reviews management and frontline treatment options for limited-stage classical Hodgkin lymphoma and nodular lymphocyte predominant Hodgkin lymphoma. Treatment of advanced stage and relapsed/refractory Hodgkin lymphoma will be discussed in a separate article.

EPIDEMIOLOGY

Hodgkin lymphoma accounts for 0.5% of all malignancies and 11.7% of all lymphomas among adults in the United States.³ The incidence of Hodgkin lymphoma has been steadily increasing over the past 4 decades and was estimated to be 8260 cases in the United States in 2017, with a slight male predominance. Hodgkin lymphoma is expected to cause 1070 deaths in 2017, accounting for 0.2% of all cancer deaths.³ First-degree relatives of patients with Hodgkin lymphoma have a 3- to 9-fold increased risk of having the disease compared to the general population,⁴ and monozygotic twin siblings of Hodgkin lymphoma patients have a greatly increased risk for developing the disease—up to 100-fold—compared to normal cohorts.⁵ The incidence is highest among Caucasians, African Americans, and Hispanics, and lower in Asians and American Indians.³ Hodgkin lymphoma incidence shows a bimodal peak distribution, with 1 peak between the ages of 15 and 44 years, and another peak after age 65 years.⁶

ETIOLOGY/PATHOGENESIS

The cause of Hodgkin lymphoma is unknown. Epstein-Barr virus (EBV) infection is present in up to 40% of Hodgkin lymphoma cases, suggesting a role of this virus in the pathogenesis of some cases. The risk of EBV-positive Hodgkin lymphoma was found to be higher following an episode of infectious mononucleosis, while the risk of EBV-negative Hodgkin lymphoma remained unchanged.⁷ The incidence of Hodgkin lymphoma is 5 to 14 times higher in HIV-infected patients than in noninfected patients.⁸ It is not considered an AIDS-defining illness, but has become more frequent with the growth and aging of the HIV-positive population.^9,10 Hodgkin lymphoma patients with HIV typically have CD4 lymphocyte counts greater than 200 cells/μL,¹¹ with the incidence of Hodgkin lymphoma actually declining with lower CD4 lymphocyte counts.¹² HIV-related Hodgkin lymphoma tends to have an aggressive course, with high rates of EBV positivity.¹³ The incidence of Hodgkin lymphoma is 1.8 times higher among smokers, and the risk appears to increase with duration of smoking.^14,15

The cell of origin of Hodgkin lymphoma, while long suspected to be the HRS cell, remained unproven until the 1990s when micro-dissection and single-cell polymerase chain reaction techniques allowed for confirmation that the HRS cell was in fact a monoclonal germinal center derived B cell.^16,17 These HRS cells lack immunoglobulin due to defective transcription regulation and not due to crippling mutations.^18,19 The cellular infiltrate in Hodgkin lymphoma appears to play a decisive role in allowing the HRS cells to survive by providing an environment that suppresses cytotoxic immune responses as well as by providing cellular interactions and cytokines that support their growth and survival. The extensive inflammatory infiltrate in classical Hodgkin lymphoma is comprised of T helper 2 (Th2) and regulatory T cells and lacks T helper 1 (Th1) cells, CD8 cytotoxic T cells, and natural killer cells.²⁰ The HRS cells escape apoptosis by several mechanisms which include latent EBV infection and constitutive nuclear factor (NF)-kB pathways, as well as other deregulated signaling pathways that promote survival, such as EBV nuclear antigen 1 (EBNA1) protein, EBV latent infection membrane protein 1 (LMP1), and LMP2.^21,22

Genetic alterations in the 9p24 locus which encodes PD-L1/PD-L2 are nearly universally present in classical Hodgkin lymphoma and are now considered a disease-defining feature.²³

According to the 2008 World Health Organization (WHO) classification, Hodgkin lymphoma has 2 clearly defined entities: classical Hodgkin lymphoma (cHL), which accounts for approximately 95% cases, and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), which accounts for the remaining cases.²⁴ These 2 entities differ in their clinical, pathological, and biological features, which in turn affect prognosis and treatment options. Classical Hodgkin lymphoma is characterized by a paucity of HRS cells surrounded by a background of mixed inflammatory infiltrate comprised of histiocytes, small lymphocytes, eosinophils, neutrophils, plasma cells, fibroblasts, and collagen. Depending on the particular combinations of these elements and the specific features of the neoplastic cells, cases can be subclassified into several cHL subtypes: the nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted types.²⁵

The diagnosis of cHL is made based on a combination of morphology of HRS cells and the other cells infiltrating the tissue, combined with immunohistochemical staining. Because of the rare nature of the malignant (clonal) cell in Hodgkin lymphoma specimens, flow cytometry is generally of little value. The HRS cells in cHL are CD30-positive and CD45 negative in virtually all cases, and CD15-positive in 85% of cases.²⁶ B-cell antigens are typically negative except for CD20, which is positive in about 20% cases.²⁷

Nodular sclerosis Hodgkin lymphoma (NSHL) is the most common subtype of cHL, accounting for 65% to 75% of cases. It is common among young adults and tends to involve the mediastinal, supraclavicular, and cervical lymph nodes. NSHL is characterized by the presence of collagen bands that divide the lymphoid tissue into circumscribed nodules. This subtype usually presents as stage I or II disease, typically with neck and/or mediastinal disease, and evidence of EBV infection is present in approximately 10% to 40% of North American cases.⁷ Patients diagnosed with NSHL generally have a very good prognosis.

Mixed cellularity Hodgkin lymphoma (MCHL) constitutes about 20% to 25% of cHL cases. It affects a somewhat older population, with a median age at diagnosis of 38 years. The typical bimodal age distribution is not seen with MCHL. MCHL has a male predominance (70%), and is more frequent in HIV-infected patients (70% of whom also have EBV infection). Lymphoid tissues have classic HRS cells and significant inflammatory infiltrates. Approximately 50% of patients with MCHL present as stage III or IV with abdominal lymphadenopathy or splenic involvement, and B symptoms are frequent.²⁴

Lymphocyte-rich Hodgkin lymphoma (LRHL) is uncommon, accounting for only 3% to 5% of cases of cHL.²⁸ The disease usually presents at an older age and has a 2:1 male predominance. HRS cells are commonly seen and a large number of reactive lymphocytes are also present. Although on the basis of morphology and immunohistochemistry LRHL belongs to the cHL group, clinically it more closely resembles LPHL. Patients usually present at early stage and rarely have B symptoms. LRHL carries an excellent prognosis, with a greater than 90% PFS after 5 years.^23,29

Lymphocyte-depleted Hodgkin lymphoma (LDHL) is the least common form of cHL, accounting for less than 5% of cases. Many cases previously placed in this category are now recognized as diffuse large B-cell lymphoma (DLBCL), anaplastic large-cell lymphoma (ALCL), or NSHL with lymphocyte depletion.³⁰ HRS cells are frequently seen, but reactive inflammatory cells are relatively sparse. EBV infection is seen in up to 90% of cases, commonly associated with HIV-infected individuals. Advanced-stage and symptomatic disease are more common. Prognosis is slightly worse compared to other categories.

NLPHL accounts for approximately 5% of cases of Hodgkin lymphoma. It has a unimodal age distribution, with the peak incidence in the fourth decade, and male predilection of 3:1.²⁸ NLPHL is characterized by large primary lymphoid follicles, with polytypic small B lymphocytes and extensive meshworks of follicular dendritic cells. The lymphocytic/histiocytic (L and H), or “popcorn,” cells scattered within the nodules differ from classic HRS cells, both in their morphology and in their biochemical profile, being frequently negative for CD15, CD30 and for the EBV genome, and usually positive for B-cell antigens such as CD20, suggesting that L and H cells may be immunoglobulin-synthesizing monoclonal B cells. CD45 is also typically positive in NLPHL, in distinction from cHL. NLPHL has an indolent course compared to cHL, and long-term survival is common.^19,31 NLPHL commonly presents with limited-stage disease. NLPHL may eventually transform into a more aggressive lymphoma, such as diffuse large B-cell lymphoma (including centroblastic, immunoblastic, or T-cell/histiocyte–rich subtypes), at a rate of 4% to 12%. This can occur even 15 to 20 years after the initial diagnosis of NLPHL.^32,33 In a recent large retrospective study of 222 patients with NLPHL, the rate of transformation to DLBCL was 7.6%, with a median time to transformation of 35 months. Overall survival was not adversely affected in patients undergoing transformation compared to those without transformation.³⁴

PRESENTATION

Classical Hodgkin lymphoma usually presents with asymptomatic mediastinal or cervical lymphadenopathy. Half of patients present with stage I or stage II disease.³⁵ A mediastinal mass is seen in most patients with NSHL, at times with bulky disease, with “bulky” defined as a mediastinal mass measuring one-third or more of the maximal thoracic diameter on chest x-ray, or 10 cm on computed tomography (CT) scan. Systemic symptoms, or "B" symptoms—fevers (> 38°C), drenching night sweats, and unexplained weight loss (> 10% of baseline body weight over the preceding 6 months or less)—are detected in approximately 25% of patients. Between 10% and 15% will have extranodal disease, most commonly involving lung, bone, and liver. NLPHL usually presents with limited-stage disease without B symptoms; it typically has a more indolent presentation and clinical course than cHL.

The initial workup includes a complete blood count (CBC), erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH), and chemistry studies to evaluate renal function and liver function. Fine-needle aspiration will usually fail to identify the infrequent HRS cells, and instead only reveal the reactive background of inflammatory cells. Generous (large gauge) core needle biopsies may provide diagnosis effectively in some cases, but in general, an excisional lymph node biopsy is preferred to ensure an accurate diagnosis and avoid the need for repeated biopsy procedures. In cases where an excisional biopsy would be difficult or risky, a core needle biopsy procedure is a reasonable first step, with the understanding that a subsequent surgical procedure may still be necessary.

Baseline imaging includes CT scans of the neck, chest, abdomen, and pelvis. Use of positron emission tomography (PET) scanning is now standard in the initial evaluation and assessment of treatment response in Hodgkin lymphoma.³⁶ Due to the increased sensitivity of PET or PET/CT scan, additional lesions may be identified that were not seen on conventional CT scans. This will alter the staging, and potentially the treatment plan, in up to 25% to 30% of patients.^37,38 PET/CT scan performed during initial evaluation also facilitates optimal interpretation of post-therapy PET/CT scans and is therefore strongly encouraged as a part of the initial staging evaluation.³⁹

Recent studies have shown that bone marrow biopsy is not routinely needed in the initial staging of cHL. A study of 454 patients concluded that bone marrow biopsy would not have altered the stage in any stage I or II patients. It was further concluded that overall treatment strategy would not have been altered for any of the patients.⁴⁰ Based on this study and others, it is now clear that FDG-PET has a high sensitivity, and when PET scan is negative (in the bone marrow and skeleton), a bone marrow biopsy provides little additional value. For patients with significant cytopenias, a bone marrow biopsy is reasonable. Such patients may benefit from a bilateral biopsy, which increases the probability of demonstrating bone marrow involvement by 16% to 33%.^41,42 Techniques such as staging laparotomy and lymphangiography are now considered obsolete.

Hodgkin lymphoma is staged according to the Ann Arbor staging system (Table 1). The original Ann Arbor staging was published in 1971,⁴³ and in 1989 the “Cotswold modifications” extended the definitions of stage IV disease and the suffix “X” was added to denote bulky disease.⁴⁴ Both systems were developed for the staging of Hodgkin lymphoma, but are now used for staging non-Hodgkin lymphoma as well.

PROGNOSTIC FACTORS

For the purposes of prognosis and selection of treatment, Hodgkin lymphoma is commonly classified into early-stage favorable, early-stage unfavorable, and advanced stage. Early-stage Hodgkin lymphoma refers to patients with Ann Arbor stage I or stage II disease. With early-stage Hodgkin lymphoma, the prognosis varies significantly based on factors such as the presence of B symptoms, elevated erythrocyte sedimentation rate ([ESR] > 50 mm/hr), number of nodal sites involved, older age, and a large mediastinal mass. For this reason, most clinical trials to evaluate treatment strategies for early-stage Hodgkin lymphoma are based on various combinations of these risk factors. The definition of early-stage unfavorable Hodgkin lymphoma varies across different clinical trial study groups, and it is important to understand the definition in interpreting the results of these trials (Table 2).^45,46

In the German Hodgkin Study Group (GHSG) trials, early-stage Hodgkin lymphoma is stratified into a high risk (“unfavorable”) group defined by any of the following: a large mediastinal mass (one third of maximum thoracic diameter), extra-nodal disease, 3 or more nodal areas, and an ESR of > 50 mm/hr in asymptomatic patients or > 30 mm/hr in patients with B symptoms. Low-risk (“favorable”) patients lack all of these factors.⁴⁷ The European Organization for Research and Treatment of Cancer (EORTC) defines the unfavorable prognostic group as older than 50 years of age, large mediastinal adenopathy (maximum width on a chest radiograph of at least one third of the internal transverse diameter of the thorax at the level of T5 through T6 or any mass of ≥ 10 cm in the largest dimension), an ESR of 50 mm/hr and no B symptoms, or with an ESR of 30 mm/hr in those who have B symptoms, and/or 4 or more regions of involvement.⁴⁸ The National Cancer Institute of Canada (NCIC) Clinical Trials Group and the Eastern Cooperative Oncology Group (ECOG) define high-risk groups as presence of B symptoms, bulky disease with a mediastinal mass width of at least one third of the maximum chest wall diameter, or any mass greater than 10 cm, and patients with intra-abdominal disease.^49,50

Gene-expression profiling in Hodgkin lymphoma has identified a gene signature of tumor-associated macrophages that was able to identify patients with a higher risk for primary treatment failure. In an independent cohort of patients, an increased number of CD68-positive macrophages was correlated with inferior outcomes.^51,52 Studies such as these underscore the importance of the tumor “microenvironment” (ie, the nonmalignant cells within a tumor) in determining the overall clinical behavior of a malignancy. While quantification of CD68-positive macrophages has potential to be applied to routine clinical practice, prospective data using CD68 as a tool for risk-adapted therapy is lacking.

Genetic alterations and amplifications in the 9p24.1 locus have recently been found to be a defining genetic feature of cHL. Amplification of 9p24.1 has been associated with unfavorable outcomes. Amplification of 9p24.1 (which includes the loci encoding the PD-L1 and PD-L2 genes) is more common in patients with advanced stage disease and is associated with shorter PFS.²³

A recent study attempted to integrate several different prognostic factors in cHL patients who were treated with ABVD (adriamycin [doxorubicin], bleomycin, vinblastine, and dacarbazine) and underwent an interim PET (iPET) scan after 2 cycles of ABVD. Focusing on those with a negative iPET scan, it was found that expression of CD68 and PD-1 in microenvironment cells, and STAT1 negativity in HRS cells identified a subset of PET-2 negative patients with a 3-year PFS significantly lower than that of the remaining PET-2 negative population (64% versus 95%). The algorithm correctly predicted the response to treatment in more than half of the patients who had relapse or disease progression despite a negative PET-2 scan. It therefore appears feasible, using tissue biomarkers at diagnosis, to identify patients at increased risk for poor outcome, even if the iPET scan is negative.⁵³

ROLE OF PET/CT IN ASSESSMENT OF RESPONSE TO THERAPY

PET/CT has been increasingly used for response assessment at various stages in lymphoma in recent years. Almost all types of lymphomas are fluorodeoxyglucose (FDG) avid; however, Hodgkin lymphoma is FDG avid in 97% to 100% of cases. In 2009, a 5-point scale was developed to score PET images with regard to treatment response, either partway through treatment (iPET) or at the end of therapy.⁵⁴ It was recommended as the standard reporting tool at the First International Workshop on PET in Lymphoma in Deauville, France, in 2009, and is thus now referred to as the Deauville score. A score of 1 is given if there is no uptake, 2 if the uptake ≤ mediastinum, 3 if > mediastinum but ≤ liver, 4 if uptake moderately higher than liver, 5 if uptake is markedly higher than liver and/or new lesions. X designates new areas of uptake unlikely to be related to lymphoma. In most trials, a score of 1 or 2 is considered a complete response and a score of 4 or 5 is considered a treatment failure. A score of 3 is sometimes considered a complete response, depending on the study. The Deauville criteria have been widely used in newer clinical trials utilizing response-adapted treatment as defined by PET response. PET/CT is recommended for staging and restaging at the end of therapy, in clinical practice, and clinical trials. Interim PET/CT scan, while commonly performed in clinical practice, is only recommended if the results will alter therapy (eg, if that information will result in the clinician omitting radiation therapy [RT] or altering the chemotherapy plan).

Early studies of iPET showed that achieving PET negativity early in the course of treatment was strongly associated with PFS and overall survival.⁵⁵ Subsequent studies confirmed the importance of achieving a negative iPET. As a result, considerable efforts have been put into designing response-adapted treatment approaches using iPET (see Treatment section), with some of these approaches now being listed in the National Comprehensive Cancer Network (NCCN) guidelines and being used in standard practice.

TREATMENT

EVOLUTION OF TREATMENT

The treatment of Hodgkin lymphoma has evolved over the past century, starting with the discovery of RT as effective treatment in the early 20th century. Long-term survival of patients with Hodgkin lymphoma treated with involved-field radiation therapy (IFRT) was first reported in the 1960s.^56,57 Outcomes improved further with the introduction of combined modality treatment (CMT) using chemotherapy and RT, with the overall 5-year relative survival for patients with Hodgkin lymphoma (all stages) treated in 2006–2012 being 85.4% to 87.3%.³ Since the majority of patients are now cured with modern therapy, treatment-related complications have become an important competing cause of mortality. Recent studies have therefore focused on maintaining efficacy while reducing toxicities, and refining the process of selecting patients who might benefit from more aggressive therapy. While RT was the first treatment modality shown to be curative for Hodgkin lymphoma,^56,57 multiple subsequent studies showed that CMT is superior to RT alone in terms of relapse-free survival.^58–63 In the GHSG H8-F trial, the estimated 5-year event-free survival and overall survival rates were significantly higher after 3 cycles of MOPP-ABV (mechlorethamine, vincristine, procarbazine, and prednisone combined with doxorubicin, bleomycin, and vinblastine) plus IFRT than after subtotal nodal radiotherapy alone. The 10-year overall survival estimates were 97% and 92%, respectively (P = 0.001).⁶⁴ As a result, CMT replaced RT alone as the standard of care for limited-stage Hodgkin lymphoma. However, for elderly or infirm patients, or those with other comorbidities making them poor chemotherapy candidates, RT alone may be a very reasonable option.⁶⁵ More recently, an increasing body of evidence has accumulated to support the use of chemotherapy alone in early stage cHL. This literature has consistently shown that omission of RT is associated with a modest increase in relapse, without a clear compromise in long-term overall survival. For some patients, the trade-off in terms of avoiding radiation (and the associated late effects) may be worth the small increase in relapse risk, since long-term survival does not appear to be substantially worse with chemo-therapy alone. Table 3 and Table 4 provide a summary of recent key studies which have defined treatment options for early-stage cHL.^48,66–71

NLPHL usually presents with limited-stage disease without B symptoms and has an indolent course with a slightly better prognosis compared to cHL.⁷² Due to the rarity of the disease, treatment guidelines are mostly based on retrospective analyses from single or multi-institution studies or subgroup analyses, often with relatively short follow-up. These studies must be interpreted with caution because of the possibility of inaccuracies in the pathologic diagnosis, small sample sizes, and selection bias. Treatment options for limited-stage NLPHL include observation, single-agent rituximab, IFRT (or involved-site radiation therapy [ISRT]) alone, or CMT.⁴⁶

Historically, patients with limited-stage NLPHL have been treated with RT alone, with 80% to 85% PFS and 85% to 95% overall survival rates.^73–75 Patients who relapse or progress after RT in general can successfully undergo salvage therapy.⁷⁴ In one study, rates of PFS and overall survival were similar among patients who had limited-field, regional-field, or extended-field RT,⁷⁵ indicating that IFRT is preferred. Studies comparing RT alone and CMT are limited. The GHSG HD7 trial included a subset of NLPHL patients, with a trend towards improved freedom from treatment failure (96% versus 83%) favoring CMT. This, however, did not translate into improved overall survival.⁴⁷ A retrospective analysis of the British Columbia Cancer Agency database compared patients with limited-stage NLPHL treated with RT alone to patients who received 2 cycles of ABVD followed by RT. A significant improvement in PFS (91% versus 65%) and overall survival (93% versus 84%) was seen, favoring CMT.⁷⁶

Chemotherapy alone is not recommended for limited-stage NLPHL since studies evaluating chemotherapy alone are quite limited and indicate relatively high rates of treatment failure. Given that the malignant cells in NLPHL are CD20-positive, single-agent rituximab has also been studied in this disease, including a study as frontline therapy in limited-stage patients. In this phase 2 trial in newly diagnosed patients with stage IA disease, an overall response rate (ORR) of 100% was seen, with an 85% complete response (CR) rate.⁷⁷ At 3 years, overall survival was 100% and PFS was 81%, indicating that the responses with single-agent rituximab are less durable than those with RT.

Advani et al evaluated rituximab followed by observation versus rituximab (R) followed by maintenance rituximab (MR) for 2 years in 39 new or previously treated patients. At 4 weeks the ORR was 100% (with CR in 67%, and partial response in 33%). At a median follow up of 9.8 years for R alone, and 5 years for R+MR, median PFS was 3 and 5.6 years, respectively (P = 0.26). Estimated 5-yr PFS and overall survival in patients treated with R versus R+MR were 39.1% and 95.7% versus 58.9% and 85.7%, with Pvalues of 0.26 (PFS) and 0.38 (overall), respectively. Maintenance rituximab therefore appears to prolong remission, although the results did not quite reach statistical significance.⁷⁸ Even though rituximab does not appear to be curative in NLPHL, it is a reasonable option for patients with early-stage NLPHL who are not good candidates for definitive RT. Whether combining rituximab with RT or CMT might further improve outcomes in early-stage NLPHL has not yet been determined.

In children, surgery alone may lead to long-term remission or possibly cure of limited-stage NLPHL. In a European multicenter retrospective study, 58 patients underwent surgery for limited-stage NLPHL. Among the 51 patients who achieved complete remission following surgery, 67% remained progression-free and 100% were alive at a median follow up of 43 months.⁷⁹ In adults, there is no data to support surgical treatment alone for NLPHL. Finally, observation may be a reasonable option in elderly or infirm patients for whom NLPHL is unlikely to affect life expectancy. For younger patients, given the excellent outcome with modern therapy and the long-term risk of transformation of NLPHL into an aggressive non-Hodgkin lymphoma, observation is generally not recommended.

The NCCN recommends RT (ISRT or IFRT, 30–36 Gy) as the preferred treatment for stage IA and IIA non-bulky NLPHL. In patients with stage IA disease with complete excision of solitary nodule, observation may be appropriate. A course of chemotherapy with ISRT with or without rituximab is recommended for patients with stage IB or IIB disease, or patients with stage IA or IIA bulky disease.

FIRST-LINE TREATMENT OF LIMITED-STAGE CHL

Early-Stage Favorable cHL

There is lack of consensus regarding the ideal treatment approach for patients with early-stage favorable cHL. However, there are several excellent options available, with overall survival rates exceeding 90%. Most of these regimens involve CMT, although some chemotherapy-alone approaches have been evaluated as well. Concurrent with the demonstration of excellent long-term remission rates with CMT, it became apparent that the long-term survival and quality of life of these patients is determined in large part by the risk of serious (and potentially fatal) treatment-related toxicities. Such toxicities consist primarily of secondary malignancies and cardiovascular events, and can continue to cause significant morbidity and mortality even 2 to 3 decades after treatment.^80–82 As a result, treatment decisions for these patients are complicated and require balancing efficacy against risk of late complications.

In the United States, until recently, CMT was generally considered the standard of care, with robust long-term data regarding efficacy. The most commonly used regimen has been ABVD for 2 to 4 cycles followed by IFRT. In some German studies, escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) has been used, but this is not a general standard of care in the United States for early-stage patients.

More recent data suggests that the rate of serious late complications in Hodgkin lymphoma patients is decreasing, likely due to less extensive radiation fields, lower radiation doses, and a movement away from the MOPP regimen to ABVD.^83,84 For patients who meet the “favorable” criteria set forth in the GHSG HD10 trial (see Table 2), 2 cycles of ABVD followed by 20 Gy of IFRT is an attractive option, with efficacy preserved and a low anticipated rate of late effects.⁶⁶ With this approach, and with long-term (10 years) follow up, all 4 arms had similar PFS (87%) and overall survival (94%), whether 2 or 4 cycles of ABVD were given. When the effects of 20-Gy and 30-Gy doses of RT were compared, there were also no significant differences in freedom from treatment failure or overall survival. Adverse events and acute toxic effects of treatment were most common in the patients who received 4 cycles of ABVD and 30 Gy of RT.^66,71

In recent years, in an attempt to reduce late effects further, regimens consisting of chemotherapy alone have been investigated. In a study by Meyer et al, at 12 years the rate of overall survival was 94% among those receiving ABVD alone, as compared with 87% among those receiving subtotal nodal RT; the rates of freedom from disease progression were 87% and 92% in the 2 groups; and the rates of event-free survival were 85% and 80%, respectively.⁵⁰ However, it is important to note that this study did not include a CMT arm for the early favorable patients, and did not utilize modern RT techniques. Nevertheless, this early study and others⁶⁰ suggested that chemotherapy alone may be a reasonable option for some early-stage cHL patients, particularly for patients who are felt to be at increased risk for late toxicities from RT. As a result, additional studies have been conducted evaluating CMT versus chemotherapy alone for early-stage cHL. Many of these studies have incorporated interim PET/CT scan to develop a response-adapted approach to decide which patients are least likely to benefit from RT.

The HD-13 study was a follow-up study for HD-10, looking at deletion of bleomycin, dacarbazine, or both from the ABVD backbone. The ABD arm was closed early, because of an excess rate of treatment failure. Among the 1243 patents assigned to either the ABVD or AVD arm at 5 years of follow-up, there was 4.3% difference in PFS. This study was not able to demonstrate that 2 cycles of AVD was noninferior to 2 cycles of ABVD, each followed by 30 Gy IFRT, even though there was no difference in all 4 groups. It confirmed 2 cycles of ABVD as the preferred regimen in early favorable Hodgkin lymphoma, when CMT is the plan of care. However, for patients over age 60 to 65 years, or those with underlying cardiac or pulmonary comorbidities, bleomycin has significant risk of toxicity. In that setting, AVD is a safer option, with only a very modest decrease in 5-year PFS.

Based on the observation that iPET scan is highly predictive of outcome in Hodgkin lymphoma,^55,85 several trials have employed the use of an iPET scan to guide therapy. It is hoped that such studies will lead to new PET-directed treatment algorithms in which patients who require more aggressive therapy (eg, with CMT, or escalated BEACOPP) can be identified, and the remaining patients can be safely treated less aggressively (eg, with chemotherapy alone).

In the EORTC H10 trial, performed to evaluate treatment adaptation on the basis of iPET scan results in stage I and II Hodgkin lymphoma, a control arm received standard combined modality treatment (3 or 4 cycles of ABVD with INRT) irrespective of PET scan results. In the experimental arm, patients with a negative PET scan after 2 cycles of ABVD continued with 1 or 2 cycles of ABVD and did not receive RT. The iPET-positive patients received either standard treatment with ABVD plus INRT or escalated BEACOPP plus INRT. The iPET-negative patients received either ABVD only or ABVD plus INRT. The final results of this study, published recently, showed that in the iPET-positive patients the 5-year PFS was improved from 77.4% with standard ABVD plus INRT to 90.6% with escalated BEACOPP plus INRT (P = 0.002). In iPET-negative patients, 5-year PFS in the favorable group was 99% versus 87.1% in favor of ABVD plus INRT. The H10 study suggested that PET results after 2 cycles of ABVD can be integrated into treatment planning, In iPET-negative patients, the study was technically not able to demonstrate the noninferiority of the ABVD only regimen, owing to a higher risk of relapse if INRT is omitted, particularly in the favorable group.⁴⁸ However, this study does show that excellent outcomes can be obtained with omission of RT in patients with a negative iPET scan. This study provides a cautionary lesson though, in that the increase in relapse rate associated with omission of RT was more substantial (12%) for favorable versus unfavorable early-stage patients (2.5%), and this difference was only apparent after longer (5 years) follow-up. Despite this, chemotherapy alone is considered a reasonable treatment option, especially for patients felt to be at increased risk for late toxicities of RT or for patients who wish to avoid the risks of RT, with over 99% of patients alive at 5 years.

Similar results were shown in the RAPID trial, in which patients with limited-stage cHL underwent 3 cycles of ABVD followed by PET assessment.⁶⁷ Patients with a negative PET (n = 426) were then randomized to RT (n = 209) versus no further therapy (n = 211). At a median of 60 months of follow-up, 3-year PFS was 94.6% in the RT group and 90.8% in the chemotherapy alone group. Similar to the H10 trial, it was concluded that chemotherapy alone was statistically inferior to CMT in terms of PFS. However, also similar to the H10 trial, the RAPID trial demonstrated that excellent results can be obtained in early-stage cHL patients with omission of RT, if iPET scan is negative after 3 cycles of ABVD, as there was no survival difference. These findings indicate that, when relapses occur as a result of omission of RT, such patients can be effectively treated later.

In the ongoing GHSG HD16 trial, patients with early-stage favorable cHL will be randomly assigned to a standard approach (ABVD × 2 cycles followed by 20-Gy IFRT) versus an experimental approach in which they receive ABVD for 2 cycles and then undergo PET scan. If the PET remains positive, they will receive 20-Gy IFRT. If the PET is negative, they will receive no further therapy. This trial could ultimately define ABVD for 2 cycles as a treatment option.

It is clear from these studies that omission of RT results in a somewhat higher rate of relapse but can be considered in selected patients. However, taking a less aggressive frontline approach may also be justified by the fact that, for those who do relapse, successful salvage therapies are available. Aggressive salvage therapy with autologous stem cell transplantation historically can cure approximately 50% of relapsed patients. With new and emerging therapies for relapsed disease, such as brentuximab vedotin and the PD-1 inhibitors (eg, nivolumab and pembrolizumab), the ability to cure relapsed patients may improve even more, further calling into question the practice of applying CMT uniformly for early-stage patients undergoing first-line therapy. Unfortunately, there is insufficient data from large randomized studies with long-term follow-up to fully address this issue currently, and there remains some controversy around this issue. NCCN recommends restaging PET/CT after 3 cycles of ABVD if a chemotherapy alone treatment modality is chosen. If the Deauville score is 1 or 2, either observation or 1 additional cycle of ABVD is recommended.⁴⁶

Early-Stage Unfavorable cHL

In the United States, historically early-stage unfavorable Hodgkin lymphoma has been treated with CMT, most commonly 4 to 6 cycles of ABVD followed by consolidative RT. With this approach one can expect a 5-year PFS of approximately 80% to 85%.^58,64,86 The GHSG HD8 trial showed that RT volume size reduction from extended-field to involved-field after COPP + ABVD chemotherapy for 2 cycles produced similar results and less toxicity in patients with early-stage unfavorable cHL.⁸⁶ The GHSG trial HD11 established ABVD for 4 cycles plus 30-Gy IFRT as a standard for early unfavorable Hodgkin lymphoma. The freedom from treatment failure at 5 years was 85.0%, and overall survival was 94.5%.⁶⁸

In the HD14 study by the GHSG, patients with early unfavorable cHL were treated with 2 cycles of escalated BEACOPP followed by 2 cycles of ABVD, versus 4 cycles of ABVD. All patients then received 30 Gy of consolidative IFRT. A 5-year PFS of 95% was seen in the experimental arm, compared with 89% in the standard (ABVD) arm. As expected, this regimen was associated with more acute hematologic toxicity, and there was no difference between the 2 regimens with respect to overall survival or fertility.⁶⁹ Given the lack of improved survival and increased toxicity, ABVD has remained the standard chemotherapy regimen for early unfavorable cHL in the United States. NCCN recommends a restaging PET scan after 2 cycles of ABVD and to continue with 2 to 4 cycles of ABVD or escalated BEACOPP with or without ISRT based on Deauville scores.

Another viable treatment option is the Stanford V regimen, a condensed, 12-week regimen that includes mechlorethamine, doxorubicin, vinblastine, prednisone, vincristine, etoposide, and bleomycin, followed by IFRT.⁸⁷ In a randomized phase 3 trial conducted by ECOG (E2496), patients with stage I/II Hodgkin lymphoma with bulky mediastinal disease or advanced-stage disease were randomized to ABVD × 6 to 8 cycles versus Stanford V. RT was given (36 Gy) for those with bulky mediastinal disease or to sites of disease greater than 5 cm in the Stanford V arm. In a subset analysis focusing only on those with stage I/II bulky mediastinal disease, the 5-year failure free survival was 85% versus 79% and the 5-year overall survival was 96% versus 92% for the ABVD versus Stanford V arms, respectively. These differences were not statistically significant.⁷⁰ While the Stanford V regimen has the advantages of a 12-week treatment duration and a lower cumulative amount of bleomycin and doxorubicin, the Stanford V arm had higher rates of grade 3 lymphopenia and grade 3 to 4 peripheral neuropathies. In addition, Stanford V requires that most patients undergo RT (to original sites of disease measuring 5 cm or more plus contiguous areas). As a result, the investigators concluded that ABVD × 4 cycles plus IFRT remains the standard of care for patients with early unfavorable Hodgkin lymphoma with bulky mediastinal disease.

Other regimens have been studied in hopes of reducing toxicity, including the EVE regimen (epirubicin, vinblastine, and etoposide). This regimen was compared to ABVD in early unfavorable Hodgkin lymphoma patients, with all patients undergoing the same RT program. No differences were observed between the ABVD and EVE arms in terms of complete remission rate and overall survival. However, patients who received EVE had a significantly worse outcome than those who received ABVD in terms of relapse-free survival and failure-free survival.⁸⁸ EBVP (epirubicin, bleomycin, vinblastine, and prednisone) followed by IFRT was less efficacious compared with MOPP/ABV–type therapy.⁵⁸

An area of active investigation is whether RT can be safely omitted in patients with early- stage unfavorable cHL. The EORTC H10 study showed that, for patients with a negative iPET scan (after 2 cycles), the 5-year PFS rates were 92.1% versus 89.6% for ABVD plus INRT versus ABVD alone, respectively. While this technically did not meet criteria for noninferiority of ABVD alone, this study demonstrated that, for those with negative iPET, ABVD × 6 cycles (without radiation) can result in long-term remission in a high proportion (89%) of patients. For iPET-positive patients, 2 cycles of escalated BEACOPP were given followed by 30 Gy of IFRT on the experimental arm. This resulted in a 5-year PFS of 90.6% versus 77.4%, suggesting this may be a preferred approach for early-stage unfavorable patients with a positive iPET.⁴⁸ Even though the noninferiority of ABVD alone could not be established based on the statistical design of the study, the current NCCN guidelines recommend restaging after 2 cycles of ABVD for stage I or II unfavorable cHL and using that iPET as a guide, based on Deauville scores. For scores 1–3, ABVD × 2 cycles (total 4 cycles) plus ISRT or AVD × 4 (total 6) with or without ISRT is recommended. For a Deauville score of 4, escalated BEACOPP × 2 cycles or ABVD × 2 cycles (total 4) followed by ISRT is recommended. If the Deauville score is 5, further treatment decisions should be made based on repeat biopsy results. A follow up PET/CT is recommended for Deauville scores of 4 and 5 to confirm complete response.⁴⁶

LATE EFFECTS AND THE EVOLUTION OF RADIATION THERAPY

The RT given in Hodgkin lymphoma has evolved considerably over the years, from extended field or subtotal nodal fields developed in the 1960s, to the more focused involved-field or even involved-site radiation commonly given now. This approach reduces radiation volumes, and it already is becoming evident that the relative risk of breast cancer among young females receiving mediastinal RT for Hodgkin lymphoma is declining.⁸⁹ Cardiac dose is reduced significantly with IFRT compared to older radiation techniques as well. The extent of radiation may be reduced even further with involved-nodal/involved site or intensity-modulated approaches.⁹⁰

With new RT techniques allowing for more focused therapy and lower doses of radiation, models predict that the rate of long-term complications will decline further.^91,92 Furthermore, response-adapted (ie, PET-directed) approaches, as discussed in detail earlier in the article, are expected to increasingly allow for identification of patients who can safely avoid radiation entirely, which will hopefully lead to an even lower rate of late complications of therapy.

MONITORING FOR RELAPSE

A number of recent studies have shown that, for patients who achieve complete remission with first-line therapy, performing repeated scheduled surveillance imaging does not improve outcomes. In fact, most relapses are detected by the patient (due to symptoms or recurrence of lymph node enlargement). It is rare that a relapse would be detected by surveillance imaging alone. Furthermore, surveillance that includes routine imaging has not been associated with improved survival.⁹³ As a result, it is now recommended that patients undergo regular follow-up with symptom review, physical exam, and basic laboratory studies. Imaging studies should be obtained as needed for patients who develop signs, symptoms, exam findings, or laboratory values concerning for relapse.

More important than scheduled surveillance imaging for relapse is monitoring for late effects of therapy. These fall into several broad categories such as cardiovascular disease (coronary disease, congestive heart failure, valvular disease, carotid artery disease), pulmonary disease, hypothyroidism, and secondary malignancies. Aggressive surveillance for breast cancer is especially warranted in female patients who underwent chest radiation.⁴⁶

CONCLUSION

Hodgkin lymphoma is characterized pathologically by the presence of HRS cells accompanied by a polymorphous cellular infiltrate. It is a disease with a bimodal age distribution, several pathologic subtypes, and numerous treatment options. Overall, the prognosis for patients with early-stage disease is excellent, and although a majority of patients can now be cured, further studies are needed to optimize treatment such that short- and long-term treatment-related toxicities are minimized, without compromising disease control and cure.

Given the limited number of geriatricians in the U.S., hospitalists commonly manage nursing home residents admitted for post-acute care.^1-4 Urinary tract infection (UTI) is one of the most common infections in nursing homes, often leading to sepsis and readmission to acute care.⁵ Inappropriate use of antibiotics to treat asymptomatic bacteriuria is both common and hazardous to nursing home residents.⁶ Up to 10% of nursing home residents will have an indwelling urinary catheter at some point during their stay.^7-9 Residents with indwelling urinary catheters are at increased risk for catheter-associated urinary tract infection (CAUTI) and bacteriuria, with an estimated 50% of catheterized residents developing symptomatic CAUTI.⁵ While urinary catheter prevalence is lower in nursing homes than in the acute care setting, duration of use is often prolonged.^7,10 In a setting where utilization is low, but use is prolonged, interventions designed to reduce UTI in acutely ill patients¹¹ may not be as helpful for preventing infection in nursing home residents.

Our objective was to review the available evidence to prevent UTIs in nursing home residents to inform both bedside care and research efforts. Two types of literature review and summary were performed. First, we conducted a systematic review of individual studies reporting outcomes of UTI, CAUTI, bacteriuria, or urinary catheter use after interventions for reducing catheter use, improving insertion and maintenance of catheters, and/or general infection prevention strategies (eg, improving hand hygiene, infection surveillance, contact precautions, standardizing UTI diagnosis, and antibiotic use). Second, we performed a narrative review to generate an overview of evidence and published recommendations in both acute care and nursing home settings to prevent UTI in catheterized and non-catheterized older adults, which is provided as a comprehensive reference table for clinicians and researchers choosing and refining interventions to reduce UTIs.

The systematic review was performed according to the criteria of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis recommendations. The protocol was registered at the PROSPERO International Prospective Register of Systematic Reviews, (CRD42013005787). The narrative review was performed using the articles obtained from the systematic search and a targeted literature review by topic for a comprehensive list of interventions, including other interventions summarized in published reviews and guidelines.

Eligibility Criteria Review

Study Design. To address the breadth and depth of literature available to inform interventions to prevent UTI in nursing homes, broad eligibility criteria were applied with the expectation of varied designs and outcomes. All included studies for the systematic review were published manuscripts reporting a comparison group. We included randomized controlled trials as well as nonrandomized trials (pretest/posttest, with or without concurrent or nonconcurrent controls), with any duration of postintervention follow-up. Observational and retrospective studies were excluded.

Participants. We were interested in interventions and outcomes reported for nursing homes, defined as facilities providing short-stay skilled nursing care and/or rehabilitation, as well as long-term care. We also included evidence derived from rehabilitation facilities and spinal cord injury programs focused on reducing CAUTI risk for chronically catheterized residents. We excluded long-term acute care hospitals, hospice, psychiatric/mental health facilities, pediatric, and community dwelling/outpatient settings.

Interventions. We included interventions involving urinary catheter use such as improving appropriate use, aseptic placement, maintenance care, and prompting removal of unnecessary catheters. We included infection prevention strategies with a particular interest in hand hygiene, barrier precautions, infection control strategies, infection surveillance, use of standardized infection definitions, and interventions to improve antibiotic use. We included single and multiple interventions.

Outcomes
1. Healthcare-associated urinary tract infection: UTI occurring after admission to a healthcare facility, not identified specifically as catheter-associated. We categorized UTI outcomes with as much detail as provided, such as whether the reported outcome included only noncatheter-associated UTIs, the time required after admission (eg, more than 2 days), and whether the UTIs were defined by only laboratory criteria, clinically diagnosed infections, symptomatic, or long-term care specific surveillance definitions.

2. Catheter-associated urinary tract infection: UTI occurring in patients during or immediately after use of a urinary catheter. We noted whether CAUTI was defined by laboratory criteria, clinical symptoms, provider diagnosis, or antimicrobial treatment for case identification. We were primarily interested in CAUTI developing after placing an indwelling urinary catheter, commonly known as a Foley, but also in CAUTI occurring with other catheter types such as intermittent straight catheters, external or “condom” catheters, and suprapubic catheters.

3. Bacteriuria: We included the laboratory-based definition of bacteriuria as an outcome to include studies that reduced asymptomatic bacteriuria.

4. Urinary catheter use measures: This includes measures such as urinary catheter utilization ratios (catheter-days/patient-days), prevalence of urinary catheter use, or percentage of catheters with an appropriate indication.

Study Characteristics for Inclusion. Our systematic search included published papers in the English language. We did not exclude studies based on the number of facilities included or eligible, residents/patients included (based on age, gender, catheter use or type, or antibiotic use), intervention details, study withdrawal, loss to follow-up, death, or duration of pre-intervention and postintervention phases.

Data Sources and Searches

The following data sources were searched: Ovid MEDLINE (1950 to June 22, 2015), Cochrane Library via Wiley (1960 to June 22, 2015), CINAHL (1981 to June 22, 2015), Web of Science (1926 to June 22, 2015), and Embase.com (1946 to June 22, 2015). Two major systematic search strategies were performed for this review (Figure). Systematic search 1 was designed broadly using all data sources described above to identify interventions aimed at reducing all UTI events (defined under “Outcomes” above) or urinary catheter use (all types), focusing on interventions evaluated in nursing homes. Systematic search 2 was conducted in Ovid MEDLINE to identify studies to reduce UTI events or urinary catheter use measures for patients with a history of long-term or chronic catheter use, including nursing homes and other post-acute care settings such as rehabilitation units or hospitals and spinal cord injury programs, which have large populations of patients with chronic catheter needs. To inform the completeness of the broader systematic searches, supplemental systematic search strategies were performed for specific topics including hydration (supplemental search 1), published work by nursing home researchers known to the authors (supplemental search 2), and contact precautions (supplemental search 3). Search 1 is available at http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42013005787. Full search strategies for search 2 and supplemental searches are available upon request.

Study Selection

One author performed an initial screen of all records retrieved by the systematic searches by title and abstract and applied the initial exclusions (eg, non-human, no outcomes of interest), identified duplicate records, and assigned potentially relevant studies into groups such as review articles, epidemiology, interventions, and articles requiring further text review before categorization (Figure). After initial screening, Dr. Meddings reviewed the records by title/abstract. Reference lists were reviewed for potential articles for inclusion. Full-text article review informed the selection of those for dual abstraction and quality scoring performed by 2 authors, with discrepancies resolved by a third author. We requested additional information from authors from whom our search had generated only an abstract or brief report, or when additional information such as pre-intervention data was needed.^12-18

Data Extraction and Quality Assessment

Relevant data regarding study design, participants, inclusion/exclusion criteria, outcomes, and quality criteria were abstracted independently by 2 authors. Methodological quality scores were assigned using a modification of the Quality index checklist developed by Downs and Black appropriate for assessing both randomized and nonrandomized studies of healthcare interventions.¹⁹ We also reviewed study funding sources and other potential quality concerns.

Data Analysis

Due to large trial heterogeneity among these studies about interventions and outcomes reported, outcome data could not be combined into summary measures for meta-analysis to give overall estimates of treatment effects.

Systematic Search Results and Study Selection

As detailed in the study flow diagram (Figure), 5794 total records were retrieved by systematic search 1 (4697 studies), search 2 (909 studies), and supplemental searches (188 studies). Hand searching of reference lists of 41 reviews (including narrative and systematic reviews) yielded 77 additional studies for consideration. Twenty-nine records on interventions that were the focus of systematic reviews, including topics of cranberry use, catheter coatings, antimicrobial prophylaxis, washout/irrigation strategies, and sterile versus clean intermittent straight catheterization, were excluded from dual abstraction. Two records were excluded after team discussion of the dual-abstraction results, because 1 study did not meet criteria as an intervention study and 1 study’s setting was not applicable in nursing homes. A total of 20 records^15,20-38 (in which 19 studies were described) were selected for final inclusion for detailed assessment and reporting for the systematic review.

Characteristics of Included Studies

Table 1 describes the 19 intervention studies in terms of design, participants, setting, and whether the study included specific categories of interventions expected to decrease UTI or catheter use. These studies included 8 randomized controlled trials (4 with cluster-randomization at the facility or unit level), 10 pre-post nonrandomized interventions, and 1 nonrandomized intervention with concurrent controls. Twelve studies included participants with or without catheters (ie, not limited to catheterized patients only) in nursing homes.^15,20-31 Seven^32-38 studies included catheterized patients only or settings with high expected catheterization rates; settings for these studies included spinal cord units (n=3), nursing homes (n=2), rehabilitation ward (n=1) and VA hospital (n=1), including acute care, nursing home, and rehabilitation units. Total quality scores for the studies ranged from 8 to 25 (median, 15), detailed in Supplemental Table 1.

As detailed in Table 1 and Supplemental Table 2, 7 studies^{22,24,26,31,32,35,36} involved single interventions and 12 studies^{15,20,21,23,25,27-30,33,34,37,38} included multiple interventions. Interventions to impact catheter use and care were evaluated in 13 studies, including appropriateness of use,^21,25,29,30 improving catheter maintenance care,^15,20,29,30 securement,^15,29,30,32 prompting removal of unnecessary catheters,^21,25,29,30 improving incontinence care,^15,21,23,25 bladder scanners,^37,38 catheter changes,³⁵and comparing alternatives (condom catheter or intermittent straight catheter) to use of an indwelling catheter.^36,38 None focused on improving aseptic insertion. General infection control practices studied included improving hand hygiene,^{20-22,29-31,33,34} improving antibiotic use,^{15,20,21,28,34} initiation of infection control programs,^20,21,28 interventions to improve identification of UTIs/CAUTIs using infection symptom/sign criteria,^15,20,21,34 infection surveillance as an intervention,^28-30,33,34 and barrier precautions,^33,34 including preemptive precautions for catheterized patients.³⁴ Hydration was assessed in 3 studies.^24-26

Outcomes of Included Studies

Table 2 describes the studies’ outcomes reported for UTI, CAUTI, or bacteriuria.^15,20-38 The outcome definitions of UTI and CAUTI varied widely. Only 2 studies^22,39 reported UTI outcomes using definitions specific for nursing home settings such as McGeer’s criteria⁴⁰ a detailed review and comparison of published CAUTI definitions used clinically and for surveillance in nursing homes is provided in Supplemental Table 3. Two studies reported symptomatic CAUTIs per 1000 catheter-days.^32,34 Another study²² reported symptomatic CAUTIs per 1000 resident-days. Three reported symptomatic CAUTIs as counts.^35,38 Saint et al³⁶ reported CAUTIs as part of a combined outcome (ie, bacteriuria, CAUTI, or death).

The 19 studies (Table 2) reported 12 UTI outcomes,^{15,20,21,23,25-31,33} 9 CAUTI outcomes,^{15,22,32,34,35,38} 4 bacteriuria outcomes,^24,36,38 and 5 catheter use outcomes.^{21,29,30,37,38} Five studies showed CAUTI reduction^{15,22,32,34,35} (1 significantly³⁴); 9 studies showed UTI reduction^{13,18,19,21,23-25,27,28,31} (none significantly); 2 studies showed bacteriuria reduction (none significantly). One study³⁶ reported 2 composite outcomes including bacteriuria or CAUTI or death, with statistically significant improvement reported for 1 composite measure. Four studies reported catheter use, with all showing reduced catheter use in the intervention group; however, only 1 achieved statistically significant reduction.³⁷

Synthesis of Systematic Review Results

Overall, many studies reported decreases in UTI, CAUTI, and urinary catheter use measures but without statistical significance, with many studies likely underpowered for our outcomes of interest. Often, the outcomes of interest in this systematic review were not the main outcome for which the study was designed and originally powered. The interventions studied included several currently implemented as part of CAUTI bundles in the acute care setting, such as improving catheter use, and care and infection control strategies. Other included interventions target common challenges specific to the nursing home setting such as removing indwelling catheters upon admission to the nursing home from an acute-care facility^21,25 and applying interventions to address incontinence by either general strategies^{21,23,25,30,38} or the use of an incontinence specialist²³ to provide individual treatment plans. The only intervention that demonstrated a statistically significant reduction in CAUTI in chronically catheterized patients employed a comprehensive program to improve antimicrobial use, hand hygiene (including hand hygiene and gloves for catheter care), and preemptive precautions for patients with devices, along with promotion of standardized CAUTI definitions and active multidrug resistant organism surveillance.³⁴

Narrative Review Results

Table 3 includes a comprehensive list of potential interventions that have been considered for prevention of UTI or CAUTI (including those in acute care and nursing home settings), as summarized from this systematic review and prior narrative or systematic reviews.^43-115

We performed a broad systematic review of strategies to decrease UTI, CAUTI, and urinary catheter use that may be helpful in nursing homes. While many studies reported decreased UTI, CAUTI, or urinary catheter use measures, few demonstrated statistically significant reductions perhaps because many were underpowered to assess statistical significance. Pooled analyses were not feasible to provide the expected impact of these interventions in the nursing home setting.

This review confirms that bundles of interventions for prevention of CAUTI have been implemented with some evidence of success in nursing home settings, with several components in common with those implemented in the acute care setting, such as hand hygiene and strategies to reduce and improve catheter use.⁴¹ Some studies focused on issues more common in nursing homes such as chronic catheterization and incontinence. A nursing home CAUTI bundle should be designed with the resources and challenges present in the nursing home environment in mind, and with recognition that, although the number of patients with catheters is less than in acute care, there will be more patients with chronic catheterization needs and incontinence.

Although catheter utilization in nursing homes is low, further reductions in catheter days and CAUTIs can be achieved. Catheter removal reminders and stop orders have demonstrated a greater than 50% reduction in CAUTIs in acute care settings;¹¹ an example of a stop-order intervention in nursing homes is trial removal of indwelling catheters present at facility admission without clear urologic need present at the time of admission.²⁵ Nursing home interventions to avoid catheter placement should include incontinence programs, discussion of alternatives to indwelling urinary catheters with patients, families, and frontline personnel, and urinary retention protocols. Programs to reduce CAUTI should include education to improve aseptic insertion, and to maintain awareness and proper care of catheters in place by regular assessment of catheter necessity, securement, hand hygiene, and preemptive barrier precautions for catheterized patients. Interventions that focus on improving appropriate use of urine tests and antibiotics to treat UTIs can also significantly affect the rates of reported symptomatic CAUTIs, with the potential to decrease unnecessary antibiotic use.^20,21

The main limitation of this review is that many studies provided little information about their intervention and definition of outcomes. The strength of this review is the detailed and broad search strategy applied with generous inclusion of interventions and outcomes to highlight the available evidence and details of interventions that have been studied and implemented.

This review synthesizes the current state of evidence and proposes strategies to reduce UTIs in nursing homes. Interventions that motivate catheter avoidance and catheter removal to prevent CAUTI in acute care¹¹ and nursing home settings are supported by the strongest available evidence, although the strength of that evidence is less in the nursing home setting. Limitations notwithstanding, interventions such as incontinence care planning and hydration programs can reduce UTI in this population and is important for overall wellbeing.

Acknowledgments

The authors appreciate the guidance that Vineet Chopra MD, MSc, provided regarding options for methodological quality assessment tools, and the assistance of Mary Rogers PhD, MS, in interpreting the published Downs and Black Quality Index items, which informed our modification of this tool for application in this study. The authors appreciate, also, the feedback provided by the Agency for Healthcare Research and Quality (AHRQ) Content and Materials Development Committee for the AHRQ Safety Program for Long-Term Care: Preventing CAUTI and other Healthcare-associated Infections.

Disclosures

Agency for Healthcare Research and Quality (AHRQ) contract #HHSA290201000025I provided funding for this study, which was developed in response to AHRQ Task Order #8 for ACTION II RFTO 26 CUSP for CAUTI in LTC. AHRQ developed the details of the task and provided comments on a draft report, which informed the report submitted to AHRQ in December 2013, used to inform the interventions for a national collaborative (http://www.hret.org/quality/projects/long-term-care-cauti.shtml). Dr. Meddings’s effort on this project was funded by concurrent effort from her AHRQ (K08 HS19767). Dr. Saint’s and Dr. Krein’s effort on this project was funded by concurrent effort from the Veterans Affairs National Center for Patient Safety, Ann Arbor Patient Safety Center of Inquiry. Dr. Meddings’s other research is funded by AHRQ (2R01HS018334-04), the NIH-LRP program, the VA National Center for Patient Safety, and the VA Ann Arbor Patient Safety Center of Inquiry. Dr. Krein’s other research is funded by a VA Health Services Research and Development Award (RCS 11-222). Dr. Mody’s other research is funded by VA Healthcare System Geriatric Research Clinical Care Center (GRECC), NIA-Pepper Center, NIA (R01AG032298, R01AG041780, K24AG050685-01). Dr. Saint has received fees for serving on advisory boards for Doximity and Jvion. All other authors report no financial conflicts of interest. The findings and conclusions in this report are those of the authors and do not necessarily represent those of the sponsor, the Agency for Healthcare Research and Quality, or the U.S. Department of Veterans Affairs. These analyses were presented in part as a poster presentation at the ID Week Annual Meeting on October 10, 2014 in Philadelphia, PA.

Given the limited number of geriatricians in the U.S., hospitalists commonly manage nursing home residents admitted for post-acute care.^1-4 Urinary tract infection (UTI) is one of the most common infections in nursing homes, often leading to sepsis and readmission to acute care.⁵ Inappropriate use of antibiotics to treat asymptomatic bacteriuria is both common and hazardous to nursing home residents.⁶ Up to 10% of nursing home residents will have an indwelling urinary catheter at some point during their stay.^7-9 Residents with indwelling urinary catheters are at increased risk for catheter-associated urinary tract infection (CAUTI) and bacteriuria, with an estimated 50% of catheterized residents developing symptomatic CAUTI.⁵ While urinary catheter prevalence is lower in nursing homes than in the acute care setting, duration of use is often prolonged.^7,10 In a setting where utilization is low, but use is prolonged, interventions designed to reduce UTI in acutely ill patients¹¹ may not be as helpful for preventing infection in nursing home residents.

Our objective was to review the available evidence to prevent UTIs in nursing home residents to inform both bedside care and research efforts. Two types of literature review and summary were performed. First, we conducted a systematic review of individual studies reporting outcomes of UTI, CAUTI, bacteriuria, or urinary catheter use after interventions for reducing catheter use, improving insertion and maintenance of catheters, and/or general infection prevention strategies (eg, improving hand hygiene, infection surveillance, contact precautions, standardizing UTI diagnosis, and antibiotic use). Second, we performed a narrative review to generate an overview of evidence and published recommendations in both acute care and nursing home settings to prevent UTI in catheterized and non-catheterized older adults, which is provided as a comprehensive reference table for clinicians and researchers choosing and refining interventions to reduce UTIs.

The systematic review was performed according to the criteria of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis recommendations. The protocol was registered at the PROSPERO International Prospective Register of Systematic Reviews, (CRD42013005787). The narrative review was performed using the articles obtained from the systematic search and a targeted literature review by topic for a comprehensive list of interventions, including other interventions summarized in published reviews and guidelines.

Eligibility Criteria Review

Study Design. To address the breadth and depth of literature available to inform interventions to prevent UTI in nursing homes, broad eligibility criteria were applied with the expectation of varied designs and outcomes. All included studies for the systematic review were published manuscripts reporting a comparison group. We included randomized controlled trials as well as nonrandomized trials (pretest/posttest, with or without concurrent or nonconcurrent controls), with any duration of postintervention follow-up. Observational and retrospective studies were excluded.

Participants. We were interested in interventions and outcomes reported for nursing homes, defined as facilities providing short-stay skilled nursing care and/or rehabilitation, as well as long-term care. We also included evidence derived from rehabilitation facilities and spinal cord injury programs focused on reducing CAUTI risk for chronically catheterized residents. We excluded long-term acute care hospitals, hospice, psychiatric/mental health facilities, pediatric, and community dwelling/outpatient settings.

Interventions. We included interventions involving urinary catheter use such as improving appropriate use, aseptic placement, maintenance care, and prompting removal of unnecessary catheters. We included infection prevention strategies with a particular interest in hand hygiene, barrier precautions, infection control strategies, infection surveillance, use of standardized infection definitions, and interventions to improve antibiotic use. We included single and multiple interventions.

Outcomes
1. Healthcare-associated urinary tract infection: UTI occurring after admission to a healthcare facility, not identified specifically as catheter-associated. We categorized UTI outcomes with as much detail as provided, such as whether the reported outcome included only noncatheter-associated UTIs, the time required after admission (eg, more than 2 days), and whether the UTIs were defined by only laboratory criteria, clinically diagnosed infections, symptomatic, or long-term care specific surveillance definitions.

2. Catheter-associated urinary tract infection: UTI occurring in patients during or immediately after use of a urinary catheter. We noted whether CAUTI was defined by laboratory criteria, clinical symptoms, provider diagnosis, or antimicrobial treatment for case identification. We were primarily interested in CAUTI developing after placing an indwelling urinary catheter, commonly known as a Foley, but also in CAUTI occurring with other catheter types such as intermittent straight catheters, external or “condom” catheters, and suprapubic catheters.

3. Bacteriuria: We included the laboratory-based definition of bacteriuria as an outcome to include studies that reduced asymptomatic bacteriuria.

4. Urinary catheter use measures: This includes measures such as urinary catheter utilization ratios (catheter-days/patient-days), prevalence of urinary catheter use, or percentage of catheters with an appropriate indication.

Study Characteristics for Inclusion. Our systematic search included published papers in the English language. We did not exclude studies based on the number of facilities included or eligible, residents/patients included (based on age, gender, catheter use or type, or antibiotic use), intervention details, study withdrawal, loss to follow-up, death, or duration of pre-intervention and postintervention phases.

Data Sources and Searches

The following data sources were searched: Ovid MEDLINE (1950 to June 22, 2015), Cochrane Library via Wiley (1960 to June 22, 2015), CINAHL (1981 to June 22, 2015), Web of Science (1926 to June 22, 2015), and Embase.com (1946 to June 22, 2015). Two major systematic search strategies were performed for this review (Figure). Systematic search 1 was designed broadly using all data sources described above to identify interventions aimed at reducing all UTI events (defined under “Outcomes” above) or urinary catheter use (all types), focusing on interventions evaluated in nursing homes. Systematic search 2 was conducted in Ovid MEDLINE to identify studies to reduce UTI events or urinary catheter use measures for patients with a history of long-term or chronic catheter use, including nursing homes and other post-acute care settings such as rehabilitation units or hospitals and spinal cord injury programs, which have large populations of patients with chronic catheter needs. To inform the completeness of the broader systematic searches, supplemental systematic search strategies were performed for specific topics including hydration (supplemental search 1), published work by nursing home researchers known to the authors (supplemental search 2), and contact precautions (supplemental search 3). Search 1 is available at http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42013005787. Full search strategies for search 2 and supplemental searches are available upon request.

Study Selection

One author performed an initial screen of all records retrieved by the systematic searches by title and abstract and applied the initial exclusions (eg, non-human, no outcomes of interest), identified duplicate records, and assigned potentially relevant studies into groups such as review articles, epidemiology, interventions, and articles requiring further text review before categorization (Figure). After initial screening, Dr. Meddings reviewed the records by title/abstract. Reference lists were reviewed for potential articles for inclusion. Full-text article review informed the selection of those for dual abstraction and quality scoring performed by 2 authors, with discrepancies resolved by a third author. We requested additional information from authors from whom our search had generated only an abstract or brief report, or when additional information such as pre-intervention data was needed.^12-18

Data Extraction and Quality Assessment

Relevant data regarding study design, participants, inclusion/exclusion criteria, outcomes, and quality criteria were abstracted independently by 2 authors. Methodological quality scores were assigned using a modification of the Quality index checklist developed by Downs and Black appropriate for assessing both randomized and nonrandomized studies of healthcare interventions.¹⁹ We also reviewed study funding sources and other potential quality concerns.

Data Analysis

Due to large trial heterogeneity among these studies about interventions and outcomes reported, outcome data could not be combined into summary measures for meta-analysis to give overall estimates of treatment effects.

Systematic Search Results and Study Selection

As detailed in the study flow diagram (Figure), 5794 total records were retrieved by systematic search 1 (4697 studies), search 2 (909 studies), and supplemental searches (188 studies). Hand searching of reference lists of 41 reviews (including narrative and systematic reviews) yielded 77 additional studies for consideration. Twenty-nine records on interventions that were the focus of systematic reviews, including topics of cranberry use, catheter coatings, antimicrobial prophylaxis, washout/irrigation strategies, and sterile versus clean intermittent straight catheterization, were excluded from dual abstraction. Two records were excluded after team discussion of the dual-abstraction results, because 1 study did not meet criteria as an intervention study and 1 study’s setting was not applicable in nursing homes. A total of 20 records^15,20-38 (in which 19 studies were described) were selected for final inclusion for detailed assessment and reporting for the systematic review.

Characteristics of Included Studies

Table 1 describes the 19 intervention studies in terms of design, participants, setting, and whether the study included specific categories of interventions expected to decrease UTI or catheter use. These studies included 8 randomized controlled trials (4 with cluster-randomization at the facility or unit level), 10 pre-post nonrandomized interventions, and 1 nonrandomized intervention with concurrent controls. Twelve studies included participants with or without catheters (ie, not limited to catheterized patients only) in nursing homes.^15,20-31 Seven^32-38 studies included catheterized patients only or settings with high expected catheterization rates; settings for these studies included spinal cord units (n=3), nursing homes (n=2), rehabilitation ward (n=1) and VA hospital (n=1), including acute care, nursing home, and rehabilitation units. Total quality scores for the studies ranged from 8 to 25 (median, 15), detailed in Supplemental Table 1.

As detailed in Table 1 and Supplemental Table 2, 7 studies^{22,24,26,31,32,35,36} involved single interventions and 12 studies^{15,20,21,23,25,27-30,33,34,37,38} included multiple interventions. Interventions to impact catheter use and care were evaluated in 13 studies, including appropriateness of use,^21,25,29,30 improving catheter maintenance care,^15,20,29,30 securement,^15,29,30,32 prompting removal of unnecessary catheters,^21,25,29,30 improving incontinence care,^15,21,23,25 bladder scanners,^37,38 catheter changes,³⁵and comparing alternatives (condom catheter or intermittent straight catheter) to use of an indwelling catheter.^36,38 None focused on improving aseptic insertion. General infection control practices studied included improving hand hygiene,^{20-22,29-31,33,34} improving antibiotic use,^{15,20,21,28,34} initiation of infection control programs,^20,21,28 interventions to improve identification of UTIs/CAUTIs using infection symptom/sign criteria,^15,20,21,34 infection surveillance as an intervention,^28-30,33,34 and barrier precautions,^33,34 including preemptive precautions for catheterized patients.³⁴ Hydration was assessed in 3 studies.^24-26

Outcomes of Included Studies

Table 2 describes the studies’ outcomes reported for UTI, CAUTI, or bacteriuria.^15,20-38 The outcome definitions of UTI and CAUTI varied widely. Only 2 studies^22,39 reported UTI outcomes using definitions specific for nursing home settings such as McGeer’s criteria⁴⁰ a detailed review and comparison of published CAUTI definitions used clinically and for surveillance in nursing homes is provided in Supplemental Table 3. Two studies reported symptomatic CAUTIs per 1000 catheter-days.^32,34 Another study²² reported symptomatic CAUTIs per 1000 resident-days. Three reported symptomatic CAUTIs as counts.^35,38 Saint et al³⁶ reported CAUTIs as part of a combined outcome (ie, bacteriuria, CAUTI, or death).

The 19 studies (Table 2) reported 12 UTI outcomes,^{15,20,21,23,25-31,33} 9 CAUTI outcomes,^{15,22,32,34,35,38} 4 bacteriuria outcomes,^24,36,38 and 5 catheter use outcomes.^{21,29,30,37,38} Five studies showed CAUTI reduction^{15,22,32,34,35} (1 significantly³⁴); 9 studies showed UTI reduction^{13,18,19,21,23-25,27,28,31} (none significantly); 2 studies showed bacteriuria reduction (none significantly). One study³⁶ reported 2 composite outcomes including bacteriuria or CAUTI or death, with statistically significant improvement reported for 1 composite measure. Four studies reported catheter use, with all showing reduced catheter use in the intervention group; however, only 1 achieved statistically significant reduction.³⁷

Synthesis of Systematic Review Results

Overall, many studies reported decreases in UTI, CAUTI, and urinary catheter use measures but without statistical significance, with many studies likely underpowered for our outcomes of interest. Often, the outcomes of interest in this systematic review were not the main outcome for which the study was designed and originally powered. The interventions studied included several currently implemented as part of CAUTI bundles in the acute care setting, such as improving catheter use, and care and infection control strategies. Other included interventions target common challenges specific to the nursing home setting such as removing indwelling catheters upon admission to the nursing home from an acute-care facility^21,25 and applying interventions to address incontinence by either general strategies^{21,23,25,30,38} or the use of an incontinence specialist²³ to provide individual treatment plans. The only intervention that demonstrated a statistically significant reduction in CAUTI in chronically catheterized patients employed a comprehensive program to improve antimicrobial use, hand hygiene (including hand hygiene and gloves for catheter care), and preemptive precautions for patients with devices, along with promotion of standardized CAUTI definitions and active multidrug resistant organism surveillance.³⁴

Narrative Review Results

Table 3 includes a comprehensive list of potential interventions that have been considered for prevention of UTI or CAUTI (including those in acute care and nursing home settings), as summarized from this systematic review and prior narrative or systematic reviews.^43-115

We performed a broad systematic review of strategies to decrease UTI, CAUTI, and urinary catheter use that may be helpful in nursing homes. While many studies reported decreased UTI, CAUTI, or urinary catheter use measures, few demonstrated statistically significant reductions perhaps because many were underpowered to assess statistical significance. Pooled analyses were not feasible to provide the expected impact of these interventions in the nursing home setting.

This review confirms that bundles of interventions for prevention of CAUTI have been implemented with some evidence of success in nursing home settings, with several components in common with those implemented in the acute care setting, such as hand hygiene and strategies to reduce and improve catheter use.⁴¹ Some studies focused on issues more common in nursing homes such as chronic catheterization and incontinence. A nursing home CAUTI bundle should be designed with the resources and challenges present in the nursing home environment in mind, and with recognition that, although the number of patients with catheters is less than in acute care, there will be more patients with chronic catheterization needs and incontinence.

Although catheter utilization in nursing homes is low, further reductions in catheter days and CAUTIs can be achieved. Catheter removal reminders and stop orders have demonstrated a greater than 50% reduction in CAUTIs in acute care settings;¹¹ an example of a stop-order intervention in nursing homes is trial removal of indwelling catheters present at facility admission without clear urologic need present at the time of admission.²⁵ Nursing home interventions to avoid catheter placement should include incontinence programs, discussion of alternatives to indwelling urinary catheters with patients, families, and frontline personnel, and urinary retention protocols. Programs to reduce CAUTI should include education to improve aseptic insertion, and to maintain awareness and proper care of catheters in place by regular assessment of catheter necessity, securement, hand hygiene, and preemptive barrier precautions for catheterized patients. Interventions that focus on improving appropriate use of urine tests and antibiotics to treat UTIs can also significantly affect the rates of reported symptomatic CAUTIs, with the potential to decrease unnecessary antibiotic use.^20,21

The main limitation of this review is that many studies provided little information about their intervention and definition of outcomes. The strength of this review is the detailed and broad search strategy applied with generous inclusion of interventions and outcomes to highlight the available evidence and details of interventions that have been studied and implemented.

This review synthesizes the current state of evidence and proposes strategies to reduce UTIs in nursing homes. Interventions that motivate catheter avoidance and catheter removal to prevent CAUTI in acute care¹¹ and nursing home settings are supported by the strongest available evidence, although the strength of that evidence is less in the nursing home setting. Limitations notwithstanding, interventions such as incontinence care planning and hydration programs can reduce UTI in this population and is important for overall wellbeing.

Acknowledgments

The authors appreciate the guidance that Vineet Chopra MD, MSc, provided regarding options for methodological quality assessment tools, and the assistance of Mary Rogers PhD, MS, in interpreting the published Downs and Black Quality Index items, which informed our modification of this tool for application in this study. The authors appreciate, also, the feedback provided by the Agency for Healthcare Research and Quality (AHRQ) Content and Materials Development Committee for the AHRQ Safety Program for Long-Term Care: Preventing CAUTI and other Healthcare-associated Infections.

Disclosures

Agency for Healthcare Research and Quality (AHRQ) contract #HHSA290201000025I provided funding for this study, which was developed in response to AHRQ Task Order #8 for ACTION II RFTO 26 CUSP for CAUTI in LTC. AHRQ developed the details of the task and provided comments on a draft report, which informed the report submitted to AHRQ in December 2013, used to inform the interventions for a national collaborative (http://www.hret.org/quality/projects/long-term-care-cauti.shtml). Dr. Meddings’s effort on this project was funded by concurrent effort from her AHRQ (K08 HS19767). Dr. Saint’s and Dr. Krein’s effort on this project was funded by concurrent effort from the Veterans Affairs National Center for Patient Safety, Ann Arbor Patient Safety Center of Inquiry. Dr. Meddings’s other research is funded by AHRQ (2R01HS018334-04), the NIH-LRP program, the VA National Center for Patient Safety, and the VA Ann Arbor Patient Safety Center of Inquiry. Dr. Krein’s other research is funded by a VA Health Services Research and Development Award (RCS 11-222). Dr. Mody’s other research is funded by VA Healthcare System Geriatric Research Clinical Care Center (GRECC), NIA-Pepper Center, NIA (R01AG032298, R01AG041780, K24AG050685-01). Dr. Saint has received fees for serving on advisory boards for Doximity and Jvion. All other authors report no financial conflicts of interest. The findings and conclusions in this report are those of the authors and do not necessarily represent those of the sponsor, the Agency for Healthcare Research and Quality, or the U.S. Department of Veterans Affairs. These analyses were presented in part as a poster presentation at the ID Week Annual Meeting on October 10, 2014 in Philadelphia, PA.

Given the limited number of geriatricians in the U.S., hospitalists commonly manage nursing home residents admitted for post-acute care.^1-4 Urinary tract infection (UTI) is one of the most common infections in nursing homes, often leading to sepsis and readmission to acute care.⁵ Inappropriate use of antibiotics to treat asymptomatic bacteriuria is both common and hazardous to nursing home residents.⁶ Up to 10% of nursing home residents will have an indwelling urinary catheter at some point during their stay.^7-9 Residents with indwelling urinary catheters are at increased risk for catheter-associated urinary tract infection (CAUTI) and bacteriuria, with an estimated 50% of catheterized residents developing symptomatic CAUTI.⁵ While urinary catheter prevalence is lower in nursing homes than in the acute care setting, duration of use is often prolonged.^7,10 In a setting where utilization is low, but use is prolonged, interventions designed to reduce UTI in acutely ill patients¹¹ may not be as helpful for preventing infection in nursing home residents.

Our objective was to review the available evidence to prevent UTIs in nursing home residents to inform both bedside care and research efforts. Two types of literature review and summary were performed. First, we conducted a systematic review of individual studies reporting outcomes of UTI, CAUTI, bacteriuria, or urinary catheter use after interventions for reducing catheter use, improving insertion and maintenance of catheters, and/or general infection prevention strategies (eg, improving hand hygiene, infection surveillance, contact precautions, standardizing UTI diagnosis, and antibiotic use). Second, we performed a narrative review to generate an overview of evidence and published recommendations in both acute care and nursing home settings to prevent UTI in catheterized and non-catheterized older adults, which is provided as a comprehensive reference table for clinicians and researchers choosing and refining interventions to reduce UTIs.

The systematic review was performed according to the criteria of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis recommendations. The protocol was registered at the PROSPERO International Prospective Register of Systematic Reviews, (CRD42013005787). The narrative review was performed using the articles obtained from the systematic search and a targeted literature review by topic for a comprehensive list of interventions, including other interventions summarized in published reviews and guidelines.

Eligibility Criteria Review

Study Design. To address the breadth and depth of literature available to inform interventions to prevent UTI in nursing homes, broad eligibility criteria were applied with the expectation of varied designs and outcomes. All included studies for the systematic review were published manuscripts reporting a comparison group. We included randomized controlled trials as well as nonrandomized trials (pretest/posttest, with or without concurrent or nonconcurrent controls), with any duration of postintervention follow-up. Observational and retrospective studies were excluded.

Participants. We were interested in interventions and outcomes reported for nursing homes, defined as facilities providing short-stay skilled nursing care and/or rehabilitation, as well as long-term care. We also included evidence derived from rehabilitation facilities and spinal cord injury programs focused on reducing CAUTI risk for chronically catheterized residents. We excluded long-term acute care hospitals, hospice, psychiatric/mental health facilities, pediatric, and community dwelling/outpatient settings.

Interventions. We included interventions involving urinary catheter use such as improving appropriate use, aseptic placement, maintenance care, and prompting removal of unnecessary catheters. We included infection prevention strategies with a particular interest in hand hygiene, barrier precautions, infection control strategies, infection surveillance, use of standardized infection definitions, and interventions to improve antibiotic use. We included single and multiple interventions.

Outcomes
1. Healthcare-associated urinary tract infection: UTI occurring after admission to a healthcare facility, not identified specifically as catheter-associated. We categorized UTI outcomes with as much detail as provided, such as whether the reported outcome included only noncatheter-associated UTIs, the time required after admission (eg, more than 2 days), and whether the UTIs were defined by only laboratory criteria, clinically diagnosed infections, symptomatic, or long-term care specific surveillance definitions.

2. Catheter-associated urinary tract infection: UTI occurring in patients during or immediately after use of a urinary catheter. We noted whether CAUTI was defined by laboratory criteria, clinical symptoms, provider diagnosis, or antimicrobial treatment for case identification. We were primarily interested in CAUTI developing after placing an indwelling urinary catheter, commonly known as a Foley, but also in CAUTI occurring with other catheter types such as intermittent straight catheters, external or “condom” catheters, and suprapubic catheters.

3. Bacteriuria: We included the laboratory-based definition of bacteriuria as an outcome to include studies that reduced asymptomatic bacteriuria.

4. Urinary catheter use measures: This includes measures such as urinary catheter utilization ratios (catheter-days/patient-days), prevalence of urinary catheter use, or percentage of catheters with an appropriate indication.

Study Characteristics for Inclusion. Our systematic search included published papers in the English language. We did not exclude studies based on the number of facilities included or eligible, residents/patients included (based on age, gender, catheter use or type, or antibiotic use), intervention details, study withdrawal, loss to follow-up, death, or duration of pre-intervention and postintervention phases.

Data Sources and Searches

The following data sources were searched: Ovid MEDLINE (1950 to June 22, 2015), Cochrane Library via Wiley (1960 to June 22, 2015), CINAHL (1981 to June 22, 2015), Web of Science (1926 to June 22, 2015), and Embase.com (1946 to June 22, 2015). Two major systematic search strategies were performed for this review (Figure). Systematic search 1 was designed broadly using all data sources described above to identify interventions aimed at reducing all UTI events (defined under “Outcomes” above) or urinary catheter use (all types), focusing on interventions evaluated in nursing homes. Systematic search 2 was conducted in Ovid MEDLINE to identify studies to reduce UTI events or urinary catheter use measures for patients with a history of long-term or chronic catheter use, including nursing homes and other post-acute care settings such as rehabilitation units or hospitals and spinal cord injury programs, which have large populations of patients with chronic catheter needs. To inform the completeness of the broader systematic searches, supplemental systematic search strategies were performed for specific topics including hydration (supplemental search 1), published work by nursing home researchers known to the authors (supplemental search 2), and contact precautions (supplemental search 3). Search 1 is available at http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42013005787. Full search strategies for search 2 and supplemental searches are available upon request.

Study Selection

One author performed an initial screen of all records retrieved by the systematic searches by title and abstract and applied the initial exclusions (eg, non-human, no outcomes of interest), identified duplicate records, and assigned potentially relevant studies into groups such as review articles, epidemiology, interventions, and articles requiring further text review before categorization (Figure). After initial screening, Dr. Meddings reviewed the records by title/abstract. Reference lists were reviewed for potential articles for inclusion. Full-text article review informed the selection of those for dual abstraction and quality scoring performed by 2 authors, with discrepancies resolved by a third author. We requested additional information from authors from whom our search had generated only an abstract or brief report, or when additional information such as pre-intervention data was needed.^12-18

Data Extraction and Quality Assessment

Relevant data regarding study design, participants, inclusion/exclusion criteria, outcomes, and quality criteria were abstracted independently by 2 authors. Methodological quality scores were assigned using a modification of the Quality index checklist developed by Downs and Black appropriate for assessing both randomized and nonrandomized studies of healthcare interventions.¹⁹ We also reviewed study funding sources and other potential quality concerns.

Data Analysis

Due to large trial heterogeneity among these studies about interventions and outcomes reported, outcome data could not be combined into summary measures for meta-analysis to give overall estimates of treatment effects.

Systematic Search Results and Study Selection

As detailed in the study flow diagram (Figure), 5794 total records were retrieved by systematic search 1 (4697 studies), search 2 (909 studies), and supplemental searches (188 studies). Hand searching of reference lists of 41 reviews (including narrative and systematic reviews) yielded 77 additional studies for consideration. Twenty-nine records on interventions that were the focus of systematic reviews, including topics of cranberry use, catheter coatings, antimicrobial prophylaxis, washout/irrigation strategies, and sterile versus clean intermittent straight catheterization, were excluded from dual abstraction. Two records were excluded after team discussion of the dual-abstraction results, because 1 study did not meet criteria as an intervention study and 1 study’s setting was not applicable in nursing homes. A total of 20 records^15,20-38 (in which 19 studies were described) were selected for final inclusion for detailed assessment and reporting for the systematic review.

Characteristics of Included Studies

Table 1 describes the 19 intervention studies in terms of design, participants, setting, and whether the study included specific categories of interventions expected to decrease UTI or catheter use. These studies included 8 randomized controlled trials (4 with cluster-randomization at the facility or unit level), 10 pre-post nonrandomized interventions, and 1 nonrandomized intervention with concurrent controls. Twelve studies included participants with or without catheters (ie, not limited to catheterized patients only) in nursing homes.^15,20-31 Seven^32-38 studies included catheterized patients only or settings with high expected catheterization rates; settings for these studies included spinal cord units (n=3), nursing homes (n=2), rehabilitation ward (n=1) and VA hospital (n=1), including acute care, nursing home, and rehabilitation units. Total quality scores for the studies ranged from 8 to 25 (median, 15), detailed in Supplemental Table 1.

As detailed in Table 1 and Supplemental Table 2, 7 studies^{22,24,26,31,32,35,36} involved single interventions and 12 studies^{15,20,21,23,25,27-30,33,34,37,38} included multiple interventions. Interventions to impact catheter use and care were evaluated in 13 studies, including appropriateness of use,^21,25,29,30 improving catheter maintenance care,^15,20,29,30 securement,^15,29,30,32 prompting removal of unnecessary catheters,^21,25,29,30 improving incontinence care,^15,21,23,25 bladder scanners,^37,38 catheter changes,³⁵and comparing alternatives (condom catheter or intermittent straight catheter) to use of an indwelling catheter.^36,38 None focused on improving aseptic insertion. General infection control practices studied included improving hand hygiene,^{20-22,29-31,33,34} improving antibiotic use,^{15,20,21,28,34} initiation of infection control programs,^20,21,28 interventions to improve identification of UTIs/CAUTIs using infection symptom/sign criteria,^15,20,21,34 infection surveillance as an intervention,^28-30,33,34 and barrier precautions,^33,34 including preemptive precautions for catheterized patients.³⁴ Hydration was assessed in 3 studies.^24-26

Outcomes of Included Studies

Table 2 describes the studies’ outcomes reported for UTI, CAUTI, or bacteriuria.^15,20-38 The outcome definitions of UTI and CAUTI varied widely. Only 2 studies^22,39 reported UTI outcomes using definitions specific for nursing home settings such as McGeer’s criteria⁴⁰ a detailed review and comparison of published CAUTI definitions used clinically and for surveillance in nursing homes is provided in Supplemental Table 3. Two studies reported symptomatic CAUTIs per 1000 catheter-days.^32,34 Another study²² reported symptomatic CAUTIs per 1000 resident-days. Three reported symptomatic CAUTIs as counts.^35,38 Saint et al³⁶ reported CAUTIs as part of a combined outcome (ie, bacteriuria, CAUTI, or death).

The 19 studies (Table 2) reported 12 UTI outcomes,^{15,20,21,23,25-31,33} 9 CAUTI outcomes,^{15,22,32,34,35,38} 4 bacteriuria outcomes,^24,36,38 and 5 catheter use outcomes.^{21,29,30,37,38} Five studies showed CAUTI reduction^{15,22,32,34,35} (1 significantly³⁴); 9 studies showed UTI reduction^{13,18,19,21,23-25,27,28,31} (none significantly); 2 studies showed bacteriuria reduction (none significantly). One study³⁶ reported 2 composite outcomes including bacteriuria or CAUTI or death, with statistically significant improvement reported for 1 composite measure. Four studies reported catheter use, with all showing reduced catheter use in the intervention group; however, only 1 achieved statistically significant reduction.³⁷

Synthesis of Systematic Review Results

Overall, many studies reported decreases in UTI, CAUTI, and urinary catheter use measures but without statistical significance, with many studies likely underpowered for our outcomes of interest. Often, the outcomes of interest in this systematic review were not the main outcome for which the study was designed and originally powered. The interventions studied included several currently implemented as part of CAUTI bundles in the acute care setting, such as improving catheter use, and care and infection control strategies. Other included interventions target common challenges specific to the nursing home setting such as removing indwelling catheters upon admission to the nursing home from an acute-care facility^21,25 and applying interventions to address incontinence by either general strategies^{21,23,25,30,38} or the use of an incontinence specialist²³ to provide individual treatment plans. The only intervention that demonstrated a statistically significant reduction in CAUTI in chronically catheterized patients employed a comprehensive program to improve antimicrobial use, hand hygiene (including hand hygiene and gloves for catheter care), and preemptive precautions for patients with devices, along with promotion of standardized CAUTI definitions and active multidrug resistant organism surveillance.³⁴

Narrative Review Results

Table 3 includes a comprehensive list of potential interventions that have been considered for prevention of UTI or CAUTI (including those in acute care and nursing home settings), as summarized from this systematic review and prior narrative or systematic reviews.^43-115

We performed a broad systematic review of strategies to decrease UTI, CAUTI, and urinary catheter use that may be helpful in nursing homes. While many studies reported decreased UTI, CAUTI, or urinary catheter use measures, few demonstrated statistically significant reductions perhaps because many were underpowered to assess statistical significance. Pooled analyses were not feasible to provide the expected impact of these interventions in the nursing home setting.

This review confirms that bundles of interventions for prevention of CAUTI have been implemented with some evidence of success in nursing home settings, with several components in common with those implemented in the acute care setting, such as hand hygiene and strategies to reduce and improve catheter use.⁴¹ Some studies focused on issues more common in nursing homes such as chronic catheterization and incontinence. A nursing home CAUTI bundle should be designed with the resources and challenges present in the nursing home environment in mind, and with recognition that, although the number of patients with catheters is less than in acute care, there will be more patients with chronic catheterization needs and incontinence.

Although catheter utilization in nursing homes is low, further reductions in catheter days and CAUTIs can be achieved. Catheter removal reminders and stop orders have demonstrated a greater than 50% reduction in CAUTIs in acute care settings;¹¹ an example of a stop-order intervention in nursing homes is trial removal of indwelling catheters present at facility admission without clear urologic need present at the time of admission.²⁵ Nursing home interventions to avoid catheter placement should include incontinence programs, discussion of alternatives to indwelling urinary catheters with patients, families, and frontline personnel, and urinary retention protocols. Programs to reduce CAUTI should include education to improve aseptic insertion, and to maintain awareness and proper care of catheters in place by regular assessment of catheter necessity, securement, hand hygiene, and preemptive barrier precautions for catheterized patients. Interventions that focus on improving appropriate use of urine tests and antibiotics to treat UTIs can also significantly affect the rates of reported symptomatic CAUTIs, with the potential to decrease unnecessary antibiotic use.^20,21

The main limitation of this review is that many studies provided little information about their intervention and definition of outcomes. The strength of this review is the detailed and broad search strategy applied with generous inclusion of interventions and outcomes to highlight the available evidence and details of interventions that have been studied and implemented.

This review synthesizes the current state of evidence and proposes strategies to reduce UTIs in nursing homes. Interventions that motivate catheter avoidance and catheter removal to prevent CAUTI in acute care¹¹ and nursing home settings are supported by the strongest available evidence, although the strength of that evidence is less in the nursing home setting. Limitations notwithstanding, interventions such as incontinence care planning and hydration programs can reduce UTI in this population and is important for overall wellbeing.

Acknowledgments

The authors appreciate the guidance that Vineet Chopra MD, MSc, provided regarding options for methodological quality assessment tools, and the assistance of Mary Rogers PhD, MS, in interpreting the published Downs and Black Quality Index items, which informed our modification of this tool for application in this study. The authors appreciate, also, the feedback provided by the Agency for Healthcare Research and Quality (AHRQ) Content and Materials Development Committee for the AHRQ Safety Program for Long-Term Care: Preventing CAUTI and other Healthcare-associated Infections.

Disclosures

Agency for Healthcare Research and Quality (AHRQ) contract #HHSA290201000025I provided funding for this study, which was developed in response to AHRQ Task Order #8 for ACTION II RFTO 26 CUSP for CAUTI in LTC. AHRQ developed the details of the task and provided comments on a draft report, which informed the report submitted to AHRQ in December 2013, used to inform the interventions for a national collaborative (http://www.hret.org/quality/projects/long-term-care-cauti.shtml). Dr. Meddings’s effort on this project was funded by concurrent effort from her AHRQ (K08 HS19767). Dr. Saint’s and Dr. Krein’s effort on this project was funded by concurrent effort from the Veterans Affairs National Center for Patient Safety, Ann Arbor Patient Safety Center of Inquiry. Dr. Meddings’s other research is funded by AHRQ (2R01HS018334-04), the NIH-LRP program, the VA National Center for Patient Safety, and the VA Ann Arbor Patient Safety Center of Inquiry. Dr. Krein’s other research is funded by a VA Health Services Research and Development Award (RCS 11-222). Dr. Mody’s other research is funded by VA Healthcare System Geriatric Research Clinical Care Center (GRECC), NIA-Pepper Center, NIA (R01AG032298, R01AG041780, K24AG050685-01). Dr. Saint has received fees for serving on advisory boards for Doximity and Jvion. All other authors report no financial conflicts of interest. The findings and conclusions in this report are those of the authors and do not necessarily represent those of the sponsor, the Agency for Healthcare Research and Quality, or the U.S. Department of Veterans Affairs. These analyses were presented in part as a poster presentation at the ID Week Annual Meeting on October 10, 2014 in Philadelphia, PA.

The United States is experiencing an epidemic of nonmedical opioid use. A concerted effort to better address pain increased the provision of prescription narcotics in the late 1990s and early 2000s.¹ Since then, there has been significant growth of opioid use and acorresponding increase in overdose-related deaths.^1-3 Public health officials have responded with initiatives to secure the opioid supply and improve outpatient treatment resources. However, the role of hospitalists in addressing opioid use disorder (OUD) is not well established. The inpatient needs for these individuals are complex and require a collaborative approach with input from outpatient clinicians, inpatient clinicians, addiction specialists, social workers, and case managers. Hospitals are often under-resourced to provide such comprehensive services. This frequently results in the hospitalist bearing significant responsibility for inpatient addiction management despite often insufficient addiction education or experience.^4,5

Therefore, there is a need for hospitalists to become leaders in the inpatient management of OUD. In this review, we will discuss the hospitalist’s role in the inpatient management of individuals with OUD.

Opioid use disorder is a medical illness resulting from neurobiological changes that cause drug tolerance, dependence, and cravings.⁶ It should be considered a treatable chronic medical condition, comparable to hypertension or diabetes,⁷ which requires a multifaceted treatment approach, including psychosocial, educational, and medical interventions.

Psychosocial Interventions

Individuals with OUD often have complicated social issues including stigmatization, involvement in the criminal justice system, unemployment, and homelessness,^5,8-10 in addition to frequent comorbid mental health issues.^11,12 Failure to address social or mental health barriers may lead to a lack of engagement in the treatment of OUD. The long-term management of OUD should involve outpatient psychotherapy and may include individual or group therapy, behavioral therapy, family counseling, or support groups.¹³ In the inpatient setting, hospitalists should use a collaborative approach to address psychosocial barriers. The authors recommend social work and case management consultations and consideration of psychiatric consultation when appropriate.

Management of Opioid Withdrawal

The prompt recognition and management of withdrawal is essential in hospitalized patients with OUD. The signs and symptoms of withdrawal can be evaluated by using the Clinical Opiate Withdrawal Scale or the Clinical Institute Narcotics Assessment, and may include lacrimation, rhinorrhea, diaphoresis, yawning, restlessness, insomnia, piloerection, myalgia, arthralgia, abdominal pain, nausea, vomiting, and diarrhea.⁴ Individuals using short-acting opioids, such as oxycodone or heroin, may develop withdrawal symptoms 8 to 12 hours after cessation of the opioid. Symptoms often peak on days 1 to 3 and can last for up to 10 days.¹⁴ Individuals taking long-acting opioids, such as methadone, may experience withdrawal symptoms for up to 21 days.¹⁴

While the goal of withdrawal treatment is to reduce the uncomfortable symptoms of withdrawal, there may be additional benefits. Around 16% of people who inject drugs will misuse drugs during their hospitalization, and 25% to 30% will be discharged against medical advice.^15,16 In hospitalizations when patients are administered methadone for management of withdrawal, there is a significant reduction in discharges against medical advice.¹⁶ This may suggest that treatment of withdrawal has the added benefit of preventing discharges against medical advice, and the authors postulate that treatment may decrease surreptitious drug use during hospitalizations, although this has not been studied.

There are 2 approaches to treating opioid withdrawal—opioid substitution treatment and alpha₂-adrenergic agonist treatment (Table 1).^4,17-20 Of note, opioid substitution treatment, especially when using buprenorphine, should be started only when a patient has at least mild withdrawal symptoms.²⁰

Medication-Assisted Treatment

It is important to recognize that treatment of withdrawal is not adequate to prevent long-term opioid misuse.²⁵ The optimal long-term management of OUD includes the use of medication-assisted treatment (MAT). The initiation and titration of MAT should always be done in conjunction with an addiction specialist or buprenorphine-waivered physician who will ensure continuation of MAT as an outpatient. This means that, while hospitalists may be critical in facilitating linkage to MAT, in general, they will not have a significant role in the long-term management of OUD. However, hospitalists should be knowledgeable about MAT because it is relatively common and can complicate hospitalizations.

There are two types of MAT: opioid-agonist treatment (OAT) and opioid-antagonist treatment. Opioid-agonist treatment involves the use of methadone, a long-acting opioid agonist, or buprenorphine, a long-acting partial opioid agonist. These medications decrease the amount and severity of cravings and limit the euphoric effects of subsequent opioid use.¹⁷ Compared to abstinence-based treatment, OAT has been associated with increased retention in addiction treatment and employment, and reductions in incarceration, human immunodeficiency virus transmission, illicit drug use, opioid-overdose events, and mortality.^26-32An alternative to OAT is naltrexone, an opioid antagonist. Naltrexone for OUD is administered as a monthly depot injection that prevents the user from experiencing opioid intoxication or dependence, and is associated with sustained abstinence.^17,33,34 The authors strongly recommend that hospitalists discuss the benefits of MAT with hospitalized individuals with OUD. In addition, when appropriate, patients should receive consultation with, or referral to, an addiction specialist.

Adverse Effects of Methadone, Buprenorphine, and Naltrexone

The benefits of MAT are substantial, but there are adverse effects, potential drug-to-drug interactions, and patient-specific characteristics that may impact the inpatient management of individuals on MAT. Selected adverse effects of OAT are listed in Table 1. The adverse effects of naltrexone include nausea, vomiting, and transaminitis. It should also be noted that the initiation of buprenorphine and naltrexone may induce opioid withdrawal when administered to an opioid-dependent patient with recent opioid use. To avoid precipitating withdrawal, buprenorphine should be used only in individuals who have at least mild withdrawal symptoms or have completed detoxification,²⁰ and naltrexone should be used only in patients who have abstained from opioids for at least 7 to 10 days.³⁵

Opioid-agonist treatments are primarily metabolized by the cytochrome P450 3A4 isoenzyme system. Medications that inhibit cytochrome P450 3A4 metabolism such as fluconazole can result in OAT toxicity, while medications that induce cytochrome P450 3A4 metabolism such as dexamethasone can lead to withdrawal symptoms.¹⁸ If these interactions are unavoidable, the dose of methadone or buprenorphine should be adjusted to prevent toxicity or withdrawal symptoms. The major drug interaction with naltrexone is ineffective analgesia from opioids.

Another major concern with MAT is the risk of overdose-related deaths. As an opioid agonist, large doses of methadone can result in respiratory depression, while buprenorphine alone, due to its partial agonist effect, is unlikely to result in respiratory depression. When methadone or buprenorphine are taken with other substances that cause respiratory depression, such as benzodiazepines or alcohol, the risk of respiratory depression and overdose is significantly increased.^36,37 Overdose-related death with naltrexone usually occurs after the medication has metabolized and results from a loss of opioid tolerance.³⁸

Special Populations

Medication-assisted treatment in individuals with acute pain. Maintenance treatment with OAT does not provide sufficient analgesia to treat episodes of acute pain.³⁹ In patients on methadone maintenance, the maintenance dose should be continued and adjunctive analgesia should be provided with nonopioid analgesics or short-acting opioids.³⁹ The management of acute pain in individuals on buprenorphine maintenance is more complicated since buprenorphine is a partial opioid agonist with high affinity to the opioid receptor, which limits the impact of adjunctive opioids. The options for analgesia in buprenorphine maintenance treatment include 1) continuing daily dosing of buprenorphine and providing nonopioid or opioid analgesics, 2) dividing buprenorphine dosing into a 3 or 4 times a day medication, 3) discontinuing buprenorphine and treating with opioid analgesics, 4) discontinuing buprenorphine and starting methadone with nonopioid or opioid analgesics.³⁹ In cases where buprenorphine is discontinued, it should be restarted before discharge upon resolution of the acute pain episode. An individual with acute pain on naltrexone may require nonopioid analgesia or regional blocks. In these patients, adequate pain control may be challenging and require the consultation of an acute pain specialist.

Pregnant or breastfeeding individuals. Opioid misuse puts the individual and fetus at risk of complications, and abrupt discontinuation can cause preterm labor, fetal distress, or fetal demise.⁴⁰ The current standard is to initiate methadone in consultation with an addiction specialist.⁴⁰ There is evidence that buprenorphine can be used during pregnancy; however, buprenorphine-naloxone is discouraged.^18,40 Of note, use of OAT in pregnancy can result in neonatal abstinence syndrome, an expected complication that can be managed by a pediatrician.⁴⁰

Methadone and buprenorphine can be found in low concentrations in breast milk.⁴¹ However, according to the Academy of Breastfeeding Medicine’s clinical guidelines, women on stable doses of methadone and buprenorphine should be encouraged to breastfeed.⁴¹ Naltrexone enters breast milk and has potential adverse effects for the newborn. Either the mother should discontinue naltrexone or should not breastfeed.³⁵

Treatment of polysubstance misuse. Individuals with OUD may also misuse other substances. The concomitant use of opioids and other central nervous system depressants, such as alcohol and benzodiazepines, is especially worrisome as they can potentiate respiratory depression. The presence of polysubstance misuse does not preclude the use of MAT for the treatment of OUD. In those with comorbid alcohol use disorder, the use of naltrexone may be appealing as it can treat both alcohol use disorder and OUD. Given the complexities of managing polysubstance misuse, addiction specialists should be involved in the care of these patients.⁴² In addition, patients should be educated on the risks of polysubstance misuse, especially when it involves 2 central nervous system depressants.

Comorbid medical disease. In general, medical comorbidities do not significantly affect the treatment of OUD; however, dysfunction of certain organ systems may necessitate a dose reduction or discontinuation of MAT. Severe liver disease may result in decreased hepatic metabolism of OAT.^35,42 Prolonged QTc, or history of arrhythmia, may preclude the use of methadone.^17,35,42 In addition, chronic hypercapnic respiratory failure or severe asthma may be contraindications for the use of methadone in an unmonitored setting.³⁵ Kidney failure is not known to be a contraindication to MAT, and there is no consensus on the need for dose reduction of MAT with decreasing glomerular filtration rate; however, some authors recommend a 25% to 50% dose reduction of methadone when the glomerular filtration rate is less than 10 milliliters per minute.⁴³ There is no such recommendation with buprenorphine, although it has not been adequately studied in individuals with renal failure. Close monitoring for evidence of toxicity is prudent in individuals on MAT with acute or chronic renal failure.³⁵

Rural or resource-limited areas. There is a significant shortage of addiction treatment options in many regions of the United States. As of 2012, there were an estimated 2.3 million individuals with OUD; however, more than 1 million of these individuals do not have access to treatment.⁴⁴ As a result, many addiction treatment programs have wait lists that can last months or even years.⁴⁵ These shortages are especially apparent in rural areas, where individuals with OUD are particularly reliant upon buprenorphine treatment because of prohibitive travel times to urban-based programs.⁴⁶ To address this problem, new models of care delivery are being developed, including models incorporating telemedicine to support rural primary care management of OUD.⁴⁷

The Future of Medication-Assisted Treatment

Currently, MAT is initiated and managed by outpatient addiction specialists. However, evidence supports initiation of MAT as an inpatient.⁴⁸ A recent study compared inpatient buprenorphine detoxification to inpatient buprenorphine induction, dose stabilization, and postdischarge linkage-of-care to outpatient opioid treatment clinics. Patients who received inpatient buprenorphine initiation and linkage-of-care had improved buprenorphine treatment retention and reported less illicit opioid use.⁴⁸ The development of partnerships between hospitals, inpatient clinicians, and outpatient addiction specialists is essential and could lead to significant advances in treating hospitalized patients with OUD.

The initiation of MAT in hospitalized patients with immediate linkage-of-care shows great promise; however, at this point, the initiation of MAT should be done only in conjunction with addiction specialists in patients with confirmed outpatient follow-up. In cases where inpatient MAT initiation is pursued, education of staff including nurses and pharmacists is essential.

Harm Reduction Interventions

Ideally, management of OUD results in abstinence from opioid misuse; however, some individuals are not ready for treatment or, despite MAT, have relapses of opioid misuse. Given this, a secondary goal in the management of OUD is the reduction of harm that can result from opioid misuse.

Many individuals inject opioids, which is associated with increased rates of viral and bacterial infections secondary to nonsterile injection practices.⁴⁹ Educating patients on sterile injection methods (Table 2),⁵⁰ including the importance of sterile-injecting equipment and water, and cleaning the skin prior to injection, may mitigate the risk of infections and should be provided for all hospitalized people who inject drugs.

Syringe-exchange programs provide sterile-injecting equipment in exchange for used needles, with a goal of increasing access to sterile supplies and removing contaminated syringes from circulation.⁵¹ While controversial, these programs may reduce the incidence of human immunodeficiency virus, hepatitis C virus, and hepatitis B virus.⁵¹

In addition, syringe-exchange programs often provide addiction treatment referrals, counseling, testing, and prevention education for human immunodeficiency virus, hepatitis C virus, and sexually transmitted infections.⁴⁹ In the United States, there are 226 programs in 33 states (see https://nasen.org/directory for a list of programs and locations. Inpatient clinicians should provide a list of local resources including syringe-exchange programs at the time of discharge for any people who inject drugs. In addition, individuals with OUD are at increased risk for overdose, especially in the postdischarge setting due to decreased opioid tolerance.⁵² In 2014, there were 28,647 opioid overdose-related deaths in the United States.² To address this troubling epidemic, opioid overdose education and naloxone distribution has been championed to educate patients at risk of opioid overdose and potential first responders on how to counteract an overdose by using naloxone, an opioid antagonist (see Table 2 for more information on opioid overdose education). The use of opioid overdose education and naloxone distribution has been observed to reduce opioid overdose-related death rates.⁵³

Hospitalists should provide opioid overdose education and naloxone to all individuals at risk of opioid overdose (including those with OUD), as well as potential first responders where the law allows (more information including individual state laws can be found at http://prescribetoprevent.org).²⁰

Considerations at Discharge

There are a number of considerations for the hospitalist at discharge (see Table 3 for a recommended discharge checklist). In addition, it is important to appreciate, and minimize, the ways that hospitalists contribute to the opioid epidemic. For instance, prescribing opioids at discharge in opioid-naïve patients increases the risk of chronic opioid use.⁵⁴ It is also essential to recognize that increased doses of opioids are associated with increased rates of opioid overdose-related deaths.⁵⁵ As such, hospitalists should maximize the use of nonopioid analgesics, prescribe opioids only when necessary, use the smallest effective dose of opioids, limit the number of opioid pills distributed to patients, and check prescription-monitoring programs for evidence of misuse.

Hospitalization serves as an important opportunity to address addiction in individuals with OUD. In addressing addiction, hospitalists should identify and intervene on psychosocial and mental health barriers, treat opioid withdrawal, and propagate harm reduction strategies. In addition, there is a growing role for hospitalists to be involved in the initiation of MAT and linkage-of-care to outpatient addiction treatment. If hospitalists become leaders in the inpatient management of OUD, they will significantly improve the care provided to this vulnerable patient population.

Disclosure

The authors report no financial conflicts of interest.

The United States is experiencing an epidemic of nonmedical opioid use. A concerted effort to better address pain increased the provision of prescription narcotics in the late 1990s and early 2000s.¹ Since then, there has been significant growth of opioid use and acorresponding increase in overdose-related deaths.^1-3 Public health officials have responded with initiatives to secure the opioid supply and improve outpatient treatment resources. However, the role of hospitalists in addressing opioid use disorder (OUD) is not well established. The inpatient needs for these individuals are complex and require a collaborative approach with input from outpatient clinicians, inpatient clinicians, addiction specialists, social workers, and case managers. Hospitals are often under-resourced to provide such comprehensive services. This frequently results in the hospitalist bearing significant responsibility for inpatient addiction management despite often insufficient addiction education or experience.^4,5

Therefore, there is a need for hospitalists to become leaders in the inpatient management of OUD. In this review, we will discuss the hospitalist’s role in the inpatient management of individuals with OUD.

Opioid use disorder is a medical illness resulting from neurobiological changes that cause drug tolerance, dependence, and cravings.⁶ It should be considered a treatable chronic medical condition, comparable to hypertension or diabetes,⁷ which requires a multifaceted treatment approach, including psychosocial, educational, and medical interventions.

Psychosocial Interventions

Individuals with OUD often have complicated social issues including stigmatization, involvement in the criminal justice system, unemployment, and homelessness,^5,8-10 in addition to frequent comorbid mental health issues.^11,12 Failure to address social or mental health barriers may lead to a lack of engagement in the treatment of OUD. The long-term management of OUD should involve outpatient psychotherapy and may include individual or group therapy, behavioral therapy, family counseling, or support groups.¹³ In the inpatient setting, hospitalists should use a collaborative approach to address psychosocial barriers. The authors recommend social work and case management consultations and consideration of psychiatric consultation when appropriate.

Management of Opioid Withdrawal

The prompt recognition and management of withdrawal is essential in hospitalized patients with OUD. The signs and symptoms of withdrawal can be evaluated by using the Clinical Opiate Withdrawal Scale or the Clinical Institute Narcotics Assessment, and may include lacrimation, rhinorrhea, diaphoresis, yawning, restlessness, insomnia, piloerection, myalgia, arthralgia, abdominal pain, nausea, vomiting, and diarrhea.⁴ Individuals using short-acting opioids, such as oxycodone or heroin, may develop withdrawal symptoms 8 to 12 hours after cessation of the opioid. Symptoms often peak on days 1 to 3 and can last for up to 10 days.¹⁴ Individuals taking long-acting opioids, such as methadone, may experience withdrawal symptoms for up to 21 days.¹⁴

While the goal of withdrawal treatment is to reduce the uncomfortable symptoms of withdrawal, there may be additional benefits. Around 16% of people who inject drugs will misuse drugs during their hospitalization, and 25% to 30% will be discharged against medical advice.^15,16 In hospitalizations when patients are administered methadone for management of withdrawal, there is a significant reduction in discharges against medical advice.¹⁶ This may suggest that treatment of withdrawal has the added benefit of preventing discharges against medical advice, and the authors postulate that treatment may decrease surreptitious drug use during hospitalizations, although this has not been studied.

There are 2 approaches to treating opioid withdrawal—opioid substitution treatment and alpha₂-adrenergic agonist treatment (Table 1).^4,17-20 Of note, opioid substitution treatment, especially when using buprenorphine, should be started only when a patient has at least mild withdrawal symptoms.²⁰

Medication-Assisted Treatment

It is important to recognize that treatment of withdrawal is not adequate to prevent long-term opioid misuse.²⁵ The optimal long-term management of OUD includes the use of medication-assisted treatment (MAT). The initiation and titration of MAT should always be done in conjunction with an addiction specialist or buprenorphine-waivered physician who will ensure continuation of MAT as an outpatient. This means that, while hospitalists may be critical in facilitating linkage to MAT, in general, they will not have a significant role in the long-term management of OUD. However, hospitalists should be knowledgeable about MAT because it is relatively common and can complicate hospitalizations.

There are two types of MAT: opioid-agonist treatment (OAT) and opioid-antagonist treatment. Opioid-agonist treatment involves the use of methadone, a long-acting opioid agonist, or buprenorphine, a long-acting partial opioid agonist. These medications decrease the amount and severity of cravings and limit the euphoric effects of subsequent opioid use.¹⁷ Compared to abstinence-based treatment, OAT has been associated with increased retention in addiction treatment and employment, and reductions in incarceration, human immunodeficiency virus transmission, illicit drug use, opioid-overdose events, and mortality.^26-32An alternative to OAT is naltrexone, an opioid antagonist. Naltrexone for OUD is administered as a monthly depot injection that prevents the user from experiencing opioid intoxication or dependence, and is associated with sustained abstinence.^17,33,34 The authors strongly recommend that hospitalists discuss the benefits of MAT with hospitalized individuals with OUD. In addition, when appropriate, patients should receive consultation with, or referral to, an addiction specialist.

Adverse Effects of Methadone, Buprenorphine, and Naltrexone

The benefits of MAT are substantial, but there are adverse effects, potential drug-to-drug interactions, and patient-specific characteristics that may impact the inpatient management of individuals on MAT. Selected adverse effects of OAT are listed in Table 1. The adverse effects of naltrexone include nausea, vomiting, and transaminitis. It should also be noted that the initiation of buprenorphine and naltrexone may induce opioid withdrawal when administered to an opioid-dependent patient with recent opioid use. To avoid precipitating withdrawal, buprenorphine should be used only in individuals who have at least mild withdrawal symptoms or have completed detoxification,²⁰ and naltrexone should be used only in patients who have abstained from opioids for at least 7 to 10 days.³⁵

Opioid-agonist treatments are primarily metabolized by the cytochrome P450 3A4 isoenzyme system. Medications that inhibit cytochrome P450 3A4 metabolism such as fluconazole can result in OAT toxicity, while medications that induce cytochrome P450 3A4 metabolism such as dexamethasone can lead to withdrawal symptoms.¹⁸ If these interactions are unavoidable, the dose of methadone or buprenorphine should be adjusted to prevent toxicity or withdrawal symptoms. The major drug interaction with naltrexone is ineffective analgesia from opioids.

Another major concern with MAT is the risk of overdose-related deaths. As an opioid agonist, large doses of methadone can result in respiratory depression, while buprenorphine alone, due to its partial agonist effect, is unlikely to result in respiratory depression. When methadone or buprenorphine are taken with other substances that cause respiratory depression, such as benzodiazepines or alcohol, the risk of respiratory depression and overdose is significantly increased.^36,37 Overdose-related death with naltrexone usually occurs after the medication has metabolized and results from a loss of opioid tolerance.³⁸

Special Populations

Medication-assisted treatment in individuals with acute pain. Maintenance treatment with OAT does not provide sufficient analgesia to treat episodes of acute pain.³⁹ In patients on methadone maintenance, the maintenance dose should be continued and adjunctive analgesia should be provided with nonopioid analgesics or short-acting opioids.³⁹ The management of acute pain in individuals on buprenorphine maintenance is more complicated since buprenorphine is a partial opioid agonist with high affinity to the opioid receptor, which limits the impact of adjunctive opioids. The options for analgesia in buprenorphine maintenance treatment include 1) continuing daily dosing of buprenorphine and providing nonopioid or opioid analgesics, 2) dividing buprenorphine dosing into a 3 or 4 times a day medication, 3) discontinuing buprenorphine and treating with opioid analgesics, 4) discontinuing buprenorphine and starting methadone with nonopioid or opioid analgesics.³⁹ In cases where buprenorphine is discontinued, it should be restarted before discharge upon resolution of the acute pain episode. An individual with acute pain on naltrexone may require nonopioid analgesia or regional blocks. In these patients, adequate pain control may be challenging and require the consultation of an acute pain specialist.

Pregnant or breastfeeding individuals. Opioid misuse puts the individual and fetus at risk of complications, and abrupt discontinuation can cause preterm labor, fetal distress, or fetal demise.⁴⁰ The current standard is to initiate methadone in consultation with an addiction specialist.⁴⁰ There is evidence that buprenorphine can be used during pregnancy; however, buprenorphine-naloxone is discouraged.^18,40 Of note, use of OAT in pregnancy can result in neonatal abstinence syndrome, an expected complication that can be managed by a pediatrician.⁴⁰

Methadone and buprenorphine can be found in low concentrations in breast milk.⁴¹ However, according to the Academy of Breastfeeding Medicine’s clinical guidelines, women on stable doses of methadone and buprenorphine should be encouraged to breastfeed.⁴¹ Naltrexone enters breast milk and has potential adverse effects for the newborn. Either the mother should discontinue naltrexone or should not breastfeed.³⁵

Treatment of polysubstance misuse. Individuals with OUD may also misuse other substances. The concomitant use of opioids and other central nervous system depressants, such as alcohol and benzodiazepines, is especially worrisome as they can potentiate respiratory depression. The presence of polysubstance misuse does not preclude the use of MAT for the treatment of OUD. In those with comorbid alcohol use disorder, the use of naltrexone may be appealing as it can treat both alcohol use disorder and OUD. Given the complexities of managing polysubstance misuse, addiction specialists should be involved in the care of these patients.⁴² In addition, patients should be educated on the risks of polysubstance misuse, especially when it involves 2 central nervous system depressants.

Comorbid medical disease. In general, medical comorbidities do not significantly affect the treatment of OUD; however, dysfunction of certain organ systems may necessitate a dose reduction or discontinuation of MAT. Severe liver disease may result in decreased hepatic metabolism of OAT.^35,42 Prolonged QTc, or history of arrhythmia, may preclude the use of methadone.^17,35,42 In addition, chronic hypercapnic respiratory failure or severe asthma may be contraindications for the use of methadone in an unmonitored setting.³⁵ Kidney failure is not known to be a contraindication to MAT, and there is no consensus on the need for dose reduction of MAT with decreasing glomerular filtration rate; however, some authors recommend a 25% to 50% dose reduction of methadone when the glomerular filtration rate is less than 10 milliliters per minute.⁴³ There is no such recommendation with buprenorphine, although it has not been adequately studied in individuals with renal failure. Close monitoring for evidence of toxicity is prudent in individuals on MAT with acute or chronic renal failure.³⁵

Rural or resource-limited areas. There is a significant shortage of addiction treatment options in many regions of the United States. As of 2012, there were an estimated 2.3 million individuals with OUD; however, more than 1 million of these individuals do not have access to treatment.⁴⁴ As a result, many addiction treatment programs have wait lists that can last months or even years.⁴⁵ These shortages are especially apparent in rural areas, where individuals with OUD are particularly reliant upon buprenorphine treatment because of prohibitive travel times to urban-based programs.⁴⁶ To address this problem, new models of care delivery are being developed, including models incorporating telemedicine to support rural primary care management of OUD.⁴⁷

The Future of Medication-Assisted Treatment

Currently, MAT is initiated and managed by outpatient addiction specialists. However, evidence supports initiation of MAT as an inpatient.⁴⁸ A recent study compared inpatient buprenorphine detoxification to inpatient buprenorphine induction, dose stabilization, and postdischarge linkage-of-care to outpatient opioid treatment clinics. Patients who received inpatient buprenorphine initiation and linkage-of-care had improved buprenorphine treatment retention and reported less illicit opioid use.⁴⁸ The development of partnerships between hospitals, inpatient clinicians, and outpatient addiction specialists is essential and could lead to significant advances in treating hospitalized patients with OUD.

The initiation of MAT in hospitalized patients with immediate linkage-of-care shows great promise; however, at this point, the initiation of MAT should be done only in conjunction with addiction specialists in patients with confirmed outpatient follow-up. In cases where inpatient MAT initiation is pursued, education of staff including nurses and pharmacists is essential.

Harm Reduction Interventions

Ideally, management of OUD results in abstinence from opioid misuse; however, some individuals are not ready for treatment or, despite MAT, have relapses of opioid misuse. Given this, a secondary goal in the management of OUD is the reduction of harm that can result from opioid misuse.

Many individuals inject opioids, which is associated with increased rates of viral and bacterial infections secondary to nonsterile injection practices.⁴⁹ Educating patients on sterile injection methods (Table 2),⁵⁰ including the importance of sterile-injecting equipment and water, and cleaning the skin prior to injection, may mitigate the risk of infections and should be provided for all hospitalized people who inject drugs.

Syringe-exchange programs provide sterile-injecting equipment in exchange for used needles, with a goal of increasing access to sterile supplies and removing contaminated syringes from circulation.⁵¹ While controversial, these programs may reduce the incidence of human immunodeficiency virus, hepatitis C virus, and hepatitis B virus.⁵¹

In addition, syringe-exchange programs often provide addiction treatment referrals, counseling, testing, and prevention education for human immunodeficiency virus, hepatitis C virus, and sexually transmitted infections.⁴⁹ In the United States, there are 226 programs in 33 states (see https://nasen.org/directory for a list of programs and locations. Inpatient clinicians should provide a list of local resources including syringe-exchange programs at the time of discharge for any people who inject drugs. In addition, individuals with OUD are at increased risk for overdose, especially in the postdischarge setting due to decreased opioid tolerance.⁵² In 2014, there were 28,647 opioid overdose-related deaths in the United States.² To address this troubling epidemic, opioid overdose education and naloxone distribution has been championed to educate patients at risk of opioid overdose and potential first responders on how to counteract an overdose by using naloxone, an opioid antagonist (see Table 2 for more information on opioid overdose education). The use of opioid overdose education and naloxone distribution has been observed to reduce opioid overdose-related death rates.⁵³

Hospitalists should provide opioid overdose education and naloxone to all individuals at risk of opioid overdose (including those with OUD), as well as potential first responders where the law allows (more information including individual state laws can be found at http://prescribetoprevent.org).²⁰

Considerations at Discharge

There are a number of considerations for the hospitalist at discharge (see Table 3 for a recommended discharge checklist). In addition, it is important to appreciate, and minimize, the ways that hospitalists contribute to the opioid epidemic. For instance, prescribing opioids at discharge in opioid-naïve patients increases the risk of chronic opioid use.⁵⁴ It is also essential to recognize that increased doses of opioids are associated with increased rates of opioid overdose-related deaths.⁵⁵ As such, hospitalists should maximize the use of nonopioid analgesics, prescribe opioids only when necessary, use the smallest effective dose of opioids, limit the number of opioid pills distributed to patients, and check prescription-monitoring programs for evidence of misuse.

Hospitalization serves as an important opportunity to address addiction in individuals with OUD. In addressing addiction, hospitalists should identify and intervene on psychosocial and mental health barriers, treat opioid withdrawal, and propagate harm reduction strategies. In addition, there is a growing role for hospitalists to be involved in the initiation of MAT and linkage-of-care to outpatient addiction treatment. If hospitalists become leaders in the inpatient management of OUD, they will significantly improve the care provided to this vulnerable patient population.

Disclosure

The authors report no financial conflicts of interest.

The United States is experiencing an epidemic of nonmedical opioid use. A concerted effort to better address pain increased the provision of prescription narcotics in the late 1990s and early 2000s.¹ Since then, there has been significant growth of opioid use and acorresponding increase in overdose-related deaths.^1-3 Public health officials have responded with initiatives to secure the opioid supply and improve outpatient treatment resources. However, the role of hospitalists in addressing opioid use disorder (OUD) is not well established. The inpatient needs for these individuals are complex and require a collaborative approach with input from outpatient clinicians, inpatient clinicians, addiction specialists, social workers, and case managers. Hospitals are often under-resourced to provide such comprehensive services. This frequently results in the hospitalist bearing significant responsibility for inpatient addiction management despite often insufficient addiction education or experience.^4,5

Therefore, there is a need for hospitalists to become leaders in the inpatient management of OUD. In this review, we will discuss the hospitalist’s role in the inpatient management of individuals with OUD.

Opioid use disorder is a medical illness resulting from neurobiological changes that cause drug tolerance, dependence, and cravings.⁶ It should be considered a treatable chronic medical condition, comparable to hypertension or diabetes,⁷ which requires a multifaceted treatment approach, including psychosocial, educational, and medical interventions.

Psychosocial Interventions

Individuals with OUD often have complicated social issues including stigmatization, involvement in the criminal justice system, unemployment, and homelessness,^5,8-10 in addition to frequent comorbid mental health issues.^11,12 Failure to address social or mental health barriers may lead to a lack of engagement in the treatment of OUD. The long-term management of OUD should involve outpatient psychotherapy and may include individual or group therapy, behavioral therapy, family counseling, or support groups.¹³ In the inpatient setting, hospitalists should use a collaborative approach to address psychosocial barriers. The authors recommend social work and case management consultations and consideration of psychiatric consultation when appropriate.

Management of Opioid Withdrawal

The prompt recognition and management of withdrawal is essential in hospitalized patients with OUD. The signs and symptoms of withdrawal can be evaluated by using the Clinical Opiate Withdrawal Scale or the Clinical Institute Narcotics Assessment, and may include lacrimation, rhinorrhea, diaphoresis, yawning, restlessness, insomnia, piloerection, myalgia, arthralgia, abdominal pain, nausea, vomiting, and diarrhea.⁴ Individuals using short-acting opioids, such as oxycodone or heroin, may develop withdrawal symptoms 8 to 12 hours after cessation of the opioid. Symptoms often peak on days 1 to 3 and can last for up to 10 days.¹⁴ Individuals taking long-acting opioids, such as methadone, may experience withdrawal symptoms for up to 21 days.¹⁴

While the goal of withdrawal treatment is to reduce the uncomfortable symptoms of withdrawal, there may be additional benefits. Around 16% of people who inject drugs will misuse drugs during their hospitalization, and 25% to 30% will be discharged against medical advice.^15,16 In hospitalizations when patients are administered methadone for management of withdrawal, there is a significant reduction in discharges against medical advice.¹⁶ This may suggest that treatment of withdrawal has the added benefit of preventing discharges against medical advice, and the authors postulate that treatment may decrease surreptitious drug use during hospitalizations, although this has not been studied.

There are 2 approaches to treating opioid withdrawal—opioid substitution treatment and alpha₂-adrenergic agonist treatment (Table 1).^4,17-20 Of note, opioid substitution treatment, especially when using buprenorphine, should be started only when a patient has at least mild withdrawal symptoms.²⁰

Medication-Assisted Treatment

It is important to recognize that treatment of withdrawal is not adequate to prevent long-term opioid misuse.²⁵ The optimal long-term management of OUD includes the use of medication-assisted treatment (MAT). The initiation and titration of MAT should always be done in conjunction with an addiction specialist or buprenorphine-waivered physician who will ensure continuation of MAT as an outpatient. This means that, while hospitalists may be critical in facilitating linkage to MAT, in general, they will not have a significant role in the long-term management of OUD. However, hospitalists should be knowledgeable about MAT because it is relatively common and can complicate hospitalizations.

There are two types of MAT: opioid-agonist treatment (OAT) and opioid-antagonist treatment. Opioid-agonist treatment involves the use of methadone, a long-acting opioid agonist, or buprenorphine, a long-acting partial opioid agonist. These medications decrease the amount and severity of cravings and limit the euphoric effects of subsequent opioid use.¹⁷ Compared to abstinence-based treatment, OAT has been associated with increased retention in addiction treatment and employment, and reductions in incarceration, human immunodeficiency virus transmission, illicit drug use, opioid-overdose events, and mortality.^26-32An alternative to OAT is naltrexone, an opioid antagonist. Naltrexone for OUD is administered as a monthly depot injection that prevents the user from experiencing opioid intoxication or dependence, and is associated with sustained abstinence.^17,33,34 The authors strongly recommend that hospitalists discuss the benefits of MAT with hospitalized individuals with OUD. In addition, when appropriate, patients should receive consultation with, or referral to, an addiction specialist.

Adverse Effects of Methadone, Buprenorphine, and Naltrexone

The benefits of MAT are substantial, but there are adverse effects, potential drug-to-drug interactions, and patient-specific characteristics that may impact the inpatient management of individuals on MAT. Selected adverse effects of OAT are listed in Table 1. The adverse effects of naltrexone include nausea, vomiting, and transaminitis. It should also be noted that the initiation of buprenorphine and naltrexone may induce opioid withdrawal when administered to an opioid-dependent patient with recent opioid use. To avoid precipitating withdrawal, buprenorphine should be used only in individuals who have at least mild withdrawal symptoms or have completed detoxification,²⁰ and naltrexone should be used only in patients who have abstained from opioids for at least 7 to 10 days.³⁵

Opioid-agonist treatments are primarily metabolized by the cytochrome P450 3A4 isoenzyme system. Medications that inhibit cytochrome P450 3A4 metabolism such as fluconazole can result in OAT toxicity, while medications that induce cytochrome P450 3A4 metabolism such as dexamethasone can lead to withdrawal symptoms.¹⁸ If these interactions are unavoidable, the dose of methadone or buprenorphine should be adjusted to prevent toxicity or withdrawal symptoms. The major drug interaction with naltrexone is ineffective analgesia from opioids.

Another major concern with MAT is the risk of overdose-related deaths. As an opioid agonist, large doses of methadone can result in respiratory depression, while buprenorphine alone, due to its partial agonist effect, is unlikely to result in respiratory depression. When methadone or buprenorphine are taken with other substances that cause respiratory depression, such as benzodiazepines or alcohol, the risk of respiratory depression and overdose is significantly increased.^36,37 Overdose-related death with naltrexone usually occurs after the medication has metabolized and results from a loss of opioid tolerance.³⁸

Special Populations

Medication-assisted treatment in individuals with acute pain. Maintenance treatment with OAT does not provide sufficient analgesia to treat episodes of acute pain.³⁹ In patients on methadone maintenance, the maintenance dose should be continued and adjunctive analgesia should be provided with nonopioid analgesics or short-acting opioids.³⁹ The management of acute pain in individuals on buprenorphine maintenance is more complicated since buprenorphine is a partial opioid agonist with high affinity to the opioid receptor, which limits the impact of adjunctive opioids. The options for analgesia in buprenorphine maintenance treatment include 1) continuing daily dosing of buprenorphine and providing nonopioid or opioid analgesics, 2) dividing buprenorphine dosing into a 3 or 4 times a day medication, 3) discontinuing buprenorphine and treating with opioid analgesics, 4) discontinuing buprenorphine and starting methadone with nonopioid or opioid analgesics.³⁹ In cases where buprenorphine is discontinued, it should be restarted before discharge upon resolution of the acute pain episode. An individual with acute pain on naltrexone may require nonopioid analgesia or regional blocks. In these patients, adequate pain control may be challenging and require the consultation of an acute pain specialist.

Pregnant or breastfeeding individuals. Opioid misuse puts the individual and fetus at risk of complications, and abrupt discontinuation can cause preterm labor, fetal distress, or fetal demise.⁴⁰ The current standard is to initiate methadone in consultation with an addiction specialist.⁴⁰ There is evidence that buprenorphine can be used during pregnancy; however, buprenorphine-naloxone is discouraged.^18,40 Of note, use of OAT in pregnancy can result in neonatal abstinence syndrome, an expected complication that can be managed by a pediatrician.⁴⁰

Methadone and buprenorphine can be found in low concentrations in breast milk.⁴¹ However, according to the Academy of Breastfeeding Medicine’s clinical guidelines, women on stable doses of methadone and buprenorphine should be encouraged to breastfeed.⁴¹ Naltrexone enters breast milk and has potential adverse effects for the newborn. Either the mother should discontinue naltrexone or should not breastfeed.³⁵

Treatment of polysubstance misuse. Individuals with OUD may also misuse other substances. The concomitant use of opioids and other central nervous system depressants, such as alcohol and benzodiazepines, is especially worrisome as they can potentiate respiratory depression. The presence of polysubstance misuse does not preclude the use of MAT for the treatment of OUD. In those with comorbid alcohol use disorder, the use of naltrexone may be appealing as it can treat both alcohol use disorder and OUD. Given the complexities of managing polysubstance misuse, addiction specialists should be involved in the care of these patients.⁴² In addition, patients should be educated on the risks of polysubstance misuse, especially when it involves 2 central nervous system depressants.

Comorbid medical disease. In general, medical comorbidities do not significantly affect the treatment of OUD; however, dysfunction of certain organ systems may necessitate a dose reduction or discontinuation of MAT. Severe liver disease may result in decreased hepatic metabolism of OAT.^35,42 Prolonged QTc, or history of arrhythmia, may preclude the use of methadone.^17,35,42 In addition, chronic hypercapnic respiratory failure or severe asthma may be contraindications for the use of methadone in an unmonitored setting.³⁵ Kidney failure is not known to be a contraindication to MAT, and there is no consensus on the need for dose reduction of MAT with decreasing glomerular filtration rate; however, some authors recommend a 25% to 50% dose reduction of methadone when the glomerular filtration rate is less than 10 milliliters per minute.⁴³ There is no such recommendation with buprenorphine, although it has not been adequately studied in individuals with renal failure. Close monitoring for evidence of toxicity is prudent in individuals on MAT with acute or chronic renal failure.³⁵

Rural or resource-limited areas. There is a significant shortage of addiction treatment options in many regions of the United States. As of 2012, there were an estimated 2.3 million individuals with OUD; however, more than 1 million of these individuals do not have access to treatment.⁴⁴ As a result, many addiction treatment programs have wait lists that can last months or even years.⁴⁵ These shortages are especially apparent in rural areas, where individuals with OUD are particularly reliant upon buprenorphine treatment because of prohibitive travel times to urban-based programs.⁴⁶ To address this problem, new models of care delivery are being developed, including models incorporating telemedicine to support rural primary care management of OUD.⁴⁷

The Future of Medication-Assisted Treatment

Currently, MAT is initiated and managed by outpatient addiction specialists. However, evidence supports initiation of MAT as an inpatient.⁴⁸ A recent study compared inpatient buprenorphine detoxification to inpatient buprenorphine induction, dose stabilization, and postdischarge linkage-of-care to outpatient opioid treatment clinics. Patients who received inpatient buprenorphine initiation and linkage-of-care had improved buprenorphine treatment retention and reported less illicit opioid use.⁴⁸ The development of partnerships between hospitals, inpatient clinicians, and outpatient addiction specialists is essential and could lead to significant advances in treating hospitalized patients with OUD.

The initiation of MAT in hospitalized patients with immediate linkage-of-care shows great promise; however, at this point, the initiation of MAT should be done only in conjunction with addiction specialists in patients with confirmed outpatient follow-up. In cases where inpatient MAT initiation is pursued, education of staff including nurses and pharmacists is essential.

Harm Reduction Interventions

Ideally, management of OUD results in abstinence from opioid misuse; however, some individuals are not ready for treatment or, despite MAT, have relapses of opioid misuse. Given this, a secondary goal in the management of OUD is the reduction of harm that can result from opioid misuse.

Many individuals inject opioids, which is associated with increased rates of viral and bacterial infections secondary to nonsterile injection practices.⁴⁹ Educating patients on sterile injection methods (Table 2),⁵⁰ including the importance of sterile-injecting equipment and water, and cleaning the skin prior to injection, may mitigate the risk of infections and should be provided for all hospitalized people who inject drugs.

Syringe-exchange programs provide sterile-injecting equipment in exchange for used needles, with a goal of increasing access to sterile supplies and removing contaminated syringes from circulation.⁵¹ While controversial, these programs may reduce the incidence of human immunodeficiency virus, hepatitis C virus, and hepatitis B virus.⁵¹

In addition, syringe-exchange programs often provide addiction treatment referrals, counseling, testing, and prevention education for human immunodeficiency virus, hepatitis C virus, and sexually transmitted infections.⁴⁹ In the United States, there are 226 programs in 33 states (see https://nasen.org/directory for a list of programs and locations. Inpatient clinicians should provide a list of local resources including syringe-exchange programs at the time of discharge for any people who inject drugs. In addition, individuals with OUD are at increased risk for overdose, especially in the postdischarge setting due to decreased opioid tolerance.⁵² In 2014, there were 28,647 opioid overdose-related deaths in the United States.² To address this troubling epidemic, opioid overdose education and naloxone distribution has been championed to educate patients at risk of opioid overdose and potential first responders on how to counteract an overdose by using naloxone, an opioid antagonist (see Table 2 for more information on opioid overdose education). The use of opioid overdose education and naloxone distribution has been observed to reduce opioid overdose-related death rates.⁵³

Hospitalists should provide opioid overdose education and naloxone to all individuals at risk of opioid overdose (including those with OUD), as well as potential first responders where the law allows (more information including individual state laws can be found at http://prescribetoprevent.org).²⁰

Considerations at Discharge

There are a number of considerations for the hospitalist at discharge (see Table 3 for a recommended discharge checklist). In addition, it is important to appreciate, and minimize, the ways that hospitalists contribute to the opioid epidemic. For instance, prescribing opioids at discharge in opioid-naïve patients increases the risk of chronic opioid use.⁵⁴ It is also essential to recognize that increased doses of opioids are associated with increased rates of opioid overdose-related deaths.⁵⁵ As such, hospitalists should maximize the use of nonopioid analgesics, prescribe opioids only when necessary, use the smallest effective dose of opioids, limit the number of opioid pills distributed to patients, and check prescription-monitoring programs for evidence of misuse.

Hospitalization serves as an important opportunity to address addiction in individuals with OUD. In addressing addiction, hospitalists should identify and intervene on psychosocial and mental health barriers, treat opioid withdrawal, and propagate harm reduction strategies. In addition, there is a growing role for hospitalists to be involved in the initiation of MAT and linkage-of-care to outpatient addiction treatment. If hospitalists become leaders in the inpatient management of OUD, they will significantly improve the care provided to this vulnerable patient population.

Disclosure

The authors report no financial conflicts of interest.

Up to 40% of Americans experience chronic pain of some kind.¹ In the United States, opioid analgesics are the most prescribed class of medications,² with 245 million prescriptions filled in 2014 alone. Thirty-five percent of these prescriptions were for long-term therapy.³ It is now apparent that opioid pain medication use presents serious risks. In 2014, 10.3 million persons reported using prescription opioids for nonmedical reasons.⁴ Between 1999 and 2014, more than 165,000 people in the United States died of overdose related to opioid medication.⁵ In addition, heroin use in the United States has increased over the past decade.⁶ Opioid agonist maintenance therapy is also increasingly used to treat patients with opioid use disorder.

Given the prevalence of opioid use in the United States, it is important for hospitalists to be able to appropriately and safely manage acute pain in patients who have been exposed long-term to opioids, whether it is therapeutic or non-medical in origin. Although nonopioid medications and nondrug treatments are essential components of managing all acute pain, opioids continue to be the mainstay of treatment for severe acute pain in both opioid-naïve and opioid-dependent patients.

Given the paucity of published trials meeting the typical criteria, we did not perform a structured meta-analysis but, instead, a case-based narrative review of the relevant published literature. Our goal in performing this review is to guide hospitalists in the appropriate and safe use of opioid analgesics in treating acute pain in hospitalized patients who are opioid-dependent.

When managing acute pain in patients with opioid dependence it is important to have a clear understanding of the definitions related to opioid use. Addiction, physical dependence and tolerance have been defined by a joint consensus statement of the American Society of Addiction Medicine, American Academy of Pain Medicine, and American Pain Society⁷: Addiction is a primary, chronic, biological disease, with genetic, psychosocial and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving.

Physical Dependence is a state of adaptation that is manifested by a drug class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.

Tolerance is the state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time.

Opioid use disorder (OUD) is defined as a problematic pattern of opioid use leading to clinically significant impairment or distress with symptoms including a strong desire for opioids, inability to control or reduce use of opioids, continued use despite adverse consequences, and development of tolerance and withdrawal symptoms.⁸

Physical dependence and tolerance are common consequences of long-term opioid use. In contrast, OUD has been reported to affect only 2% to 6% of individuals exposed to opioids.⁹ The underlying mechanisms that lead an individual to abuse or become addicted to opioids largely due to the effects opioids have on endogenous μ-opioid receptors. As analgesics, opioids exert their effects by binding primarily to these μ-opioid receptors, with a large concentration in the brain regions regulating pain perception.^10,11 There is also a large concentration of μ-opioid receptors in the brain reward regions, leading to perceptions of pleasure and euphoria. Repeated administration of opioids conditions the brain to a learned association between receiving the opiate and euphoria.^12,13 This association becomes stronger as the frequency and duration of administration increases over time, ultimately leading to the desire or craving of the opioid’s effect.

The effect of tolerance also contributes to the pathophysiology of opioid abuse as it leads to a decrease in opioid potency with repeated administration.^14-16 To achieve analgesia as well as the reward effect, opioid dosage and/or frequency must be increased, strengthening the association between receipt of opioid and reward. Tolerance to the reward effect occurs quickly, whereas tolerance to respiratory depression occurs much more slowly.¹⁷ This mismatch in tolerance of effect may lead to increase in opioid doses to maintain analgesia or euphoria, and also places patients at a higher risk of overdose.¹⁸

Clinical Example: Heroin User

A 47-year-old man is admitted with fever, chills, and severe mid-back pain and receives a diagnosis of sepsis. The patient admits to using intravenous heroin 500 mg (five 100 mg “bags”) on a daily basis. He is admitted, fluid resuscitated and started on broad spectrum antibiotics. Blood cultures quickly grow Staphylococcus aureus. Magnetic resonance imaging of the spine shows cervical vertebral osteomyelitis. On examination, the patient is diaphoretic and complains of diffuse myalgias and diarrhea. The patient’s back pain is so severe that he cannot ambulate. What is the best way to manage this patient’s acute pain and communicate with him about his pain management?

Managing acute pain in a patient using heroin can be challenging for many reasons. First, both physicians and pharmacists report a lack of confidence in their ability to prescribe opioids safely or to treat patients with a history of opioid abuse.¹⁹ Second, there is a paucity of evidence in treating acute pain in heroin users. Finally, due to the clandestine manufacturing of illicit drugs, the actual purity of the drug is often unknown making it difficult to assess the dose of opioids in heroin users. Drug Enforcement Agency seizure data indicate a wide range of heroin purity: 30% to 70%.²⁰

In the hospital setting, acute pain is often undertreated in patients with a history of active opioid abuse. This may be due to providers’ misconceptions regarding pain and behavior in opioid addicts, including worrying that the patient’s pain is exaggerated in order to obtain drugs, thinking that a regular opioid habit eliminates pain, believing that opioid therapy is not effective in drug addicts, or worrying that prescribing opioids will exacerbate drug addiction.²¹ Data demonstrates that the presence of opioid addiction seems to worsen the experience of acute pain.²² These patients also often have a higher tolerance and thus require higher dosages and more frequent dosing of opioids to adequately treat their pain.²³

Converting daily heroin use to morphine equivalents is necessary to establish a baseline analgesic requirement and to prevent withdrawal. It is challenging to convert illicit heroin to morphine equivalents however, as one must take into account the wide variation in purity and understand that the stated use of heroin (e.g. 500 mg daily) reflects weight and not dosage of heroin.²⁰

In these patients, treatment of acute pain should be individualized according to presenting illness and comorbidities. Previous data and an average purity of 40% suggest that the parenteral morphine equivalent to a bag of heroin (100 mg) is 15 to 30 mg.^20,24,25 Common equianalgesic doses of opioid medications are listed in Table 1. Because of increased tolerance, the frequency of administration should be shortened, from every 4 hours to every 2 or 3 hours. Except for a shorter onset of action, there has not been a difference shown in superiority between oral and parenteral routes of administration. Finally, patients should receive both long-acting basal and short-acting as-needed analgesics based on their daily use of opioids.²³

Clinical Example: Patient on Chronic Opioid Therapy for Chronic Pain

A 64 year-old man was involved in a motorcycle accident and suffered a right distal tibia-fibula fracture and several broken ribs with a secondary pneumothorax. The patient’s past medical history is significant for chronic low back pain for which he states he takes morphine sustained release 30 mg orally every 8 hours and morphine immediate release 15 mg orally four times daily for breakthrough pain. The patient states his pain is much worse than prior to the accident. Trauma surgery requests recommendations on appropriate pain management. What is the best way to manage this patient’s acute pain and communicate with him about his pain management?

When treating acute pain in patients with chronic pain on opioid therapy, it is vital to establish the patient’s baseline pain level and to accurately reconcile the patient’s outpatient daily opioid use. The patient’s prescription record should be verified in the state’s prescription drug monitoring program. On admission, a urine drug test should be obtained to assess for use of other potential illicit substances (eg, cocaine). Patients who test positive for illicit substances are at high risk for a substance use disorder. Management and discharge plans should be as outlined in the above case. It is important to know that the first-tier immunoassay urine toxicology screens used by hospitals test for natural opioids (morphine, codeine, heroin). Semi-synthetic (example, oxycodone) or synthetic (example, fentanyl) opioids are unlikely to be detected and thus the urine drug screen may not be helpful to determine adherence to certain prescription opioids. Gas chromatography/mass spectrometry is the most sensitive and specific type of urine screen and can be ordered to confirm a prescribed opioid if needed.²⁶

Pain management should begin with calculating the TDD of oral opioids that the patient was taking prior to admission, and converting to morphine equivalents. For moderate acute pain, TDD can be increased by 25% to 50%. The revised TDD can then be prescribed as a long-acting opioid every 8 to 12 hours to provide basal analgesia. The dose of additional immediate-release medication available throughout the day to manage breakthrough pain is determined by dividing the new TDD into every 3 to 4 hours as-needed dosing (Table 2).

If severe pain is anticipated, patient controlled analgesia (PCA) is an effective alternative to deliver opioids. The use of PCA allows self-titration, on demand analgesia, and minimizes the likelihood of under-dosing the patient.²⁷ The revised TDD is a useful starting point when calculating the PCA dosage regimen. Ideally, the revised TDD should be prescribed as a long acting oral opioid medication every 8 to 12 hours for basal analgesia, with PCA administered as an as-needed bolus. If a patient cannot tolerate oral medications, PCA can provide continuous infusion of medication to provide basal analgesia, though the risk of oversedation and respiratory depression is increased.²⁸

For our clinical example, we recommend increasing the preadmission TDD of opioids (180 mg morphine equivalents) by 25% (225 mg) and administering as morphine 75 mg sustained-release every 8 hours to provide baseline analgesia and prevent withdrawal symptoms. The acute pain can be managed by initiating morphine PCA without continuous infusion at 0.5 mg bolus every 8 minutes as needed for breakthrough pain or oral morphine 30 mg immediate-release tablets every 3 hours as needed for pain. The patient should be assessed frequently, and naloxone kept readily available. In addition, nonopioid and nondrug treatments should be optimized.

When communicating with patients with underlying chronic pain on chronic opioid therapy, it is important to discuss the treatment plan early, including addressing that they will likely not be pain free during their hospitalization, but rather goals of pain relief and improved function should be established. The plan to change to oral opioid analgesics as soon as possible and importance of multi-modal treatment should be emphasized. The patient should be informed that medication changes are for the short-term only and that the underlying chronic pain will likely remain unchanged.

Clinical Example: Patient on Medication-Assisted Therapy

A 42-year-old woman presents with acute epigastric pain and receives a diagnosis of acute gallstone pancreatitis. She states that her pain is very severe and appears uncomfortable. Her past medical history is significant for heroin addiction, but she has been successfully treated for opioid-use disorder with buprenorphine 16 mg daily for the past three years. What is the best way to manage this patient’s acute pain and communicate with her about her pain management?

Medication-assisted therapies (MATs) for treatment of opioid abuse, which include methadone and buprenorphine (Table 3), have been shown to be effective in helping patients recover in opioid-use disorder, are cost-effective and reduce the risk of opioid overdose.²⁹ However, treatment for acute pain in patients who are receiving methadone or buprenorphine MAT is a challenge because of pharmacokinetic changes that occur with prolonged use. It is important to know that patients receiving opioid agonist MAT are usually treated with 1 dose every 24 to 48 hours and do not receive sustained analgesia.³⁰

• Continue maintenance therapy with buprenorphine and treat acute pain with short acting opioid agonists. Higher doses of opioid agonists and more frequent dosing may be needed to provide adequate pain relief since they compete with buprenorphine at the mu receptor. Opioids with higher affinity for the mu receptor (morphine, hydromorphone, fentanyl) may be more efficacious.
• Discontinue buprenorphine and treat the patient with scheduled full opioid analgesics, titrating the dose initially to try to avoid withdrawal and then to provide pain relief. The partial agonism of the mu-receptor from buprenorphine and the blockade of other opioids can persist for as long as 72 hours. During this period, close monitoring and keeping naloxone available are important. When acute pain resolves, discontinue full opioid agonist therapy and resume buprenorphine using an induction protocol.

For our clinical example, we recommend continuing buprenorphine at 16 mg daily, optimizing nonopioid treatment strategies, and using a higher dose parenteral full opioid agonist every 3 hours as needed to achieve adequate analgesia. The patient should be frequently monitored for adverse effects, and naloxone kept available. Full opioid analgesics should be tapered and discontinued as the acute pain resolves. The patient should be reassured that there is no evidence that using opioids to treat acute pain episodes increases the risk of relapse and that untreated acute pain is a more likely trigger for relapse. The patient’s buprenorphine provider should be contacted at admission to verify dose as well as at discharge.

Early discharge planning is essential for appropriate and safe management of acute pain in hospitalized patients with opioid dependence. The major goals are to treat acute pain effectively, improve function, and return care to the patient’s usual treating physician or methadone clinic. Patients on chronic opioid therapy often have a written opioid treatment agreement specifying only 1 prescriber. Therefore, verbal communication with the patient’s authorized prescriber at admission and at discharge is essential, particularly given that the discharge summary may not be available at follow-up. Additional or higher doses of opioids should not be prescribed at discharge unless discussed with the patient’s authorized prescriber. If it is believed necessary to provide opioid medication at discharge it should only be provided for a short period: 3 to 7 days.³⁵ Patients with OUD should be referred for addiction treatment, including MAT, and should be educated on harm-reduction strategies, including safe injecting, obtaining clean needles, and recognizing, avoiding, and treating opioid overdose. Prescribing intranasal naloxone should be strongly considered for patients with OUD and for patients who are taking more than 50 mg oral morphine equivalents for chronic pain.³⁴

Management of acute pain in opioid-dependent patients is a complex and increasingly common problem encountered by hospitalists. In addition, given the OUD epidemic in the United States, safe opioid prescribing has become a paramount goal for all physicians. Although acute pain management will be individualized and will encompass clinical judgment, this review provides an evidence-based guide to effective and safe acute pain management and optimal opioid prescribing for hospitalized opioid-dependent patients.

Disclosure

Nothing to report.

Up to 40% of Americans experience chronic pain of some kind.¹ In the United States, opioid analgesics are the most prescribed class of medications,² with 245 million prescriptions filled in 2014 alone. Thirty-five percent of these prescriptions were for long-term therapy.³ It is now apparent that opioid pain medication use presents serious risks. In 2014, 10.3 million persons reported using prescription opioids for nonmedical reasons.⁴ Between 1999 and 2014, more than 165,000 people in the United States died of overdose related to opioid medication.⁵ In addition, heroin use in the United States has increased over the past decade.⁶ Opioid agonist maintenance therapy is also increasingly used to treat patients with opioid use disorder.

Given the prevalence of opioid use in the United States, it is important for hospitalists to be able to appropriately and safely manage acute pain in patients who have been exposed long-term to opioids, whether it is therapeutic or non-medical in origin. Although nonopioid medications and nondrug treatments are essential components of managing all acute pain, opioids continue to be the mainstay of treatment for severe acute pain in both opioid-naïve and opioid-dependent patients.

Given the paucity of published trials meeting the typical criteria, we did not perform a structured meta-analysis but, instead, a case-based narrative review of the relevant published literature. Our goal in performing this review is to guide hospitalists in the appropriate and safe use of opioid analgesics in treating acute pain in hospitalized patients who are opioid-dependent.

When managing acute pain in patients with opioid dependence it is important to have a clear understanding of the definitions related to opioid use. Addiction, physical dependence and tolerance have been defined by a joint consensus statement of the American Society of Addiction Medicine, American Academy of Pain Medicine, and American Pain Society⁷: Addiction is a primary, chronic, biological disease, with genetic, psychosocial and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving.

Physical Dependence is a state of adaptation that is manifested by a drug class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.

Tolerance is the state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time.

Opioid use disorder (OUD) is defined as a problematic pattern of opioid use leading to clinically significant impairment or distress with symptoms including a strong desire for opioids, inability to control or reduce use of opioids, continued use despite adverse consequences, and development of tolerance and withdrawal symptoms.⁸

Physical dependence and tolerance are common consequences of long-term opioid use. In contrast, OUD has been reported to affect only 2% to 6% of individuals exposed to opioids.⁹ The underlying mechanisms that lead an individual to abuse or become addicted to opioids largely due to the effects opioids have on endogenous μ-opioid receptors. As analgesics, opioids exert their effects by binding primarily to these μ-opioid receptors, with a large concentration in the brain regions regulating pain perception.^10,11 There is also a large concentration of μ-opioid receptors in the brain reward regions, leading to perceptions of pleasure and euphoria. Repeated administration of opioids conditions the brain to a learned association between receiving the opiate and euphoria.^12,13 This association becomes stronger as the frequency and duration of administration increases over time, ultimately leading to the desire or craving of the opioid’s effect.

The effect of tolerance also contributes to the pathophysiology of opioid abuse as it leads to a decrease in opioid potency with repeated administration.^14-16 To achieve analgesia as well as the reward effect, opioid dosage and/or frequency must be increased, strengthening the association between receipt of opioid and reward. Tolerance to the reward effect occurs quickly, whereas tolerance to respiratory depression occurs much more slowly.¹⁷ This mismatch in tolerance of effect may lead to increase in opioid doses to maintain analgesia or euphoria, and also places patients at a higher risk of overdose.¹⁸

Clinical Example: Heroin User

A 47-year-old man is admitted with fever, chills, and severe mid-back pain and receives a diagnosis of sepsis. The patient admits to using intravenous heroin 500 mg (five 100 mg “bags”) on a daily basis. He is admitted, fluid resuscitated and started on broad spectrum antibiotics. Blood cultures quickly grow Staphylococcus aureus. Magnetic resonance imaging of the spine shows cervical vertebral osteomyelitis. On examination, the patient is diaphoretic and complains of diffuse myalgias and diarrhea. The patient’s back pain is so severe that he cannot ambulate. What is the best way to manage this patient’s acute pain and communicate with him about his pain management?

Managing acute pain in a patient using heroin can be challenging for many reasons. First, both physicians and pharmacists report a lack of confidence in their ability to prescribe opioids safely or to treat patients with a history of opioid abuse.¹⁹ Second, there is a paucity of evidence in treating acute pain in heroin users. Finally, due to the clandestine manufacturing of illicit drugs, the actual purity of the drug is often unknown making it difficult to assess the dose of opioids in heroin users. Drug Enforcement Agency seizure data indicate a wide range of heroin purity: 30% to 70%.²⁰

In the hospital setting, acute pain is often undertreated in patients with a history of active opioid abuse. This may be due to providers’ misconceptions regarding pain and behavior in opioid addicts, including worrying that the patient’s pain is exaggerated in order to obtain drugs, thinking that a regular opioid habit eliminates pain, believing that opioid therapy is not effective in drug addicts, or worrying that prescribing opioids will exacerbate drug addiction.²¹ Data demonstrates that the presence of opioid addiction seems to worsen the experience of acute pain.²² These patients also often have a higher tolerance and thus require higher dosages and more frequent dosing of opioids to adequately treat their pain.²³

Converting daily heroin use to morphine equivalents is necessary to establish a baseline analgesic requirement and to prevent withdrawal. It is challenging to convert illicit heroin to morphine equivalents however, as one must take into account the wide variation in purity and understand that the stated use of heroin (e.g. 500 mg daily) reflects weight and not dosage of heroin.²⁰

In these patients, treatment of acute pain should be individualized according to presenting illness and comorbidities. Previous data and an average purity of 40% suggest that the parenteral morphine equivalent to a bag of heroin (100 mg) is 15 to 30 mg.^20,24,25 Common equianalgesic doses of opioid medications are listed in Table 1. Because of increased tolerance, the frequency of administration should be shortened, from every 4 hours to every 2 or 3 hours. Except for a shorter onset of action, there has not been a difference shown in superiority between oral and parenteral routes of administration. Finally, patients should receive both long-acting basal and short-acting as-needed analgesics based on their daily use of opioids.²³

Clinical Example: Patient on Chronic Opioid Therapy for Chronic Pain

A 64 year-old man was involved in a motorcycle accident and suffered a right distal tibia-fibula fracture and several broken ribs with a secondary pneumothorax. The patient’s past medical history is significant for chronic low back pain for which he states he takes morphine sustained release 30 mg orally every 8 hours and morphine immediate release 15 mg orally four times daily for breakthrough pain. The patient states his pain is much worse than prior to the accident. Trauma surgery requests recommendations on appropriate pain management. What is the best way to manage this patient’s acute pain and communicate with him about his pain management?

When treating acute pain in patients with chronic pain on opioid therapy, it is vital to establish the patient’s baseline pain level and to accurately reconcile the patient’s outpatient daily opioid use. The patient’s prescription record should be verified in the state’s prescription drug monitoring program. On admission, a urine drug test should be obtained to assess for use of other potential illicit substances (eg, cocaine). Patients who test positive for illicit substances are at high risk for a substance use disorder. Management and discharge plans should be as outlined in the above case. It is important to know that the first-tier immunoassay urine toxicology screens used by hospitals test for natural opioids (morphine, codeine, heroin). Semi-synthetic (example, oxycodone) or synthetic (example, fentanyl) opioids are unlikely to be detected and thus the urine drug screen may not be helpful to determine adherence to certain prescription opioids. Gas chromatography/mass spectrometry is the most sensitive and specific type of urine screen and can be ordered to confirm a prescribed opioid if needed.²⁶

Pain management should begin with calculating the TDD of oral opioids that the patient was taking prior to admission, and converting to morphine equivalents. For moderate acute pain, TDD can be increased by 25% to 50%. The revised TDD can then be prescribed as a long-acting opioid every 8 to 12 hours to provide basal analgesia. The dose of additional immediate-release medication available throughout the day to manage breakthrough pain is determined by dividing the new TDD into every 3 to 4 hours as-needed dosing (Table 2).

If severe pain is anticipated, patient controlled analgesia (PCA) is an effective alternative to deliver opioids. The use of PCA allows self-titration, on demand analgesia, and minimizes the likelihood of under-dosing the patient.²⁷ The revised TDD is a useful starting point when calculating the PCA dosage regimen. Ideally, the revised TDD should be prescribed as a long acting oral opioid medication every 8 to 12 hours for basal analgesia, with PCA administered as an as-needed bolus. If a patient cannot tolerate oral medications, PCA can provide continuous infusion of medication to provide basal analgesia, though the risk of oversedation and respiratory depression is increased.²⁸

For our clinical example, we recommend increasing the preadmission TDD of opioids (180 mg morphine equivalents) by 25% (225 mg) and administering as morphine 75 mg sustained-release every 8 hours to provide baseline analgesia and prevent withdrawal symptoms. The acute pain can be managed by initiating morphine PCA without continuous infusion at 0.5 mg bolus every 8 minutes as needed for breakthrough pain or oral morphine 30 mg immediate-release tablets every 3 hours as needed for pain. The patient should be assessed frequently, and naloxone kept readily available. In addition, nonopioid and nondrug treatments should be optimized.

When communicating with patients with underlying chronic pain on chronic opioid therapy, it is important to discuss the treatment plan early, including addressing that they will likely not be pain free during their hospitalization, but rather goals of pain relief and improved function should be established. The plan to change to oral opioid analgesics as soon as possible and importance of multi-modal treatment should be emphasized. The patient should be informed that medication changes are for the short-term only and that the underlying chronic pain will likely remain unchanged.

Clinical Example: Patient on Medication-Assisted Therapy

A 42-year-old woman presents with acute epigastric pain and receives a diagnosis of acute gallstone pancreatitis. She states that her pain is very severe and appears uncomfortable. Her past medical history is significant for heroin addiction, but she has been successfully treated for opioid-use disorder with buprenorphine 16 mg daily for the past three years. What is the best way to manage this patient’s acute pain and communicate with her about her pain management?

Medication-assisted therapies (MATs) for treatment of opioid abuse, which include methadone and buprenorphine (Table 3), have been shown to be effective in helping patients recover in opioid-use disorder, are cost-effective and reduce the risk of opioid overdose.²⁹ However, treatment for acute pain in patients who are receiving methadone or buprenorphine MAT is a challenge because of pharmacokinetic changes that occur with prolonged use. It is important to know that patients receiving opioid agonist MAT are usually treated with 1 dose every 24 to 48 hours and do not receive sustained analgesia.³⁰

• Continue maintenance therapy with buprenorphine and treat acute pain with short acting opioid agonists. Higher doses of opioid agonists and more frequent dosing may be needed to provide adequate pain relief since they compete with buprenorphine at the mu receptor. Opioids with higher affinity for the mu receptor (morphine, hydromorphone, fentanyl) may be more efficacious.
• Discontinue buprenorphine and treat the patient with scheduled full opioid analgesics, titrating the dose initially to try to avoid withdrawal and then to provide pain relief. The partial agonism of the mu-receptor from buprenorphine and the blockade of other opioids can persist for as long as 72 hours. During this period, close monitoring and keeping naloxone available are important. When acute pain resolves, discontinue full opioid agonist therapy and resume buprenorphine using an induction protocol.

For our clinical example, we recommend continuing buprenorphine at 16 mg daily, optimizing nonopioid treatment strategies, and using a higher dose parenteral full opioid agonist every 3 hours as needed to achieve adequate analgesia. The patient should be frequently monitored for adverse effects, and naloxone kept available. Full opioid analgesics should be tapered and discontinued as the acute pain resolves. The patient should be reassured that there is no evidence that using opioids to treat acute pain episodes increases the risk of relapse and that untreated acute pain is a more likely trigger for relapse. The patient’s buprenorphine provider should be contacted at admission to verify dose as well as at discharge.

Early discharge planning is essential for appropriate and safe management of acute pain in hospitalized patients with opioid dependence. The major goals are to treat acute pain effectively, improve function, and return care to the patient’s usual treating physician or methadone clinic. Patients on chronic opioid therapy often have a written opioid treatment agreement specifying only 1 prescriber. Therefore, verbal communication with the patient’s authorized prescriber at admission and at discharge is essential, particularly given that the discharge summary may not be available at follow-up. Additional or higher doses of opioids should not be prescribed at discharge unless discussed with the patient’s authorized prescriber. If it is believed necessary to provide opioid medication at discharge it should only be provided for a short period: 3 to 7 days.³⁵ Patients with OUD should be referred for addiction treatment, including MAT, and should be educated on harm-reduction strategies, including safe injecting, obtaining clean needles, and recognizing, avoiding, and treating opioid overdose. Prescribing intranasal naloxone should be strongly considered for patients with OUD and for patients who are taking more than 50 mg oral morphine equivalents for chronic pain.³⁴

Management of acute pain in opioid-dependent patients is a complex and increasingly common problem encountered by hospitalists. In addition, given the OUD epidemic in the United States, safe opioid prescribing has become a paramount goal for all physicians. Although acute pain management will be individualized and will encompass clinical judgment, this review provides an evidence-based guide to effective and safe acute pain management and optimal opioid prescribing for hospitalized opioid-dependent patients.

Disclosure

Nothing to report.

Up to 40% of Americans experience chronic pain of some kind.¹ In the United States, opioid analgesics are the most prescribed class of medications,² with 245 million prescriptions filled in 2014 alone. Thirty-five percent of these prescriptions were for long-term therapy.³ It is now apparent that opioid pain medication use presents serious risks. In 2014, 10.3 million persons reported using prescription opioids for nonmedical reasons.⁴ Between 1999 and 2014, more than 165,000 people in the United States died of overdose related to opioid medication.⁵ In addition, heroin use in the United States has increased over the past decade.⁶ Opioid agonist maintenance therapy is also increasingly used to treat patients with opioid use disorder.

Given the prevalence of opioid use in the United States, it is important for hospitalists to be able to appropriately and safely manage acute pain in patients who have been exposed long-term to opioids, whether it is therapeutic or non-medical in origin. Although nonopioid medications and nondrug treatments are essential components of managing all acute pain, opioids continue to be the mainstay of treatment for severe acute pain in both opioid-naïve and opioid-dependent patients.

Given the paucity of published trials meeting the typical criteria, we did not perform a structured meta-analysis but, instead, a case-based narrative review of the relevant published literature. Our goal in performing this review is to guide hospitalists in the appropriate and safe use of opioid analgesics in treating acute pain in hospitalized patients who are opioid-dependent.

When managing acute pain in patients with opioid dependence it is important to have a clear understanding of the definitions related to opioid use. Addiction, physical dependence and tolerance have been defined by a joint consensus statement of the American Society of Addiction Medicine, American Academy of Pain Medicine, and American Pain Society⁷: Addiction is a primary, chronic, biological disease, with genetic, psychosocial and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving.

Physical Dependence is a state of adaptation that is manifested by a drug class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.

Tolerance is the state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time.

Opioid use disorder (OUD) is defined as a problematic pattern of opioid use leading to clinically significant impairment or distress with symptoms including a strong desire for opioids, inability to control or reduce use of opioids, continued use despite adverse consequences, and development of tolerance and withdrawal symptoms.⁸

Physical dependence and tolerance are common consequences of long-term opioid use. In contrast, OUD has been reported to affect only 2% to 6% of individuals exposed to opioids.⁹ The underlying mechanisms that lead an individual to abuse or become addicted to opioids largely due to the effects opioids have on endogenous μ-opioid receptors. As analgesics, opioids exert their effects by binding primarily to these μ-opioid receptors, with a large concentration in the brain regions regulating pain perception.^10,11 There is also a large concentration of μ-opioid receptors in the brain reward regions, leading to perceptions of pleasure and euphoria. Repeated administration of opioids conditions the brain to a learned association between receiving the opiate and euphoria.^12,13 This association becomes stronger as the frequency and duration of administration increases over time, ultimately leading to the desire or craving of the opioid’s effect.

The effect of tolerance also contributes to the pathophysiology of opioid abuse as it leads to a decrease in opioid potency with repeated administration.^14-16 To achieve analgesia as well as the reward effect, opioid dosage and/or frequency must be increased, strengthening the association between receipt of opioid and reward. Tolerance to the reward effect occurs quickly, whereas tolerance to respiratory depression occurs much more slowly.¹⁷ This mismatch in tolerance of effect may lead to increase in opioid doses to maintain analgesia or euphoria, and also places patients at a higher risk of overdose.¹⁸

Clinical Example: Heroin User

A 47-year-old man is admitted with fever, chills, and severe mid-back pain and receives a diagnosis of sepsis. The patient admits to using intravenous heroin 500 mg (five 100 mg “bags”) on a daily basis. He is admitted, fluid resuscitated and started on broad spectrum antibiotics. Blood cultures quickly grow Staphylococcus aureus. Magnetic resonance imaging of the spine shows cervical vertebral osteomyelitis. On examination, the patient is diaphoretic and complains of diffuse myalgias and diarrhea. The patient’s back pain is so severe that he cannot ambulate. What is the best way to manage this patient’s acute pain and communicate with him about his pain management?

Managing acute pain in a patient using heroin can be challenging for many reasons. First, both physicians and pharmacists report a lack of confidence in their ability to prescribe opioids safely or to treat patients with a history of opioid abuse.¹⁹ Second, there is a paucity of evidence in treating acute pain in heroin users. Finally, due to the clandestine manufacturing of illicit drugs, the actual purity of the drug is often unknown making it difficult to assess the dose of opioids in heroin users. Drug Enforcement Agency seizure data indicate a wide range of heroin purity: 30% to 70%.²⁰

In the hospital setting, acute pain is often undertreated in patients with a history of active opioid abuse. This may be due to providers’ misconceptions regarding pain and behavior in opioid addicts, including worrying that the patient’s pain is exaggerated in order to obtain drugs, thinking that a regular opioid habit eliminates pain, believing that opioid therapy is not effective in drug addicts, or worrying that prescribing opioids will exacerbate drug addiction.²¹ Data demonstrates that the presence of opioid addiction seems to worsen the experience of acute pain.²² These patients also often have a higher tolerance and thus require higher dosages and more frequent dosing of opioids to adequately treat their pain.²³

Converting daily heroin use to morphine equivalents is necessary to establish a baseline analgesic requirement and to prevent withdrawal. It is challenging to convert illicit heroin to morphine equivalents however, as one must take into account the wide variation in purity and understand that the stated use of heroin (e.g. 500 mg daily) reflects weight and not dosage of heroin.²⁰

In these patients, treatment of acute pain should be individualized according to presenting illness and comorbidities. Previous data and an average purity of 40% suggest that the parenteral morphine equivalent to a bag of heroin (100 mg) is 15 to 30 mg.^20,24,25 Common equianalgesic doses of opioid medications are listed in Table 1. Because of increased tolerance, the frequency of administration should be shortened, from every 4 hours to every 2 or 3 hours. Except for a shorter onset of action, there has not been a difference shown in superiority between oral and parenteral routes of administration. Finally, patients should receive both long-acting basal and short-acting as-needed analgesics based on their daily use of opioids.²³

Clinical Example: Patient on Chronic Opioid Therapy for Chronic Pain

A 64 year-old man was involved in a motorcycle accident and suffered a right distal tibia-fibula fracture and several broken ribs with a secondary pneumothorax. The patient’s past medical history is significant for chronic low back pain for which he states he takes morphine sustained release 30 mg orally every 8 hours and morphine immediate release 15 mg orally four times daily for breakthrough pain. The patient states his pain is much worse than prior to the accident. Trauma surgery requests recommendations on appropriate pain management. What is the best way to manage this patient’s acute pain and communicate with him about his pain management?

When treating acute pain in patients with chronic pain on opioid therapy, it is vital to establish the patient’s baseline pain level and to accurately reconcile the patient’s outpatient daily opioid use. The patient’s prescription record should be verified in the state’s prescription drug monitoring program. On admission, a urine drug test should be obtained to assess for use of other potential illicit substances (eg, cocaine). Patients who test positive for illicit substances are at high risk for a substance use disorder. Management and discharge plans should be as outlined in the above case. It is important to know that the first-tier immunoassay urine toxicology screens used by hospitals test for natural opioids (morphine, codeine, heroin). Semi-synthetic (example, oxycodone) or synthetic (example, fentanyl) opioids are unlikely to be detected and thus the urine drug screen may not be helpful to determine adherence to certain prescription opioids. Gas chromatography/mass spectrometry is the most sensitive and specific type of urine screen and can be ordered to confirm a prescribed opioid if needed.²⁶

Pain management should begin with calculating the TDD of oral opioids that the patient was taking prior to admission, and converting to morphine equivalents. For moderate acute pain, TDD can be increased by 25% to 50%. The revised TDD can then be prescribed as a long-acting opioid every 8 to 12 hours to provide basal analgesia. The dose of additional immediate-release medication available throughout the day to manage breakthrough pain is determined by dividing the new TDD into every 3 to 4 hours as-needed dosing (Table 2).

If severe pain is anticipated, patient controlled analgesia (PCA) is an effective alternative to deliver opioids. The use of PCA allows self-titration, on demand analgesia, and minimizes the likelihood of under-dosing the patient.²⁷ The revised TDD is a useful starting point when calculating the PCA dosage regimen. Ideally, the revised TDD should be prescribed as a long acting oral opioid medication every 8 to 12 hours for basal analgesia, with PCA administered as an as-needed bolus. If a patient cannot tolerate oral medications, PCA can provide continuous infusion of medication to provide basal analgesia, though the risk of oversedation and respiratory depression is increased.²⁸

For our clinical example, we recommend increasing the preadmission TDD of opioids (180 mg morphine equivalents) by 25% (225 mg) and administering as morphine 75 mg sustained-release every 8 hours to provide baseline analgesia and prevent withdrawal symptoms. The acute pain can be managed by initiating morphine PCA without continuous infusion at 0.5 mg bolus every 8 minutes as needed for breakthrough pain or oral morphine 30 mg immediate-release tablets every 3 hours as needed for pain. The patient should be assessed frequently, and naloxone kept readily available. In addition, nonopioid and nondrug treatments should be optimized.

When communicating with patients with underlying chronic pain on chronic opioid therapy, it is important to discuss the treatment plan early, including addressing that they will likely not be pain free during their hospitalization, but rather goals of pain relief and improved function should be established. The plan to change to oral opioid analgesics as soon as possible and importance of multi-modal treatment should be emphasized. The patient should be informed that medication changes are for the short-term only and that the underlying chronic pain will likely remain unchanged.

Clinical Example: Patient on Medication-Assisted Therapy

A 42-year-old woman presents with acute epigastric pain and receives a diagnosis of acute gallstone pancreatitis. She states that her pain is very severe and appears uncomfortable. Her past medical history is significant for heroin addiction, but she has been successfully treated for opioid-use disorder with buprenorphine 16 mg daily for the past three years. What is the best way to manage this patient’s acute pain and communicate with her about her pain management?

Medication-assisted therapies (MATs) for treatment of opioid abuse, which include methadone and buprenorphine (Table 3), have been shown to be effective in helping patients recover in opioid-use disorder, are cost-effective and reduce the risk of opioid overdose.²⁹ However, treatment for acute pain in patients who are receiving methadone or buprenorphine MAT is a challenge because of pharmacokinetic changes that occur with prolonged use. It is important to know that patients receiving opioid agonist MAT are usually treated with 1 dose every 24 to 48 hours and do not receive sustained analgesia.³⁰

• Continue maintenance therapy with buprenorphine and treat acute pain with short acting opioid agonists. Higher doses of opioid agonists and more frequent dosing may be needed to provide adequate pain relief since they compete with buprenorphine at the mu receptor. Opioids with higher affinity for the mu receptor (morphine, hydromorphone, fentanyl) may be more efficacious.
• Discontinue buprenorphine and treat the patient with scheduled full opioid analgesics, titrating the dose initially to try to avoid withdrawal and then to provide pain relief. The partial agonism of the mu-receptor from buprenorphine and the blockade of other opioids can persist for as long as 72 hours. During this period, close monitoring and keeping naloxone available are important. When acute pain resolves, discontinue full opioid agonist therapy and resume buprenorphine using an induction protocol.

For our clinical example, we recommend continuing buprenorphine at 16 mg daily, optimizing nonopioid treatment strategies, and using a higher dose parenteral full opioid agonist every 3 hours as needed to achieve adequate analgesia. The patient should be frequently monitored for adverse effects, and naloxone kept available. Full opioid analgesics should be tapered and discontinued as the acute pain resolves. The patient should be reassured that there is no evidence that using opioids to treat acute pain episodes increases the risk of relapse and that untreated acute pain is a more likely trigger for relapse. The patient’s buprenorphine provider should be contacted at admission to verify dose as well as at discharge.

Early discharge planning is essential for appropriate and safe management of acute pain in hospitalized patients with opioid dependence. The major goals are to treat acute pain effectively, improve function, and return care to the patient’s usual treating physician or methadone clinic. Patients on chronic opioid therapy often have a written opioid treatment agreement specifying only 1 prescriber. Therefore, verbal communication with the patient’s authorized prescriber at admission and at discharge is essential, particularly given that the discharge summary may not be available at follow-up. Additional or higher doses of opioids should not be prescribed at discharge unless discussed with the patient’s authorized prescriber. If it is believed necessary to provide opioid medication at discharge it should only be provided for a short period: 3 to 7 days.³⁵ Patients with OUD should be referred for addiction treatment, including MAT, and should be educated on harm-reduction strategies, including safe injecting, obtaining clean needles, and recognizing, avoiding, and treating opioid overdose. Prescribing intranasal naloxone should be strongly considered for patients with OUD and for patients who are taking more than 50 mg oral morphine equivalents for chronic pain.³⁴

Management of acute pain in opioid-dependent patients is a complex and increasingly common problem encountered by hospitalists. In addition, given the OUD epidemic in the United States, safe opioid prescribing has become a paramount goal for all physicians. Although acute pain management will be individualized and will encompass clinical judgment, this review provides an evidence-based guide to effective and safe acute pain management and optimal opioid prescribing for hospitalized opioid-dependent patients.

Disclosure

Nothing to report.

An ambitious new report by the National Academies of Sciences, Engineering, and Medicine lays out a detailed path by which some 90,000 deaths from hepatitis B and C infection could be prevented by 2030.

The National Academies, a group of nongovernmental advisory bodies that includes the former Institute of Medicine, said that “the tools to prevent these deaths” exist – namely vaccination to prevent new hepatitis B infections and antiviral drugs, including new oral medications that can cure chronic hepatitis C infections within months.

The authors of the 200-plus-page report, led by Brian Strom, MD, MPH, of Rutgers University in Newark, NJ, calculate that deaths from hepatitis B infection could be halved by 2030 if 90% of patients are diagnosed, if 90% of those diagnosed are connected to care, and if 80% of those for whom treatment is indicated receive it. Treating everyone with chronic hepatitis C would reduce new infections by 90% by 2030, while reducing related deaths by 65%, Dr. Strom and his colleagues estimate.

But the authors also concede that drastic changes to current health policy would be required to reach these goals. These include the adoption of “aggressive testing, diagnosis, treatment, and prevention methods, such as needle exchange.”

They propose that the federal government seek a unique licensing arrangement with one or more manufacturers to bring down the notoriously high cost of direct-acting drugs used in hepatitis C, as a way of raising treatment rates. Currently, fewer than half the patients on Medicaid who are eligible for hepatitis C treatment receive it, and fewer than 1% of prisoners, who have high rates of infection.

Dr. Joseph Lim, director of the viral hepatitis program at Yale University in New Haven. Conn., who was not involved in the National Academies report, called it helpful in the sense that “it casts a spotlight on something that those of us involved in the care of people with viral hepatitis have long known – which is that this is a national and global public health burden that has been under the radar and in the shadow of other important health priorities.”

Both hepatitis B and C increase the risk of liver cancer and are associated with significant morbidity and mortality. Though approximately 4 million people in the United States are estimated to be infected with chronic hepatitis B (1.3 million) or C (2.7 million), these diseases account for less than 1% of the research budget at the National Institutes of Health, the report said. This compares unfavorably to funding for HIV, which affects about 1 million Americans.

As the report states, the tools to radically reduce hepatitis B and C deaths already exist. However, Dr. Lim cautioned in an interview, “the public health infrastructure to address viral hepatitis has been woefully inadequate.” In the United States, he noted, most states receive federal funding for at most a single person in charge of viral hepatitis epidemiology. “The resources currently available are in no way adequate to achieve the very aggressive goals described in the report,” he said.

Even among people with a known diagnosis of hepatitis B or C, only some receive confirmatory testing, Dr. Lim said. And of those with confirmed infections, “only a fraction are linked to care from the diagnosing clinician to a provider with the capacity to assess the state of liver disease and determine whether antiviral therapy is warranted.” Finally, he said, “many patients continue to face barriers to curative therapy due to cost and restrictions by public and private payers.”

Among the recommendations contained in the report is that unrestricted, mass treatment of hepatitis C infections be undertaken – regardless of disease stage. Currently, direct-acting antiviral agents remain costly and are poorly covered, notably by Medicaid. The National Academies advise that the government rectify this by purchasing “a license or assignment to the patent on a direct-acting antiviral drug, and use it only in those market segments where the government pays for treatment and access is now limited, such as Medicaid and prisons.” 

Dr. Lim called the licensing proposal “very novel and bold,” but noted that there is no precedent in the United States for diseases such as hepatitis C. “If it could be done it would be an incredible model of government-pharma partnership for the public health good, and have a very significant impact.”

Steven Flamm, MD, chief of the liver transplantation program at Northwestern University in Chicago, who like Dr. Lim was not involved in the creation of the report, said in an interview that it contained innovative ideas and helped underscore the fact that “hepatitis has been given short shrift. The NIH and other agencies do not devote time and energy to this particular medical issue for reasons that are not completely clear.”

But “the problem with these kinds of analyses,” he said, “is that carrying them out is harder than making the recommendations.”

Dr. Flamm echoed Dr. Lim’s concerns about the practicability of implementing some of the recommendations in what he considers a resource-deprived health care environment for viral hepatitis.

“Is elimination possible or can you take a big bite out of it? The answer to that question is yes. We now have agents that can treat chronic viral hepatitis well, which we didn’t have a few years ago.”

Still, he emphasized, having the tools is only one part of the picture. Hepatitis C diagnostic tests have been available since the early 1990s. Yet, Dr. Flamm pointed out, fewer than half of patients have been diagnosed. “If the new CDC screening guidelines gain traction, we will do better than that.”

Dr. Flamm said that he considered the report’s call for a unique government licensing agreement for hepatitis C drugs a tall order. The drugs are already heavily discounted by manufacturers in many cases, he said, yet remain unavailable to those in need of them. In Illinois, Dr. Flamm said, few Medicaid patients with confirmed hepatitis C are given the short-acting antivirals that have revolutionized treatment. “The vast majority have no access to the therapy at all,” he said.

One of the report’s strengths, he said, is in detailing innovative prevention strategies such as delivering and promoting hepatitis B vaccinations to adults through local pharmacies, after the model of influenza vaccinations, and also conducting needle exchanges through pharmacies for intravenous drug users, who are at high risk of contracting both hepatitis B and C.

“Many of these strategies are not very costly,” he said. “The problem is you run into moral platitudes – to eliminate hepatitis, we will have to overcome that,” Dr. Flamm said, something that cannot be taken for granted in the current political environment.

But even if the goals outlined in the report seem ambitious, its authors have done an important service in underscoring the burden of viral hepatitis and laying out how some barriers to prevention, diagnosis, and treatment might be broken, he said.

Viral hepatitis “is a big deal, and it does cost a tremendous amount of money,” he added. “Everybody focuses on the therapeutic cost, but nobody focuses on the costs, direct and indirect, of all the sick people that are out there.”

An ambitious new report by the National Academies of Sciences, Engineering, and Medicine lays out a detailed path by which some 90,000 deaths from hepatitis B and C infection could be prevented by 2030.

The National Academies, a group of nongovernmental advisory bodies that includes the former Institute of Medicine, said that “the tools to prevent these deaths” exist – namely vaccination to prevent new hepatitis B infections and antiviral drugs, including new oral medications that can cure chronic hepatitis C infections within months.

The authors of the 200-plus-page report, led by Brian Strom, MD, MPH, of Rutgers University in Newark, NJ, calculate that deaths from hepatitis B infection could be halved by 2030 if 90% of patients are diagnosed, if 90% of those diagnosed are connected to care, and if 80% of those for whom treatment is indicated receive it. Treating everyone with chronic hepatitis C would reduce new infections by 90% by 2030, while reducing related deaths by 65%, Dr. Strom and his colleagues estimate.

But the authors also concede that drastic changes to current health policy would be required to reach these goals. These include the adoption of “aggressive testing, diagnosis, treatment, and prevention methods, such as needle exchange.”

They propose that the federal government seek a unique licensing arrangement with one or more manufacturers to bring down the notoriously high cost of direct-acting drugs used in hepatitis C, as a way of raising treatment rates. Currently, fewer than half the patients on Medicaid who are eligible for hepatitis C treatment receive it, and fewer than 1% of prisoners, who have high rates of infection.

Dr. Joseph Lim, director of the viral hepatitis program at Yale University in New Haven. Conn., who was not involved in the National Academies report, called it helpful in the sense that “it casts a spotlight on something that those of us involved in the care of people with viral hepatitis have long known – which is that this is a national and global public health burden that has been under the radar and in the shadow of other important health priorities.”

Both hepatitis B and C increase the risk of liver cancer and are associated with significant morbidity and mortality. Though approximately 4 million people in the United States are estimated to be infected with chronic hepatitis B (1.3 million) or C (2.7 million), these diseases account for less than 1% of the research budget at the National Institutes of Health, the report said. This compares unfavorably to funding for HIV, which affects about 1 million Americans.

As the report states, the tools to radically reduce hepatitis B and C deaths already exist. However, Dr. Lim cautioned in an interview, “the public health infrastructure to address viral hepatitis has been woefully inadequate.” In the United States, he noted, most states receive federal funding for at most a single person in charge of viral hepatitis epidemiology. “The resources currently available are in no way adequate to achieve the very aggressive goals described in the report,” he said.

Even among people with a known diagnosis of hepatitis B or C, only some receive confirmatory testing, Dr. Lim said. And of those with confirmed infections, “only a fraction are linked to care from the diagnosing clinician to a provider with the capacity to assess the state of liver disease and determine whether antiviral therapy is warranted.” Finally, he said, “many patients continue to face barriers to curative therapy due to cost and restrictions by public and private payers.”

Among the recommendations contained in the report is that unrestricted, mass treatment of hepatitis C infections be undertaken – regardless of disease stage. Currently, direct-acting antiviral agents remain costly and are poorly covered, notably by Medicaid. The National Academies advise that the government rectify this by purchasing “a license or assignment to the patent on a direct-acting antiviral drug, and use it only in those market segments where the government pays for treatment and access is now limited, such as Medicaid and prisons.” 

Dr. Lim called the licensing proposal “very novel and bold,” but noted that there is no precedent in the United States for diseases such as hepatitis C. “If it could be done it would be an incredible model of government-pharma partnership for the public health good, and have a very significant impact.”

Steven Flamm, MD, chief of the liver transplantation program at Northwestern University in Chicago, who like Dr. Lim was not involved in the creation of the report, said in an interview that it contained innovative ideas and helped underscore the fact that “hepatitis has been given short shrift. The NIH and other agencies do not devote time and energy to this particular medical issue for reasons that are not completely clear.”

But “the problem with these kinds of analyses,” he said, “is that carrying them out is harder than making the recommendations.”

Dr. Flamm echoed Dr. Lim’s concerns about the practicability of implementing some of the recommendations in what he considers a resource-deprived health care environment for viral hepatitis.

“Is elimination possible or can you take a big bite out of it? The answer to that question is yes. We now have agents that can treat chronic viral hepatitis well, which we didn’t have a few years ago.”

Still, he emphasized, having the tools is only one part of the picture. Hepatitis C diagnostic tests have been available since the early 1990s. Yet, Dr. Flamm pointed out, fewer than half of patients have been diagnosed. “If the new CDC screening guidelines gain traction, we will do better than that.”

Dr. Flamm said that he considered the report’s call for a unique government licensing agreement for hepatitis C drugs a tall order. The drugs are already heavily discounted by manufacturers in many cases, he said, yet remain unavailable to those in need of them. In Illinois, Dr. Flamm said, few Medicaid patients with confirmed hepatitis C are given the short-acting antivirals that have revolutionized treatment. “The vast majority have no access to the therapy at all,” he said.

One of the report’s strengths, he said, is in detailing innovative prevention strategies such as delivering and promoting hepatitis B vaccinations to adults through local pharmacies, after the model of influenza vaccinations, and also conducting needle exchanges through pharmacies for intravenous drug users, who are at high risk of contracting both hepatitis B and C.

“Many of these strategies are not very costly,” he said. “The problem is you run into moral platitudes – to eliminate hepatitis, we will have to overcome that,” Dr. Flamm said, something that cannot be taken for granted in the current political environment.

But even if the goals outlined in the report seem ambitious, its authors have done an important service in underscoring the burden of viral hepatitis and laying out how some barriers to prevention, diagnosis, and treatment might be broken, he said.

Viral hepatitis “is a big deal, and it does cost a tremendous amount of money,” he added. “Everybody focuses on the therapeutic cost, but nobody focuses on the costs, direct and indirect, of all the sick people that are out there.”

An ambitious new report by the National Academies of Sciences, Engineering, and Medicine lays out a detailed path by which some 90,000 deaths from hepatitis B and C infection could be prevented by 2030.

The National Academies, a group of nongovernmental advisory bodies that includes the former Institute of Medicine, said that “the tools to prevent these deaths” exist – namely vaccination to prevent new hepatitis B infections and antiviral drugs, including new oral medications that can cure chronic hepatitis C infections within months.

The authors of the 200-plus-page report, led by Brian Strom, MD, MPH, of Rutgers University in Newark, NJ, calculate that deaths from hepatitis B infection could be halved by 2030 if 90% of patients are diagnosed, if 90% of those diagnosed are connected to care, and if 80% of those for whom treatment is indicated receive it. Treating everyone with chronic hepatitis C would reduce new infections by 90% by 2030, while reducing related deaths by 65%, Dr. Strom and his colleagues estimate.

But the authors also concede that drastic changes to current health policy would be required to reach these goals. These include the adoption of “aggressive testing, diagnosis, treatment, and prevention methods, such as needle exchange.”

They propose that the federal government seek a unique licensing arrangement with one or more manufacturers to bring down the notoriously high cost of direct-acting drugs used in hepatitis C, as a way of raising treatment rates. Currently, fewer than half the patients on Medicaid who are eligible for hepatitis C treatment receive it, and fewer than 1% of prisoners, who have high rates of infection.

Dr. Joseph Lim, director of the viral hepatitis program at Yale University in New Haven. Conn., who was not involved in the National Academies report, called it helpful in the sense that “it casts a spotlight on something that those of us involved in the care of people with viral hepatitis have long known – which is that this is a national and global public health burden that has been under the radar and in the shadow of other important health priorities.”

Both hepatitis B and C increase the risk of liver cancer and are associated with significant morbidity and mortality. Though approximately 4 million people in the United States are estimated to be infected with chronic hepatitis B (1.3 million) or C (2.7 million), these diseases account for less than 1% of the research budget at the National Institutes of Health, the report said. This compares unfavorably to funding for HIV, which affects about 1 million Americans.

As the report states, the tools to radically reduce hepatitis B and C deaths already exist. However, Dr. Lim cautioned in an interview, “the public health infrastructure to address viral hepatitis has been woefully inadequate.” In the United States, he noted, most states receive federal funding for at most a single person in charge of viral hepatitis epidemiology. “The resources currently available are in no way adequate to achieve the very aggressive goals described in the report,” he said.

Even among people with a known diagnosis of hepatitis B or C, only some receive confirmatory testing, Dr. Lim said. And of those with confirmed infections, “only a fraction are linked to care from the diagnosing clinician to a provider with the capacity to assess the state of liver disease and determine whether antiviral therapy is warranted.” Finally, he said, “many patients continue to face barriers to curative therapy due to cost and restrictions by public and private payers.”

Among the recommendations contained in the report is that unrestricted, mass treatment of hepatitis C infections be undertaken – regardless of disease stage. Currently, direct-acting antiviral agents remain costly and are poorly covered, notably by Medicaid. The National Academies advise that the government rectify this by purchasing “a license or assignment to the patent on a direct-acting antiviral drug, and use it only in those market segments where the government pays for treatment and access is now limited, such as Medicaid and prisons.” 

Dr. Lim called the licensing proposal “very novel and bold,” but noted that there is no precedent in the United States for diseases such as hepatitis C. “If it could be done it would be an incredible model of government-pharma partnership for the public health good, and have a very significant impact.”

Steven Flamm, MD, chief of the liver transplantation program at Northwestern University in Chicago, who like Dr. Lim was not involved in the creation of the report, said in an interview that it contained innovative ideas and helped underscore the fact that “hepatitis has been given short shrift. The NIH and other agencies do not devote time and energy to this particular medical issue for reasons that are not completely clear.”

But “the problem with these kinds of analyses,” he said, “is that carrying them out is harder than making the recommendations.”

Dr. Flamm echoed Dr. Lim’s concerns about the practicability of implementing some of the recommendations in what he considers a resource-deprived health care environment for viral hepatitis.

“Is elimination possible or can you take a big bite out of it? The answer to that question is yes. We now have agents that can treat chronic viral hepatitis well, which we didn’t have a few years ago.”

Still, he emphasized, having the tools is only one part of the picture. Hepatitis C diagnostic tests have been available since the early 1990s. Yet, Dr. Flamm pointed out, fewer than half of patients have been diagnosed. “If the new CDC screening guidelines gain traction, we will do better than that.”

Dr. Flamm said that he considered the report’s call for a unique government licensing agreement for hepatitis C drugs a tall order. The drugs are already heavily discounted by manufacturers in many cases, he said, yet remain unavailable to those in need of them. In Illinois, Dr. Flamm said, few Medicaid patients with confirmed hepatitis C are given the short-acting antivirals that have revolutionized treatment. “The vast majority have no access to the therapy at all,” he said.

One of the report’s strengths, he said, is in detailing innovative prevention strategies such as delivering and promoting hepatitis B vaccinations to adults through local pharmacies, after the model of influenza vaccinations, and also conducting needle exchanges through pharmacies for intravenous drug users, who are at high risk of contracting both hepatitis B and C.

“Many of these strategies are not very costly,” he said. “The problem is you run into moral platitudes – to eliminate hepatitis, we will have to overcome that,” Dr. Flamm said, something that cannot be taken for granted in the current political environment.

But even if the goals outlined in the report seem ambitious, its authors have done an important service in underscoring the burden of viral hepatitis and laying out how some barriers to prevention, diagnosis, and treatment might be broken, he said.

Viral hepatitis “is a big deal, and it does cost a tremendous amount of money,” he added. “Everybody focuses on the therapeutic cost, but nobody focuses on the costs, direct and indirect, of all the sick people that are out there.”

In 2015, about 1.6 million Americans received a diagnosis of cancer.¹ In 2012, when 13.7 million people were living with cancer in the United States, the estimated 5-year survival rate of all cancers was 66.5%.¹ Today, breast, prostate, and colon cancers have 5-year survival rates of 89.4%, 98.9%, and 64.9%, respectively.

With this rising trend in survival, primary care physicians have been steadily assuming the long-term care of these patients. The phrase “cancer survivorship” was coined by the National Comprehensive Cancer Network to describe the experience of living with, through, and beyond a cancer diagnosis.²

As cancer becomes a chronic medical condition, the primary care physician assumes a vital role in the treatment of the unique and evolving needs of this patient population.

This article discusses the specific needs of patients surviving breast, prostate, and colon cancer with special focus on surveillance guidelines for recurrence, development of concomitant malignancies, assessment of psychosocial and physical effects, and disease conditions related to the treatment of cancer itself.

FOLLOW-UP CARE AND SURVEILLANCE

Follow-up care in patients being treated for cancer is vital to survivorship. It includes promoting healthy living, managing treatment side effects, and monitoring for long-term side effects and possible recurrence.

Patients previously treated for malignancy are more susceptible to second primary cancers, for an array of reasons including the effects of prior treatment, shared environmental exposures such as smoking, and genetic susceptibility.² Therefore, it is important for the primary care physician to recognize signs and symptoms and to screen cancer survivors appropriately. The American Society of Clinical Oncology (ASCO) has developed evidence-based recommendations for follow-up care,³ which we review here.

Breast cancer

For breast cancer patients, history and physical examinations are recommended every 3 to 6 months for the first 3 years, every 6 to 12 months in years 4 and 5, and annually thereafter.³

A repeat mammogram should be performed 1 year after the initial mammogram that led to the diagnosis. If the patient underwent radiation therapy, a repeat mammogram of the affected breast should be done 6 months after completion of radiation. Finally, a mammogram should be done every 6 to 12 months thereafter.³ It is also recommended that patients perform a monthly breast self-examination, but this does not replace the annual mammogram.³

Women who are treated with tamoxifen should have an annual gynecologic assessment if they have a uterus and should be encouraged to discuss any abnormal vaginal bleeding with their physician, given the increased risk of uterine cancer.²

ASCO does not recommend routine use of complete blood cell counts, complete metabolic panels, bone scans, chest radiography, computed tomography, ultrasonography, positron-emission tomography, or tumor markers in patients who are asymptomatic.³

Prostate cancer

ASCO’s recommendations for patients recovering from prostate cancer include regular histories and physical examinations and general health promotion. Prostate-specific antigen (PSA) testing is recommended every 6 to 12 months for the first 5 years after treatment and annually thereafter. More frequent PSA testing may be required in men at higher risk of recurrence or in patients who may undergo additional treatment, including radiation and surgery.⁴ Higher risk of disease recurrence is thought to depend on disease-specific factors at the time of original diagnosis including pretreatment PSA, Gleason score, and tumor stage.⁴ This should be discussed between the oncologist and primary care physician.

In regard to digital rectal examinations, the oncologist and primary care physician should jointly determine the frequency of examination. The frequency of digital rectal examinations remains an area of controversy due to their low sensitivity for detecting recurrences. Digital rectal examinations may be omitted in patients with undetectable levels of PSA.⁴

In regard to second primary malignancies, prostate cancer survivors who have undergone pelvic radiation therapy have a slightly higher risk of bladder and colorectal cancer. The lifetime incidence of bladder cancer after pelvic radiation is 5% to 6%, compared with 2.4% in the general population.^1,5 A prostate cancer survivor presenting with hematuria should be referred to a urologist for cystoscopy and evaluation of the upper urinary tract to rule out cancer.⁴

Similarly, patients presenting with rectal bleeding should be referred to a gastroenterologist and the treating radiation oncologist for complete evaluation. The risk of rectal cancer after pelvic radiation therapy increases to about the same level as in someone who has a first-degree relative with colorectal cancer.⁵ Therefore, it is recommended that patients undergo screening for colorectal cancer in conjunction with existing evidence-based guidelines. There is no evidence to suggest that increased intensity of screening improves overall or disease-specific survival.⁴

Colon cancer

In patients with resected colorectal cancer, continued surveillance is important to evaluate for recurrent cancer as well as for metachronous neoplasms. Consensus statements indicate that surveillance colonoscopy should be continued for those who have undergone surgical resection for stage I, II, or III colon or rectal cancers, and for those patients with stage IV who have undergone surgical resection with curative intent.⁶

Patients who undergo curative resection of rectal or colon cancer should have a colonoscopy 1 year after resection or 1 year after the colonoscopy was performed, to clear the colon of synchronous disease. Subsequently, if the colonoscopy done at 1 year is normal, the interval before the next colonoscopy is 3 years. If that colonoscopy is normal, the next colonoscopy is in 5 years. Time intervals may be shorter if there is evidence of hereditary nonpolyposis colorectal cancer or adenoma.

Patients who underwent low anterior resection of rectal cancer should undergo periodic examination of the rectum to evaluate for local recurrence. Although effectiveness is not proven, endoscopic ultrasonography or flexible sigmoidoscopy is suggested at 3- to 6-month intervals for the first 2 to 3 years after resection. This is independent of colonoscopy.^6,7

Additionally, ASCO recommends a history and physical examination and carcinoembryonic antigen testing every 3 to 6 months for the first 5 years. Computed tomography  of the chest, abdomen, and pelvis should be done annually for the first 3 years after the end of treatment.⁷

Maintaining a healthy body weight and a nutritionally balanced diet should be encouraged in all cancer survivors. Poor diet, lack of exercise, excessive alcohol consumption, and smoking reduce quality of life and increase the risk of cancer.²

Diet

Numerous studies have looked at dietary modifications and risk reduction, and although there is no consensus on specific dietary guidelines, there is consensus that diet modification to maintain normal body weight will improve overall quality of life.⁸ Patients should be encouraged to consume a well-balanced diet consisting mostly of fruits, vegetables, whole grains, and beans, and to limit consumption of animal protein.⁸

There is little evidence to support taking vitamins or other dietary supplements to prevent or control cancer or to prevent its recurrence. The primary care physician should assess supplement use on a regular basis during office visits.²

Exercise

Rest is an important component of the initial recovery process. Too much inactivity, however, leads to loss of physical conditioning and muscle strength. This in turn may negatively affect a patient’s ability to perform activities of daily living and may worsen fatigue associated with treatment.

Accordingly, the National Comprehensive Cancer Network recommends at least 150 minutes of moderate activity and up to 75 minutes of more rigorous activity divided throughout the week.^2,8 The regimen should include endurance and muscle strength training, which aid in balance, bone, health, and functional status. The intensity of exercise should be increased in a stepwise fashion, taking into account individual capabilities and limitations.²

Cancer survivors may need specific exercise recommendations and supervised programs to ensure safety and limit long-term side effects of their treatment. For example:

Patients with neuropathy should have their stability, balance, and gait assessed before starting a new program. These patients may benefit from an aerobic exercise program that includes riding a stationary bike rather than running.

Patients with poor bone health should have their fracture risk assessed.

Those with an ostomy bag should empty the bag before physical activity. They should avoid contact sports and activities that increase intra-abdominal pressure.

Patients suffering from lymphedema should wear compression garments when engaging in physical activity. They should undergo baseline and periodic reevaluation of the lymphedema and initiate strength training in the affected body part only if the lymphedema is stable (ie, no need for therapy for 3 months, no recent infections requiring antibiotics, and no change in circumference > 10%).²

Mental health

Health promotion should focus not only on the physical health of the patient, but also on his or her emotional and psychological well-being. As they make the transition from cancer patient to survivor, many individuals may develop or have worsening depression and anxiety due to fear of recurrence. These feelings of powerlessness can linger for years after the initial treatment.

Patients should be screened regularly for signs and symptoms of depression by asking about their family and social support. Referral to support groups, psychologists, and psychiatrists may be warranted.⁹

MITIGATING CANCER-RELATED FATIGUE

Cancer-related fatigue involves a patient’s subjective sense of physical, emotional, and cognitive exhaustion related to cancer or treatment that is disproportionate to that expected from recent daily activity.² Fatigue is a common complaint among survivors and can occur months to years after treatment ends.¹⁰

Patients should be screened for fatigue at regular intervals. The primary care physician should focus the history to include information regarding the onset, pattern, duration, associated factors, assessment of other treatable comorbidities, medications, psychological well-being, nutritional status, and pain level of each patient who complains of fatigue.

Laboratory tests for treatable causes of fatigue include:

• A complete blood cell count to evaluate for anemia
• A comprehensive metabolic panel to evaluate electrolytes, renal function, and hepatic function
• The thyroid-stimulating hormone level to evaluate thyroid function, particularly in breast cancer patients who have received radiation therapy.²

If no organic cause is uncovered, the focus should shift to lifestyle interventions as the treatment of choice. The treatment of fatigue in this situation is increased physical activity with the goals discussed above. Psychological intervention may be required with cognitive behavioral therapy, psychological and supportive therapies, education on sleep hygiene, and possible sleep restriction.

If alternative causes of fatigue are ruled out and physical and psychological support fails to reduce symptoms, the practitioner can consider a psychostimulant such as methylphenidate, but this should be used cautiously.²

SEXUAL DYSFUNCTION

Intimate relationships and sexuality are an important part of life and are affected by a variety of factors including physical health, psychological well-being, body image perception, and overall status of relationships. As a side effect of chemotherapy, cancer survivors may complain of erectile dysfunction, penile shortening, dyspareunia, vaginal dryness, decreased libido, anorgasmy, and changes in body image. These issues are frequently unaddressed, whether due to the physician’s discomfort in discussing the topic or to the patient’s embarrassment and reluctance to discuss the matter.¹¹

Breast cancer patients may experience sexual dysfunction both during and after treatment due to a combination of systemic effects of treatment, changes in physical appearance leading to impaired body image, strains on partner relationships, and psychological sequelae of diagnosis and treatment of cancer.¹² Manipulation and radiation to the breast affect sexual functioning by altering body contour and image. Additionally, chemotherapy can lead to early menopause and hormonal alterations due to endocrine therapies, which can negatively affect sexual organs.¹¹

Studies have shown that treatment with tamoxifen causes less sexual dysfunction than do aromatase inhibitors. In the Arimidex, Tamoxifen, Alone or in Combination trial, therapy with anastrozole was associated with more vaginal dryness, dyspareunia, and decreased libido compared with tamoxifen.¹²

Treatment requires a comprehensive history, a physical examination, and a discussion of relationship satisfaction with the patient.

Vaginal dryness and dyspareunia can be treated with vaginal lubricants and moisturizers. Moisturizers are effective if used multiple times per week, whereas lubricants can be used on demand. Low-dose vaginal estrogen preparations can be used in select patients with severe vaginal dryness; the goal should be discussed. Hormone replacement therapy is contraindicated in breast cancer survivors due to the risk of recurrence.¹¹

Prostate cancer survivors. Up to 70% of men felt their quality of life and sexual function were adversely affected after the diagnosis and treatment.^13,14 Erectile dysfunction following radical prostatectomy and radiation therapy remains one of the leading causes of sexual dysfunction.^14–15 Erectile dysfunction is multifactorial, with both psychogenic and organic causes. Comorbidities must be considered including hypertension, diabetes, hyperlipidemia, and smoking. Early penile rehabilitation is a proposed treatment strategy.¹⁴

First-line therapy for penile rehabilitation includes introduction of daily low-dose phosphodiesterase type 5 inhibitors as early as the time of catheter removal to within the first month after surgery. The need for daily dosing vs on-demand dosing has been controversial.¹⁵ Two large multicenter, double-blind studies had conflicting outcomes. The first reported that in men receiving nightly sildenafil (50 or 100 mg) after radical prostatectomy, 27% had increased return of spontaneous erectile function vs 4% with placebo¹⁶; the second study showed no difference between nightly and on-demand dosing.¹⁷ The consensus is that a phosphodiesterase type 5 inhibitor should be initiated early.

Second-line therapy includes intracavernosal injections and vacuum erection devices. Finally, a penile prosthesis implant can be offered to patients who have responded poorly to medical therapy.¹³

Colorectal cancer survivors suffer from sexually related problems similar to those stated above, including erectile dysfunction, ejaculation problems, dyspareunia, vaginal dryness, and decreased enjoyment.¹⁸ These patients should be provided treatments similar to those described above. In addition, they may suffer from body image issues, particularly those with a permanent ostomy.⁹

Sexual dysfunction is a multifaceted problem for patients. Encouraging couples to discuss sexual intimacy frequently helps to reveal and cope with the problems, whether physical or psychological. It is the primary care physician’s role to recognize any sexual concerns and refer to the appropriate specialist.

Osteoporosis is a metabolic bone disease characterized by low bone mineral density. As a result, bones become weak and fracture more easily from minor injuries.

Risk factors for osteoporosis include female sex, family history, advanced age, low body weight, low calcium and vitamin D levels, sedentary lifestyle, smoking, and low estrogen levels.¹⁹ Cancer treatment places patients at a greater risk for osteoporosis, particularly for those patients with chemotherapy-induced ovarian failure, those treated with aromatase inhibitors, men receiving androgen-deprivation therapy, and patients on glucocorticoid therapy. The morbidity and mortality associated with bone loss can be prevented with appropriate screening, lifestyle changes, and therapy.²

According to the National Osteoporosis Foundation Guideline for Preventing and Treating Osteoporosis, all men and postmenopausal women age 50 and older should be evaluated clinically for osteoporosis risk to determine the need for bone mineral density testing.^2,19 The US Preventive Services Task Force recommends bone mineral density testing in all women age 65 and older, and for women 60 to 64 who are at high risk for bone loss. ASCO agrees, and further suggests bone mineral density screening for women with breast cancer who have risk factors such as positive family history, body weight less than 70 kg, and prior nontraumatic fracture, as well as for postmenopausal women of any age receiving aromatase inhibitors and for premenopausal women with therapy-induced ovarian failure.¹¹

Androgen deprivation therapy is a mainstay of treatment in recurrent and metastatic prostate cancer. The effect is severe hypogonadism with reductions in serum testosterone levels. Androgen deprivation therapy accelerates bone turnover, decreases bone mineral density, and contributes to fracture risk. The National Comprehensive Cancer Network additionally suggests measuring bone mineral density at baseline for all men receiving androgen deprivation therapy or other medications associated with bone loss, repeating it 1 year after androgen deprivation therapy and then every 2 years, or as clinically indicated.²⁰

The gold standard for measuring bone mineral density is dual-energy x-ray absorptiometry. The World Health Organization FRAX tool uses bone mineral density and several clinical factors to estimate the risk of fracture in the next 10 years, which can help guide therapy. Cancer patients with elevated fracture risk should be evaluated every 2 years. Counseling should be provided to address modifiable risk factors such as smoking, alcohol consumption, physical inactivity, and low calcium and vitamin D intake. Therapy should be strongly considered in patients with a bone mineral density below a T-score of –2.0. ^2,19

Treatment begins with lifestyle modifications such as weight-bearing exercises to improve balance and muscle strength and to prevent falls, and adequate intake of calcium (≥ 1,200 mg daily) and vitamin D (800–1,000 IU daily) for adults age 50 and older. Treatment with bisphosphonates may be required.^2,11,20

NEUROPATHY

Many chemotherapeutic agents can lead to neuropathy and can result in long-term disability in patients. Patients treated with taxane- and platinum-based chemotherapy are at particular risk.

Paclitaxel, used in the treatment of breast, ovarian, and lung cancer, can lead to distal neuropathy. This neuropathy commonly has a stocking-and-glove distribution and is primarily sensory; however, it may have motor and autonomic components. The neuropathy typically lessens when the medication is stopped, although in some patients it can persist and lead to long-term disability.

Treatment can include massage. Medications such as gabapentin and pregabalin can also be used, but randomized controlled trials do not support them, as they predominantly treat the tingling rather than the numbness.¹¹

BLADDER AND BOWEL DYSFUNCTION

Urinary incontinence and dysfunction are frequent complications in prostate cancer survivors. Urinary function should be discussed regularly with patients, addressing quality of the urinary stream, difficulty emptying the bladder, timing, and incontinence.⁴ Urinary incontinence is frequently seen in postprostatectomy patients.

The cornerstone of treating urinary incontinence is determining the cause of the incontinence, whether it is stress or urge incontinence, or both.²¹ For those patients with urge incontinence alone, practitioners can address the problem with a combination of behavior modification, pelvic floor exercises, and anticholinergic medications such as oxybutynin. If the problem stems from difficulty initiating or a slow stream, physicians may consider alpha-blockers.^4,21 If the incontinence is persistent, bothersome, and has components of stress incontinence, the patient should be referred to a urologist for urodynamic testing, cystoscopy, and surgical evaluation for possible placement of a male urethral sling or artificial urinary sphincter.²¹

Colorectal cancer survivors, particularly those who received radiation therapy, are at high risk of bowel dysfunction such as chronic diarrhea and stool incontinence. Patients should be educated about this possible side effect. Symptoms of bowel dysfunction can affect body image and interfere with social functioning and overall quality of life. Patients should be provided with coping tools such as antidiarrheal medication, stool bulking agents, changes in diet, and protective underwear.

CARDIOVASCULAR DISEASE

Evidence suggests that certain types of chemotherapy and radiation therapy increase the risk of cardiovascular disease. Prostate cancer survivors treated with androgen deprivation therapy, particularly those more than 75 years old, are at increased risk of cardiovascular disease and diabetes.²²

It is recommended that men be screened with fasting plasma glucose at baseline and yearly thereafter while receiving androgen deprivation therapy. Lipid panel testing should be done 1 year from initiation of androgen deprivation therapy and then, if results are normal, every 5 years or as clinically warranted. The focus should be on primary prevention with emphasis on smoking cessation, treating hypertension per guidelines, lifestyle modifications, and treatment with aspirin and statins when clinically appropriate.²⁰

Radiation therapy, chemotherapy, and endocrine therapy have all been suggested to lead to cardiotoxicity in breast cancer patients. Anthracycline-based chemotherapies have a well-recognized association with cardiomyopathy. Factors associated with increased risk of anthracycline-induced cardiomyopathy include older age, hypertension, pre-existing coronary artery disease, and previous mediastinal radiation.

Early detection of cardiomyopathy may lead to avoidance of irreversible cardiotoxicity, but there are currently no clear guidelines for cardiac screening in breast cancer survivors. If cardiomyopathy is detected, treatment should include beta-blockers and angiotensin-converting enzyme inhibitors as well as modification of other cardiovascular risk factors.¹¹

A SURVIVORSHIP CARE PLAN

There is life beyond the diagnosis of cancer. As patients are living longer, with an estimated 5-year survival rate of 66.5% of all cancers in the United States, there must be a transition of care from the oncologist to the primary care physician.¹ While the oncologist will remain involved in the initial years of follow-up care, these visits will go from twice a year to once a year, and eventually the patient will make a full transition to care by the primary care physician. The timing of this changeover varies from physician to physician, but the primary care physician is ultimately responsible for the follow-up.

A tool to ease this transition is a survivorship care plan. The goal of a survivorship care plan is to individualize a follow-up plan while keeping in mind the necessary surveillance as outlined. These care plans are created with the patient and oncologist and then brought to the primary care physician. While there is an abundance of literature regarding the creation and initiation of survivorship care plans, the success of these plans is uncertain. Ultimately, the goal of a survivorship care plan is to create open dialogue among the oncologist, the primary care physician, and the patient. This unique patient population requires close follow-up by a multidisciplinary team with the primary care physician serving as the steward.

In 2015, about 1.6 million Americans received a diagnosis of cancer.¹ In 2012, when 13.7 million people were living with cancer in the United States, the estimated 5-year survival rate of all cancers was 66.5%.¹ Today, breast, prostate, and colon cancers have 5-year survival rates of 89.4%, 98.9%, and 64.9%, respectively.

With this rising trend in survival, primary care physicians have been steadily assuming the long-term care of these patients. The phrase “cancer survivorship” was coined by the National Comprehensive Cancer Network to describe the experience of living with, through, and beyond a cancer diagnosis.²

As cancer becomes a chronic medical condition, the primary care physician assumes a vital role in the treatment of the unique and evolving needs of this patient population.

This article discusses the specific needs of patients surviving breast, prostate, and colon cancer with special focus on surveillance guidelines for recurrence, development of concomitant malignancies, assessment of psychosocial and physical effects, and disease conditions related to the treatment of cancer itself.

FOLLOW-UP CARE AND SURVEILLANCE

Follow-up care in patients being treated for cancer is vital to survivorship. It includes promoting healthy living, managing treatment side effects, and monitoring for long-term side effects and possible recurrence.

Patients previously treated for malignancy are more susceptible to second primary cancers, for an array of reasons including the effects of prior treatment, shared environmental exposures such as smoking, and genetic susceptibility.² Therefore, it is important for the primary care physician to recognize signs and symptoms and to screen cancer survivors appropriately. The American Society of Clinical Oncology (ASCO) has developed evidence-based recommendations for follow-up care,³ which we review here.

Breast cancer

For breast cancer patients, history and physical examinations are recommended every 3 to 6 months for the first 3 years, every 6 to 12 months in years 4 and 5, and annually thereafter.³

A repeat mammogram should be performed 1 year after the initial mammogram that led to the diagnosis. If the patient underwent radiation therapy, a repeat mammogram of the affected breast should be done 6 months after completion of radiation. Finally, a mammogram should be done every 6 to 12 months thereafter.³ It is also recommended that patients perform a monthly breast self-examination, but this does not replace the annual mammogram.³

Women who are treated with tamoxifen should have an annual gynecologic assessment if they have a uterus and should be encouraged to discuss any abnormal vaginal bleeding with their physician, given the increased risk of uterine cancer.²

ASCO does not recommend routine use of complete blood cell counts, complete metabolic panels, bone scans, chest radiography, computed tomography, ultrasonography, positron-emission tomography, or tumor markers in patients who are asymptomatic.³

Prostate cancer

ASCO’s recommendations for patients recovering from prostate cancer include regular histories and physical examinations and general health promotion. Prostate-specific antigen (PSA) testing is recommended every 6 to 12 months for the first 5 years after treatment and annually thereafter. More frequent PSA testing may be required in men at higher risk of recurrence or in patients who may undergo additional treatment, including radiation and surgery.⁴ Higher risk of disease recurrence is thought to depend on disease-specific factors at the time of original diagnosis including pretreatment PSA, Gleason score, and tumor stage.⁴ This should be discussed between the oncologist and primary care physician.

In regard to digital rectal examinations, the oncologist and primary care physician should jointly determine the frequency of examination. The frequency of digital rectal examinations remains an area of controversy due to their low sensitivity for detecting recurrences. Digital rectal examinations may be omitted in patients with undetectable levels of PSA.⁴

In regard to second primary malignancies, prostate cancer survivors who have undergone pelvic radiation therapy have a slightly higher risk of bladder and colorectal cancer. The lifetime incidence of bladder cancer after pelvic radiation is 5% to 6%, compared with 2.4% in the general population.^1,5 A prostate cancer survivor presenting with hematuria should be referred to a urologist for cystoscopy and evaluation of the upper urinary tract to rule out cancer.⁴

Similarly, patients presenting with rectal bleeding should be referred to a gastroenterologist and the treating radiation oncologist for complete evaluation. The risk of rectal cancer after pelvic radiation therapy increases to about the same level as in someone who has a first-degree relative with colorectal cancer.⁵ Therefore, it is recommended that patients undergo screening for colorectal cancer in conjunction with existing evidence-based guidelines. There is no evidence to suggest that increased intensity of screening improves overall or disease-specific survival.⁴

Colon cancer

In patients with resected colorectal cancer, continued surveillance is important to evaluate for recurrent cancer as well as for metachronous neoplasms. Consensus statements indicate that surveillance colonoscopy should be continued for those who have undergone surgical resection for stage I, II, or III colon or rectal cancers, and for those patients with stage IV who have undergone surgical resection with curative intent.⁶

Patients who undergo curative resection of rectal or colon cancer should have a colonoscopy 1 year after resection or 1 year after the colonoscopy was performed, to clear the colon of synchronous disease. Subsequently, if the colonoscopy done at 1 year is normal, the interval before the next colonoscopy is 3 years. If that colonoscopy is normal, the next colonoscopy is in 5 years. Time intervals may be shorter if there is evidence of hereditary nonpolyposis colorectal cancer or adenoma.

Patients who underwent low anterior resection of rectal cancer should undergo periodic examination of the rectum to evaluate for local recurrence. Although effectiveness is not proven, endoscopic ultrasonography or flexible sigmoidoscopy is suggested at 3- to 6-month intervals for the first 2 to 3 years after resection. This is independent of colonoscopy.^6,7

Additionally, ASCO recommends a history and physical examination and carcinoembryonic antigen testing every 3 to 6 months for the first 5 years. Computed tomography  of the chest, abdomen, and pelvis should be done annually for the first 3 years after the end of treatment.⁷

Maintaining a healthy body weight and a nutritionally balanced diet should be encouraged in all cancer survivors. Poor diet, lack of exercise, excessive alcohol consumption, and smoking reduce quality of life and increase the risk of cancer.²

Diet

Numerous studies have looked at dietary modifications and risk reduction, and although there is no consensus on specific dietary guidelines, there is consensus that diet modification to maintain normal body weight will improve overall quality of life.⁸ Patients should be encouraged to consume a well-balanced diet consisting mostly of fruits, vegetables, whole grains, and beans, and to limit consumption of animal protein.⁸

There is little evidence to support taking vitamins or other dietary supplements to prevent or control cancer or to prevent its recurrence. The primary care physician should assess supplement use on a regular basis during office visits.²

Exercise

Rest is an important component of the initial recovery process. Too much inactivity, however, leads to loss of physical conditioning and muscle strength. This in turn may negatively affect a patient’s ability to perform activities of daily living and may worsen fatigue associated with treatment.

Accordingly, the National Comprehensive Cancer Network recommends at least 150 minutes of moderate activity and up to 75 minutes of more rigorous activity divided throughout the week.^2,8 The regimen should include endurance and muscle strength training, which aid in balance, bone, health, and functional status. The intensity of exercise should be increased in a stepwise fashion, taking into account individual capabilities and limitations.²

Cancer survivors may need specific exercise recommendations and supervised programs to ensure safety and limit long-term side effects of their treatment. For example:

Patients with neuropathy should have their stability, balance, and gait assessed before starting a new program. These patients may benefit from an aerobic exercise program that includes riding a stationary bike rather than running.

Patients with poor bone health should have their fracture risk assessed.

Those with an ostomy bag should empty the bag before physical activity. They should avoid contact sports and activities that increase intra-abdominal pressure.

Patients suffering from lymphedema should wear compression garments when engaging in physical activity. They should undergo baseline and periodic reevaluation of the lymphedema and initiate strength training in the affected body part only if the lymphedema is stable (ie, no need for therapy for 3 months, no recent infections requiring antibiotics, and no change in circumference > 10%).²

Mental health

Health promotion should focus not only on the physical health of the patient, but also on his or her emotional and psychological well-being. As they make the transition from cancer patient to survivor, many individuals may develop or have worsening depression and anxiety due to fear of recurrence. These feelings of powerlessness can linger for years after the initial treatment.

Patients should be screened regularly for signs and symptoms of depression by asking about their family and social support. Referral to support groups, psychologists, and psychiatrists may be warranted.⁹

MITIGATING CANCER-RELATED FATIGUE

Cancer-related fatigue involves a patient’s subjective sense of physical, emotional, and cognitive exhaustion related to cancer or treatment that is disproportionate to that expected from recent daily activity.² Fatigue is a common complaint among survivors and can occur months to years after treatment ends.¹⁰

Patients should be screened for fatigue at regular intervals. The primary care physician should focus the history to include information regarding the onset, pattern, duration, associated factors, assessment of other treatable comorbidities, medications, psychological well-being, nutritional status, and pain level of each patient who complains of fatigue.

Laboratory tests for treatable causes of fatigue include:

• A complete blood cell count to evaluate for anemia
• A comprehensive metabolic panel to evaluate electrolytes, renal function, and hepatic function
• The thyroid-stimulating hormone level to evaluate thyroid function, particularly in breast cancer patients who have received radiation therapy.²

If no organic cause is uncovered, the focus should shift to lifestyle interventions as the treatment of choice. The treatment of fatigue in this situation is increased physical activity with the goals discussed above. Psychological intervention may be required with cognitive behavioral therapy, psychological and supportive therapies, education on sleep hygiene, and possible sleep restriction.

If alternative causes of fatigue are ruled out and physical and psychological support fails to reduce symptoms, the practitioner can consider a psychostimulant such as methylphenidate, but this should be used cautiously.²

SEXUAL DYSFUNCTION

Intimate relationships and sexuality are an important part of life and are affected by a variety of factors including physical health, psychological well-being, body image perception, and overall status of relationships. As a side effect of chemotherapy, cancer survivors may complain of erectile dysfunction, penile shortening, dyspareunia, vaginal dryness, decreased libido, anorgasmy, and changes in body image. These issues are frequently unaddressed, whether due to the physician’s discomfort in discussing the topic or to the patient’s embarrassment and reluctance to discuss the matter.¹¹

Breast cancer patients may experience sexual dysfunction both during and after treatment due to a combination of systemic effects of treatment, changes in physical appearance leading to impaired body image, strains on partner relationships, and psychological sequelae of diagnosis and treatment of cancer.¹² Manipulation and radiation to the breast affect sexual functioning by altering body contour and image. Additionally, chemotherapy can lead to early menopause and hormonal alterations due to endocrine therapies, which can negatively affect sexual organs.¹¹

Studies have shown that treatment with tamoxifen causes less sexual dysfunction than do aromatase inhibitors. In the Arimidex, Tamoxifen, Alone or in Combination trial, therapy with anastrozole was associated with more vaginal dryness, dyspareunia, and decreased libido compared with tamoxifen.¹²

Treatment requires a comprehensive history, a physical examination, and a discussion of relationship satisfaction with the patient.

Vaginal dryness and dyspareunia can be treated with vaginal lubricants and moisturizers. Moisturizers are effective if used multiple times per week, whereas lubricants can be used on demand. Low-dose vaginal estrogen preparations can be used in select patients with severe vaginal dryness; the goal should be discussed. Hormone replacement therapy is contraindicated in breast cancer survivors due to the risk of recurrence.¹¹

Prostate cancer survivors. Up to 70% of men felt their quality of life and sexual function were adversely affected after the diagnosis and treatment.^13,14 Erectile dysfunction following radical prostatectomy and radiation therapy remains one of the leading causes of sexual dysfunction.^14–15 Erectile dysfunction is multifactorial, with both psychogenic and organic causes. Comorbidities must be considered including hypertension, diabetes, hyperlipidemia, and smoking. Early penile rehabilitation is a proposed treatment strategy.¹⁴

First-line therapy for penile rehabilitation includes introduction of daily low-dose phosphodiesterase type 5 inhibitors as early as the time of catheter removal to within the first month after surgery. The need for daily dosing vs on-demand dosing has been controversial.¹⁵ Two large multicenter, double-blind studies had conflicting outcomes. The first reported that in men receiving nightly sildenafil (50 or 100 mg) after radical prostatectomy, 27% had increased return of spontaneous erectile function vs 4% with placebo¹⁶; the second study showed no difference between nightly and on-demand dosing.¹⁷ The consensus is that a phosphodiesterase type 5 inhibitor should be initiated early.

Second-line therapy includes intracavernosal injections and vacuum erection devices. Finally, a penile prosthesis implant can be offered to patients who have responded poorly to medical therapy.¹³

Colorectal cancer survivors suffer from sexually related problems similar to those stated above, including erectile dysfunction, ejaculation problems, dyspareunia, vaginal dryness, and decreased enjoyment.¹⁸ These patients should be provided treatments similar to those described above. In addition, they may suffer from body image issues, particularly those with a permanent ostomy.⁹

Sexual dysfunction is a multifaceted problem for patients. Encouraging couples to discuss sexual intimacy frequently helps to reveal and cope with the problems, whether physical or psychological. It is the primary care physician’s role to recognize any sexual concerns and refer to the appropriate specialist.

Osteoporosis is a metabolic bone disease characterized by low bone mineral density. As a result, bones become weak and fracture more easily from minor injuries.

Risk factors for osteoporosis include female sex, family history, advanced age, low body weight, low calcium and vitamin D levels, sedentary lifestyle, smoking, and low estrogen levels.¹⁹ Cancer treatment places patients at a greater risk for osteoporosis, particularly for those patients with chemotherapy-induced ovarian failure, those treated with aromatase inhibitors, men receiving androgen-deprivation therapy, and patients on glucocorticoid therapy. The morbidity and mortality associated with bone loss can be prevented with appropriate screening, lifestyle changes, and therapy.²

According to the National Osteoporosis Foundation Guideline for Preventing and Treating Osteoporosis, all men and postmenopausal women age 50 and older should be evaluated clinically for osteoporosis risk to determine the need for bone mineral density testing.^2,19 The US Preventive Services Task Force recommends bone mineral density testing in all women age 65 and older, and for women 60 to 64 who are at high risk for bone loss. ASCO agrees, and further suggests bone mineral density screening for women with breast cancer who have risk factors such as positive family history, body weight less than 70 kg, and prior nontraumatic fracture, as well as for postmenopausal women of any age receiving aromatase inhibitors and for premenopausal women with therapy-induced ovarian failure.¹¹

Androgen deprivation therapy is a mainstay of treatment in recurrent and metastatic prostate cancer. The effect is severe hypogonadism with reductions in serum testosterone levels. Androgen deprivation therapy accelerates bone turnover, decreases bone mineral density, and contributes to fracture risk. The National Comprehensive Cancer Network additionally suggests measuring bone mineral density at baseline for all men receiving androgen deprivation therapy or other medications associated with bone loss, repeating it 1 year after androgen deprivation therapy and then every 2 years, or as clinically indicated.²⁰

The gold standard for measuring bone mineral density is dual-energy x-ray absorptiometry. The World Health Organization FRAX tool uses bone mineral density and several clinical factors to estimate the risk of fracture in the next 10 years, which can help guide therapy. Cancer patients with elevated fracture risk should be evaluated every 2 years. Counseling should be provided to address modifiable risk factors such as smoking, alcohol consumption, physical inactivity, and low calcium and vitamin D intake. Therapy should be strongly considered in patients with a bone mineral density below a T-score of –2.0. ^2,19

Treatment begins with lifestyle modifications such as weight-bearing exercises to improve balance and muscle strength and to prevent falls, and adequate intake of calcium (≥ 1,200 mg daily) and vitamin D (800–1,000 IU daily) for adults age 50 and older. Treatment with bisphosphonates may be required.^2,11,20

NEUROPATHY

Many chemotherapeutic agents can lead to neuropathy and can result in long-term disability in patients. Patients treated with taxane- and platinum-based chemotherapy are at particular risk.

Paclitaxel, used in the treatment of breast, ovarian, and lung cancer, can lead to distal neuropathy. This neuropathy commonly has a stocking-and-glove distribution and is primarily sensory; however, it may have motor and autonomic components. The neuropathy typically lessens when the medication is stopped, although in some patients it can persist and lead to long-term disability.

Treatment can include massage. Medications such as gabapentin and pregabalin can also be used, but randomized controlled trials do not support them, as they predominantly treat the tingling rather than the numbness.¹¹

BLADDER AND BOWEL DYSFUNCTION

Urinary incontinence and dysfunction are frequent complications in prostate cancer survivors. Urinary function should be discussed regularly with patients, addressing quality of the urinary stream, difficulty emptying the bladder, timing, and incontinence.⁴ Urinary incontinence is frequently seen in postprostatectomy patients.

The cornerstone of treating urinary incontinence is determining the cause of the incontinence, whether it is stress or urge incontinence, or both.²¹ For those patients with urge incontinence alone, practitioners can address the problem with a combination of behavior modification, pelvic floor exercises, and anticholinergic medications such as oxybutynin. If the problem stems from difficulty initiating or a slow stream, physicians may consider alpha-blockers.^4,21 If the incontinence is persistent, bothersome, and has components of stress incontinence, the patient should be referred to a urologist for urodynamic testing, cystoscopy, and surgical evaluation for possible placement of a male urethral sling or artificial urinary sphincter.²¹

Colorectal cancer survivors, particularly those who received radiation therapy, are at high risk of bowel dysfunction such as chronic diarrhea and stool incontinence. Patients should be educated about this possible side effect. Symptoms of bowel dysfunction can affect body image and interfere with social functioning and overall quality of life. Patients should be provided with coping tools such as antidiarrheal medication, stool bulking agents, changes in diet, and protective underwear.

CARDIOVASCULAR DISEASE

Evidence suggests that certain types of chemotherapy and radiation therapy increase the risk of cardiovascular disease. Prostate cancer survivors treated with androgen deprivation therapy, particularly those more than 75 years old, are at increased risk of cardiovascular disease and diabetes.²²

It is recommended that men be screened with fasting plasma glucose at baseline and yearly thereafter while receiving androgen deprivation therapy. Lipid panel testing should be done 1 year from initiation of androgen deprivation therapy and then, if results are normal, every 5 years or as clinically warranted. The focus should be on primary prevention with emphasis on smoking cessation, treating hypertension per guidelines, lifestyle modifications, and treatment with aspirin and statins when clinically appropriate.²⁰

Radiation therapy, chemotherapy, and endocrine therapy have all been suggested to lead to cardiotoxicity in breast cancer patients. Anthracycline-based chemotherapies have a well-recognized association with cardiomyopathy. Factors associated with increased risk of anthracycline-induced cardiomyopathy include older age, hypertension, pre-existing coronary artery disease, and previous mediastinal radiation.

Early detection of cardiomyopathy may lead to avoidance of irreversible cardiotoxicity, but there are currently no clear guidelines for cardiac screening in breast cancer survivors. If cardiomyopathy is detected, treatment should include beta-blockers and angiotensin-converting enzyme inhibitors as well as modification of other cardiovascular risk factors.¹¹

A SURVIVORSHIP CARE PLAN

There is life beyond the diagnosis of cancer. As patients are living longer, with an estimated 5-year survival rate of 66.5% of all cancers in the United States, there must be a transition of care from the oncologist to the primary care physician.¹ While the oncologist will remain involved in the initial years of follow-up care, these visits will go from twice a year to once a year, and eventually the patient will make a full transition to care by the primary care physician. The timing of this changeover varies from physician to physician, but the primary care physician is ultimately responsible for the follow-up.

A tool to ease this transition is a survivorship care plan. The goal of a survivorship care plan is to individualize a follow-up plan while keeping in mind the necessary surveillance as outlined. These care plans are created with the patient and oncologist and then brought to the primary care physician. While there is an abundance of literature regarding the creation and initiation of survivorship care plans, the success of these plans is uncertain. Ultimately, the goal of a survivorship care plan is to create open dialogue among the oncologist, the primary care physician, and the patient. This unique patient population requires close follow-up by a multidisciplinary team with the primary care physician serving as the steward.

In 2015, about 1.6 million Americans received a diagnosis of cancer.¹ In 2012, when 13.7 million people were living with cancer in the United States, the estimated 5-year survival rate of all cancers was 66.5%.¹ Today, breast, prostate, and colon cancers have 5-year survival rates of 89.4%, 98.9%, and 64.9%, respectively.

With this rising trend in survival, primary care physicians have been steadily assuming the long-term care of these patients. The phrase “cancer survivorship” was coined by the National Comprehensive Cancer Network to describe the experience of living with, through, and beyond a cancer diagnosis.²

As cancer becomes a chronic medical condition, the primary care physician assumes a vital role in the treatment of the unique and evolving needs of this patient population.

This article discusses the specific needs of patients surviving breast, prostate, and colon cancer with special focus on surveillance guidelines for recurrence, development of concomitant malignancies, assessment of psychosocial and physical effects, and disease conditions related to the treatment of cancer itself.

FOLLOW-UP CARE AND SURVEILLANCE

Follow-up care in patients being treated for cancer is vital to survivorship. It includes promoting healthy living, managing treatment side effects, and monitoring for long-term side effects and possible recurrence.

Patients previously treated for malignancy are more susceptible to second primary cancers, for an array of reasons including the effects of prior treatment, shared environmental exposures such as smoking, and genetic susceptibility.² Therefore, it is important for the primary care physician to recognize signs and symptoms and to screen cancer survivors appropriately. The American Society of Clinical Oncology (ASCO) has developed evidence-based recommendations for follow-up care,³ which we review here.

Breast cancer

For breast cancer patients, history and physical examinations are recommended every 3 to 6 months for the first 3 years, every 6 to 12 months in years 4 and 5, and annually thereafter.³

A repeat mammogram should be performed 1 year after the initial mammogram that led to the diagnosis. If the patient underwent radiation therapy, a repeat mammogram of the affected breast should be done 6 months after completion of radiation. Finally, a mammogram should be done every 6 to 12 months thereafter.³ It is also recommended that patients perform a monthly breast self-examination, but this does not replace the annual mammogram.³

Women who are treated with tamoxifen should have an annual gynecologic assessment if they have a uterus and should be encouraged to discuss any abnormal vaginal bleeding with their physician, given the increased risk of uterine cancer.²

ASCO does not recommend routine use of complete blood cell counts, complete metabolic panels, bone scans, chest radiography, computed tomography, ultrasonography, positron-emission tomography, or tumor markers in patients who are asymptomatic.³

Prostate cancer

ASCO’s recommendations for patients recovering from prostate cancer include regular histories and physical examinations and general health promotion. Prostate-specific antigen (PSA) testing is recommended every 6 to 12 months for the first 5 years after treatment and annually thereafter. More frequent PSA testing may be required in men at higher risk of recurrence or in patients who may undergo additional treatment, including radiation and surgery.⁴ Higher risk of disease recurrence is thought to depend on disease-specific factors at the time of original diagnosis including pretreatment PSA, Gleason score, and tumor stage.⁴ This should be discussed between the oncologist and primary care physician.

In regard to digital rectal examinations, the oncologist and primary care physician should jointly determine the frequency of examination. The frequency of digital rectal examinations remains an area of controversy due to their low sensitivity for detecting recurrences. Digital rectal examinations may be omitted in patients with undetectable levels of PSA.⁴

In regard to second primary malignancies, prostate cancer survivors who have undergone pelvic radiation therapy have a slightly higher risk of bladder and colorectal cancer. The lifetime incidence of bladder cancer after pelvic radiation is 5% to 6%, compared with 2.4% in the general population.^1,5 A prostate cancer survivor presenting with hematuria should be referred to a urologist for cystoscopy and evaluation of the upper urinary tract to rule out cancer.⁴

Similarly, patients presenting with rectal bleeding should be referred to a gastroenterologist and the treating radiation oncologist for complete evaluation. The risk of rectal cancer after pelvic radiation therapy increases to about the same level as in someone who has a first-degree relative with colorectal cancer.⁵ Therefore, it is recommended that patients undergo screening for colorectal cancer in conjunction with existing evidence-based guidelines. There is no evidence to suggest that increased intensity of screening improves overall or disease-specific survival.⁴

Colon cancer

In patients with resected colorectal cancer, continued surveillance is important to evaluate for recurrent cancer as well as for metachronous neoplasms. Consensus statements indicate that surveillance colonoscopy should be continued for those who have undergone surgical resection for stage I, II, or III colon or rectal cancers, and for those patients with stage IV who have undergone surgical resection with curative intent.⁶

Patients who undergo curative resection of rectal or colon cancer should have a colonoscopy 1 year after resection or 1 year after the colonoscopy was performed, to clear the colon of synchronous disease. Subsequently, if the colonoscopy done at 1 year is normal, the interval before the next colonoscopy is 3 years. If that colonoscopy is normal, the next colonoscopy is in 5 years. Time intervals may be shorter if there is evidence of hereditary nonpolyposis colorectal cancer or adenoma.

Patients who underwent low anterior resection of rectal cancer should undergo periodic examination of the rectum to evaluate for local recurrence. Although effectiveness is not proven, endoscopic ultrasonography or flexible sigmoidoscopy is suggested at 3- to 6-month intervals for the first 2 to 3 years after resection. This is independent of colonoscopy.^6,7

Additionally, ASCO recommends a history and physical examination and carcinoembryonic antigen testing every 3 to 6 months for the first 5 years. Computed tomography  of the chest, abdomen, and pelvis should be done annually for the first 3 years after the end of treatment.⁷

Maintaining a healthy body weight and a nutritionally balanced diet should be encouraged in all cancer survivors. Poor diet, lack of exercise, excessive alcohol consumption, and smoking reduce quality of life and increase the risk of cancer.²

Diet

Numerous studies have looked at dietary modifications and risk reduction, and although there is no consensus on specific dietary guidelines, there is consensus that diet modification to maintain normal body weight will improve overall quality of life.⁸ Patients should be encouraged to consume a well-balanced diet consisting mostly of fruits, vegetables, whole grains, and beans, and to limit consumption of animal protein.⁸

There is little evidence to support taking vitamins or other dietary supplements to prevent or control cancer or to prevent its recurrence. The primary care physician should assess supplement use on a regular basis during office visits.²

Exercise

Rest is an important component of the initial recovery process. Too much inactivity, however, leads to loss of physical conditioning and muscle strength. This in turn may negatively affect a patient’s ability to perform activities of daily living and may worsen fatigue associated with treatment.

Accordingly, the National Comprehensive Cancer Network recommends at least 150 minutes of moderate activity and up to 75 minutes of more rigorous activity divided throughout the week.^2,8 The regimen should include endurance and muscle strength training, which aid in balance, bone, health, and functional status. The intensity of exercise should be increased in a stepwise fashion, taking into account individual capabilities and limitations.²

Cancer survivors may need specific exercise recommendations and supervised programs to ensure safety and limit long-term side effects of their treatment. For example:

Patients with neuropathy should have their stability, balance, and gait assessed before starting a new program. These patients may benefit from an aerobic exercise program that includes riding a stationary bike rather than running.

Patients with poor bone health should have their fracture risk assessed.

Those with an ostomy bag should empty the bag before physical activity. They should avoid contact sports and activities that increase intra-abdominal pressure.

Patients suffering from lymphedema should wear compression garments when engaging in physical activity. They should undergo baseline and periodic reevaluation of the lymphedema and initiate strength training in the affected body part only if the lymphedema is stable (ie, no need for therapy for 3 months, no recent infections requiring antibiotics, and no change in circumference > 10%).²

Mental health

Health promotion should focus not only on the physical health of the patient, but also on his or her emotional and psychological well-being. As they make the transition from cancer patient to survivor, many individuals may develop or have worsening depression and anxiety due to fear of recurrence. These feelings of powerlessness can linger for years after the initial treatment.

Patients should be screened regularly for signs and symptoms of depression by asking about their family and social support. Referral to support groups, psychologists, and psychiatrists may be warranted.⁹

MITIGATING CANCER-RELATED FATIGUE

Cancer-related fatigue involves a patient’s subjective sense of physical, emotional, and cognitive exhaustion related to cancer or treatment that is disproportionate to that expected from recent daily activity.² Fatigue is a common complaint among survivors and can occur months to years after treatment ends.¹⁰

Patients should be screened for fatigue at regular intervals. The primary care physician should focus the history to include information regarding the onset, pattern, duration, associated factors, assessment of other treatable comorbidities, medications, psychological well-being, nutritional status, and pain level of each patient who complains of fatigue.

Laboratory tests for treatable causes of fatigue include:

• A complete blood cell count to evaluate for anemia
• A comprehensive metabolic panel to evaluate electrolytes, renal function, and hepatic function
• The thyroid-stimulating hormone level to evaluate thyroid function, particularly in breast cancer patients who have received radiation therapy.²

If no organic cause is uncovered, the focus should shift to lifestyle interventions as the treatment of choice. The treatment of fatigue in this situation is increased physical activity with the goals discussed above. Psychological intervention may be required with cognitive behavioral therapy, psychological and supportive therapies, education on sleep hygiene, and possible sleep restriction.

If alternative causes of fatigue are ruled out and physical and psychological support fails to reduce symptoms, the practitioner can consider a psychostimulant such as methylphenidate, but this should be used cautiously.²

SEXUAL DYSFUNCTION

Intimate relationships and sexuality are an important part of life and are affected by a variety of factors including physical health, psychological well-being, body image perception, and overall status of relationships. As a side effect of chemotherapy, cancer survivors may complain of erectile dysfunction, penile shortening, dyspareunia, vaginal dryness, decreased libido, anorgasmy, and changes in body image. These issues are frequently unaddressed, whether due to the physician’s discomfort in discussing the topic or to the patient’s embarrassment and reluctance to discuss the matter.¹¹

Breast cancer patients may experience sexual dysfunction both during and after treatment due to a combination of systemic effects of treatment, changes in physical appearance leading to impaired body image, strains on partner relationships, and psychological sequelae of diagnosis and treatment of cancer.¹² Manipulation and radiation to the breast affect sexual functioning by altering body contour and image. Additionally, chemotherapy can lead to early menopause and hormonal alterations due to endocrine therapies, which can negatively affect sexual organs.¹¹

Studies have shown that treatment with tamoxifen causes less sexual dysfunction than do aromatase inhibitors. In the Arimidex, Tamoxifen, Alone or in Combination trial, therapy with anastrozole was associated with more vaginal dryness, dyspareunia, and decreased libido compared with tamoxifen.¹²

Treatment requires a comprehensive history, a physical examination, and a discussion of relationship satisfaction with the patient.

Vaginal dryness and dyspareunia can be treated with vaginal lubricants and moisturizers. Moisturizers are effective if used multiple times per week, whereas lubricants can be used on demand. Low-dose vaginal estrogen preparations can be used in select patients with severe vaginal dryness; the goal should be discussed. Hormone replacement therapy is contraindicated in breast cancer survivors due to the risk of recurrence.¹¹

Prostate cancer survivors. Up to 70% of men felt their quality of life and sexual function were adversely affected after the diagnosis and treatment.^13,14 Erectile dysfunction following radical prostatectomy and radiation therapy remains one of the leading causes of sexual dysfunction.^14–15 Erectile dysfunction is multifactorial, with both psychogenic and organic causes. Comorbidities must be considered including hypertension, diabetes, hyperlipidemia, and smoking. Early penile rehabilitation is a proposed treatment strategy.¹⁴

First-line therapy for penile rehabilitation includes introduction of daily low-dose phosphodiesterase type 5 inhibitors as early as the time of catheter removal to within the first month after surgery. The need for daily dosing vs on-demand dosing has been controversial.¹⁵ Two large multicenter, double-blind studies had conflicting outcomes. The first reported that in men receiving nightly sildenafil (50 or 100 mg) after radical prostatectomy, 27% had increased return of spontaneous erectile function vs 4% with placebo¹⁶; the second study showed no difference between nightly and on-demand dosing.¹⁷ The consensus is that a phosphodiesterase type 5 inhibitor should be initiated early.

Second-line therapy includes intracavernosal injections and vacuum erection devices. Finally, a penile prosthesis implant can be offered to patients who have responded poorly to medical therapy.¹³

Colorectal cancer survivors suffer from sexually related problems similar to those stated above, including erectile dysfunction, ejaculation problems, dyspareunia, vaginal dryness, and decreased enjoyment.¹⁸ These patients should be provided treatments similar to those described above. In addition, they may suffer from body image issues, particularly those with a permanent ostomy.⁹

Sexual dysfunction is a multifaceted problem for patients. Encouraging couples to discuss sexual intimacy frequently helps to reveal and cope with the problems, whether physical or psychological. It is the primary care physician’s role to recognize any sexual concerns and refer to the appropriate specialist.

Osteoporosis is a metabolic bone disease characterized by low bone mineral density. As a result, bones become weak and fracture more easily from minor injuries.

Risk factors for osteoporosis include female sex, family history, advanced age, low body weight, low calcium and vitamin D levels, sedentary lifestyle, smoking, and low estrogen levels.¹⁹ Cancer treatment places patients at a greater risk for osteoporosis, particularly for those patients with chemotherapy-induced ovarian failure, those treated with aromatase inhibitors, men receiving androgen-deprivation therapy, and patients on glucocorticoid therapy. The morbidity and mortality associated with bone loss can be prevented with appropriate screening, lifestyle changes, and therapy.²

According to the National Osteoporosis Foundation Guideline for Preventing and Treating Osteoporosis, all men and postmenopausal women age 50 and older should be evaluated clinically for osteoporosis risk to determine the need for bone mineral density testing.^2,19 The US Preventive Services Task Force recommends bone mineral density testing in all women age 65 and older, and for women 60 to 64 who are at high risk for bone loss. ASCO agrees, and further suggests bone mineral density screening for women with breast cancer who have risk factors such as positive family history, body weight less than 70 kg, and prior nontraumatic fracture, as well as for postmenopausal women of any age receiving aromatase inhibitors and for premenopausal women with therapy-induced ovarian failure.¹¹

Androgen deprivation therapy is a mainstay of treatment in recurrent and metastatic prostate cancer. The effect is severe hypogonadism with reductions in serum testosterone levels. Androgen deprivation therapy accelerates bone turnover, decreases bone mineral density, and contributes to fracture risk. The National Comprehensive Cancer Network additionally suggests measuring bone mineral density at baseline for all men receiving androgen deprivation therapy or other medications associated with bone loss, repeating it 1 year after androgen deprivation therapy and then every 2 years, or as clinically indicated.²⁰

The gold standard for measuring bone mineral density is dual-energy x-ray absorptiometry. The World Health Organization FRAX tool uses bone mineral density and several clinical factors to estimate the risk of fracture in the next 10 years, which can help guide therapy. Cancer patients with elevated fracture risk should be evaluated every 2 years. Counseling should be provided to address modifiable risk factors such as smoking, alcohol consumption, physical inactivity, and low calcium and vitamin D intake. Therapy should be strongly considered in patients with a bone mineral density below a T-score of –2.0. ^2,19

Treatment begins with lifestyle modifications such as weight-bearing exercises to improve balance and muscle strength and to prevent falls, and adequate intake of calcium (≥ 1,200 mg daily) and vitamin D (800–1,000 IU daily) for adults age 50 and older. Treatment with bisphosphonates may be required.^2,11,20

NEUROPATHY

Many chemotherapeutic agents can lead to neuropathy and can result in long-term disability in patients. Patients treated with taxane- and platinum-based chemotherapy are at particular risk.

Paclitaxel, used in the treatment of breast, ovarian, and lung cancer, can lead to distal neuropathy. This neuropathy commonly has a stocking-and-glove distribution and is primarily sensory; however, it may have motor and autonomic components. The neuropathy typically lessens when the medication is stopped, although in some patients it can persist and lead to long-term disability.

Treatment can include massage. Medications such as gabapentin and pregabalin can also be used, but randomized controlled trials do not support them, as they predominantly treat the tingling rather than the numbness.¹¹

BLADDER AND BOWEL DYSFUNCTION

Urinary incontinence and dysfunction are frequent complications in prostate cancer survivors. Urinary function should be discussed regularly with patients, addressing quality of the urinary stream, difficulty emptying the bladder, timing, and incontinence.⁴ Urinary incontinence is frequently seen in postprostatectomy patients.

The cornerstone of treating urinary incontinence is determining the cause of the incontinence, whether it is stress or urge incontinence, or both.²¹ For those patients with urge incontinence alone, practitioners can address the problem with a combination of behavior modification, pelvic floor exercises, and anticholinergic medications such as oxybutynin. If the problem stems from difficulty initiating or a slow stream, physicians may consider alpha-blockers.^4,21 If the incontinence is persistent, bothersome, and has components of stress incontinence, the patient should be referred to a urologist for urodynamic testing, cystoscopy, and surgical evaluation for possible placement of a male urethral sling or artificial urinary sphincter.²¹

Colorectal cancer survivors, particularly those who received radiation therapy, are at high risk of bowel dysfunction such as chronic diarrhea and stool incontinence. Patients should be educated about this possible side effect. Symptoms of bowel dysfunction can affect body image and interfere with social functioning and overall quality of life. Patients should be provided with coping tools such as antidiarrheal medication, stool bulking agents, changes in diet, and protective underwear.

CARDIOVASCULAR DISEASE

Evidence suggests that certain types of chemotherapy and radiation therapy increase the risk of cardiovascular disease. Prostate cancer survivors treated with androgen deprivation therapy, particularly those more than 75 years old, are at increased risk of cardiovascular disease and diabetes.²²

It is recommended that men be screened with fasting plasma glucose at baseline and yearly thereafter while receiving androgen deprivation therapy. Lipid panel testing should be done 1 year from initiation of androgen deprivation therapy and then, if results are normal, every 5 years or as clinically warranted. The focus should be on primary prevention with emphasis on smoking cessation, treating hypertension per guidelines, lifestyle modifications, and treatment with aspirin and statins when clinically appropriate.²⁰

Radiation therapy, chemotherapy, and endocrine therapy have all been suggested to lead to cardiotoxicity in breast cancer patients. Anthracycline-based chemotherapies have a well-recognized association with cardiomyopathy. Factors associated with increased risk of anthracycline-induced cardiomyopathy include older age, hypertension, pre-existing coronary artery disease, and previous mediastinal radiation.

Early detection of cardiomyopathy may lead to avoidance of irreversible cardiotoxicity, but there are currently no clear guidelines for cardiac screening in breast cancer survivors. If cardiomyopathy is detected, treatment should include beta-blockers and angiotensin-converting enzyme inhibitors as well as modification of other cardiovascular risk factors.¹¹

A SURVIVORSHIP CARE PLAN

There is life beyond the diagnosis of cancer. As patients are living longer, with an estimated 5-year survival rate of 66.5% of all cancers in the United States, there must be a transition of care from the oncologist to the primary care physician.¹ While the oncologist will remain involved in the initial years of follow-up care, these visits will go from twice a year to once a year, and eventually the patient will make a full transition to care by the primary care physician. The timing of this changeover varies from physician to physician, but the primary care physician is ultimately responsible for the follow-up.

A tool to ease this transition is a survivorship care plan. The goal of a survivorship care plan is to individualize a follow-up plan while keeping in mind the necessary surveillance as outlined. These care plans are created with the patient and oncologist and then brought to the primary care physician. While there is an abundance of literature regarding the creation and initiation of survivorship care plans, the success of these plans is uncertain. Ultimately, the goal of a survivorship care plan is to create open dialogue among the oncologist, the primary care physician, and the patient. This unique patient population requires close follow-up by a multidisciplinary team with the primary care physician serving as the steward.

The incidence of maternal asthma is rising. Based on US national health surveys, the prevalence of asthma during pregnancy is between 3.7% and 8.4%.¹ It is the most common respiratory illness of pregnancy.² Hence, clinicians need to know how asthma affects the mother and the fetus. Appropriate care of asthma during pregnancy is based on several management principles, as reviewed here, and is key to ensuring good outcomes for the mother and the baby.

EFFECT OF PREGNANCY ON ASTHMA CONTROL

Asthma control can vary in pregnancy. About a third of asthmatic women experience a worsening of asthma control with pregnancy, a third remain unchanged, and another third have improvement in asthma symptoms.³ The peak worsening of asthma tends to occur in the sixth month.⁴ Asthma control also tends to be better in the last month of pregnancy.³

The peak expiratory flow rate was noted to increase with each trimester in a small study of 43 women.⁵ The authors speculated that a rising progesterone level stimulates cyclic adenosine monophosphate to cause bronchodilation, thereby improving the expiratory flow rate and asthma control. Asthma control tends to follow the pattern experienced in the previous pregnancy: ie, if asthma worsened during the previous pregnancy, the same will be likely in the subsequent pregnancy.³

Two maternal factors that adversely affect asthma severity during pregnancy are the use of asthma medications contrary to guidelines such as those of the Global Initiative for Asthma (http://ginasthma.org/2017-gina-report-global-strategy-for-asthma-management-and-prevention) and inadquate control of asthma before becoming pregnant.⁶ Pregnancy can bring on stress, and stress is known to worsen asthma. In addition, when patients themselves were interviewed to elucidate the reasons for poor adherence to asthma medications during pregnancy, concerns about medication use, especially corticosteroids, stood out.⁷ A study based on prescription claims data showed that in the first trimester, there was a significant decline in asthma prescription medications (a 23% decline in inhaled corticosteroids, a 13% decline in short-acting bronchodilator agents, and a 54% decline in rescue corticosteroids).⁸ Lack of physician education about management of asthma in pregnancy and discomfort with prescribing to pregnant women also affect asthma control.

EFFECT OF ASTHMA ON MATERNAL AND FETAL OUTCOMES

Studies of the effects of asthma on fetal and maternal outcomes have yielded mixed and conflicting results.⁹ Adverse outcomes that have been shown to be associated with maternal asthma are listed in Table 1. Other studies have not demonstrated an association between asthma in pregnancy and maternal or fetal adverse events.⁹ Such discrepant findings are due to differences in study population characteristics that make comparisons difficult. A meta-analysis involving more than 1.6 million asthmatic women showed maternal asthma was associated with a 40% greater risk of low birth weight and preterm delivery, a 50% greater risk of preeclampsia, and a 20% greater risk of the baby being small for its gestational age.¹⁰

The association of maternal asthma and preterm birth may pose short-term and long-term health risks to the child associated with prematurity.⁹ Short-term risks with prematurity include infection, respiratory distress syndrome, brain injury, and necrotizing enterocolitis. Long-term risks include neuro­developmental and behavioral sequelae. Furthermore, asthma exacerbations during pregnancy are associated with a twofold higher risk of low birth weight.¹¹ The benefits of good adherence to asthma regimens during pregnancy outweigh the risks associated with frequent symptoms and exacerbations caused by untreated asthma.¹²

OUTPATIENT MANAGEMENT OF MATERNAL ASTHMA

Goals

In the 2004 update of the National Asthma Education and Prevention Program (NAEPP) Working Group Report on Managing Asthma During Pregnancy, goals focused mainly on adequate asthma control for maternal health and quality of life, as well as normal fetal maturation (Table 2),¹² goals similar to those in nonpregnant asthmatic women.

Assessment and monitoring

Monthly physician visits during pregnancy are recommended for assessment of symptoms and pulmonary function. If symptoms are uncontrolled, therapy must be stepped up, and any trigger for exacerbation, such as gastroesophageal reflux disease (GERD), exposure, or rhinitis, must be treated and eliminated. NAEPP guidelines recommend baseline spirometry at the time of initial assessment.¹² At follow-up visits, spirometry is preferred, but measurement of the peak expiratory flow rate usually suffices. Such objective data can help differentiate dyspnea from asthma and from dyspnea that usually accompanies the physiologic changes of pregnancy. In addition, patients should be advised to monitor for adequate fetal activity. If asthma is uncontrolled or poorly controlled, serial fetal ultrasonography should be considered from 32 weeks of gestation, as well as after recovery from an asthma exacerbation. Regular monitoring of the pregnant asthmatic patient by a multidisciplinary team can improve outcomes.¹³

Avoiding triggers

Patients should be advised to avoid asthma triggers such as pet dander, dust mites, pollen, smoke, mold, and perfumes, as this can decrease symptoms and allow for use of lower doses of medications.¹² Additionally, smoking cessation must be strongly encouraged, not only to control maternal asthma, but also to prevent harm to the fetus.

MANAGEMENT OF SPECIFIC TRIGGERS

GERD

Reflux disease often worsens during pregnancy, and it can coexist with asthma and can also exacerbate it.¹⁴ Optimal control of GERD helps maintain adequate asthma control. For mild reflux symptoms, lifestyle modifications such as elevating the head of bed, avoiding eating too close to bedtime, and avoiding foods that cause heartburn may be adequate.^15,16 If medications are needed, antacids (but not sodium bicarbonate, for fear of metabolic alkalosis) and sucralfate should be considered before using a histamine 2 receptor antagonist such as ranitidine. Proton pump inhibitors should be considered only if reflux symptoms are refractory to other therapies.

Allergic rhinitis

Intranasal corticosteroids are effective against allergic rhinitis in pregnancy (Table 3).¹² Montelukast, a leukotriene receptor antagonist, can be used, but data to support its use for allergic rhinitis in pregnancy are limited.

Among antihistamines, second-generation drugs such as cetirizine or loratadine can be considered.¹² Oral decongestants such as pseudoephedrine in early pregnancy are associated with a rare congenital fetal abnormality called gastroschisis, caused by vascular disruption.¹⁷ Hence, if a nasal decongestant is required in early pregnancy, a local therapy such as an intranasal corticosteroid, short-term oxymetazoline, or an external nasal dilator may be considered.¹² These therapies must be combined with avoidance of allergens whenever possible.

Allergies

Diagnostic allergy and skin tests during pregnancy pose a risk of anaphylaxis and thus should be avoided. Instead, the focus should be on obtaining a thorough medical history about exposures and eliminating specific asthma triggers. It is also inadvisable to start allergen immunotherapy during pregnancy because of the risk of anaphylaxis and the effect of treatment on the mother and fetus.¹⁸ However, maintenance doses of allergen immunotherapy can be continued during pregnancy.¹⁸

Patient education

Because of concern about the risks of taking medications during pregnancy, many women with asthma stop using their inhalers during pregnancy, thus compromising asthma control.^8,13 The physician and multidisciplinary team must use every opportunity to emphasize the importance of good asthma control during pregnancy. Inhaler technique should also be reviewed and, if defective, corrected. Again, trigger avoidance and tobacco cessation should be addressed.

Drugs

The NAEPP recommendations state that asthma therapy should be continued during pregnancy, as it is safer both for mother and fetus to avoid exacerbations and uncontrolled asthma.¹² Despite this, 25% of primary care physicians instruct their patients to decrease or discontinue their inhaled corticosteroid during pregnancy.¹⁹ As with asthma in general, treatment should involve using the lowest dose of drugs that achieves adequate control of symptoms.

In 2015, the US Food and Drug Administration (FDA) amended the labeling rule for medications used in pregnancy and lactation. The previous risk categories A (safest), B, C, D, and X (highest risk) are in the process of being removed from labels for all human prescription drugs and biologic products, to be replaced with a summary of the risks of taking the drug during pregnancy and lactation, a discussion of the data supporting the use, and relevant information to help healthcare providers make prescribing decisions and counsel women about the use of drugs during pregnancy and lactation (www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm093307.htm).

ROLES OF CONTROLLER THERAPY AND RESCUE THERAPY

Inhaled corticosteroids

Inhaled corticosteroids are the mainstay of asthma controller therapy during pregnancy. A meta-analysis of 16 studies showed no increased risk of congenital malformations, cesarean delivery, or stillbirth among mothers who used these agents during pregnancy.²⁰ Because there are more safety data for budesonide, it is currently the preferred inhaled corticosteroid during pregnancy.⁹ However, if a patient’s asthma is controlled with a different corticosteroid before pregnancy, that agent may be continued during pregnancy, especially if it is thought that switching formulations could adversely affect asthma control.¹² This is mainly because current data do not prove that other inhaled corticosteroids are unsafe.

Inhaled beta-agonists

Inhaled beta-agonists, both short-acting and long-acting, are used for rescue therapy. Al­buterol is the preferred short-acting agent for rescue therapy in pregnant women with asthma.¹² Meta-analysis has shown no increased risk of major or minor congenital malformations in pregnant patients who use bronchodilators.²⁰ Long-acting beta-agonists typically are used as add-on therapy when asthma cannot be controlled by an inhaled corticosteroid. They should not be used without a controller medication (ie, an inhaled corticosteroid).

Guidelines for rescue therapy are similar to those for nonpregnant asthmatic patients. Although data are limited as to the gestational effects of long-acting beta-agonists (ie, formoterol, salmeterol), it can be assumed that the toxicologic and pharmacologic profiles are similar to those of the short-acting bronchodilators. Thus, the safety of albuterol can be extended potentially to the long-acting beta-agonists.¹²

Combining controller and rescue therapy

When asthma is not adequately controlled on inhaled corticosteroids, a long-acting beta-agonist can be added or the dose of corticosteroid can be increased. The 2004 NAEPP guidelines stated that based on available literature, there was no clear advantage of one option over the other.¹² A study that compared the 2 approaches found no difference in rates of congenital malformations.²¹

Leukotriene receptor antagonists

There is little in the literature regarding the use of leukotriene receptor antagonists during pregnancy. However, animal safety data are reassuring,¹² and human studies have not found a higher risk of major congenital malformations.^22,23 Thus, they are an alternative for patients whose asthma has been well controlled on these agents before pregnancy. Montelukast and zafirlukast are in former FDA pregnancy risk factor category B (probably safe) (Table 3). However, 5-lipoxygenase inhibitors such as zileuton are contraindicated based on animal studies showing teratogenicity.²⁴

Omalizumab

Omalizumab, a recombinant anti-immunoglobulin E antibody, can be used for allergic asthma not controlled with inhaled corticosteroids (Table 3). An analysis of the omalizumab pregnancy registry²⁵ found no significant increase in the rate of major congenital malformations, prematurity, or babies small for gestational age in asthmatic women taking omalizumab 8 weeks before conception or during pregnancy vs pregnant asthmatic women not taking omalizumab. However, this drug carries a risk of anaphylaxis and so should not be started during pregnancy.²⁵

Theophylline

Because of potential toxicity, use of theophylline during pregnancy requires careful monitoring to ensure the serum concentration remains between 5 and 12 µg/mL.¹² Drug interactions are also common: for example, alcohol may increase the serum concentration of theophylline, and theophylline may increase the toxic effect of formoterol.

Systemic corticosteroids

Pregnant women with asthma that is not well controlled despite the therapies described above may require a daily oral corticosteroid such as prednisone to achieve adequate control. Oral steroids are also a mainstay of treatment of asthma exacerbation.

Although use of corticosteroids in the first trimester was associated with orofacial cleft in infants,¹² these studies did not include many women with asthma. In 2011, a nationwide cohort study from Denmark showed no increase in the risk of orofacial cleft with the use of corticosteroids during pregnancy.²⁶

Preeclampsia, low birth weight, and preterm delivery have been described with corticosteroid use in pregnancy. It is not known whether these problems were a result of corticosteroid use or were due to the uncontrolled nature of the underlying condition that led to the steroid use. Since the risk of uncontrolled asthma to mother and fetus outweighs the risk of systemic corticosteroids, these drugs are recommended when indicated for management of maternal asthma.¹²

ACUTE EXACERBATIONS REQUIRE AGGRESSIVE MANAGEMENT

Based on a systematic review, 20% of pregnant women with asthma require some intervention for an asthma exacerbation during pregnancy, and 5.8% are admitted to the hospital for an exacerbation.¹¹ Exacerbations were associated with a higher risk of low birth weight compared with rates in women without asthma.

Exacerbations are more common late in the second trimester and are unlikely to occur during labor and delivery.²  The incidence of exacerbations increases with the severity of asthma, from 8% in mild asthma, to 47% in moderate asthma, to 65% in severe asthma.²⁷ Risk factors for exacerbations include poor prenatal care, obesity, and lack of appropriate treatment with inhaled corticosteroids.² The main triggers are viral respiratory infections and noncompliance with inhaled corticosteroid therapy.¹¹

Asthma exacerbations during pregnancy should be managed aggressively (Table 4),¹² as the risk to the fetus of hypoxia far outweighs any risk from asthma medications. Close collaboration between the primary care physician and the obstetrician allows closer monitoring of mother and fetus.

The goal oxygen saturation must be above 95%.¹² Signs of acute respiratory failure in a pregnant patient include a partial pressure of arterial oxygen less than 70 mm Hg or a partial pressure of carbon dioxide greater than 35 mm Hg.

In a multicenter study comparing nonpregnant and pregnant women visiting the emergency room for asthma exacerbations,²⁸ pregnant women were less likely to be prescribed systemic corticosteroids either in the emergency room or at the time of hospital discharge, and they were also more likely to describe an ongoing exacerbation at 2-week follow-up. However, a recent study showed a significant increase in systemic corticosteroid treatment in the emergency room (51% to 78% across the time periods, odds ratio 3.11, 95% confidence interval 1.27–7.60, P = .01). There was also an increase in steroid treatment at discharge (42% to 63%, odds ratio 2.49, 95% confidence interval 0.97–6.37, P = .054), though the increase was not statistically significant.²⁹ Although emergency room care for pregnant asthmatic women has improved, this group concluded that further improvement is still warranted, as 1 in 3 women is discharged without corticosteroid treatment.

The incidence of maternal asthma is rising. Based on US national health surveys, the prevalence of asthma during pregnancy is between 3.7% and 8.4%.¹ It is the most common respiratory illness of pregnancy.² Hence, clinicians need to know how asthma affects the mother and the fetus. Appropriate care of asthma during pregnancy is based on several management principles, as reviewed here, and is key to ensuring good outcomes for the mother and the baby.

EFFECT OF PREGNANCY ON ASTHMA CONTROL

Asthma control can vary in pregnancy. About a third of asthmatic women experience a worsening of asthma control with pregnancy, a third remain unchanged, and another third have improvement in asthma symptoms.³ The peak worsening of asthma tends to occur in the sixth month.⁴ Asthma control also tends to be better in the last month of pregnancy.³

The peak expiratory flow rate was noted to increase with each trimester in a small study of 43 women.⁵ The authors speculated that a rising progesterone level stimulates cyclic adenosine monophosphate to cause bronchodilation, thereby improving the expiratory flow rate and asthma control. Asthma control tends to follow the pattern experienced in the previous pregnancy: ie, if asthma worsened during the previous pregnancy, the same will be likely in the subsequent pregnancy.³

Two maternal factors that adversely affect asthma severity during pregnancy are the use of asthma medications contrary to guidelines such as those of the Global Initiative for Asthma (http://ginasthma.org/2017-gina-report-global-strategy-for-asthma-management-and-prevention) and inadquate control of asthma before becoming pregnant.⁶ Pregnancy can bring on stress, and stress is known to worsen asthma. In addition, when patients themselves were interviewed to elucidate the reasons for poor adherence to asthma medications during pregnancy, concerns about medication use, especially corticosteroids, stood out.⁷ A study based on prescription claims data showed that in the first trimester, there was a significant decline in asthma prescription medications (a 23% decline in inhaled corticosteroids, a 13% decline in short-acting bronchodilator agents, and a 54% decline in rescue corticosteroids).⁸ Lack of physician education about management of asthma in pregnancy and discomfort with prescribing to pregnant women also affect asthma control.

EFFECT OF ASTHMA ON MATERNAL AND FETAL OUTCOMES

Studies of the effects of asthma on fetal and maternal outcomes have yielded mixed and conflicting results.⁹ Adverse outcomes that have been shown to be associated with maternal asthma are listed in Table 1. Other studies have not demonstrated an association between asthma in pregnancy and maternal or fetal adverse events.⁹ Such discrepant findings are due to differences in study population characteristics that make comparisons difficult. A meta-analysis involving more than 1.6 million asthmatic women showed maternal asthma was associated with a 40% greater risk of low birth weight and preterm delivery, a 50% greater risk of preeclampsia, and a 20% greater risk of the baby being small for its gestational age.¹⁰

The association of maternal asthma and preterm birth may pose short-term and long-term health risks to the child associated with prematurity.⁹ Short-term risks with prematurity include infection, respiratory distress syndrome, brain injury, and necrotizing enterocolitis. Long-term risks include neuro­developmental and behavioral sequelae. Furthermore, asthma exacerbations during pregnancy are associated with a twofold higher risk of low birth weight.¹¹ The benefits of good adherence to asthma regimens during pregnancy outweigh the risks associated with frequent symptoms and exacerbations caused by untreated asthma.¹²

OUTPATIENT MANAGEMENT OF MATERNAL ASTHMA

Goals

In the 2004 update of the National Asthma Education and Prevention Program (NAEPP) Working Group Report on Managing Asthma During Pregnancy, goals focused mainly on adequate asthma control for maternal health and quality of life, as well as normal fetal maturation (Table 2),¹² goals similar to those in nonpregnant asthmatic women.

Assessment and monitoring

Monthly physician visits during pregnancy are recommended for assessment of symptoms and pulmonary function. If symptoms are uncontrolled, therapy must be stepped up, and any trigger for exacerbation, such as gastroesophageal reflux disease (GERD), exposure, or rhinitis, must be treated and eliminated. NAEPP guidelines recommend baseline spirometry at the time of initial assessment.¹² At follow-up visits, spirometry is preferred, but measurement of the peak expiratory flow rate usually suffices. Such objective data can help differentiate dyspnea from asthma and from dyspnea that usually accompanies the physiologic changes of pregnancy. In addition, patients should be advised to monitor for adequate fetal activity. If asthma is uncontrolled or poorly controlled, serial fetal ultrasonography should be considered from 32 weeks of gestation, as well as after recovery from an asthma exacerbation. Regular monitoring of the pregnant asthmatic patient by a multidisciplinary team can improve outcomes.¹³

Avoiding triggers

Patients should be advised to avoid asthma triggers such as pet dander, dust mites, pollen, smoke, mold, and perfumes, as this can decrease symptoms and allow for use of lower doses of medications.¹² Additionally, smoking cessation must be strongly encouraged, not only to control maternal asthma, but also to prevent harm to the fetus.

MANAGEMENT OF SPECIFIC TRIGGERS

GERD

Reflux disease often worsens during pregnancy, and it can coexist with asthma and can also exacerbate it.¹⁴ Optimal control of GERD helps maintain adequate asthma control. For mild reflux symptoms, lifestyle modifications such as elevating the head of bed, avoiding eating too close to bedtime, and avoiding foods that cause heartburn may be adequate.^15,16 If medications are needed, antacids (but not sodium bicarbonate, for fear of metabolic alkalosis) and sucralfate should be considered before using a histamine 2 receptor antagonist such as ranitidine. Proton pump inhibitors should be considered only if reflux symptoms are refractory to other therapies.

Allergic rhinitis

Intranasal corticosteroids are effective against allergic rhinitis in pregnancy (Table 3).¹² Montelukast, a leukotriene receptor antagonist, can be used, but data to support its use for allergic rhinitis in pregnancy are limited.

Among antihistamines, second-generation drugs such as cetirizine or loratadine can be considered.¹² Oral decongestants such as pseudoephedrine in early pregnancy are associated with a rare congenital fetal abnormality called gastroschisis, caused by vascular disruption.¹⁷ Hence, if a nasal decongestant is required in early pregnancy, a local therapy such as an intranasal corticosteroid, short-term oxymetazoline, or an external nasal dilator may be considered.¹² These therapies must be combined with avoidance of allergens whenever possible.

Allergies

Diagnostic allergy and skin tests during pregnancy pose a risk of anaphylaxis and thus should be avoided. Instead, the focus should be on obtaining a thorough medical history about exposures and eliminating specific asthma triggers. It is also inadvisable to start allergen immunotherapy during pregnancy because of the risk of anaphylaxis and the effect of treatment on the mother and fetus.¹⁸ However, maintenance doses of allergen immunotherapy can be continued during pregnancy.¹⁸

Patient education

Because of concern about the risks of taking medications during pregnancy, many women with asthma stop using their inhalers during pregnancy, thus compromising asthma control.^8,13 The physician and multidisciplinary team must use every opportunity to emphasize the importance of good asthma control during pregnancy. Inhaler technique should also be reviewed and, if defective, corrected. Again, trigger avoidance and tobacco cessation should be addressed.

Drugs

The NAEPP recommendations state that asthma therapy should be continued during pregnancy, as it is safer both for mother and fetus to avoid exacerbations and uncontrolled asthma.¹² Despite this, 25% of primary care physicians instruct their patients to decrease or discontinue their inhaled corticosteroid during pregnancy.¹⁹ As with asthma in general, treatment should involve using the lowest dose of drugs that achieves adequate control of symptoms.

In 2015, the US Food and Drug Administration (FDA) amended the labeling rule for medications used in pregnancy and lactation. The previous risk categories A (safest), B, C, D, and X (highest risk) are in the process of being removed from labels for all human prescription drugs and biologic products, to be replaced with a summary of the risks of taking the drug during pregnancy and lactation, a discussion of the data supporting the use, and relevant information to help healthcare providers make prescribing decisions and counsel women about the use of drugs during pregnancy and lactation (www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm093307.htm).

ROLES OF CONTROLLER THERAPY AND RESCUE THERAPY

Inhaled corticosteroids

Inhaled corticosteroids are the mainstay of asthma controller therapy during pregnancy. A meta-analysis of 16 studies showed no increased risk of congenital malformations, cesarean delivery, or stillbirth among mothers who used these agents during pregnancy.²⁰ Because there are more safety data for budesonide, it is currently the preferred inhaled corticosteroid during pregnancy.⁹ However, if a patient’s asthma is controlled with a different corticosteroid before pregnancy, that agent may be continued during pregnancy, especially if it is thought that switching formulations could adversely affect asthma control.¹² This is mainly because current data do not prove that other inhaled corticosteroids are unsafe.

Inhaled beta-agonists

Inhaled beta-agonists, both short-acting and long-acting, are used for rescue therapy. Al­buterol is the preferred short-acting agent for rescue therapy in pregnant women with asthma.¹² Meta-analysis has shown no increased risk of major or minor congenital malformations in pregnant patients who use bronchodilators.²⁰ Long-acting beta-agonists typically are used as add-on therapy when asthma cannot be controlled by an inhaled corticosteroid. They should not be used without a controller medication (ie, an inhaled corticosteroid).

Guidelines for rescue therapy are similar to those for nonpregnant asthmatic patients. Although data are limited as to the gestational effects of long-acting beta-agonists (ie, formoterol, salmeterol), it can be assumed that the toxicologic and pharmacologic profiles are similar to those of the short-acting bronchodilators. Thus, the safety of albuterol can be extended potentially to the long-acting beta-agonists.¹²

Combining controller and rescue therapy

When asthma is not adequately controlled on inhaled corticosteroids, a long-acting beta-agonist can be added or the dose of corticosteroid can be increased. The 2004 NAEPP guidelines stated that based on available literature, there was no clear advantage of one option over the other.¹² A study that compared the 2 approaches found no difference in rates of congenital malformations.²¹

Leukotriene receptor antagonists

There is little in the literature regarding the use of leukotriene receptor antagonists during pregnancy. However, animal safety data are reassuring,¹² and human studies have not found a higher risk of major congenital malformations.^22,23 Thus, they are an alternative for patients whose asthma has been well controlled on these agents before pregnancy. Montelukast and zafirlukast are in former FDA pregnancy risk factor category B (probably safe) (Table 3). However, 5-lipoxygenase inhibitors such as zileuton are contraindicated based on animal studies showing teratogenicity.²⁴

Omalizumab

Omalizumab, a recombinant anti-immunoglobulin E antibody, can be used for allergic asthma not controlled with inhaled corticosteroids (Table 3). An analysis of the omalizumab pregnancy registry²⁵ found no significant increase in the rate of major congenital malformations, prematurity, or babies small for gestational age in asthmatic women taking omalizumab 8 weeks before conception or during pregnancy vs pregnant asthmatic women not taking omalizumab. However, this drug carries a risk of anaphylaxis and so should not be started during pregnancy.²⁵

Theophylline

Because of potential toxicity, use of theophylline during pregnancy requires careful monitoring to ensure the serum concentration remains between 5 and 12 µg/mL.¹² Drug interactions are also common: for example, alcohol may increase the serum concentration of theophylline, and theophylline may increase the toxic effect of formoterol.

Systemic corticosteroids

Pregnant women with asthma that is not well controlled despite the therapies described above may require a daily oral corticosteroid such as prednisone to achieve adequate control. Oral steroids are also a mainstay of treatment of asthma exacerbation.

Although use of corticosteroids in the first trimester was associated with orofacial cleft in infants,¹² these studies did not include many women with asthma. In 2011, a nationwide cohort study from Denmark showed no increase in the risk of orofacial cleft with the use of corticosteroids during pregnancy.²⁶

Preeclampsia, low birth weight, and preterm delivery have been described with corticosteroid use in pregnancy. It is not known whether these problems were a result of corticosteroid use or were due to the uncontrolled nature of the underlying condition that led to the steroid use. Since the risk of uncontrolled asthma to mother and fetus outweighs the risk of systemic corticosteroids, these drugs are recommended when indicated for management of maternal asthma.¹²

ACUTE EXACERBATIONS REQUIRE AGGRESSIVE MANAGEMENT

Based on a systematic review, 20% of pregnant women with asthma require some intervention for an asthma exacerbation during pregnancy, and 5.8% are admitted to the hospital for an exacerbation.¹¹ Exacerbations were associated with a higher risk of low birth weight compared with rates in women without asthma.

Exacerbations are more common late in the second trimester and are unlikely to occur during labor and delivery.²  The incidence of exacerbations increases with the severity of asthma, from 8% in mild asthma, to 47% in moderate asthma, to 65% in severe asthma.²⁷ Risk factors for exacerbations include poor prenatal care, obesity, and lack of appropriate treatment with inhaled corticosteroids.² The main triggers are viral respiratory infections and noncompliance with inhaled corticosteroid therapy.¹¹

Asthma exacerbations during pregnancy should be managed aggressively (Table 4),¹² as the risk to the fetus of hypoxia far outweighs any risk from asthma medications. Close collaboration between the primary care physician and the obstetrician allows closer monitoring of mother and fetus.

The goal oxygen saturation must be above 95%.¹² Signs of acute respiratory failure in a pregnant patient include a partial pressure of arterial oxygen less than 70 mm Hg or a partial pressure of carbon dioxide greater than 35 mm Hg.

In a multicenter study comparing nonpregnant and pregnant women visiting the emergency room for asthma exacerbations,²⁸ pregnant women were less likely to be prescribed systemic corticosteroids either in the emergency room or at the time of hospital discharge, and they were also more likely to describe an ongoing exacerbation at 2-week follow-up. However, a recent study showed a significant increase in systemic corticosteroid treatment in the emergency room (51% to 78% across the time periods, odds ratio 3.11, 95% confidence interval 1.27–7.60, P = .01). There was also an increase in steroid treatment at discharge (42% to 63%, odds ratio 2.49, 95% confidence interval 0.97–6.37, P = .054), though the increase was not statistically significant.²⁹ Although emergency room care for pregnant asthmatic women has improved, this group concluded that further improvement is still warranted, as 1 in 3 women is discharged without corticosteroid treatment.

The incidence of maternal asthma is rising. Based on US national health surveys, the prevalence of asthma during pregnancy is between 3.7% and 8.4%.¹ It is the most common respiratory illness of pregnancy.² Hence, clinicians need to know how asthma affects the mother and the fetus. Appropriate care of asthma during pregnancy is based on several management principles, as reviewed here, and is key to ensuring good outcomes for the mother and the baby.

EFFECT OF PREGNANCY ON ASTHMA CONTROL

Asthma control can vary in pregnancy. About a third of asthmatic women experience a worsening of asthma control with pregnancy, a third remain unchanged, and another third have improvement in asthma symptoms.³ The peak worsening of asthma tends to occur in the sixth month.⁴ Asthma control also tends to be better in the last month of pregnancy.³

The peak expiratory flow rate was noted to increase with each trimester in a small study of 43 women.⁵ The authors speculated that a rising progesterone level stimulates cyclic adenosine monophosphate to cause bronchodilation, thereby improving the expiratory flow rate and asthma control. Asthma control tends to follow the pattern experienced in the previous pregnancy: ie, if asthma worsened during the previous pregnancy, the same will be likely in the subsequent pregnancy.³

Two maternal factors that adversely affect asthma severity during pregnancy are the use of asthma medications contrary to guidelines such as those of the Global Initiative for Asthma (http://ginasthma.org/2017-gina-report-global-strategy-for-asthma-management-and-prevention) and inadquate control of asthma before becoming pregnant.⁶ Pregnancy can bring on stress, and stress is known to worsen asthma. In addition, when patients themselves were interviewed to elucidate the reasons for poor adherence to asthma medications during pregnancy, concerns about medication use, especially corticosteroids, stood out.⁷ A study based on prescription claims data showed that in the first trimester, there was a significant decline in asthma prescription medications (a 23% decline in inhaled corticosteroids, a 13% decline in short-acting bronchodilator agents, and a 54% decline in rescue corticosteroids).⁸ Lack of physician education about management of asthma in pregnancy and discomfort with prescribing to pregnant women also affect asthma control.

EFFECT OF ASTHMA ON MATERNAL AND FETAL OUTCOMES

Studies of the effects of asthma on fetal and maternal outcomes have yielded mixed and conflicting results.⁹ Adverse outcomes that have been shown to be associated with maternal asthma are listed in Table 1. Other studies have not demonstrated an association between asthma in pregnancy and maternal or fetal adverse events.⁹ Such discrepant findings are due to differences in study population characteristics that make comparisons difficult. A meta-analysis involving more than 1.6 million asthmatic women showed maternal asthma was associated with a 40% greater risk of low birth weight and preterm delivery, a 50% greater risk of preeclampsia, and a 20% greater risk of the baby being small for its gestational age.¹⁰

The association of maternal asthma and preterm birth may pose short-term and long-term health risks to the child associated with prematurity.⁹ Short-term risks with prematurity include infection, respiratory distress syndrome, brain injury, and necrotizing enterocolitis. Long-term risks include neuro­developmental and behavioral sequelae. Furthermore, asthma exacerbations during pregnancy are associated with a twofold higher risk of low birth weight.¹¹ The benefits of good adherence to asthma regimens during pregnancy outweigh the risks associated with frequent symptoms and exacerbations caused by untreated asthma.¹²

OUTPATIENT MANAGEMENT OF MATERNAL ASTHMA

Goals

In the 2004 update of the National Asthma Education and Prevention Program (NAEPP) Working Group Report on Managing Asthma During Pregnancy, goals focused mainly on adequate asthma control for maternal health and quality of life, as well as normal fetal maturation (Table 2),¹² goals similar to those in nonpregnant asthmatic women.

Assessment and monitoring

Monthly physician visits during pregnancy are recommended for assessment of symptoms and pulmonary function. If symptoms are uncontrolled, therapy must be stepped up, and any trigger for exacerbation, such as gastroesophageal reflux disease (GERD), exposure, or rhinitis, must be treated and eliminated. NAEPP guidelines recommend baseline spirometry at the time of initial assessment.¹² At follow-up visits, spirometry is preferred, but measurement of the peak expiratory flow rate usually suffices. Such objective data can help differentiate dyspnea from asthma and from dyspnea that usually accompanies the physiologic changes of pregnancy. In addition, patients should be advised to monitor for adequate fetal activity. If asthma is uncontrolled or poorly controlled, serial fetal ultrasonography should be considered from 32 weeks of gestation, as well as after recovery from an asthma exacerbation. Regular monitoring of the pregnant asthmatic patient by a multidisciplinary team can improve outcomes.¹³

Avoiding triggers

Patients should be advised to avoid asthma triggers such as pet dander, dust mites, pollen, smoke, mold, and perfumes, as this can decrease symptoms and allow for use of lower doses of medications.¹² Additionally, smoking cessation must be strongly encouraged, not only to control maternal asthma, but also to prevent harm to the fetus.

MANAGEMENT OF SPECIFIC TRIGGERS

GERD

Reflux disease often worsens during pregnancy, and it can coexist with asthma and can also exacerbate it.¹⁴ Optimal control of GERD helps maintain adequate asthma control. For mild reflux symptoms, lifestyle modifications such as elevating the head of bed, avoiding eating too close to bedtime, and avoiding foods that cause heartburn may be adequate.^15,16 If medications are needed, antacids (but not sodium bicarbonate, for fear of metabolic alkalosis) and sucralfate should be considered before using a histamine 2 receptor antagonist such as ranitidine. Proton pump inhibitors should be considered only if reflux symptoms are refractory to other therapies.

Allergic rhinitis

Intranasal corticosteroids are effective against allergic rhinitis in pregnancy (Table 3).¹² Montelukast, a leukotriene receptor antagonist, can be used, but data to support its use for allergic rhinitis in pregnancy are limited.

Among antihistamines, second-generation drugs such as cetirizine or loratadine can be considered.¹² Oral decongestants such as pseudoephedrine in early pregnancy are associated with a rare congenital fetal abnormality called gastroschisis, caused by vascular disruption.¹⁷ Hence, if a nasal decongestant is required in early pregnancy, a local therapy such as an intranasal corticosteroid, short-term oxymetazoline, or an external nasal dilator may be considered.¹² These therapies must be combined with avoidance of allergens whenever possible.

Allergies

Diagnostic allergy and skin tests during pregnancy pose a risk of anaphylaxis and thus should be avoided. Instead, the focus should be on obtaining a thorough medical history about exposures and eliminating specific asthma triggers. It is also inadvisable to start allergen immunotherapy during pregnancy because of the risk of anaphylaxis and the effect of treatment on the mother and fetus.¹⁸ However, maintenance doses of allergen immunotherapy can be continued during pregnancy.¹⁸

Patient education

Because of concern about the risks of taking medications during pregnancy, many women with asthma stop using their inhalers during pregnancy, thus compromising asthma control.^8,13 The physician and multidisciplinary team must use every opportunity to emphasize the importance of good asthma control during pregnancy. Inhaler technique should also be reviewed and, if defective, corrected. Again, trigger avoidance and tobacco cessation should be addressed.

Drugs

The NAEPP recommendations state that asthma therapy should be continued during pregnancy, as it is safer both for mother and fetus to avoid exacerbations and uncontrolled asthma.¹² Despite this, 25% of primary care physicians instruct their patients to decrease or discontinue their inhaled corticosteroid during pregnancy.¹⁹ As with asthma in general, treatment should involve using the lowest dose of drugs that achieves adequate control of symptoms.

In 2015, the US Food and Drug Administration (FDA) amended the labeling rule for medications used in pregnancy and lactation. The previous risk categories A (safest), B, C, D, and X (highest risk) are in the process of being removed from labels for all human prescription drugs and biologic products, to be replaced with a summary of the risks of taking the drug during pregnancy and lactation, a discussion of the data supporting the use, and relevant information to help healthcare providers make prescribing decisions and counsel women about the use of drugs during pregnancy and lactation (www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm093307.htm).

ROLES OF CONTROLLER THERAPY AND RESCUE THERAPY

Inhaled corticosteroids

Inhaled corticosteroids are the mainstay of asthma controller therapy during pregnancy. A meta-analysis of 16 studies showed no increased risk of congenital malformations, cesarean delivery, or stillbirth among mothers who used these agents during pregnancy.²⁰ Because there are more safety data for budesonide, it is currently the preferred inhaled corticosteroid during pregnancy.⁹ However, if a patient’s asthma is controlled with a different corticosteroid before pregnancy, that agent may be continued during pregnancy, especially if it is thought that switching formulations could adversely affect asthma control.¹² This is mainly because current data do not prove that other inhaled corticosteroids are unsafe.

Inhaled beta-agonists

Inhaled beta-agonists, both short-acting and long-acting, are used for rescue therapy. Al­buterol is the preferred short-acting agent for rescue therapy in pregnant women with asthma.¹² Meta-analysis has shown no increased risk of major or minor congenital malformations in pregnant patients who use bronchodilators.²⁰ Long-acting beta-agonists typically are used as add-on therapy when asthma cannot be controlled by an inhaled corticosteroid. They should not be used without a controller medication (ie, an inhaled corticosteroid).

Guidelines for rescue therapy are similar to those for nonpregnant asthmatic patients. Although data are limited as to the gestational effects of long-acting beta-agonists (ie, formoterol, salmeterol), it can be assumed that the toxicologic and pharmacologic profiles are similar to those of the short-acting bronchodilators. Thus, the safety of albuterol can be extended potentially to the long-acting beta-agonists.¹²

Combining controller and rescue therapy

When asthma is not adequately controlled on inhaled corticosteroids, a long-acting beta-agonist can be added or the dose of corticosteroid can be increased. The 2004 NAEPP guidelines stated that based on available literature, there was no clear advantage of one option over the other.¹² A study that compared the 2 approaches found no difference in rates of congenital malformations.²¹

Leukotriene receptor antagonists

There is little in the literature regarding the use of leukotriene receptor antagonists during pregnancy. However, animal safety data are reassuring,¹² and human studies have not found a higher risk of major congenital malformations.^22,23 Thus, they are an alternative for patients whose asthma has been well controlled on these agents before pregnancy. Montelukast and zafirlukast are in former FDA pregnancy risk factor category B (probably safe) (Table 3). However, 5-lipoxygenase inhibitors such as zileuton are contraindicated based on animal studies showing teratogenicity.²⁴

Omalizumab

Omalizumab, a recombinant anti-immunoglobulin E antibody, can be used for allergic asthma not controlled with inhaled corticosteroids (Table 3). An analysis of the omalizumab pregnancy registry²⁵ found no significant increase in the rate of major congenital malformations, prematurity, or babies small for gestational age in asthmatic women taking omalizumab 8 weeks before conception or during pregnancy vs pregnant asthmatic women not taking omalizumab. However, this drug carries a risk of anaphylaxis and so should not be started during pregnancy.²⁵

Theophylline

Because of potential toxicity, use of theophylline during pregnancy requires careful monitoring to ensure the serum concentration remains between 5 and 12 µg/mL.¹² Drug interactions are also common: for example, alcohol may increase the serum concentration of theophylline, and theophylline may increase the toxic effect of formoterol.

Systemic corticosteroids

Pregnant women with asthma that is not well controlled despite the therapies described above may require a daily oral corticosteroid such as prednisone to achieve adequate control. Oral steroids are also a mainstay of treatment of asthma exacerbation.

Although use of corticosteroids in the first trimester was associated with orofacial cleft in infants,¹² these studies did not include many women with asthma. In 2011, a nationwide cohort study from Denmark showed no increase in the risk of orofacial cleft with the use of corticosteroids during pregnancy.²⁶

Preeclampsia, low birth weight, and preterm delivery have been described with corticosteroid use in pregnancy. It is not known whether these problems were a result of corticosteroid use or were due to the uncontrolled nature of the underlying condition that led to the steroid use. Since the risk of uncontrolled asthma to mother and fetus outweighs the risk of systemic corticosteroids, these drugs are recommended when indicated for management of maternal asthma.¹²

ACUTE EXACERBATIONS REQUIRE AGGRESSIVE MANAGEMENT

Based on a systematic review, 20% of pregnant women with asthma require some intervention for an asthma exacerbation during pregnancy, and 5.8% are admitted to the hospital for an exacerbation.¹¹ Exacerbations were associated with a higher risk of low birth weight compared with rates in women without asthma.

Exacerbations are more common late in the second trimester and are unlikely to occur during labor and delivery.²  The incidence of exacerbations increases with the severity of asthma, from 8% in mild asthma, to 47% in moderate asthma, to 65% in severe asthma.²⁷ Risk factors for exacerbations include poor prenatal care, obesity, and lack of appropriate treatment with inhaled corticosteroids.² The main triggers are viral respiratory infections and noncompliance with inhaled corticosteroid therapy.¹¹

Asthma exacerbations during pregnancy should be managed aggressively (Table 4),¹² as the risk to the fetus of hypoxia far outweighs any risk from asthma medications. Close collaboration between the primary care physician and the obstetrician allows closer monitoring of mother and fetus.

The goal oxygen saturation must be above 95%.¹² Signs of acute respiratory failure in a pregnant patient include a partial pressure of arterial oxygen less than 70 mm Hg or a partial pressure of carbon dioxide greater than 35 mm Hg.

In a multicenter study comparing nonpregnant and pregnant women visiting the emergency room for asthma exacerbations,²⁸ pregnant women were less likely to be prescribed systemic corticosteroids either in the emergency room or at the time of hospital discharge, and they were also more likely to describe an ongoing exacerbation at 2-week follow-up. However, a recent study showed a significant increase in systemic corticosteroid treatment in the emergency room (51% to 78% across the time periods, odds ratio 3.11, 95% confidence interval 1.27–7.60, P = .01). There was also an increase in steroid treatment at discharge (42% to 63%, odds ratio 2.49, 95% confidence interval 0.97–6.37, P = .054), though the increase was not statistically significant.²⁹ Although emergency room care for pregnant asthmatic women has improved, this group concluded that further improvement is still warranted, as 1 in 3 women is discharged without corticosteroid treatment.

Helicobacter pylori infection is an infectious disease and should be treated like one, with due consideration of antibiotic resistance and stewardship.^1–4

This was the consensus of the 2015 Kyoto H pylori conference,² and it signaled a fundamental shift in thinking. Up to now, H pylori treatment has not been based on infectious disease principles, leading to suboptimal results and antibiotic resistance. In addition, the conference recommended that H pylori infection be treated whenever it is found unless there are compelling reasons not to.

Here we review current and possible future regimens for eradicating H pylori that we hope will be more effective and will lead to less resistance than in the past.

H PYLORI AS AN INFECTIOUS DISEASE

Not until the late 1980s was H pylori recognized as the cause of peptic ulcer disease, which until then accounted for hundreds of thousands of hospitalizations and more than 100,000 surgical procedures each year.⁵ Now, peptic ulcer disease is routinely treated by eradicating H pylori. In addition, the World Health Organization has recommended considering H pylori eradication to reduce the risk of gastric cancer,⁶ which causes 738,000 deaths worldwide per year.⁷

The problems of how to diagnose and treat H pylori infection were taken on by gastroenterologists, and not by specialists in infectious disease.¹ Even now, almost all the major reviews and consensus statements on H pylori come from gastroenterologists and are published in gastroenterology journals.^2,8,9

But infectious diseases differ from most gastrointestinal diseases. In gastrointestinal problems such as constipation or inflammatory bowel disease,¹⁰ the causes are generally unknown, and there is a large placebo response to therapy. In contrast, in infectious diseases, the cause is generally known, there is no placebo response, and treatment success depends on susceptibility of the organism. Failure of proven regimens is generally due to resistant organisms, poor adherence, or, in the case of H pylori, poorly designed regimens in terms of doses, frequency of administration, or duration of therapy.

The differences extend to clinical trials of treatment.³ In other infectious diseases, treatment is based on susceptibility. The usual comparative approach in infectious diseases is a noninferiority trial in which the new treatment is compared with standard care, ie, a regimen that reliably achieves nearly 100% cure rates. Not so with H pylori. Most trials of H pylori therapy compared regimens in populations with high but unknown prevalences of resistance and therefore are of limited or no help to the clinician in choosing the best regimen for an individual patient.³

Many thousands of H pylori-infected patients participated in clinical trials in which the results would have been predictable if the researchers had assessed susceptibility before giving the drugs.^11–13 Worse, many patients were also randomized to receive regimens that the investigators knew provided poor cure rates in the population being studied. This knowledge was generally not shared with the patients. This approach was used to demonstrate that a new regimen was superior to an old one, even though the new one was already known to be less affected by resistance to the key element in the comparator.

Clinicians generally do not test for susceptibility when treating H pylori, one reason being that such testing is often unavailable.³ However, almost every hospital, clinic, and major laboratory in the world provides susceptibility testing for other common local pathogens. H pylori is easy to grow, and laboratories could test for susceptibility if we asked them to.

Current H pylori recommendations may also contribute to the global increase in antimicrobal resistance.

As discussed below, all recent guidelines have recommended 4-drug non-bismuth-containing concomitant therapy as first-line therapy. An infectious disease colleague described it as a “hope therapy” because the prescriber hoped that the infection would be susceptible to either metronidazole or clarithromycin. All who receive this combination receive an antibiotic they do not need. This is an expedient rather than a medically rational choice resulting from failure to deal with H pylori as an infectious disease.

H PYLORI THERAPIES

Conceptually, treating infectious disease is straightforward: one should prescribe antimicrobial drugs to which the organism is susceptible³ (Table 1). However, clinical success lies in the details, which include the doses, frequency of doses, duration of therapy, timing of doses in relation to meals, and use of adjuvants such as antisecretory drugs, antacids, and probiotics. A number of regimens reliably yield high cure rates—95% or higher—if the organism is susceptible and the patients are adherent.

The effectiveness of any regimen may vary depending on the population it is used in, due to polymorphisms in drug-metabolizing enzymes such as CYP2C19.

Sequential therapy is obsolete

Sequential therapy for H pylori infection consisted of amoxicillin plus a proton pump inhibitor for 7 days, followed by clarithromycin, tinidazole, or metronidazole plus a proton pump inhibitor for a further 7 days. This regimen should not be used any more because concomitant therapy will always be superior (see below).

H pylori occupies a number of different niches in the body ranging from gastric mucus (which is technically outside the body) to inside gastric epithelial cells. As a general rule, 14-day therapy provides the best results, in part because the longer duration helps kill the organisms that persist in different niches.^14,15

In addition, proton pump inhibitors, which are part of all the currently recommended regimens, require 3 or more days to reach their full antisecretory effectiveness, which further limits the effectiveness of short-duration therapies.

Shorter regimens should be used only if they are proved to be as good as 14-day regimens and if both achieve 95% or greater cure rates with susceptible infections.

How to choose a therapy

Since rational infectious-disease therapy is based on susceptibility, one should start by considering the susceptibility pattern in the local population and, therefore, the likely susceptibility in the patient in front of us.

Unfortunately, we do not yet have local or regional susceptibility data on H pylori for most locales. Until those data are available, we must use the indirect information that is available, such as the patient’s history of antibiotic use.

Triple therapy should not be used empirically

Triple therapy (Table 1) consists of the combination of:

• Clarithromycin or metronidazole or a fluoroquinolone
• Amoxicillin
• A proton pump inhibitor.

However, prior use of a macrolide (eg, erythromycin, clarithromycin, or azithromycin), metronidazole, or a fluoroquinolone (eg, ciprofloxacin, levofloxacin) almost guarantees resistance to those drugs. In the United States, resistance to clarithromycin, metronidazole, levofloxacin, and related drugs is already widespread, and none should be used empirically in triple therapies. In contrast, amoxicillin, tetracycline, and furazolidone can often be used again, as resistance to them is rare even with prior use.

For example, 14 days of clarithromycin triple therapy (clarithromycin, amoxicillin, and a proton pump inhibitor) can be expected to cure more than 95% of patients who have susceptible infections and about 20% of those with resistant infections.¹⁶ This 20% is due to the proton pump inhibitor and amoxicillin, as the contribution to the cure rate from clarithromycin is close to zero.

If the prevalence of resistance to clarithromycin is 25%, the cure rate in the entire population will be a little more than 75%—97% in the 75% of the population with susceptible infections and 20% in patients who previously received clarithromycin (Figure 1).

Based on Graham DY. Hp-normogram (normo-graham) for assessing the outcome of H. pylori therapy: effect of resistance, duration, and CYP2C19 genotype. Helicobacter 2015; 21:85–90.

If we know that our patient has an infection that is susceptible to clarithromycin, metronidazole, or levofloxacin, good results could be achieved with triple therapy that includes a proton pump inhibitor, for 14 days. Fluoroquinolones have a number of black-box warnings from the US Food and Drug Administration (www.fda.gov/Drugs/DrugSafety/ucm500143.htm) and should always be a last choice. However, in the United States, lacking definite data about susceptibility to clarithromycin, metronidazole, and levofloxacin, we should assume resistance is present and use a 4-drug regimen (eg, concomitant therapy or bismuth quadruple therapy).

Concomitant therapy is preferred

Concomitant therapy is the combination of:

• Amoxicillin
• Metronidazole
• Clarithromycin
• A proton pump inhibitor.

Functionally, this is a combination of clarithromycin and metronidazole triple therapies, given simultaneously.¹⁷ The premise is that even though the prevalence of metronidazole resistance in the United States is high (20%–40%), and so is the prevalence of clarithromycin resistance (about 20%), the prevalence of resistance to both drugs at the same time is expected to be low (eg, 0.4 × 0.2 = 0.08, or 8%) unless the drugs had previously been used together, as in some older regimens that contained both. Thus, the metronidazole will kill the clarithromycin-resistant but metronidazole-susceptible strains, and the clarithromycin will kill the clarithromycin-susceptible, metronidazole-resistant strains. Only with dual resistant strains will this regimen fail (with a 20% cure rate due to the proton pump inhibitor and amoxicillin and a population cure rate of slightly more than 90%).

The downside of this highly recommended therapy is that all who receive it are getting an antibiotic that they don’t need, which is, in a global sense, inappropriate. In other words, all those who are cured by clarithromycin also receive metronidazole, which plays no role in treatment success, and those cured by metronidazole receive unneeded clarithromycin (Figure 2). Had susceptibility testing been available, those with susceptible strains would have received appropriate triple therapies, and those with dual resistance would not have received either antibiotic.

Thus, while we recommend concomitant therapy as an empiric regimen in populations that do not have high levels of resistance to metronidazole or clarithromycin (as those would also have a high prevalence of dual resistance), one must be aware of the “dirty little secret” of inappropriate antibiotic use that accompanies it and some other H pylori therapies (eg, vonoprazan triple therapy in Japan).^18–20

Bismuth quadruple therapy (Table 1) consists of:

• Bismuth
• Tetracycline
• Metronidazole
• A proton pump inhibitor.

This was the first truly effective regimen for H pylori. Its advantage is that it can partially or completely overcome metronidazole resistance.^21,22 As such, it is potentially ideal, as it should be effective despite resistance to clarithromycin, metronidazole, or levofloxacin, and it can be used in patients allergic to penicillin.

The major downside is a high frequency of side effects, particularly abdominal pain, nausea, and vomiting, often resulting in poor adherence. Most regimens that contain antibiotics have side effects, but adherence seems to be more of a problem with bismuth quadruple therapy, probably because of the combination of the high doses of metronidazole and tetracycline.²² In our experience, this regimen can be effective if the physician takes the time to explain to the patient that side effects are common but treatment success depends on completing the full course of 14 days.

Another problem is that tetracycline has become difficult to obtain in many areas, and doxycycline cannot be substituted in those with metronidazole resistance. To date, it has been difficult or impossible to obtain the same excellent results with doxycycline as can be obtained with tetracycline. It is not clear why.²¹

To use bismuth quadruple therapy one must often use a name-brand product, Pylera. Pylera is packaged as a 10-day course, which is effective against metronidazole-susceptible infections. However, 14 days are generally required to achieve a high cure rate with metronidazole-resistant infections, which are the main indication for use of this product. Moreover, Pylera does not include a proton pump inhibitor, which must be prescribed separately.

In the United States, Pylera is expensive, costing $740 to $790 with a coupon for a 10-day supply and proportionally more for the required 14-day supply (www.goodrx.com/pylera?drug-name=pylera), whereas in Europe it costs less than 70 Euros ($73).²¹ If generic tetracycline is available, the US cost for 14 days of generic bismuth quadruple therapy is less than $50.

An alternate and simpler approach is to substitute amoxicillin for tetracycline.²³ This regimen has been used successfully in China and was shown to be noninferior to the tetracycline-containing regimen in a head-to-head comparison.²⁴

Recent studies have confirmed earlier Italian studies suggesting that twice-a-day bismuth and tetracycline is effective, which would further simplify therapy and possibly reduce side effects.^21,23,24 These variations on bismuth quadruple therapy have not yet been optimized to where one can reliably achieve 95% or greater cure rates, and further studies are needed.

Why include more than 1 antibiotic?

The H pylori load in the stomach is typically large, which increases the odds that a subpopulation of resistant organisms is present. Resistance may be due to a relatively high rate of mutation in certain bacterial genes.²⁵ This is particularly a problem with clarithromycin, metronidazole, and fluoroquinolones and is reflected in a high rate of resistance among patients for whom single-drug regimens have failed. These drugs are always given with a second antimicrobial to which H pylori rarely becomes resistant, such as amoxicillin or tetracycline.

Why include a proton pump inhibitor?

An antisecretory drug is needed to increase the gastric pH, which makes antimicrobial therapy more effective. It also decreases antibiotic washout from the stomach and likely protects and increases the gastric concentration of some antibiotics.

The activities of amoxicillin, fluoroquinolones, and to a lesser degree clarithromycin are pH-dependent. For example, keeping the gastric pH above 6.0 promotes H pylori replication,^26,27 making it is more susceptible to amoxicillin (reviewed in detail by Dore et al²¹). A gastric pH of 6.0 or more is very difficult to achieve with proton pump inhibitors, and has been accomplished regularly only in people who metabolize these drugs slowly (“slow metabolizers”) who received both the proton pump inhibitor and amoxicillin every 6 hours for 14 days.²¹

With standard clarithromycin, metronidazole, or fluoroquinolone triple therapy, proton pump inhibitors appear to provide satisfactory cure rates when given for 14 days in standard doses. However, double doses (eg, 40 mg of omeprazole or an equivalent) may be slightly better, especially in the presence of resistance.

The cure rate reflects the sum of the 2 populations of organisms: the susceptible and the resistant. In triple therapy, increasing the gastric pH with a proton pump inhibitor makes the amoxicillin component of the regimen more effective against resistant organisms and thus increases the cure rate. For example, in Western countries, esomeprazole  40 mg (approximately equivalent to rabeprazole 40 mg, omeprazole or lansoprazole 60 mg, or pantoprazole 240 mg)²⁸ given twice a day in a 14-day triple therapy regimen cures about 40% to 50% of resistant infections. This benefit will be evident in an improvement in cure rates in populations in which resistance has reduced the average cure rate. This is also why meta-analyses have shown better results with second-generation proton pump inhibitors and with longer duration of therapy.^29,30

Generally, we recommend omeprazole 40 mg twice a day or an equivalent (Tables 1–3).

Would a potassium-competitive acid blocker be better than a proton pump inhibitor?

Vonoprazan is a potassium-competitive acid blocker. It does not require intermediate complex formation and is stable at low pH. It has a longer half-life than proton pump inhibitors, and its bioavailability is unaffected by food.³¹ It was recently approved in Japan for H pylori eradication in combination with clarithromycin or metronidazole plus amoxicillin.¹⁸

Vonoprazan is more effective than current proton pump inhibitors for keeping the gastric pH high. There are no published studies of vonoprazan dual therapy in Western countries, but given twice a day for 7 days along with twice-daily amoxicillin it cured only approximately 80% of clarithromycin-resistant strains. Further studies are needed to identify the optimum proton pump inhibitor or potassium-competitive acid blocker, dose, and duration.

In triple therapy, the second antimicrobial drug (eg, amoxicillin) is given in part to prevent resistance from developing. It is not clear whether the combination is additive or synergistic, but until we can reliably maintain the intragastric pH above 6.0, which would increase the effectiveness of the amoxicillin component of the regimen, this practice cannot be considered as misuse of antibiotics.

In contrast, in the 4-drug nonbismuth combinations (concomitant, sequential, and hybrid therapies) and the new vonoprazan, clarithromycin, and metronidazole triple therapies, 1 of the antibiotics provides no benefit to some, often most, of the patients.^18–20,32 This practice should end when susceptibility data become more widely available and when vonoprazan becomes available, so that we can deliver effective vonoprazan-amoxicillin dual therapy.

First-, second-, and third-line therapies

Many recommendations give advice in terms of first-, second-, and third-line therapies. In practice, a physician should have at least 2 first-line regimens (a first and a second choice). Both should be proven highly successful as empiric therapies in one’s patient population but differ in terms of primary antibiotics. This approach allows the clinician to tailor therapy depending on whether he or she suspects antibiotic resistance (eg, if the patient has taken clarithromycin before) or the patient is allergic or cannot take 1 or more drugs.

Two treatment failures with 2 different regimens known to be effective suggest poor compliance (a difficult patient) or a multiple-drug-resistant infection (a difficult infection). That patient would require salvage therapy (Table 2), which logically should be based on antimicrobial testing or, at a minimum, consultation with someone who frequently deals with this problem.

Test of cure

Monitoring the outcome of therapy (testing for cure) is essential, as it provides a reliable measure of the local effectiveness of particular therapies and also serves as an early warning of development of resistance in one’s patient population.¹⁴

Unless there are compelling reasons, testing for cure should use noninvasive testing with the urea breath test or stool antigen test. It is recommended that this be delayed at least 4 weeks to allow the organisms if still present to repopulate the stomach sufficiently for the tests to become positive. Because antibiotics, bismuth, and proton pump inhibitors reduce the bacterial load, they should be withheld at least 2 weeks before testing. Histamine-2 receptor antagonists can be substituted for proton pump inhibitors if antisecretory therapy is needed for symptoms, and continued up to the day before testing. The urea breath test should contain citric acid to overcome any residual pH effects. Physician groups should share their experience so as to alert the community about which therapies should likely be avoided.³³

Salvage therapy

Salvage therapy is given after 2 or more treatment failures with different antibiotics. Ideally, the regimen should be based on the results of antimicrobial testing. Current regimens include rifabutin triple therapy, dual therapy (a protein pump inhibitor or vonoprazan and amoxicillin), or furazolidone quadruple therapy (Table 2).

Furazolidone is a synthetic nitrofuran derivative that is effective against many enteric organisms, including gram-negative bacteria and protozoa. It is not available in most Western countries but is available in many other parts of the world.^34,35 It is also a monoamine oxidase inhibitor and thus interacts with many drugs and foods (eg, soy sauce, aged cheeses), leading to a relatively high rate of side effects such as fever, palpitations, and skin rash.

Rifabutin-containing regimens, generally, a proton pump inhibitor, amoxicillin 1 g, and rifabutin 150 mg, all twice a day (Table 3) provide average cure rates of less than 80% (typically in the mid-70% range).³⁶ Borody et al³⁷ reported greater than 95% success with a 12-day regimen consisting of rifabutin 150 mg once daily (half-dose), amoxicillin 1.5 g 3 times a day, and pantoprazole 80 mg (approximately equivalent to omeprazole 20 mg) 3 times a day. Ciccaglione et al,³⁸ in a small study, used a 10-day quadruple regimen containing a proton pump inhibitor, amoxicillin, rifabutin, and bismuth (all twice a day), with high cure rates. The results of these studies are yet to be confirmed, and the optimal rifabutin-containing regimen remains to be determined.

PROBIOTICS

There is considerable interest in using probiotics to enhance the effectiveness of antimicrobial therapy for H pylori by increasing tolerability, reducing side effects, and therefore improving compliance.^39,40

In a meta-analysis of 14 randomized trials (N = 1,671), when probiotics were added, pooled H pylori eradication rates were only slightly improved: 83.6% (95% CI 80.5%–86.7%) with probiotics and 74.8% (95% CI 71.1%–78.5%) without probiotics by intent-to-treat analysis.⁴¹

Another meta-analysis of probiotics suggested that those containing Saccharomyces boulardii, Lactobacillus, and Bifidobacterium significantly increased the eradication rate of triple therapy in populations with high rates of antimicrobial resistance and reduced the risk of overall H pylori therapy-related adverse effects, especially diarrhea.^42,43

At present, we recommend that probiotics be considered only for patients who are likely not to comply with treatment (eg, those with irritable bowel syndrome or difficulty taking antibiotics), to try to take advantage of their ability to improve antibiotic tolerability.

Helicobacter pylori infection is an infectious disease and should be treated like one, with due consideration of antibiotic resistance and stewardship.^1–4

This was the consensus of the 2015 Kyoto H pylori conference,² and it signaled a fundamental shift in thinking. Up to now, H pylori treatment has not been based on infectious disease principles, leading to suboptimal results and antibiotic resistance. In addition, the conference recommended that H pylori infection be treated whenever it is found unless there are compelling reasons not to.

Here we review current and possible future regimens for eradicating H pylori that we hope will be more effective and will lead to less resistance than in the past.

H PYLORI AS AN INFECTIOUS DISEASE

Not until the late 1980s was H pylori recognized as the cause of peptic ulcer disease, which until then accounted for hundreds of thousands of hospitalizations and more than 100,000 surgical procedures each year.⁵ Now, peptic ulcer disease is routinely treated by eradicating H pylori. In addition, the World Health Organization has recommended considering H pylori eradication to reduce the risk of gastric cancer,⁶ which causes 738,000 deaths worldwide per year.⁷

The problems of how to diagnose and treat H pylori infection were taken on by gastroenterologists, and not by specialists in infectious disease.¹ Even now, almost all the major reviews and consensus statements on H pylori come from gastroenterologists and are published in gastroenterology journals.^2,8,9

But infectious diseases differ from most gastrointestinal diseases. In gastrointestinal problems such as constipation or inflammatory bowel disease,¹⁰ the causes are generally unknown, and there is a large placebo response to therapy. In contrast, in infectious diseases, the cause is generally known, there is no placebo response, and treatment success depends on susceptibility of the organism. Failure of proven regimens is generally due to resistant organisms, poor adherence, or, in the case of H pylori, poorly designed regimens in terms of doses, frequency of administration, or duration of therapy.

The differences extend to clinical trials of treatment.³ In other infectious diseases, treatment is based on susceptibility. The usual comparative approach in infectious diseases is a noninferiority trial in which the new treatment is compared with standard care, ie, a regimen that reliably achieves nearly 100% cure rates. Not so with H pylori. Most trials of H pylori therapy compared regimens in populations with high but unknown prevalences of resistance and therefore are of limited or no help to the clinician in choosing the best regimen for an individual patient.³

Many thousands of H pylori-infected patients participated in clinical trials in which the results would have been predictable if the researchers had assessed susceptibility before giving the drugs.^11–13 Worse, many patients were also randomized to receive regimens that the investigators knew provided poor cure rates in the population being studied. This knowledge was generally not shared with the patients. This approach was used to demonstrate that a new regimen was superior to an old one, even though the new one was already known to be less affected by resistance to the key element in the comparator.

Clinicians generally do not test for susceptibility when treating H pylori, one reason being that such testing is often unavailable.³ However, almost every hospital, clinic, and major laboratory in the world provides susceptibility testing for other common local pathogens. H pylori is easy to grow, and laboratories could test for susceptibility if we asked them to.

Current H pylori recommendations may also contribute to the global increase in antimicrobal resistance.

As discussed below, all recent guidelines have recommended 4-drug non-bismuth-containing concomitant therapy as first-line therapy. An infectious disease colleague described it as a “hope therapy” because the prescriber hoped that the infection would be susceptible to either metronidazole or clarithromycin. All who receive this combination receive an antibiotic they do not need. This is an expedient rather than a medically rational choice resulting from failure to deal with H pylori as an infectious disease.

H PYLORI THERAPIES

Conceptually, treating infectious disease is straightforward: one should prescribe antimicrobial drugs to which the organism is susceptible³ (Table 1). However, clinical success lies in the details, which include the doses, frequency of doses, duration of therapy, timing of doses in relation to meals, and use of adjuvants such as antisecretory drugs, antacids, and probiotics. A number of regimens reliably yield high cure rates—95% or higher—if the organism is susceptible and the patients are adherent.

The effectiveness of any regimen may vary depending on the population it is used in, due to polymorphisms in drug-metabolizing enzymes such as CYP2C19.

Sequential therapy is obsolete

Sequential therapy for H pylori infection consisted of amoxicillin plus a proton pump inhibitor for 7 days, followed by clarithromycin, tinidazole, or metronidazole plus a proton pump inhibitor for a further 7 days. This regimen should not be used any more because concomitant therapy will always be superior (see below).

H pylori occupies a number of different niches in the body ranging from gastric mucus (which is technically outside the body) to inside gastric epithelial cells. As a general rule, 14-day therapy provides the best results, in part because the longer duration helps kill the organisms that persist in different niches.^14,15

In addition, proton pump inhibitors, which are part of all the currently recommended regimens, require 3 or more days to reach their full antisecretory effectiveness, which further limits the effectiveness of short-duration therapies.

Shorter regimens should be used only if they are proved to be as good as 14-day regimens and if both achieve 95% or greater cure rates with susceptible infections.

How to choose a therapy

Since rational infectious-disease therapy is based on susceptibility, one should start by considering the susceptibility pattern in the local population and, therefore, the likely susceptibility in the patient in front of us.

Unfortunately, we do not yet have local or regional susceptibility data on H pylori for most locales. Until those data are available, we must use the indirect information that is available, such as the patient’s history of antibiotic use.

Triple therapy should not be used empirically

Triple therapy (Table 1) consists of the combination of:

• Clarithromycin or metronidazole or a fluoroquinolone
• Amoxicillin
• A proton pump inhibitor.

However, prior use of a macrolide (eg, erythromycin, clarithromycin, or azithromycin), metronidazole, or a fluoroquinolone (eg, ciprofloxacin, levofloxacin) almost guarantees resistance to those drugs. In the United States, resistance to clarithromycin, metronidazole, levofloxacin, and related drugs is already widespread, and none should be used empirically in triple therapies. In contrast, amoxicillin, tetracycline, and furazolidone can often be used again, as resistance to them is rare even with prior use.

For example, 14 days of clarithromycin triple therapy (clarithromycin, amoxicillin, and a proton pump inhibitor) can be expected to cure more than 95% of patients who have susceptible infections and about 20% of those with resistant infections.¹⁶ This 20% is due to the proton pump inhibitor and amoxicillin, as the contribution to the cure rate from clarithromycin is close to zero.

If the prevalence of resistance to clarithromycin is 25%, the cure rate in the entire population will be a little more than 75%—97% in the 75% of the population with susceptible infections and 20% in patients who previously received clarithromycin (Figure 1).

Based on Graham DY. Hp-normogram (normo-graham) for assessing the outcome of H. pylori therapy: effect of resistance, duration, and CYP2C19 genotype. Helicobacter 2015; 21:85–90.

If we know that our patient has an infection that is susceptible to clarithromycin, metronidazole, or levofloxacin, good results could be achieved with triple therapy that includes a proton pump inhibitor, for 14 days. Fluoroquinolones have a number of black-box warnings from the US Food and Drug Administration (www.fda.gov/Drugs/DrugSafety/ucm500143.htm) and should always be a last choice. However, in the United States, lacking definite data about susceptibility to clarithromycin, metronidazole, and levofloxacin, we should assume resistance is present and use a 4-drug regimen (eg, concomitant therapy or bismuth quadruple therapy).

Concomitant therapy is preferred

Concomitant therapy is the combination of:

• Amoxicillin
• Metronidazole
• Clarithromycin
• A proton pump inhibitor.

Functionally, this is a combination of clarithromycin and metronidazole triple therapies, given simultaneously.¹⁷ The premise is that even though the prevalence of metronidazole resistance in the United States is high (20%–40%), and so is the prevalence of clarithromycin resistance (about 20%), the prevalence of resistance to both drugs at the same time is expected to be low (eg, 0.4 × 0.2 = 0.08, or 8%) unless the drugs had previously been used together, as in some older regimens that contained both. Thus, the metronidazole will kill the clarithromycin-resistant but metronidazole-susceptible strains, and the clarithromycin will kill the clarithromycin-susceptible, metronidazole-resistant strains. Only with dual resistant strains will this regimen fail (with a 20% cure rate due to the proton pump inhibitor and amoxicillin and a population cure rate of slightly more than 90%).

The downside of this highly recommended therapy is that all who receive it are getting an antibiotic that they don’t need, which is, in a global sense, inappropriate. In other words, all those who are cured by clarithromycin also receive metronidazole, which plays no role in treatment success, and those cured by metronidazole receive unneeded clarithromycin (Figure 2). Had susceptibility testing been available, those with susceptible strains would have received appropriate triple therapies, and those with dual resistance would not have received either antibiotic.

Thus, while we recommend concomitant therapy as an empiric regimen in populations that do not have high levels of resistance to metronidazole or clarithromycin (as those would also have a high prevalence of dual resistance), one must be aware of the “dirty little secret” of inappropriate antibiotic use that accompanies it and some other H pylori therapies (eg, vonoprazan triple therapy in Japan).^18–20

Bismuth quadruple therapy (Table 1) consists of:

• Bismuth
• Tetracycline
• Metronidazole
• A proton pump inhibitor.

This was the first truly effective regimen for H pylori. Its advantage is that it can partially or completely overcome metronidazole resistance.^21,22 As such, it is potentially ideal, as it should be effective despite resistance to clarithromycin, metronidazole, or levofloxacin, and it can be used in patients allergic to penicillin.

The major downside is a high frequency of side effects, particularly abdominal pain, nausea, and vomiting, often resulting in poor adherence. Most regimens that contain antibiotics have side effects, but adherence seems to be more of a problem with bismuth quadruple therapy, probably because of the combination of the high doses of metronidazole and tetracycline.²² In our experience, this regimen can be effective if the physician takes the time to explain to the patient that side effects are common but treatment success depends on completing the full course of 14 days.

Another problem is that tetracycline has become difficult to obtain in many areas, and doxycycline cannot be substituted in those with metronidazole resistance. To date, it has been difficult or impossible to obtain the same excellent results with doxycycline as can be obtained with tetracycline. It is not clear why.²¹

To use bismuth quadruple therapy one must often use a name-brand product, Pylera. Pylera is packaged as a 10-day course, which is effective against metronidazole-susceptible infections. However, 14 days are generally required to achieve a high cure rate with metronidazole-resistant infections, which are the main indication for use of this product. Moreover, Pylera does not include a proton pump inhibitor, which must be prescribed separately.

In the United States, Pylera is expensive, costing $740 to $790 with a coupon for a 10-day supply and proportionally more for the required 14-day supply (www.goodrx.com/pylera?drug-name=pylera), whereas in Europe it costs less than 70 Euros ($73).²¹ If generic tetracycline is available, the US cost for 14 days of generic bismuth quadruple therapy is less than $50.

An alternate and simpler approach is to substitute amoxicillin for tetracycline.²³ This regimen has been used successfully in China and was shown to be noninferior to the tetracycline-containing regimen in a head-to-head comparison.²⁴

Recent studies have confirmed earlier Italian studies suggesting that twice-a-day bismuth and tetracycline is effective, which would further simplify therapy and possibly reduce side effects.^21,23,24 These variations on bismuth quadruple therapy have not yet been optimized to where one can reliably achieve 95% or greater cure rates, and further studies are needed.

Why include more than 1 antibiotic?

The H pylori load in the stomach is typically large, which increases the odds that a subpopulation of resistant organisms is present. Resistance may be due to a relatively high rate of mutation in certain bacterial genes.²⁵ This is particularly a problem with clarithromycin, metronidazole, and fluoroquinolones and is reflected in a high rate of resistance among patients for whom single-drug regimens have failed. These drugs are always given with a second antimicrobial to which H pylori rarely becomes resistant, such as amoxicillin or tetracycline.

Why include a proton pump inhibitor?

An antisecretory drug is needed to increase the gastric pH, which makes antimicrobial therapy more effective. It also decreases antibiotic washout from the stomach and likely protects and increases the gastric concentration of some antibiotics.

The activities of amoxicillin, fluoroquinolones, and to a lesser degree clarithromycin are pH-dependent. For example, keeping the gastric pH above 6.0 promotes H pylori replication,^26,27 making it is more susceptible to amoxicillin (reviewed in detail by Dore et al²¹). A gastric pH of 6.0 or more is very difficult to achieve with proton pump inhibitors, and has been accomplished regularly only in people who metabolize these drugs slowly (“slow metabolizers”) who received both the proton pump inhibitor and amoxicillin every 6 hours for 14 days.²¹

With standard clarithromycin, metronidazole, or fluoroquinolone triple therapy, proton pump inhibitors appear to provide satisfactory cure rates when given for 14 days in standard doses. However, double doses (eg, 40 mg of omeprazole or an equivalent) may be slightly better, especially in the presence of resistance.

The cure rate reflects the sum of the 2 populations of organisms: the susceptible and the resistant. In triple therapy, increasing the gastric pH with a proton pump inhibitor makes the amoxicillin component of the regimen more effective against resistant organisms and thus increases the cure rate. For example, in Western countries, esomeprazole  40 mg (approximately equivalent to rabeprazole 40 mg, omeprazole or lansoprazole 60 mg, or pantoprazole 240 mg)²⁸ given twice a day in a 14-day triple therapy regimen cures about 40% to 50% of resistant infections. This benefit will be evident in an improvement in cure rates in populations in which resistance has reduced the average cure rate. This is also why meta-analyses have shown better results with second-generation proton pump inhibitors and with longer duration of therapy.^29,30

Generally, we recommend omeprazole 40 mg twice a day or an equivalent (Tables 1–3).

Would a potassium-competitive acid blocker be better than a proton pump inhibitor?

Vonoprazan is a potassium-competitive acid blocker. It does not require intermediate complex formation and is stable at low pH. It has a longer half-life than proton pump inhibitors, and its bioavailability is unaffected by food.³¹ It was recently approved in Japan for H pylori eradication in combination with clarithromycin or metronidazole plus amoxicillin.¹⁸

Vonoprazan is more effective than current proton pump inhibitors for keeping the gastric pH high. There are no published studies of vonoprazan dual therapy in Western countries, but given twice a day for 7 days along with twice-daily amoxicillin it cured only approximately 80% of clarithromycin-resistant strains. Further studies are needed to identify the optimum proton pump inhibitor or potassium-competitive acid blocker, dose, and duration.

In triple therapy, the second antimicrobial drug (eg, amoxicillin) is given in part to prevent resistance from developing. It is not clear whether the combination is additive or synergistic, but until we can reliably maintain the intragastric pH above 6.0, which would increase the effectiveness of the amoxicillin component of the regimen, this practice cannot be considered as misuse of antibiotics.

In contrast, in the 4-drug nonbismuth combinations (concomitant, sequential, and hybrid therapies) and the new vonoprazan, clarithromycin, and metronidazole triple therapies, 1 of the antibiotics provides no benefit to some, often most, of the patients.^18–20,32 This practice should end when susceptibility data become more widely available and when vonoprazan becomes available, so that we can deliver effective vonoprazan-amoxicillin dual therapy.

First-, second-, and third-line therapies

Many recommendations give advice in terms of first-, second-, and third-line therapies. In practice, a physician should have at least 2 first-line regimens (a first and a second choice). Both should be proven highly successful as empiric therapies in one’s patient population but differ in terms of primary antibiotics. This approach allows the clinician to tailor therapy depending on whether he or she suspects antibiotic resistance (eg, if the patient has taken clarithromycin before) or the patient is allergic or cannot take 1 or more drugs.

Two treatment failures with 2 different regimens known to be effective suggest poor compliance (a difficult patient) or a multiple-drug-resistant infection (a difficult infection). That patient would require salvage therapy (Table 2), which logically should be based on antimicrobial testing or, at a minimum, consultation with someone who frequently deals with this problem.

Test of cure

Monitoring the outcome of therapy (testing for cure) is essential, as it provides a reliable measure of the local effectiveness of particular therapies and also serves as an early warning of development of resistance in one’s patient population.¹⁴

Unless there are compelling reasons, testing for cure should use noninvasive testing with the urea breath test or stool antigen test. It is recommended that this be delayed at least 4 weeks to allow the organisms if still present to repopulate the stomach sufficiently for the tests to become positive. Because antibiotics, bismuth, and proton pump inhibitors reduce the bacterial load, they should be withheld at least 2 weeks before testing. Histamine-2 receptor antagonists can be substituted for proton pump inhibitors if antisecretory therapy is needed for symptoms, and continued up to the day before testing. The urea breath test should contain citric acid to overcome any residual pH effects. Physician groups should share their experience so as to alert the community about which therapies should likely be avoided.³³

Salvage therapy

Salvage therapy is given after 2 or more treatment failures with different antibiotics. Ideally, the regimen should be based on the results of antimicrobial testing. Current regimens include rifabutin triple therapy, dual therapy (a protein pump inhibitor or vonoprazan and amoxicillin), or furazolidone quadruple therapy (Table 2).

Furazolidone is a synthetic nitrofuran derivative that is effective against many enteric organisms, including gram-negative bacteria and protozoa. It is not available in most Western countries but is available in many other parts of the world.^34,35 It is also a monoamine oxidase inhibitor and thus interacts with many drugs and foods (eg, soy sauce, aged cheeses), leading to a relatively high rate of side effects such as fever, palpitations, and skin rash.

Rifabutin-containing regimens, generally, a proton pump inhibitor, amoxicillin 1 g, and rifabutin 150 mg, all twice a day (Table 3) provide average cure rates of less than 80% (typically in the mid-70% range).³⁶ Borody et al³⁷ reported greater than 95% success with a 12-day regimen consisting of rifabutin 150 mg once daily (half-dose), amoxicillin 1.5 g 3 times a day, and pantoprazole 80 mg (approximately equivalent to omeprazole 20 mg) 3 times a day. Ciccaglione et al,³⁸ in a small study, used a 10-day quadruple regimen containing a proton pump inhibitor, amoxicillin, rifabutin, and bismuth (all twice a day), with high cure rates. The results of these studies are yet to be confirmed, and the optimal rifabutin-containing regimen remains to be determined.

PROBIOTICS

There is considerable interest in using probiotics to enhance the effectiveness of antimicrobial therapy for H pylori by increasing tolerability, reducing side effects, and therefore improving compliance.^39,40

In a meta-analysis of 14 randomized trials (N = 1,671), when probiotics were added, pooled H pylori eradication rates were only slightly improved: 83.6% (95% CI 80.5%–86.7%) with probiotics and 74.8% (95% CI 71.1%–78.5%) without probiotics by intent-to-treat analysis.⁴¹

Another meta-analysis of probiotics suggested that those containing Saccharomyces boulardii, Lactobacillus, and Bifidobacterium significantly increased the eradication rate of triple therapy in populations with high rates of antimicrobial resistance and reduced the risk of overall H pylori therapy-related adverse effects, especially diarrhea.^42,43