Vibration-controlled transient elastography (VCTE) can accurately diagnose cirrhosis in most patients with chronic liver disease, particularly those with chronic hepatitis B or C, states a new guideline from the AGA Institute, published in the May issue of Gastroenterology (doi: 10.1053/j.gastro.2017.03.017).

However, magnetic resonance elastography (MRE) is somewhat more accurate for detecting cirrhosis in nonalcoholic fatty liver disease, wrote Joseph K. Lim, MD, AGAF, of Yale University in New Haven, Conn., with his associates from the Clinical Guidelines Committee of the AGA. VCTE is convenient but performs unevenly in some liver conditions and is especially unreliable in patients with acute hepatitis, alcohol abuse, food intake within 2-3 hours, congestive heart failure, or extrahepatic cholestasis, the guideline notes. Yet, VCTE remains the most common imaging tool for diagnosing fibrosis in the United States, and the guideline addresses “focused, clinically relevant questions” to guide its use.

When possible, clinicians should use VCTE instead of noninvasive serum tests for cirrhosis in patients with chronic hepatitis C, the guideline asserts. In pooled analyses of 62 studies, VCTE detected about 89% of cirrhosis cases (95% confidence interval, 84%-92%), Fibrosis-4 test (FIB-4) detected 87% (95% CI, 74%-94%), and aspartate aminotransferase to platelet ratio index (APRI) detected 77% (95% CI, 73%-81%). The specificity of VCTE (91%) also equaled or exceeded that of FIB-4 (91%) or APRI (78%), the guideline noted.

For chronic hepatitis C, MRE had “poorer specificity with higher false-positive rates, suggesting poorer diagnostic performance,” compared with VCTE. Lower cost and lower point-of-care availability make VCTE “an attractive solution compared to MRE,” the guideline adds. It conditionally recommends VCTE cutoffs of 12.5 kPa for cirrhosis and 9.5 kPa for advanced (F3-F4) liver fibrosis after patients have a sustained virologic response to therapy. The 9.5-kPa cutoff would misclassify only 1% of low-risk patients and 7% of high-risk patients, but noncirrhotic patients (less than 9.5 kPa) may reasonably choose to continue specialty care if they prioritize avoiding “the small risk” of hepatocellular carcinoma over the “inconvenience and risks of continued laboratory and fibrosis testing.”

For chronic hepatitis B, the guideline conditionally recommends VCTE with an 11.0-kPa cutoff over APRI or FIB-4. In a pooled analysis of 28 studies, VCTE detected cirrhosis with a sensitivity of 86% and a specificity of 85%, compared with 66% and 74%, respectively, for APRI, and 87% and 65%, respectively, for FIB-4. However, the overall diagnostic performance of VCTE resembled that of the serum tests, and clinicians should interpret VCTE in the context of other clinical cirrhosis data, the guideline states.

Among 17 studies of VCTE cutoffs in hepatitis B, an 11.0-kPa threshold diagnosed cirrhosis with a sensitivity of 81% and a specificity of 83%. This cutoff would miss cirrhosis in less than 1% of low-risk patients and about 5% of high-risk patients and would yield false positives in 10%-15% of patients. Thus, its cutoff minimizes false negatives, reflecting “a judgment that the harm of missing cirrhosis is greater than the harm of over diagnosis,” the authors write.

For chronic alcoholic liver disease, the AGA conditionally recommends VCTE with a cirrhosis cutoff of 12.5 kPa. In pooled analyses, this value had a sensitivity of 95% and a specificity of 71%. For suspected compensated cirrhosis, the guideline conditionally suggests a 19.5-kPa cutoff when assessing the need for esophagogastroduodenoscopy (EGD) to identify high-risk esophageal varices. Patients who fall below this cutoff can reasonably pursue screening endoscopy if they are concerned about the small risk of acute variceal hemorrhage, the guideline adds.

The guideline also conditionally recommends a 17-kPa cutoff to detect clinically significant portal hypertension in patients with suspected chronic liver disease who are undergoing elective nonhepatic surgeries. This cutoff will miss about 0.1% of very low-risk patients, 0.8% of low-risk patients, and 7% of high-risk patients. Because the failure to detect portal hypertension contributes to operative morbidity and mortality, higher-risk patients might “reasonably” pursue screening endoscopy even if their kPa is below the cutoff, the guideline states.

The guideline made no recommendation about VCTE versus APRI or FIB-4 in adults with nonalcoholic fatty liver disease (NAFLD), citing “unacceptable bias” in 12 studies that excluded obese patients, used per-protocol rather than intention-to-diagnose analyses, and ignored “unsuccessful or inadequate” liver stiffness measurements, which are relatively common in NAFLD, the guideline notes. It conditionally recommends MRE over VCTE in high-risk adults with NAFLD, including those who are older, diabetic, or obese (especially with central adiposity) or who have alanine levels more than twice the upper limit of normal. However, it cites insufficient evidence to extend this recommendation to low-risk patients who only have imaging evidence of fatty liver.

Overall, the guideline focuses on “routine clinical management issues, and [does] not address comparisons with proprietary serum fibrosis assays, other emerging imaging-based fibrosis assessment techniques, or combinations of more than one noninvasive fibrosis test,” the authors note. They also limited VCTE cutoffs to single thresholds that prioritized sensitivity over specificity. “Additional studies are needed to further define the role of VCTE, MRE, and emerging diagnostic studies in the assessment of liver fibrosis, for which a significant unmet medical need remains, particularly in conditions such as NAFLD/[nonalcoholic steatohepatitis],” they add. “In particular, defining the implications for serial liver stiffness measurements over time on management decisions is of great interest.”

Dr. Muir has served as a consultant for AbbVie, Bristol-Myers Squibb, Gilead, and Merck. Dr. Lim has served as a consultant for Bristol Myers-Squibb, Gilead, Merck, and Boehringer Ingelheim. Dr. Flamm has served as a consultant or received research support from Gilead, Bristol-Myers Squibb, AbbVie, Salix Pharmaceuticals, and Intercept Pharmaceuticals. Dr. Dieterich has presented lectures for Gilead and Merck products. The rest of the authors disclosed no conflicts related to the content of this guideline.

Vibration-controlled transient elastography (VCTE) can accurately diagnose cirrhosis in most patients with chronic liver disease, particularly those with chronic hepatitis B or C, states a new guideline from the AGA Institute, published in the May issue of Gastroenterology (doi: 10.1053/j.gastro.2017.03.017).

However, magnetic resonance elastography (MRE) is somewhat more accurate for detecting cirrhosis in nonalcoholic fatty liver disease, wrote Joseph K. Lim, MD, AGAF, of Yale University in New Haven, Conn., with his associates from the Clinical Guidelines Committee of the AGA. VCTE is convenient but performs unevenly in some liver conditions and is especially unreliable in patients with acute hepatitis, alcohol abuse, food intake within 2-3 hours, congestive heart failure, or extrahepatic cholestasis, the guideline notes. Yet, VCTE remains the most common imaging tool for diagnosing fibrosis in the United States, and the guideline addresses “focused, clinically relevant questions” to guide its use.

When possible, clinicians should use VCTE instead of noninvasive serum tests for cirrhosis in patients with chronic hepatitis C, the guideline asserts. In pooled analyses of 62 studies, VCTE detected about 89% of cirrhosis cases (95% confidence interval, 84%-92%), Fibrosis-4 test (FIB-4) detected 87% (95% CI, 74%-94%), and aspartate aminotransferase to platelet ratio index (APRI) detected 77% (95% CI, 73%-81%). The specificity of VCTE (91%) also equaled or exceeded that of FIB-4 (91%) or APRI (78%), the guideline noted.

For chronic hepatitis C, MRE had “poorer specificity with higher false-positive rates, suggesting poorer diagnostic performance,” compared with VCTE. Lower cost and lower point-of-care availability make VCTE “an attractive solution compared to MRE,” the guideline adds. It conditionally recommends VCTE cutoffs of 12.5 kPa for cirrhosis and 9.5 kPa for advanced (F3-F4) liver fibrosis after patients have a sustained virologic response to therapy. The 9.5-kPa cutoff would misclassify only 1% of low-risk patients and 7% of high-risk patients, but noncirrhotic patients (less than 9.5 kPa) may reasonably choose to continue specialty care if they prioritize avoiding “the small risk” of hepatocellular carcinoma over the “inconvenience and risks of continued laboratory and fibrosis testing.”

For chronic hepatitis B, the guideline conditionally recommends VCTE with an 11.0-kPa cutoff over APRI or FIB-4. In a pooled analysis of 28 studies, VCTE detected cirrhosis with a sensitivity of 86% and a specificity of 85%, compared with 66% and 74%, respectively, for APRI, and 87% and 65%, respectively, for FIB-4. However, the overall diagnostic performance of VCTE resembled that of the serum tests, and clinicians should interpret VCTE in the context of other clinical cirrhosis data, the guideline states.

Among 17 studies of VCTE cutoffs in hepatitis B, an 11.0-kPa threshold diagnosed cirrhosis with a sensitivity of 81% and a specificity of 83%. This cutoff would miss cirrhosis in less than 1% of low-risk patients and about 5% of high-risk patients and would yield false positives in 10%-15% of patients. Thus, its cutoff minimizes false negatives, reflecting “a judgment that the harm of missing cirrhosis is greater than the harm of over diagnosis,” the authors write.

For chronic alcoholic liver disease, the AGA conditionally recommends VCTE with a cirrhosis cutoff of 12.5 kPa. In pooled analyses, this value had a sensitivity of 95% and a specificity of 71%. For suspected compensated cirrhosis, the guideline conditionally suggests a 19.5-kPa cutoff when assessing the need for esophagogastroduodenoscopy (EGD) to identify high-risk esophageal varices. Patients who fall below this cutoff can reasonably pursue screening endoscopy if they are concerned about the small risk of acute variceal hemorrhage, the guideline adds.

The guideline also conditionally recommends a 17-kPa cutoff to detect clinically significant portal hypertension in patients with suspected chronic liver disease who are undergoing elective nonhepatic surgeries. This cutoff will miss about 0.1% of very low-risk patients, 0.8% of low-risk patients, and 7% of high-risk patients. Because the failure to detect portal hypertension contributes to operative morbidity and mortality, higher-risk patients might “reasonably” pursue screening endoscopy even if their kPa is below the cutoff, the guideline states.

The guideline made no recommendation about VCTE versus APRI or FIB-4 in adults with nonalcoholic fatty liver disease (NAFLD), citing “unacceptable bias” in 12 studies that excluded obese patients, used per-protocol rather than intention-to-diagnose analyses, and ignored “unsuccessful or inadequate” liver stiffness measurements, which are relatively common in NAFLD, the guideline notes. It conditionally recommends MRE over VCTE in high-risk adults with NAFLD, including those who are older, diabetic, or obese (especially with central adiposity) or who have alanine levels more than twice the upper limit of normal. However, it cites insufficient evidence to extend this recommendation to low-risk patients who only have imaging evidence of fatty liver.

Overall, the guideline focuses on “routine clinical management issues, and [does] not address comparisons with proprietary serum fibrosis assays, other emerging imaging-based fibrosis assessment techniques, or combinations of more than one noninvasive fibrosis test,” the authors note. They also limited VCTE cutoffs to single thresholds that prioritized sensitivity over specificity. “Additional studies are needed to further define the role of VCTE, MRE, and emerging diagnostic studies in the assessment of liver fibrosis, for which a significant unmet medical need remains, particularly in conditions such as NAFLD/[nonalcoholic steatohepatitis],” they add. “In particular, defining the implications for serial liver stiffness measurements over time on management decisions is of great interest.”

Dr. Muir has served as a consultant for AbbVie, Bristol-Myers Squibb, Gilead, and Merck. Dr. Lim has served as a consultant for Bristol Myers-Squibb, Gilead, Merck, and Boehringer Ingelheim. Dr. Flamm has served as a consultant or received research support from Gilead, Bristol-Myers Squibb, AbbVie, Salix Pharmaceuticals, and Intercept Pharmaceuticals. Dr. Dieterich has presented lectures for Gilead and Merck products. The rest of the authors disclosed no conflicts related to the content of this guideline.

Vibration-controlled transient elastography (VCTE) can accurately diagnose cirrhosis in most patients with chronic liver disease, particularly those with chronic hepatitis B or C, states a new guideline from the AGA Institute, published in the May issue of Gastroenterology (doi: 10.1053/j.gastro.2017.03.017).

However, magnetic resonance elastography (MRE) is somewhat more accurate for detecting cirrhosis in nonalcoholic fatty liver disease, wrote Joseph K. Lim, MD, AGAF, of Yale University in New Haven, Conn., with his associates from the Clinical Guidelines Committee of the AGA. VCTE is convenient but performs unevenly in some liver conditions and is especially unreliable in patients with acute hepatitis, alcohol abuse, food intake within 2-3 hours, congestive heart failure, or extrahepatic cholestasis, the guideline notes. Yet, VCTE remains the most common imaging tool for diagnosing fibrosis in the United States, and the guideline addresses “focused, clinically relevant questions” to guide its use.

When possible, clinicians should use VCTE instead of noninvasive serum tests for cirrhosis in patients with chronic hepatitis C, the guideline asserts. In pooled analyses of 62 studies, VCTE detected about 89% of cirrhosis cases (95% confidence interval, 84%-92%), Fibrosis-4 test (FIB-4) detected 87% (95% CI, 74%-94%), and aspartate aminotransferase to platelet ratio index (APRI) detected 77% (95% CI, 73%-81%). The specificity of VCTE (91%) also equaled or exceeded that of FIB-4 (91%) or APRI (78%), the guideline noted.

For chronic hepatitis C, MRE had “poorer specificity with higher false-positive rates, suggesting poorer diagnostic performance,” compared with VCTE. Lower cost and lower point-of-care availability make VCTE “an attractive solution compared to MRE,” the guideline adds. It conditionally recommends VCTE cutoffs of 12.5 kPa for cirrhosis and 9.5 kPa for advanced (F3-F4) liver fibrosis after patients have a sustained virologic response to therapy. The 9.5-kPa cutoff would misclassify only 1% of low-risk patients and 7% of high-risk patients, but noncirrhotic patients (less than 9.5 kPa) may reasonably choose to continue specialty care if they prioritize avoiding “the small risk” of hepatocellular carcinoma over the “inconvenience and risks of continued laboratory and fibrosis testing.”

For chronic hepatitis B, the guideline conditionally recommends VCTE with an 11.0-kPa cutoff over APRI or FIB-4. In a pooled analysis of 28 studies, VCTE detected cirrhosis with a sensitivity of 86% and a specificity of 85%, compared with 66% and 74%, respectively, for APRI, and 87% and 65%, respectively, for FIB-4. However, the overall diagnostic performance of VCTE resembled that of the serum tests, and clinicians should interpret VCTE in the context of other clinical cirrhosis data, the guideline states.

Among 17 studies of VCTE cutoffs in hepatitis B, an 11.0-kPa threshold diagnosed cirrhosis with a sensitivity of 81% and a specificity of 83%. This cutoff would miss cirrhosis in less than 1% of low-risk patients and about 5% of high-risk patients and would yield false positives in 10%-15% of patients. Thus, its cutoff minimizes false negatives, reflecting “a judgment that the harm of missing cirrhosis is greater than the harm of over diagnosis,” the authors write.

For chronic alcoholic liver disease, the AGA conditionally recommends VCTE with a cirrhosis cutoff of 12.5 kPa. In pooled analyses, this value had a sensitivity of 95% and a specificity of 71%. For suspected compensated cirrhosis, the guideline conditionally suggests a 19.5-kPa cutoff when assessing the need for esophagogastroduodenoscopy (EGD) to identify high-risk esophageal varices. Patients who fall below this cutoff can reasonably pursue screening endoscopy if they are concerned about the small risk of acute variceal hemorrhage, the guideline adds.

The guideline also conditionally recommends a 17-kPa cutoff to detect clinically significant portal hypertension in patients with suspected chronic liver disease who are undergoing elective nonhepatic surgeries. This cutoff will miss about 0.1% of very low-risk patients, 0.8% of low-risk patients, and 7% of high-risk patients. Because the failure to detect portal hypertension contributes to operative morbidity and mortality, higher-risk patients might “reasonably” pursue screening endoscopy even if their kPa is below the cutoff, the guideline states.

The guideline made no recommendation about VCTE versus APRI or FIB-4 in adults with nonalcoholic fatty liver disease (NAFLD), citing “unacceptable bias” in 12 studies that excluded obese patients, used per-protocol rather than intention-to-diagnose analyses, and ignored “unsuccessful or inadequate” liver stiffness measurements, which are relatively common in NAFLD, the guideline notes. It conditionally recommends MRE over VCTE in high-risk adults with NAFLD, including those who are older, diabetic, or obese (especially with central adiposity) or who have alanine levels more than twice the upper limit of normal. However, it cites insufficient evidence to extend this recommendation to low-risk patients who only have imaging evidence of fatty liver.

Overall, the guideline focuses on “routine clinical management issues, and [does] not address comparisons with proprietary serum fibrosis assays, other emerging imaging-based fibrosis assessment techniques, or combinations of more than one noninvasive fibrosis test,” the authors note. They also limited VCTE cutoffs to single thresholds that prioritized sensitivity over specificity. “Additional studies are needed to further define the role of VCTE, MRE, and emerging diagnostic studies in the assessment of liver fibrosis, for which a significant unmet medical need remains, particularly in conditions such as NAFLD/[nonalcoholic steatohepatitis],” they add. “In particular, defining the implications for serial liver stiffness measurements over time on management decisions is of great interest.”

Dr. Muir has served as a consultant for AbbVie, Bristol-Myers Squibb, Gilead, and Merck. Dr. Lim has served as a consultant for Bristol Myers-Squibb, Gilead, Merck, and Boehringer Ingelheim. Dr. Flamm has served as a consultant or received research support from Gilead, Bristol-Myers Squibb, AbbVie, Salix Pharmaceuticals, and Intercept Pharmaceuticals. Dr. Dieterich has presented lectures for Gilead and Merck products. The rest of the authors disclosed no conflicts related to the content of this guideline.

The AGA Institute issued a clinical practice update for managing hepatitis C virus–infected patients who achieve a sustained virologic response after antiviral therapy, who still require ongoing care for their liver disease. The expert review appears in the May issue of Gastroenterology (doi: 10.1053/j.gastro.2017.03.018).

Even though direct-acting antiviral regimens have produced remarkably high sustained virologic response (SVR) rates and it appears that fewer than 1% of patients relapse, and even though liver fibrosis and cirrhosis may regress with this therapy, continued surveillance and even intervention may be needed “to reduce complications arising from liver damage that has already accrued by the time SVR was attained,” said Ira M. Jacobson, MD, AGAF, chair of the department of medicine, Mount Sinai Beth Israel Medical Center, New York, and his associates.

The AGA Institute issued a clinical practice update for managing hepatitis C virus–infected patients who achieve a sustained virologic response after antiviral therapy, who still require ongoing care for their liver disease. The expert review appears in the May issue of Gastroenterology (doi: 10.1053/j.gastro.2017.03.018).

Even though direct-acting antiviral regimens have produced remarkably high sustained virologic response (SVR) rates and it appears that fewer than 1% of patients relapse, and even though liver fibrosis and cirrhosis may regress with this therapy, continued surveillance and even intervention may be needed “to reduce complications arising from liver damage that has already accrued by the time SVR was attained,” said Ira M. Jacobson, MD, AGAF, chair of the department of medicine, Mount Sinai Beth Israel Medical Center, New York, and his associates.

The AGA Institute issued a clinical practice update for managing hepatitis C virus–infected patients who achieve a sustained virologic response after antiviral therapy, who still require ongoing care for their liver disease. The expert review appears in the May issue of Gastroenterology (doi: 10.1053/j.gastro.2017.03.018).

Even though direct-acting antiviral regimens have produced remarkably high sustained virologic response (SVR) rates and it appears that fewer than 1% of patients relapse, and even though liver fibrosis and cirrhosis may regress with this therapy, continued surveillance and even intervention may be needed “to reduce complications arising from liver damage that has already accrued by the time SVR was attained,” said Ira M. Jacobson, MD, AGAF, chair of the department of medicine, Mount Sinai Beth Israel Medical Center, New York, and his associates.

INTRODUCTION

Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a leading nonobstetric cause of maternal death in the United States and in developed countries.^1,2 During pregnancy, the risk for VTE increases four- to six-fold, and although the risk is present throughout pregnancy, the mother is at highest risk immediately postpartum.^3–5

VTE risk is increased due to physiologic and anatomic changes that occur in pregnancy. These changes include hypercoagulability, progesterone-induced venous stasis, decreased venous outflow, compression of the inferior vena cava and pelvic veins by the expanding uterus, and decreased mobility. The hypercoagulability of pregnancy is due to increased levels of coagulation factors I (fibrinogen), VII, VIII, and X, and von Willebrand factor; decreased free protein S, a natural anticoagulant; acquired resistance to activated protein C; and decreased fibrinolysis due to increased levels of plasminogen activator inhibitor-1 and -2.^6,7 These changes confer increased hemostasis to the mother for delivery but also place her at higher risk for thrombosis.

A review of the literature found that more than 70% of pregnancy-associated DVTs are located in the ileofemoral region, as compared with approximately 9% in non-pregnant patients.⁸ The proximal location is associated with a higher risk for post-thrombotic syndrome and embolization as compared with calf DVTs.⁹ Proximal postnatal thrombosis, smoking, and older age are independent predictors of the development of post-thrombotic syndrome.¹⁰

RISK FACTORS

Clinical risk factors that increase the risk for VTE during pregnancy include a prior history of estrogen-related or unprovoked VTE, being a carrier of severe inherited thrombophilia (homozygotes for factor V Leiden or factor II G20210A variants, double heterozygotes, or persons with antithrombin, protein C, or protein S deficiencies), and the presence of antiphospholipid (aPL) antibodies.¹¹ Women with systemic lupus erythematosus, diabetes, sickle cell disease, and heart disease also have a high risk for VTE during pregnancy.¹² Other risk factors predisposing to thrombosis include black ethnicity, smoking, operative procedures, conception after assisted reproductive techniques, high body mass index, antepartum immobilization, severe preeclampsia, advanced age and parity, and a family history of VTE.¹³ A prospective cohort study of 1,297,037 pregnancies and related puerperium identified the following risk factors for thrombosis: hospitalization, infection, hyperemesis, multiple pregnancies, preeclampsia, obesity, cesarean section, major postpartum hemorrhage, intrauterine growth restriction, and fetal death.¹⁴ Risk factors identified in an Agency for Healthcare Research and Quality study include: age 35 or older, black ethnicity, lupus, sickle cell disease, heart disease, postpartum infection, and transfusion.¹⁵ The combination of more than one risk factor increases the risk for VTE. All these factors have to be considered when deciding on prophylactic or therapeutic anticoagulation therapy in pregnancy. In addition, the risks of anticoagulation, including bruising, bleeding, and other side effects (eg, reduced bone mineral density with therapeutic-dose unfractionated heparin), allergic reactions, and rarely thrombocytopenia, must be considered.

EVALUATION AND DIAGNOSIS

CASE PRESENTATION I

A 31-year-old woman G1P0 at 10 weeks’ gestation with no personal or family history of thrombosis presents with acute onset of shortness of breath and left-sided chest pain that awoke her the morning of presentation. Her vital signs are significant for a heart rate of 106 beats/min, respiration rate of 22 breaths/min, blood pressure of 105/76 mm Hg, and pulse oximetry of 98% on room air. The patient denies previous exposure to oral contraceptives. She does not smoke. She reports that she had noticed left calf pain and swelling, which worsened with walking after a 4-hour drive 2 days prior.

• What is the approach to diagnosis of thromboembolism in pregnant patients?

DEEP VEIN THROMBOSIS

Although a clinical diagnosis of DVT in pregnancy is unreliable, a history and physical examination are necessary to exclude other diagnoses and to assess the likelihood of thrombosis. Unfortunately, studies of the accuracy of history and physical examination for detecting DVT and PE have not included pregnant patients. In most pregnant patients with clinically suspected DVT, the diagnosis is not confirmed. Other causes of leg pain and swelling are not uncommon during pregnancy and include cellulitis, ruptured Baker’s cyst, or muscular pain.

A cross-sectional study described the derivation of the LEFt clinical decision rule, which relies on 3 variables in pregnant women with suspected DVT: left leg presentation (L), ≥ 2 cm calf circumference difference (E for edema), and first trimester presentation (Ft). If none of these variables is present, the negative predictive value is 100%.¹⁶ A validation study suggested that a negative LEFt rule accurately identifies pregnant women in whom the risk for confirmed DVT appears to be very low. The rule should not be used as an individual test for excluding DVT during pregnancy, but could be applied in a diagnostic approach in association with D-dimer measurement and compression ultrasonography (CUS); however, it has not been prospectively validated for safety and efficacy.¹⁷ In a study of 149 consecutive pregnant women with suspected DVT, a whole-blood agglutination D-dimer had a sensitivity of 100% and specificity of 60%.¹⁸ A 2006 systematic review found only 4 diagnostic studies of VTE in pregnancy in the literature. One of these studies showed that a combination of a negative CUS and normal D-dimer can accurately exclude DVT.¹⁹

Serial CUS is necessary for pregnant women with a high clinical suspicion of DVT but a negative initial investigation. In a study of 221 pregnant women in whom DVT was clinically suspected, 16 women (7.2%) were diagnosed with DVT by initial CUS, and none were diagnosed with DVT onserial testing.²⁰ During follow-up (≥ 3 months), 6 of the 205 women with normal serial CUS results presented with symptoms of DVT, PE, or both, and 1 of them was diagnosed with DVT and PE. The sensitivity of serial CUS with Doppler imaging was 94.1% (95% confidence interval [CI] 69.2% to 99.7%), and the negative predictive value was 99.5% (95% CI 96.9% to 100%).²⁰ All ultrasounds undertaken for investigation of pregnancy-associated DVT should include imaging of the iliac veins if there is a high index of suspicion and the CUS is negative for femoral DVT. Serial CUS with Doppler imaging of the iliac vein performed over a 7-day period excludes DVT in symptomatic pregnant women.²⁰ Repeat CUS may be done 2 to 4 days and 6 to 8 days after the initial scan.

Ileofemoral vein thrombosis accounts for approximately 90% of proximal thromboses in pregnancy, occurring most often in the left lower extremity.²⁰ The incidence of isolated iliac vein thrombosis in pregnancy is low, but when it does occur, delay in diagnosis can lead to significant morbidity. Therefore, for women with suspected isolated iliac vein thrombosis in whom CUS is negative or nondiagnostic, magnetic resonance direct thrombus imaging (MRDTI) should be performed.²¹ Patients with iliac vein thrombosis may present with unexplained inguinal, pelvic, or abdominal pain, which may be accompanied by back pain, and they usually present with swelling of the entire leg. MRDTI does not require gadolinium contrast and its accuracy appears to be similar to that of venography for iliac vein thrombi in the nonpregnant population.²¹ Exposure to gadolinium during pregnancy is associated with an increased risk for rheumatologic, inflammatory, or infiltrative skin conditions and stillbirth or neonatal death.²²

Ovarian vein thrombosis is a rare but serious diagnosis. It occurs mostly in the postpartum period, mainly after cesarean delivery, and usually affects the right ovarian vein. The diagnosis is confirmed by ultrasound, computed tomography (CT), or magnetic resonance imaging.²³

PULMONARY EMBOLISM

PE is more difficult to diagnose than DVT, particularly because clinical signs of PE are unreliable in the pregnant patient. The mortality rate of untreated PE is high, ranging from 18% to 38%, and approximately one-third of patients with untreated thromboembolic disease develop recurrent embolism.²⁴ Studies have reported a PE prevalence between 1.4% and 4.2% in pregnant women with suspected clinical diagnosis of PE.²⁵

The clinical presentation of PE and associated laboratory testing results may be subtler in pregnant than in nonpregnant patients. Arterial blood gases (ABG) may show hypoxemia or hypocapnia. The ABG in pregnancy has a sensitivity of 76.9%, specificity of 20.2%, and negative and positive predictive values of 80% and 11.5% for PE, respectively.²⁶ The alveolar-arterial oxygen gradient is a poor screening test for PE during pregnancy and postpartum. A retrospective chart review of 17 pregnant women with documented PE showed that 58% had normal alveolar-arterial gradients.²⁷ Therefore, in a pregnant woman with a history suspicious for PE, objective imaging studies should be performed even if the patient has normal ABG.

The 2011 guidelines from the American Thoracic Society (ATS) and the Society of Thoracic Radiology (STR) recommend against using D-dimer to diagnose PE in pregnancy.²⁸ In addition, lower extremity CUS should only be performed as the first diagnostic imaging procedure if the patient has signs or symptoms of DVT. Instead, the ATS/STR guidelines recommend a plain radiograph of the chest as the first imaging test. If the chest radiograph is normal, a ventilation/perfusion scan (V/Q) scan is preferred over CT pulmonary angiography (CTPA). Diagnostic accuracy of the V/Q scan may be superior to CTPA in pregnancy, and it is preferable because of the lower prevalence of indeterminate V/Q scan in pregnant women.²⁹ Moreover, there is lower radiation exposure to the maternal breast and lung tissue with a V/Q scan than with CTPA. CTPA confers lower fetal radiation doses than V/Q scans (0.03–0.66 mGy versus 0.32–0.74 mGy, respectively) but higher total body maternal radiation (4–16 mSv versus 1–2.5 mSv).³⁰ A quantitative approach to lung scan interpretation, based on the distribution histogram of V/Q ratios, may be helpful in categorizing patients with suspected PE.²⁸ A study of 121 suspected episodes of PE in 120 pregnant women showed that 104 women with normal or nondiagnostic scans did not develop subsequent episodes of VTE during a mean follow-up period of 20 months.³¹

If the baseline chest radiograph is abnormal in a pregnant woman with clinical suspicion of PE, a CTPA should be performed. As noted, fetal radiation doses for CTPA examinations in which the fetus is not directly imaged are minimal. If CTPA is recommended for the diagnosis of PE, the patient should be informed that radiation to the breast may increase her baseline risk for breast cancer. The ATS guidelines state that “given the lack of evidence documenting clear superiority of any one diagnostic test, the values and preferences of a patient and her physician likely will and should determine the final choice and sequence of tests performed.”²⁸

CASE I CONTINUED

Upon presentation to the emergency department, the circumference of the patient’s left leg is not significantly greater than that of her right leg, and her leg pain has resolved. Bilateral CUS is negative for proximal or distal DVT. Chest radiograph shows an opacification of her left lower lobe. CTPA shows bilateral segmental and subsegmental lower lobe pulmonary emboli.

• How does risk for VTE change throughout pregnancy?

Women are at increased risk for VTE throughout the entire pregnancy, starting from conception, but mainly during the postpartum period. A Danish historical controlled cohort study of 819,751 pregnant women (ages 15–49 years) over a 10-year period identified 727 women with VTE. The absolute risk for VTE per 10,000 pregnancy-years increased from 4.1 (95% CI 3.2 to 5.2) during weeks 1 to 11 to 59.0 (95% CI 46.1 to 76.4) in week 40 and decreased in the postpartum period from 60 (95% CI 47.2 to 76.4) during the first week after birth to 2.1 during weeks 9–12 after birth (95% CI 1.1 to 4.2).³² This study showed that the risk of VTE increases throughout pregnancy and reaches its maximum during the peripartum period and is not significantly increased after 6 weeks post-delivery. In a retrospective cross-over cohort study of 1,687,930 women in California who delivered their first newborn, an elevated risk of VTE persisted until at least 12 weeks after delivery. However, the absolute increase in risk after 6 weeks postpartum was low.³³

CASE 1 CONCLUSION

The patient is started on anticoagulation therapy and carefully monitored during the remainder of the pregnancy and postpartum period. Anticoagulation is discontinued 6 weeks after delivery.

TREATMENT

ANTICOAGULATION THERAPY

The treatment of VTE can be lifesaving. In a study comparing 35 patients with PE randomly assigned to treatment with anticoagulants versus no treatment, 5 of 19 patients in the untreated group died from PE and an additional 5 had nonfatal recurrences, as compared with none in the treated group.²⁴ Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are both safe and effective anticoagulants during pregnancy as neither crosses the placenta. In a review of 186 reports of fetal and infant outcomes following anticoagulant therapy during pregnancy in 1325 pregnancies, outcomes in UFH-treated patients were similar to those in the normal population after excluding pregnancies with comorbid conditions independently associated with adverse outcomes.³⁴ A 2005 systematic review of LMWH for prophylaxis and treatment of VTE during pregnancy included 64 studies of 277 pregnancies. There were no maternal deaths, live births resulted from 94.7% of the pregnancies, VTE or arterial thrombosis occurred in 0.86%, and significant bleeding occurred in 1.98%.³⁵

The standard UFH regimen is an initial bolus of 5000 units subcutaneously and 17,500 units every 12 hours, with dose adjustment made based on a mid-interval activated partial thromboplastin time (aPTT).³⁶ Although still controversial, it has been suggested that the anti-Xa assay with a mid-dosing interval target of 0.3 to 0.7 U/mL is a more reliable measure of therapeutic UFH activity than the aPTT, as the aPTT response is suppressed due to a pregnancy-related increase in factor VIII. LMWH is dosed based on weight; regimens are enoxaparin 1 mg/kg subcutaneously twice daily or 1.5 mg/kg subcutaneously once daily, and dalteparin 100 units/kg every 12 hours or 150 units/kg daily.

A 2017 Cochrane review of the effect of LMWH compared with UFH for the treatment of VTE in the nonpregnant setting included 23 studies with 9587 patients. Thrombotic complications (odds ratio [OR] 0.70 [CI 0.57 to 0.85]) and major hemorrhage (OR 0.58 [CI 0.40 to 0.83]) were lower in patients receiving LMWH, with a trend toward lower mortality.³⁷ In addition, the incidence of bleeding complications in patients treated with subcutaneous LMWH versus intravenous heparin was compared in a 2012 systematic review of 27 randomized controlled trials with a total of 28,637 patients. In patients treated with LMWH, there was a nonstatistically significant lower incidence of major bleeding events (OR 0.79 [95% CI 0.60 to 1.04]) and a statistically significant reduction in bleeding risk (OR 0.68 [95% CI 0.47 to 1.00]) compared to patients treated with UFH.³⁸ Additionally, a trial comparing the use of standard UFH versus LMWH found a significantly lower incidence of thrombocytopenia in patients treated with LMWH.^39,40 Overall, LMWH is more effective at decreasing both thrombotic and bleeding complications, and the risk for osteoporosis is lower with LMWH. Based on these results, the American College of Chest Physicians (ACCP) recommends LMWH as the first-line treatment for VTE in pregnancy.⁴¹

In specific clinical situations, such as patients with renal dysfunction with creatinine clearance (CrCl) less than 30 mL/min, UFH is indicated. In a study of 103 pregnancies in 93 women given anti-coagulation during pregnancy, 89.3% received UFH. There were no maternal deaths, and fetal demise occurred in 8 pregnancies (7.8%) at a median of 14 weeks’ gestation. There were 2 episodes of PE (1.9%) and 2 major bleeding events requiring transfusion (1.9%).⁴² UFH costs much less than LMWH, and therefore UFH remains an important, inexpensive, and efficacious anticoagulant option for pregnant women who require anticoagulation and cannot afford LMWH.⁴³

Due to the physiologic changes associated with pregnancy, LMWH and UFH dosages may need to be adjusted. An observational study of 20 pregnant women with acute VTE found no recurrent VTE or major bleeding after treatment with dalteparin. Dalteparin doses approximately 10% to 20% higher than those recommended in nonpregnant women were required to reach therapeutic target anti-Xa activity.⁴⁴

Caution Regarding Oral Anticoagulants

Due to its teratogenicity, warfarin is not a first-line anticoagulation option. It is strictly contraindicated during the first trimester during organogenesis, and its use during pregnancy is restricted to women with mechanical heart valves. Warfarin crosses the placenta and has been associated with nasal hypoplasia, stippled epiphyses, and growth restriction, particularly between 6 to 9 weeks’ gestation. Every effort should be made to substitute UFH or LMWH for warfarin between 6 and 12 weeks of gestation. The bridging process should begin as early in the gestational age as possible due to the long half-life of warfarin.⁴⁵ When used later in gestation, warfarin has been associated with fetal hemorrhage and central nervous system abnormalities. Other complications from use during the second and third trimesters include microcephaly, blindness, deafness, and fetal growth restriction.^46,47 Its use also increases the risk for abortion and fetal death in utero.^48–50

The direct oral anticoagulants (DOACs) are not approved for use in pregnancy. Although there are limited anecdotal reports of DOAC use in pregnancy,⁵¹ there is preclinical evidence of placental transfer with the DOACs rivaroxaban and apixaban (direct Xa inhibitors) and the oral thrombin inhibitor dabigatran, thus increasing the risk to the fetus.^52–54 Edoxaban, another direct Xa inhibitor, should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It should be discontinued in nursing mothers.⁵⁵

THROMBOLYSIS

Fetal as well as maternal survival is dependent on adequate maternal perfusion and oxygenation. The risk of death from PE is significant, with a cross-sectional study of 58 patients with acute, massive PE showing a 55% mortality rate.⁵⁶ Thus, pregnancy is not an absolute contraindication to mechanical or systemic (recombinant tissue plasminogen activator or streptokinase) thrombolysis in an unstable patient at high risk for death.^57–59 There are no major studies of this approach, although a small review of 13 cases using systemic thrombolysis showed no increased risk of maternal mortality.⁵⁸ Thrombolysis should be considered for appropriate indications in pregnant patients as it would be in nonpregnant patients. However, caution is required when drawing conclusions regarding maternal and fetal safety, given the lack of controlled clinical trials including pregnant women.

SURGICAL PULMONARY EMBOLECTOMY

Surgical pulmonary embolectomy is an important therapeutic and potentially life-saving option in women presenting with massive PE in the immediate postpartum period. Because of the risk of massive uterine bleeding immediately postpartum, thrombolytic therapy should not be used.⁶⁰

INFERIOR VENA CAVA FILTER

Placement of an inferior vena cava (IVC) filter is indicated in patients who have an acute VTE with absolute contraindications for anticoagulation. In addition, it can be considered in patients with extensive ileofemoral venous thrombosis within 2 weeks prior to expected delivery.⁶¹ In a systematic review of 44 studies of IVC filters placed in pregnant patients, the IVC filter complication rate was 8.87% and the failure-to-retrieve rate was 11.25%.⁶² The complication rate is similar to that found in the nonpregnant population. Thus, IVC filters may be used when appropriately indicated and should be removed as soon as clinically feasible.

RECURRENT THROMBOSIS AND THROMBOPHILIAS

CASE PRESENTATION 2

A 34-year-old pregnant woman G1P0 at 38 weeks’ gestation presents with a painful, swollen left calf that is associated with difficulty on walking; the circumference of the left calf is 2 cm greater than that of the right. She has no shortness of breath or chest pain. She has a prior history of distal right lower extremity DVT while on combined oral contraceptives. Her mother also has a history of DVT while bedbound during a prolonged hospitalization at an older age. CUS is negative, and the patient is discharged home. However, 24 hours later she returns to the hospital with worsening swelling and pain in her left leg. Magnetic resonance venography demonstrates a large left external iliac and common iliac DVT. She is admitted and is started on UFH, and a retrievable IVC filter is placed in anticipation of delivery.

• What is the risk for VTE recurrence during pregnancy?

A personal and family history of VTE should be obtained when evaluating pregnant patients. A retrospective study of 109 women with prior history of VTE showed recurrence rates per patient-year of 10.9% during pregnancy and 3.7% in the nonpregnant period; the relative risk of recurrent VTE during pregnancy was 3.5 (95% CI 1.6 to 7.8).⁶³ Two large European retrospective cohort studies of VTE in pregnancy showed that the recurrence rate of VTE in women with a history of thrombosis is around 6% during pregnancy, equally distributed among trimesters. The highest incidence of recurrence was in the postpartum period, ranging from 8.3% to 10%.⁶⁴ The recurrence risk during pregnancy in women with a history of a single episode of VTE was 2.4% antepartum (95% CI 0.2% to 6.9%).⁶⁵ These risks may be lower in women without thrombophilia or with a temporary risk factor associated with their previous thromboembolic event.⁶⁵ Recurrence risk is higher if the previous VTE was estrogen-related, either due to pregnancy or through hormonal contraception (10%), than if the previous VTE was non-estrogen-related (2.7%).^64,66

The timing of the case patient’s presentation is consistent with reports of increased risk of VTE during the peripartum period. Her prior history of estrogen-related DVT is concerning for a risk of recurrence, particularly during pregnancy. A retrospective cohort study of 1104 women with previous VTE, 88 of whom became pregnant without receiving thromboprophylaxis, showed that the overall rate of VTE recurrence was 5.8% (95% CI 3.0% to 10.6%) and 8.3% (95% CI 4.5% to 14.6%) during pregnancy and postpartum, respectively. The risk of VTE recurrence was absent if the first VTE was related to a transient risk factor other than pregnancy, postpartum period, or hormonal contraception.⁶⁷ However, the recurrence rate of VTE in women with prior unprovoked VTE and/or thrombophilia has been reported as 5.9% (95% CI 1.2% to 16.2%).⁶⁵ The presence of an underlying hypercoagulable state can increase the recurrence risk by 25% to 50%, depending on the disorder.⁶⁸ A retrospective cohort study of 270 pregnancies in 105 carriers of factor V Leiden, identified because of a symptomatic relative with the factor V Leiden mutation, found a VTE risk (mostly in the postpartum period) of 6.4% for heterozygous women, 16.7% for homozygous women, 20% for double heterozygous women, and 1.2% for noncarriers.⁶⁹

• Should the patient be screened for a thrombophilia disorder?

Half of all index thromboses in patients with thrombophilia occur in association with an additional risk factor. In women of child-bearing age, pregnancy, the postpartum period, and the use of combined hormonal contraception are all risk factors for VTE. A 2010 guideline from the British hematology community recommended testing for thrombophilia in women with prior VTE secondary to a minor provoking factor before or during pregnancy, but not testing women with unprovoked VTE (who would receive prophylaxis regardless) or those with VTE secondary to a major provoking factor (who would not require prophylaxis).⁷⁰ Indications to screen for aPL antibodies include: women with (1) 3 unexplained recurrent first-trimester pregnancy losses or 1 second or third trimester fetal loss of morphologically normal fetuses; (2) severe preeclampsia; (3) intrauterine growth restriction; or (4) premature labor (< 34 weeks’ gestation).^71,72

CASE 2 CONCLUSION

The patient is subsequently screened for inherited thrombophilia disorders and is found to be heterozygous for factor V Leiden.

CASE PRESENTATION 3

A 25-year-old woman is diagnosed with antiphospholipid syndrome (APS) during her second pregnancy when she experiences fetal loss during her second trimester. Pathologic examination of the placenta reveals infarcts. Laboratory evaluation reveals positive high-titer anticardiolipin and anti-beta-2 glycoprotein 1 antibodies (IgG isotype) and lupus anticoagulant on 2 separate occasions 12 weeks apart. In a subsequent pregnancy, she is started on prophylactic LMWH and daily low-dose aspirin (81 mg). At 36 weeks’ gestation, she presents with a blood pressure of 210/104 mm Hg and a platelet count of 94,000 cells/µL. She is diagnosed with preeclampsia and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome and is induced for early delivery. About 2 weeks after vaginal delivery, she notices shortness of breath and chest pain. A CTPA demonstrates a right lower lobe lobar defect consistent with a PE. Her anticoagulation is increased to therapeutic dosage LMWH.

• To what extent does thrombophilia increase the risk for VTE in pregnancy?

Approximately 50% of pregnancy-related VTEs are associated with inherited thrombophilia. A systematic review of 79 studies, in which 9 studies (n = 2526 patients) assessed the risk of VTE associated with inherited thrombophilia in pregnancy, revealed that the odds ratio for individuals with thrombophilia to develop VTE ranged from 0.74 to 34.40.⁷³ Although women with thrombophilia have an increased relative risk of developing VTE in pregnancy, the absolute risk of VTE remains low (Table 1).^41,73,74

• How is APS managed in pregnant patients?

Women with history of recurrent early pregnancy loss (< 10 weeks’ gestation) related to the presence of aPL antibodies are managed with low-dose aspirin and prophylactic-dose UFH or LMWH. This treatment increases the rate of subsequent successful pregnancy outcomes and reduces the risk for thrombosis. A 2010 systematic review and meta-analysis of UFH plus low-dose aspirin compared with low-dose aspirin alone in patients with APS and recurrent pregnancy loss included 5 trials and 334 patients. Patients receiving dual therapy had higher rates of live births (74.3%; relative risk [RR] 1.30 [CI 1.04 to 1.63]) compared to the aspirin-only group (55.8%).⁷⁵ A 2009 randomized controlled trial compared low-dose aspirin to low-dose aspirin plus LMWH in women with recurrent pregnancy loss and either aPL antibodies, antinuclear antibody, or inherited thrombophilia. The study was stopped early after 4 years and found no difference in rates of live births between the groups (77.8% versus 79.1%).⁷⁶ However, a randomized case-control trial of women with aPL antibodies and recurrent miscarriage found a 72% live birth rate in 47 women randomly assigned to low-dose aspirin and LMWH.⁷⁷ A 2012 guideline from the American College of Chest Physicians (ACCP) recommends that women with aPL antibodies with a history of 3 or more pregnancy losses receive low-dose aspirin plus prophylactic-dose LMWH or UFH.⁷⁸ A 2014 systematic review and meta-analysis showed that the combination of low-dose aspirin and UFH resulted in a higher live-birth rate than aspirin alone in 803 women with APS (RR 1.54 [95% CI 1.25 to 1.89]).⁷⁹ Further large randomized controlled trials are needed to confirm optimal management of recurrent miscarriage and aPL antibodies.

The addition of prednisone to aspirin, heparin, or both has shown no benefits in pregnant women with aPL antibodies. Indeed, prolonged use of steroids may cause serious pregnancy complications, such as prematurity and hypertension.^80–83 Intravenous infusions of immunoglobulin (IVIG) have not been shown to be superior to heparin and aspirin. This finding was confirmed in a multicenter clinical trial that tested the effects of IVIG compared with LMWH plus low-dose aspirin for the treatment of women with aPL antibodies and recurrent miscarriage. The rate of live-birth was 72.5% in the group treated with heparin plus low-dose aspirin compared with 39.5% in the IVIG group.⁸⁴

Preeclampsia and HELLP syndrome complicated the case patient’s pregnancy even though she was being treated with prophylactic-dose LMWH and low-dose aspirin, the current standard of care for pregnant women with APS (UFH can be used as well). It is important to note that complications may still occur despite standard treatment. Indeed, PE is more common in the postpartum than in the antepartum period. Prompt diagnosis is paramount to initiate the appropriate treatment; in this case the dose of LMWH was increased from prophylactic to therapeutic dose. However, additional therapeutic modalities are necessary to improve outcomes. A randomized controlled trial comparing standard of care with or without hydroxychloroquine is under way to address this issue.

PROPHYLAXIS

CASE PRESENTATION 4

A 34-year-old woman G1P0 at 6 weeks’ gestation with a past medical history of a proximal lower extremity DVT while on oral contraception is treated with warfarin anticoagulation for 6 months. Her obstetrician consults the hematologist to advise regarding antithrombotic management during this pregnancy.

• What is the approach to prophylaxis in women at high risk for pregnancy-associated VTE?

All women at high risk for pregnancy-associated VTE should be counseled about the signs and symptoms of DVT or PE during preconception and pregnancy and have a plan developed should these symptoms arise. The ACCP guidelines on antithrombotic therapy outline recommendations ranging from clinical vigilance to prophylactic and intermediate-dose anticoagulation, depending on the risk for VTE recurrence, based on the personal and family history of VTE and type of thrombophilia (Table 2).⁷⁸ These recommendations range from grade 2B to 2C.

For women with a history of estrogen-related VTE, single unprovoked VTE, or recurrent unprovoked VTE not on chronic anticoagulation, antepartum and postpartum pharmacologic thromboprophylaxis with either prophylactic or intermediate-dose LMWH is recommended (grade 2C). In patients with prior history of provoked VTE (non-estrogen related), antepartum clinical vigilance and postpartum pharmacologic thromboprophylaxis is recommended (grade 2C, 2B).

In asymptomatic pregnant women who are homozygote carriers for factor V Leiden or prothrombin G20210A variants and have a positive family history of thrombosis, antepartum and postpartum pharmacologic thromboprophylaxis is recommended (grade 2B). In asymptomatic homozygote carriers of factor V Leiden or prothrombin G20210A variants with no family history of thrombosis and women with all other thrombophilias with a positive family history of thrombosis, postpartum pharmacologic thromboprophylaxis is indicated (grade 2B and 2C, respectively). For women with confirmed APS and clinical criteria of obstetric APS with recurrent pregnancy loss, antepartum thromboprophylaxis with LMWH and low-dose aspirin is recommended (grade 1B). For pregnant women with all other thrombophilias with no personal or family history of thrombosis, clinical vigilance is suggested (grade 2 C).⁷⁸

As an alternative to LMWH, vitamin K antagonists (VKA) such as warfarin can be used for postpartum thromboprophylaxis; in patients with protein C or S deficiency, due to the risk of warfarin-induced skin necrosis, a rapid-onset anticoagulant must be concomitantly administered. Warfarin and LMWH are safe anticoagulants during lactation, but there are no clinical data on the effects of the DOACs on infants during lactation. Data from animal studies indicate that DOACs are secreted into breast milk.⁸⁵

• What risks are associated with anticoagulant therapy in pregnancy?

VKAs cross the placenta and can cause teratogenicity, pregnancy loss, fetal bleeding, and neurodevelopmental deficits. Therefore, discontinuation of VKAs prior to the sixth week of gestation is necessary to avoid warfarin embryopathy. DOACs have been shown to readily cross the placenta but with unknown human reproductive risks. Fondaparinux, a synthetic pentasaccharide, crosses the placenta in small quantities. Though there are reports of the successful use of fondaparinux in pregnancy, there is limited reported experience of its use in the first trimester.⁸⁶

The risk for bleeding with anticoagulation is notably acceptable. In a case-control study of 88 pregnant women receiving therapeutic-dose anticoagulation, the risk of postpartum hemorrhage (PPH) after vaginal delivery was 30% in those who received LMWH anticoagulation versus 18% in those who did not (OR 1.9 [95% CI 1.1 to 3.5]).⁸⁷ However, the risk for severe PPH (≥ 500 mL) was similar (5.6% versus 5.0%; OR 1.1 [95% CI 0.4 to 3.6]). The risk for PPH after cesarean section was 12% in LMWH users versus 4% in LMWH non-users (OR 2.9 [95% CI 0.5 to 19.4]). The risk for PPH associated with delivery within 24 hours after the last dose of LMWH was 1.2 times higher (95% CI 0.4 to 3.6) compared to a longer interval. Therefore, therapeutic LMWH increases the risk for blood loss after vaginal delivery, but not the risk for severe PPH. The risk for PPH is influenced by the interval between the last dose of LMWH and delivery. Of note in this study, per the institution’s protocol, the anticoagulation was stopped with signs of labor or determination of need for delivery. The risk for blood loss may be mitigated in more planned delivery scenarios.⁸⁷

CASE 4 CONTINUED

The patient is placed on prophylactic-dose LMWH with good tolerance and delivers at 39 weeks' gestation via caesarian section due to nonprogression of labor. Postpartum she is restarted on prophylactic-dose anticoagulation with LMWH. Two weeks after discharge from the hospital, she presents with right calf pain and mild shortness of breath. On physical exam, her leg circumferences are equal. A D-dimer assay is 3375 ng/mL (normal 0–229). CUS of the right leg shows a complete occlusive DVT of the mid-distal superficial femoral and popliteal veins and partially occlusive acute DVT of the right posterior tibial and peroneal veins. CTPA reveals a right lower lobe PE. Because she had developed VTE despite prophylactic LMWH, her anticoagulation is changed to therapeutic dose. She is treated with anticoagulation with LMWH for a total of 3 months, after which a repeat CUS shows no residual thrombosis.

• What is the recommended dosing of heparin and LMWH during pregnancy?

A prospective study of 14 pregnant women receiving UFH prophylaxis found that a prophylactic dose of 5000 units twice a day was inadequate to achieve prophylactic heparin levels in any patient in the second or third trimester.⁸⁸ Similar to treatment dosage, there is no consensus evidence for prophylactic dosing, and dosage recommendations are based on expert opinion. In a retrospective study of 25 pregnant women on intermediate-dose UFH, the mean UFH dose required to achieve a target anti-factor Xa level of 0.1 to 0.3 units/mL was 236.9 units/kg/day.⁸⁹ However, the use of anti-factor Xa levels for monitoring is controversial as there is no data to support a difference in outcomes with its use in prophylactic or therapeutic dosing.

The timing of the previous VTE history is important when deciding on the anticoagulant dose in pregnancy. In pregnant women with a VTE that occurred within the previous 4 to 6 weeks, full-dose anticoagulation with LMWH should be considered; an intermediate dose (three-fourths of a therapeutic dose) may be used if the thrombotic episode occurred more than 6 weeks earlier but still within a year. Prophylactic dosing may be sufficient if the episode occurred more than a year earlier.⁹⁰ A clinical trial (High-Low) is under way to explore the optimal dose of LMWH in pregnant women with prior history of VTE who are not on chronic anticoagulation therapy.⁹¹

• How is anticoagulation therapy managed in the peripartum period?

Neuraxial anesthesia during active labor while on anticoagulation increases the risk for central nervous system bleeding. Therefore, if spontaneous labor occurs in women on therapeutic dose anticoagulation, neuraxial anesthesia cannot be used. However, in the event of elective induction of labor or caesarean section, neuroaxial anesthesia may be performed 12 hours after the administration of the last prophylactic dose of LMWH or 24 hours after the last therapeutic dose of LMWH. Intravenous UFH should be stopped for 6 hours before induction of labor with a confirmed normal aPTT before placement of neuraxial anesthesia. There is no contraindication for using neuraxial anesthesia during subcutaneous standard UFH at total doses of 10,000 units daily. The risk of spinal hematoma with larger daily subcutaneous doses is unclear; therefore, a documented normal aPTT must be obtained before placement of neuroaxial anesthesia.

Postpartum, reinitiation of prophylactic-dose LMWH should be delayed for at least 12 hours after the removal of an epidural catheter. Therapeutic-dose LMWH should be administered no earlier than 24 hours after neuraxial anesthesia, providing that proper hemostasis is achieved. In the absence of persistent bleeding, if no regional anesthesia was used, LMWH may be resumed 12 hours after delivery.⁹² Anticoagulation with either LMWH or warfarin is recommended for at least 6 to 12 weeks postpartum.³³

COUNSELING

Patients should be advised to manage controllable risk factors, including avoiding prolonged immobilization, avoiding excessive weight gain in pregnancy, and stopping smoking. Periods of immobilization tend to cause reduced blood flow (stasis), which predisposes to thrombosis. In a systematic review of records of all patients with confirmed PE after arrival at Charles de Gaulle airport in Paris during a 13-year period, women had a higher risk of PE after a long-distance flight than men, with an estimated incidence of 0.61 per million passengers versus 0.20, respectively; the incidence reached 7.24 and 2.35 cases, respectively, in passengers traveling more than 10,000 kilometers.^93,94

The risk of air travel-related thrombosis in pregnant women is estimated to be between 0.03% and 0.1%. Physicians must decide on an individual basis how to prevent travel-related thrombosis in their pregnant patients. In most passengers, prevention can be limited to encouraging exercise, avoidance of long sleeping periods, and not using a window seat. Women at high risk for VTE, such as women with a prior history of VTE who are not on anticoagulation or women with known asymptomatic thrombophilia or other risk factors for thrombosis such as obesity, may benefit from a short period (1–3 days) of LMWH starting 2 hours before a long-distance flight.⁹⁵

Activation of the coagulation system has been demonstrated in cigarette smokers.⁹⁶ Heavy smoking was found to be a significant risk factor for VTE in a cross-sectional analysis of 2404 men and women.⁹⁷ An increased risk for thrombosis during pregnancy is seen in cigarette smokers^15,98 and is enhanced with the concomitant use of illicit drugs.⁹⁹ Other obstetric complications associated with smoking and illicit drug use during pregnancy include preterm labor, spontaneous abortion, perinatal death, low birth weight, and abruption placenta. The efficacy of nicotine replacement therapy in pregnancy is uncertain.¹⁰⁰ Recommendations are to advise patients to stop smoking, obtain psychosocial counseling, and utilize adjunctive therapies, which have been shown to have some effect on abstinence rates.¹⁰¹

CONCLUSION

Women are at increased risk for VTE during pregnancy and the postpartum period. Awareness of risk factors and the signs and symptoms of VTE is paramount. Prompt diagnosis and treatment is mandatory to decrease complications of VTE. LMWH is the mainstay treatment of VTE in pregnancy, as it does not cross the placenta. Both LMWH and warfarin are safe during lactation. Close communication among the patient, obstetrician, hematologist, anesthesiologist, and neonatologist is crucial to optimize the care of these patients.

INTRODUCTION

Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a leading nonobstetric cause of maternal death in the United States and in developed countries.^1,2 During pregnancy, the risk for VTE increases four- to six-fold, and although the risk is present throughout pregnancy, the mother is at highest risk immediately postpartum.^3–5

VTE risk is increased due to physiologic and anatomic changes that occur in pregnancy. These changes include hypercoagulability, progesterone-induced venous stasis, decreased venous outflow, compression of the inferior vena cava and pelvic veins by the expanding uterus, and decreased mobility. The hypercoagulability of pregnancy is due to increased levels of coagulation factors I (fibrinogen), VII, VIII, and X, and von Willebrand factor; decreased free protein S, a natural anticoagulant; acquired resistance to activated protein C; and decreased fibrinolysis due to increased levels of plasminogen activator inhibitor-1 and -2.^6,7 These changes confer increased hemostasis to the mother for delivery but also place her at higher risk for thrombosis.

A review of the literature found that more than 70% of pregnancy-associated DVTs are located in the ileofemoral region, as compared with approximately 9% in non-pregnant patients.⁸ The proximal location is associated with a higher risk for post-thrombotic syndrome and embolization as compared with calf DVTs.⁹ Proximal postnatal thrombosis, smoking, and older age are independent predictors of the development of post-thrombotic syndrome.¹⁰

RISK FACTORS

Clinical risk factors that increase the risk for VTE during pregnancy include a prior history of estrogen-related or unprovoked VTE, being a carrier of severe inherited thrombophilia (homozygotes for factor V Leiden or factor II G20210A variants, double heterozygotes, or persons with antithrombin, protein C, or protein S deficiencies), and the presence of antiphospholipid (aPL) antibodies.¹¹ Women with systemic lupus erythematosus, diabetes, sickle cell disease, and heart disease also have a high risk for VTE during pregnancy.¹² Other risk factors predisposing to thrombosis include black ethnicity, smoking, operative procedures, conception after assisted reproductive techniques, high body mass index, antepartum immobilization, severe preeclampsia, advanced age and parity, and a family history of VTE.¹³ A prospective cohort study of 1,297,037 pregnancies and related puerperium identified the following risk factors for thrombosis: hospitalization, infection, hyperemesis, multiple pregnancies, preeclampsia, obesity, cesarean section, major postpartum hemorrhage, intrauterine growth restriction, and fetal death.¹⁴ Risk factors identified in an Agency for Healthcare Research and Quality study include: age 35 or older, black ethnicity, lupus, sickle cell disease, heart disease, postpartum infection, and transfusion.¹⁵ The combination of more than one risk factor increases the risk for VTE. All these factors have to be considered when deciding on prophylactic or therapeutic anticoagulation therapy in pregnancy. In addition, the risks of anticoagulation, including bruising, bleeding, and other side effects (eg, reduced bone mineral density with therapeutic-dose unfractionated heparin), allergic reactions, and rarely thrombocytopenia, must be considered.

EVALUATION AND DIAGNOSIS

CASE PRESENTATION I

A 31-year-old woman G1P0 at 10 weeks’ gestation with no personal or family history of thrombosis presents with acute onset of shortness of breath and left-sided chest pain that awoke her the morning of presentation. Her vital signs are significant for a heart rate of 106 beats/min, respiration rate of 22 breaths/min, blood pressure of 105/76 mm Hg, and pulse oximetry of 98% on room air. The patient denies previous exposure to oral contraceptives. She does not smoke. She reports that she had noticed left calf pain and swelling, which worsened with walking after a 4-hour drive 2 days prior.

• What is the approach to diagnosis of thromboembolism in pregnant patients?

DEEP VEIN THROMBOSIS

Although a clinical diagnosis of DVT in pregnancy is unreliable, a history and physical examination are necessary to exclude other diagnoses and to assess the likelihood of thrombosis. Unfortunately, studies of the accuracy of history and physical examination for detecting DVT and PE have not included pregnant patients. In most pregnant patients with clinically suspected DVT, the diagnosis is not confirmed. Other causes of leg pain and swelling are not uncommon during pregnancy and include cellulitis, ruptured Baker’s cyst, or muscular pain.

A cross-sectional study described the derivation of the LEFt clinical decision rule, which relies on 3 variables in pregnant women with suspected DVT: left leg presentation (L), ≥ 2 cm calf circumference difference (E for edema), and first trimester presentation (Ft). If none of these variables is present, the negative predictive value is 100%.¹⁶ A validation study suggested that a negative LEFt rule accurately identifies pregnant women in whom the risk for confirmed DVT appears to be very low. The rule should not be used as an individual test for excluding DVT during pregnancy, but could be applied in a diagnostic approach in association with D-dimer measurement and compression ultrasonography (CUS); however, it has not been prospectively validated for safety and efficacy.¹⁷ In a study of 149 consecutive pregnant women with suspected DVT, a whole-blood agglutination D-dimer had a sensitivity of 100% and specificity of 60%.¹⁸ A 2006 systematic review found only 4 diagnostic studies of VTE in pregnancy in the literature. One of these studies showed that a combination of a negative CUS and normal D-dimer can accurately exclude DVT.¹⁹

Serial CUS is necessary for pregnant women with a high clinical suspicion of DVT but a negative initial investigation. In a study of 221 pregnant women in whom DVT was clinically suspected, 16 women (7.2%) were diagnosed with DVT by initial CUS, and none were diagnosed with DVT onserial testing.²⁰ During follow-up (≥ 3 months), 6 of the 205 women with normal serial CUS results presented with symptoms of DVT, PE, or both, and 1 of them was diagnosed with DVT and PE. The sensitivity of serial CUS with Doppler imaging was 94.1% (95% confidence interval [CI] 69.2% to 99.7%), and the negative predictive value was 99.5% (95% CI 96.9% to 100%).²⁰ All ultrasounds undertaken for investigation of pregnancy-associated DVT should include imaging of the iliac veins if there is a high index of suspicion and the CUS is negative for femoral DVT. Serial CUS with Doppler imaging of the iliac vein performed over a 7-day period excludes DVT in symptomatic pregnant women.²⁰ Repeat CUS may be done 2 to 4 days and 6 to 8 days after the initial scan.

Ileofemoral vein thrombosis accounts for approximately 90% of proximal thromboses in pregnancy, occurring most often in the left lower extremity.²⁰ The incidence of isolated iliac vein thrombosis in pregnancy is low, but when it does occur, delay in diagnosis can lead to significant morbidity. Therefore, for women with suspected isolated iliac vein thrombosis in whom CUS is negative or nondiagnostic, magnetic resonance direct thrombus imaging (MRDTI) should be performed.²¹ Patients with iliac vein thrombosis may present with unexplained inguinal, pelvic, or abdominal pain, which may be accompanied by back pain, and they usually present with swelling of the entire leg. MRDTI does not require gadolinium contrast and its accuracy appears to be similar to that of venography for iliac vein thrombi in the nonpregnant population.²¹ Exposure to gadolinium during pregnancy is associated with an increased risk for rheumatologic, inflammatory, or infiltrative skin conditions and stillbirth or neonatal death.²²

Ovarian vein thrombosis is a rare but serious diagnosis. It occurs mostly in the postpartum period, mainly after cesarean delivery, and usually affects the right ovarian vein. The diagnosis is confirmed by ultrasound, computed tomography (CT), or magnetic resonance imaging.²³

PULMONARY EMBOLISM

PE is more difficult to diagnose than DVT, particularly because clinical signs of PE are unreliable in the pregnant patient. The mortality rate of untreated PE is high, ranging from 18% to 38%, and approximately one-third of patients with untreated thromboembolic disease develop recurrent embolism.²⁴ Studies have reported a PE prevalence between 1.4% and 4.2% in pregnant women with suspected clinical diagnosis of PE.²⁵

The clinical presentation of PE and associated laboratory testing results may be subtler in pregnant than in nonpregnant patients. Arterial blood gases (ABG) may show hypoxemia or hypocapnia. The ABG in pregnancy has a sensitivity of 76.9%, specificity of 20.2%, and negative and positive predictive values of 80% and 11.5% for PE, respectively.²⁶ The alveolar-arterial oxygen gradient is a poor screening test for PE during pregnancy and postpartum. A retrospective chart review of 17 pregnant women with documented PE showed that 58% had normal alveolar-arterial gradients.²⁷ Therefore, in a pregnant woman with a history suspicious for PE, objective imaging studies should be performed even if the patient has normal ABG.

The 2011 guidelines from the American Thoracic Society (ATS) and the Society of Thoracic Radiology (STR) recommend against using D-dimer to diagnose PE in pregnancy.²⁸ In addition, lower extremity CUS should only be performed as the first diagnostic imaging procedure if the patient has signs or symptoms of DVT. Instead, the ATS/STR guidelines recommend a plain radiograph of the chest as the first imaging test. If the chest radiograph is normal, a ventilation/perfusion scan (V/Q) scan is preferred over CT pulmonary angiography (CTPA). Diagnostic accuracy of the V/Q scan may be superior to CTPA in pregnancy, and it is preferable because of the lower prevalence of indeterminate V/Q scan in pregnant women.²⁹ Moreover, there is lower radiation exposure to the maternal breast and lung tissue with a V/Q scan than with CTPA. CTPA confers lower fetal radiation doses than V/Q scans (0.03–0.66 mGy versus 0.32–0.74 mGy, respectively) but higher total body maternal radiation (4–16 mSv versus 1–2.5 mSv).³⁰ A quantitative approach to lung scan interpretation, based on the distribution histogram of V/Q ratios, may be helpful in categorizing patients with suspected PE.²⁸ A study of 121 suspected episodes of PE in 120 pregnant women showed that 104 women with normal or nondiagnostic scans did not develop subsequent episodes of VTE during a mean follow-up period of 20 months.³¹

If the baseline chest radiograph is abnormal in a pregnant woman with clinical suspicion of PE, a CTPA should be performed. As noted, fetal radiation doses for CTPA examinations in which the fetus is not directly imaged are minimal. If CTPA is recommended for the diagnosis of PE, the patient should be informed that radiation to the breast may increase her baseline risk for breast cancer. The ATS guidelines state that “given the lack of evidence documenting clear superiority of any one diagnostic test, the values and preferences of a patient and her physician likely will and should determine the final choice and sequence of tests performed.”²⁸

CASE I CONTINUED

Upon presentation to the emergency department, the circumference of the patient’s left leg is not significantly greater than that of her right leg, and her leg pain has resolved. Bilateral CUS is negative for proximal or distal DVT. Chest radiograph shows an opacification of her left lower lobe. CTPA shows bilateral segmental and subsegmental lower lobe pulmonary emboli.

• How does risk for VTE change throughout pregnancy?

Women are at increased risk for VTE throughout the entire pregnancy, starting from conception, but mainly during the postpartum period. A Danish historical controlled cohort study of 819,751 pregnant women (ages 15–49 years) over a 10-year period identified 727 women with VTE. The absolute risk for VTE per 10,000 pregnancy-years increased from 4.1 (95% CI 3.2 to 5.2) during weeks 1 to 11 to 59.0 (95% CI 46.1 to 76.4) in week 40 and decreased in the postpartum period from 60 (95% CI 47.2 to 76.4) during the first week after birth to 2.1 during weeks 9–12 after birth (95% CI 1.1 to 4.2).³² This study showed that the risk of VTE increases throughout pregnancy and reaches its maximum during the peripartum period and is not significantly increased after 6 weeks post-delivery. In a retrospective cross-over cohort study of 1,687,930 women in California who delivered their first newborn, an elevated risk of VTE persisted until at least 12 weeks after delivery. However, the absolute increase in risk after 6 weeks postpartum was low.³³

CASE 1 CONCLUSION

The patient is started on anticoagulation therapy and carefully monitored during the remainder of the pregnancy and postpartum period. Anticoagulation is discontinued 6 weeks after delivery.

TREATMENT

ANTICOAGULATION THERAPY

The treatment of VTE can be lifesaving. In a study comparing 35 patients with PE randomly assigned to treatment with anticoagulants versus no treatment, 5 of 19 patients in the untreated group died from PE and an additional 5 had nonfatal recurrences, as compared with none in the treated group.²⁴ Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are both safe and effective anticoagulants during pregnancy as neither crosses the placenta. In a review of 186 reports of fetal and infant outcomes following anticoagulant therapy during pregnancy in 1325 pregnancies, outcomes in UFH-treated patients were similar to those in the normal population after excluding pregnancies with comorbid conditions independently associated with adverse outcomes.³⁴ A 2005 systematic review of LMWH for prophylaxis and treatment of VTE during pregnancy included 64 studies of 277 pregnancies. There were no maternal deaths, live births resulted from 94.7% of the pregnancies, VTE or arterial thrombosis occurred in 0.86%, and significant bleeding occurred in 1.98%.³⁵

The standard UFH regimen is an initial bolus of 5000 units subcutaneously and 17,500 units every 12 hours, with dose adjustment made based on a mid-interval activated partial thromboplastin time (aPTT).³⁶ Although still controversial, it has been suggested that the anti-Xa assay with a mid-dosing interval target of 0.3 to 0.7 U/mL is a more reliable measure of therapeutic UFH activity than the aPTT, as the aPTT response is suppressed due to a pregnancy-related increase in factor VIII. LMWH is dosed based on weight; regimens are enoxaparin 1 mg/kg subcutaneously twice daily or 1.5 mg/kg subcutaneously once daily, and dalteparin 100 units/kg every 12 hours or 150 units/kg daily.

A 2017 Cochrane review of the effect of LMWH compared with UFH for the treatment of VTE in the nonpregnant setting included 23 studies with 9587 patients. Thrombotic complications (odds ratio [OR] 0.70 [CI 0.57 to 0.85]) and major hemorrhage (OR 0.58 [CI 0.40 to 0.83]) were lower in patients receiving LMWH, with a trend toward lower mortality.³⁷ In addition, the incidence of bleeding complications in patients treated with subcutaneous LMWH versus intravenous heparin was compared in a 2012 systematic review of 27 randomized controlled trials with a total of 28,637 patients. In patients treated with LMWH, there was a nonstatistically significant lower incidence of major bleeding events (OR 0.79 [95% CI 0.60 to 1.04]) and a statistically significant reduction in bleeding risk (OR 0.68 [95% CI 0.47 to 1.00]) compared to patients treated with UFH.³⁸ Additionally, a trial comparing the use of standard UFH versus LMWH found a significantly lower incidence of thrombocytopenia in patients treated with LMWH.^39,40 Overall, LMWH is more effective at decreasing both thrombotic and bleeding complications, and the risk for osteoporosis is lower with LMWH. Based on these results, the American College of Chest Physicians (ACCP) recommends LMWH as the first-line treatment for VTE in pregnancy.⁴¹

In specific clinical situations, such as patients with renal dysfunction with creatinine clearance (CrCl) less than 30 mL/min, UFH is indicated. In a study of 103 pregnancies in 93 women given anti-coagulation during pregnancy, 89.3% received UFH. There were no maternal deaths, and fetal demise occurred in 8 pregnancies (7.8%) at a median of 14 weeks’ gestation. There were 2 episodes of PE (1.9%) and 2 major bleeding events requiring transfusion (1.9%).⁴² UFH costs much less than LMWH, and therefore UFH remains an important, inexpensive, and efficacious anticoagulant option for pregnant women who require anticoagulation and cannot afford LMWH.⁴³

Due to the physiologic changes associated with pregnancy, LMWH and UFH dosages may need to be adjusted. An observational study of 20 pregnant women with acute VTE found no recurrent VTE or major bleeding after treatment with dalteparin. Dalteparin doses approximately 10% to 20% higher than those recommended in nonpregnant women were required to reach therapeutic target anti-Xa activity.⁴⁴

Caution Regarding Oral Anticoagulants

Due to its teratogenicity, warfarin is not a first-line anticoagulation option. It is strictly contraindicated during the first trimester during organogenesis, and its use during pregnancy is restricted to women with mechanical heart valves. Warfarin crosses the placenta and has been associated with nasal hypoplasia, stippled epiphyses, and growth restriction, particularly between 6 to 9 weeks’ gestation. Every effort should be made to substitute UFH or LMWH for warfarin between 6 and 12 weeks of gestation. The bridging process should begin as early in the gestational age as possible due to the long half-life of warfarin.⁴⁵ When used later in gestation, warfarin has been associated with fetal hemorrhage and central nervous system abnormalities. Other complications from use during the second and third trimesters include microcephaly, blindness, deafness, and fetal growth restriction.^46,47 Its use also increases the risk for abortion and fetal death in utero.^48–50

The direct oral anticoagulants (DOACs) are not approved for use in pregnancy. Although there are limited anecdotal reports of DOAC use in pregnancy,⁵¹ there is preclinical evidence of placental transfer with the DOACs rivaroxaban and apixaban (direct Xa inhibitors) and the oral thrombin inhibitor dabigatran, thus increasing the risk to the fetus.^52–54 Edoxaban, another direct Xa inhibitor, should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It should be discontinued in nursing mothers.⁵⁵

THROMBOLYSIS

Fetal as well as maternal survival is dependent on adequate maternal perfusion and oxygenation. The risk of death from PE is significant, with a cross-sectional study of 58 patients with acute, massive PE showing a 55% mortality rate.⁵⁶ Thus, pregnancy is not an absolute contraindication to mechanical or systemic (recombinant tissue plasminogen activator or streptokinase) thrombolysis in an unstable patient at high risk for death.^57–59 There are no major studies of this approach, although a small review of 13 cases using systemic thrombolysis showed no increased risk of maternal mortality.⁵⁸ Thrombolysis should be considered for appropriate indications in pregnant patients as it would be in nonpregnant patients. However, caution is required when drawing conclusions regarding maternal and fetal safety, given the lack of controlled clinical trials including pregnant women.

SURGICAL PULMONARY EMBOLECTOMY

Surgical pulmonary embolectomy is an important therapeutic and potentially life-saving option in women presenting with massive PE in the immediate postpartum period. Because of the risk of massive uterine bleeding immediately postpartum, thrombolytic therapy should not be used.⁶⁰

INFERIOR VENA CAVA FILTER

Placement of an inferior vena cava (IVC) filter is indicated in patients who have an acute VTE with absolute contraindications for anticoagulation. In addition, it can be considered in patients with extensive ileofemoral venous thrombosis within 2 weeks prior to expected delivery.⁶¹ In a systematic review of 44 studies of IVC filters placed in pregnant patients, the IVC filter complication rate was 8.87% and the failure-to-retrieve rate was 11.25%.⁶² The complication rate is similar to that found in the nonpregnant population. Thus, IVC filters may be used when appropriately indicated and should be removed as soon as clinically feasible.

RECURRENT THROMBOSIS AND THROMBOPHILIAS

CASE PRESENTATION 2

A 34-year-old pregnant woman G1P0 at 38 weeks’ gestation presents with a painful, swollen left calf that is associated with difficulty on walking; the circumference of the left calf is 2 cm greater than that of the right. She has no shortness of breath or chest pain. She has a prior history of distal right lower extremity DVT while on combined oral contraceptives. Her mother also has a history of DVT while bedbound during a prolonged hospitalization at an older age. CUS is negative, and the patient is discharged home. However, 24 hours later she returns to the hospital with worsening swelling and pain in her left leg. Magnetic resonance venography demonstrates a large left external iliac and common iliac DVT. She is admitted and is started on UFH, and a retrievable IVC filter is placed in anticipation of delivery.

• What is the risk for VTE recurrence during pregnancy?

A personal and family history of VTE should be obtained when evaluating pregnant patients. A retrospective study of 109 women with prior history of VTE showed recurrence rates per patient-year of 10.9% during pregnancy and 3.7% in the nonpregnant period; the relative risk of recurrent VTE during pregnancy was 3.5 (95% CI 1.6 to 7.8).⁶³ Two large European retrospective cohort studies of VTE in pregnancy showed that the recurrence rate of VTE in women with a history of thrombosis is around 6% during pregnancy, equally distributed among trimesters. The highest incidence of recurrence was in the postpartum period, ranging from 8.3% to 10%.⁶⁴ The recurrence risk during pregnancy in women with a history of a single episode of VTE was 2.4% antepartum (95% CI 0.2% to 6.9%).⁶⁵ These risks may be lower in women without thrombophilia or with a temporary risk factor associated with their previous thromboembolic event.⁶⁵ Recurrence risk is higher if the previous VTE was estrogen-related, either due to pregnancy or through hormonal contraception (10%), than if the previous VTE was non-estrogen-related (2.7%).^64,66

The timing of the case patient’s presentation is consistent with reports of increased risk of VTE during the peripartum period. Her prior history of estrogen-related DVT is concerning for a risk of recurrence, particularly during pregnancy. A retrospective cohort study of 1104 women with previous VTE, 88 of whom became pregnant without receiving thromboprophylaxis, showed that the overall rate of VTE recurrence was 5.8% (95% CI 3.0% to 10.6%) and 8.3% (95% CI 4.5% to 14.6%) during pregnancy and postpartum, respectively. The risk of VTE recurrence was absent if the first VTE was related to a transient risk factor other than pregnancy, postpartum period, or hormonal contraception.⁶⁷ However, the recurrence rate of VTE in women with prior unprovoked VTE and/or thrombophilia has been reported as 5.9% (95% CI 1.2% to 16.2%).⁶⁵ The presence of an underlying hypercoagulable state can increase the recurrence risk by 25% to 50%, depending on the disorder.⁶⁸ A retrospective cohort study of 270 pregnancies in 105 carriers of factor V Leiden, identified because of a symptomatic relative with the factor V Leiden mutation, found a VTE risk (mostly in the postpartum period) of 6.4% for heterozygous women, 16.7% for homozygous women, 20% for double heterozygous women, and 1.2% for noncarriers.⁶⁹

• Should the patient be screened for a thrombophilia disorder?

Half of all index thromboses in patients with thrombophilia occur in association with an additional risk factor. In women of child-bearing age, pregnancy, the postpartum period, and the use of combined hormonal contraception are all risk factors for VTE. A 2010 guideline from the British hematology community recommended testing for thrombophilia in women with prior VTE secondary to a minor provoking factor before or during pregnancy, but not testing women with unprovoked VTE (who would receive prophylaxis regardless) or those with VTE secondary to a major provoking factor (who would not require prophylaxis).⁷⁰ Indications to screen for aPL antibodies include: women with (1) 3 unexplained recurrent first-trimester pregnancy losses or 1 second or third trimester fetal loss of morphologically normal fetuses; (2) severe preeclampsia; (3) intrauterine growth restriction; or (4) premature labor (< 34 weeks’ gestation).^71,72

CASE 2 CONCLUSION

The patient is subsequently screened for inherited thrombophilia disorders and is found to be heterozygous for factor V Leiden.

CASE PRESENTATION 3

A 25-year-old woman is diagnosed with antiphospholipid syndrome (APS) during her second pregnancy when she experiences fetal loss during her second trimester. Pathologic examination of the placenta reveals infarcts. Laboratory evaluation reveals positive high-titer anticardiolipin and anti-beta-2 glycoprotein 1 antibodies (IgG isotype) and lupus anticoagulant on 2 separate occasions 12 weeks apart. In a subsequent pregnancy, she is started on prophylactic LMWH and daily low-dose aspirin (81 mg). At 36 weeks’ gestation, she presents with a blood pressure of 210/104 mm Hg and a platelet count of 94,000 cells/µL. She is diagnosed with preeclampsia and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome and is induced for early delivery. About 2 weeks after vaginal delivery, she notices shortness of breath and chest pain. A CTPA demonstrates a right lower lobe lobar defect consistent with a PE. Her anticoagulation is increased to therapeutic dosage LMWH.

• To what extent does thrombophilia increase the risk for VTE in pregnancy?

Approximately 50% of pregnancy-related VTEs are associated with inherited thrombophilia. A systematic review of 79 studies, in which 9 studies (n = 2526 patients) assessed the risk of VTE associated with inherited thrombophilia in pregnancy, revealed that the odds ratio for individuals with thrombophilia to develop VTE ranged from 0.74 to 34.40.⁷³ Although women with thrombophilia have an increased relative risk of developing VTE in pregnancy, the absolute risk of VTE remains low (Table 1).^41,73,74

• How is APS managed in pregnant patients?

Women with history of recurrent early pregnancy loss (< 10 weeks’ gestation) related to the presence of aPL antibodies are managed with low-dose aspirin and prophylactic-dose UFH or LMWH. This treatment increases the rate of subsequent successful pregnancy outcomes and reduces the risk for thrombosis. A 2010 systematic review and meta-analysis of UFH plus low-dose aspirin compared with low-dose aspirin alone in patients with APS and recurrent pregnancy loss included 5 trials and 334 patients. Patients receiving dual therapy had higher rates of live births (74.3%; relative risk [RR] 1.30 [CI 1.04 to 1.63]) compared to the aspirin-only group (55.8%).⁷⁵ A 2009 randomized controlled trial compared low-dose aspirin to low-dose aspirin plus LMWH in women with recurrent pregnancy loss and either aPL antibodies, antinuclear antibody, or inherited thrombophilia. The study was stopped early after 4 years and found no difference in rates of live births between the groups (77.8% versus 79.1%).⁷⁶ However, a randomized case-control trial of women with aPL antibodies and recurrent miscarriage found a 72% live birth rate in 47 women randomly assigned to low-dose aspirin and LMWH.⁷⁷ A 2012 guideline from the American College of Chest Physicians (ACCP) recommends that women with aPL antibodies with a history of 3 or more pregnancy losses receive low-dose aspirin plus prophylactic-dose LMWH or UFH.⁷⁸ A 2014 systematic review and meta-analysis showed that the combination of low-dose aspirin and UFH resulted in a higher live-birth rate than aspirin alone in 803 women with APS (RR 1.54 [95% CI 1.25 to 1.89]).⁷⁹ Further large randomized controlled trials are needed to confirm optimal management of recurrent miscarriage and aPL antibodies.

The addition of prednisone to aspirin, heparin, or both has shown no benefits in pregnant women with aPL antibodies. Indeed, prolonged use of steroids may cause serious pregnancy complications, such as prematurity and hypertension.^80–83 Intravenous infusions of immunoglobulin (IVIG) have not been shown to be superior to heparin and aspirin. This finding was confirmed in a multicenter clinical trial that tested the effects of IVIG compared with LMWH plus low-dose aspirin for the treatment of women with aPL antibodies and recurrent miscarriage. The rate of live-birth was 72.5% in the group treated with heparin plus low-dose aspirin compared with 39.5% in the IVIG group.⁸⁴

Preeclampsia and HELLP syndrome complicated the case patient’s pregnancy even though she was being treated with prophylactic-dose LMWH and low-dose aspirin, the current standard of care for pregnant women with APS (UFH can be used as well). It is important to note that complications may still occur despite standard treatment. Indeed, PE is more common in the postpartum than in the antepartum period. Prompt diagnosis is paramount to initiate the appropriate treatment; in this case the dose of LMWH was increased from prophylactic to therapeutic dose. However, additional therapeutic modalities are necessary to improve outcomes. A randomized controlled trial comparing standard of care with or without hydroxychloroquine is under way to address this issue.

PROPHYLAXIS

CASE PRESENTATION 4

A 34-year-old woman G1P0 at 6 weeks’ gestation with a past medical history of a proximal lower extremity DVT while on oral contraception is treated with warfarin anticoagulation for 6 months. Her obstetrician consults the hematologist to advise regarding antithrombotic management during this pregnancy.

• What is the approach to prophylaxis in women at high risk for pregnancy-associated VTE?

All women at high risk for pregnancy-associated VTE should be counseled about the signs and symptoms of DVT or PE during preconception and pregnancy and have a plan developed should these symptoms arise. The ACCP guidelines on antithrombotic therapy outline recommendations ranging from clinical vigilance to prophylactic and intermediate-dose anticoagulation, depending on the risk for VTE recurrence, based on the personal and family history of VTE and type of thrombophilia (Table 2).⁷⁸ These recommendations range from grade 2B to 2C.

For women with a history of estrogen-related VTE, single unprovoked VTE, or recurrent unprovoked VTE not on chronic anticoagulation, antepartum and postpartum pharmacologic thromboprophylaxis with either prophylactic or intermediate-dose LMWH is recommended (grade 2C). In patients with prior history of provoked VTE (non-estrogen related), antepartum clinical vigilance and postpartum pharmacologic thromboprophylaxis is recommended (grade 2C, 2B).

In asymptomatic pregnant women who are homozygote carriers for factor V Leiden or prothrombin G20210A variants and have a positive family history of thrombosis, antepartum and postpartum pharmacologic thromboprophylaxis is recommended (grade 2B). In asymptomatic homozygote carriers of factor V Leiden or prothrombin G20210A variants with no family history of thrombosis and women with all other thrombophilias with a positive family history of thrombosis, postpartum pharmacologic thromboprophylaxis is indicated (grade 2B and 2C, respectively). For women with confirmed APS and clinical criteria of obstetric APS with recurrent pregnancy loss, antepartum thromboprophylaxis with LMWH and low-dose aspirin is recommended (grade 1B). For pregnant women with all other thrombophilias with no personal or family history of thrombosis, clinical vigilance is suggested (grade 2 C).⁷⁸

As an alternative to LMWH, vitamin K antagonists (VKA) such as warfarin can be used for postpartum thromboprophylaxis; in patients with protein C or S deficiency, due to the risk of warfarin-induced skin necrosis, a rapid-onset anticoagulant must be concomitantly administered. Warfarin and LMWH are safe anticoagulants during lactation, but there are no clinical data on the effects of the DOACs on infants during lactation. Data from animal studies indicate that DOACs are secreted into breast milk.⁸⁵

• What risks are associated with anticoagulant therapy in pregnancy?

VKAs cross the placenta and can cause teratogenicity, pregnancy loss, fetal bleeding, and neurodevelopmental deficits. Therefore, discontinuation of VKAs prior to the sixth week of gestation is necessary to avoid warfarin embryopathy. DOACs have been shown to readily cross the placenta but with unknown human reproductive risks. Fondaparinux, a synthetic pentasaccharide, crosses the placenta in small quantities. Though there are reports of the successful use of fondaparinux in pregnancy, there is limited reported experience of its use in the first trimester.⁸⁶

The risk for bleeding with anticoagulation is notably acceptable. In a case-control study of 88 pregnant women receiving therapeutic-dose anticoagulation, the risk of postpartum hemorrhage (PPH) after vaginal delivery was 30% in those who received LMWH anticoagulation versus 18% in those who did not (OR 1.9 [95% CI 1.1 to 3.5]).⁸⁷ However, the risk for severe PPH (≥ 500 mL) was similar (5.6% versus 5.0%; OR 1.1 [95% CI 0.4 to 3.6]). The risk for PPH after cesarean section was 12% in LMWH users versus 4% in LMWH non-users (OR 2.9 [95% CI 0.5 to 19.4]). The risk for PPH associated with delivery within 24 hours after the last dose of LMWH was 1.2 times higher (95% CI 0.4 to 3.6) compared to a longer interval. Therefore, therapeutic LMWH increases the risk for blood loss after vaginal delivery, but not the risk for severe PPH. The risk for PPH is influenced by the interval between the last dose of LMWH and delivery. Of note in this study, per the institution’s protocol, the anticoagulation was stopped with signs of labor or determination of need for delivery. The risk for blood loss may be mitigated in more planned delivery scenarios.⁸⁷

CASE 4 CONTINUED

The patient is placed on prophylactic-dose LMWH with good tolerance and delivers at 39 weeks' gestation via caesarian section due to nonprogression of labor. Postpartum she is restarted on prophylactic-dose anticoagulation with LMWH. Two weeks after discharge from the hospital, she presents with right calf pain and mild shortness of breath. On physical exam, her leg circumferences are equal. A D-dimer assay is 3375 ng/mL (normal 0–229). CUS of the right leg shows a complete occlusive DVT of the mid-distal superficial femoral and popliteal veins and partially occlusive acute DVT of the right posterior tibial and peroneal veins. CTPA reveals a right lower lobe PE. Because she had developed VTE despite prophylactic LMWH, her anticoagulation is changed to therapeutic dose. She is treated with anticoagulation with LMWH for a total of 3 months, after which a repeat CUS shows no residual thrombosis.

• What is the recommended dosing of heparin and LMWH during pregnancy?

A prospective study of 14 pregnant women receiving UFH prophylaxis found that a prophylactic dose of 5000 units twice a day was inadequate to achieve prophylactic heparin levels in any patient in the second or third trimester.⁸⁸ Similar to treatment dosage, there is no consensus evidence for prophylactic dosing, and dosage recommendations are based on expert opinion. In a retrospective study of 25 pregnant women on intermediate-dose UFH, the mean UFH dose required to achieve a target anti-factor Xa level of 0.1 to 0.3 units/mL was 236.9 units/kg/day.⁸⁹ However, the use of anti-factor Xa levels for monitoring is controversial as there is no data to support a difference in outcomes with its use in prophylactic or therapeutic dosing.

The timing of the previous VTE history is important when deciding on the anticoagulant dose in pregnancy. In pregnant women with a VTE that occurred within the previous 4 to 6 weeks, full-dose anticoagulation with LMWH should be considered; an intermediate dose (three-fourths of a therapeutic dose) may be used if the thrombotic episode occurred more than 6 weeks earlier but still within a year. Prophylactic dosing may be sufficient if the episode occurred more than a year earlier.⁹⁰ A clinical trial (High-Low) is under way to explore the optimal dose of LMWH in pregnant women with prior history of VTE who are not on chronic anticoagulation therapy.⁹¹

• How is anticoagulation therapy managed in the peripartum period?

Neuraxial anesthesia during active labor while on anticoagulation increases the risk for central nervous system bleeding. Therefore, if spontaneous labor occurs in women on therapeutic dose anticoagulation, neuraxial anesthesia cannot be used. However, in the event of elective induction of labor or caesarean section, neuroaxial anesthesia may be performed 12 hours after the administration of the last prophylactic dose of LMWH or 24 hours after the last therapeutic dose of LMWH. Intravenous UFH should be stopped for 6 hours before induction of labor with a confirmed normal aPTT before placement of neuraxial anesthesia. There is no contraindication for using neuraxial anesthesia during subcutaneous standard UFH at total doses of 10,000 units daily. The risk of spinal hematoma with larger daily subcutaneous doses is unclear; therefore, a documented normal aPTT must be obtained before placement of neuroaxial anesthesia.

Postpartum, reinitiation of prophylactic-dose LMWH should be delayed for at least 12 hours after the removal of an epidural catheter. Therapeutic-dose LMWH should be administered no earlier than 24 hours after neuraxial anesthesia, providing that proper hemostasis is achieved. In the absence of persistent bleeding, if no regional anesthesia was used, LMWH may be resumed 12 hours after delivery.⁹² Anticoagulation with either LMWH or warfarin is recommended for at least 6 to 12 weeks postpartum.³³

COUNSELING

Patients should be advised to manage controllable risk factors, including avoiding prolonged immobilization, avoiding excessive weight gain in pregnancy, and stopping smoking. Periods of immobilization tend to cause reduced blood flow (stasis), which predisposes to thrombosis. In a systematic review of records of all patients with confirmed PE after arrival at Charles de Gaulle airport in Paris during a 13-year period, women had a higher risk of PE after a long-distance flight than men, with an estimated incidence of 0.61 per million passengers versus 0.20, respectively; the incidence reached 7.24 and 2.35 cases, respectively, in passengers traveling more than 10,000 kilometers.^93,94

The risk of air travel-related thrombosis in pregnant women is estimated to be between 0.03% and 0.1%. Physicians must decide on an individual basis how to prevent travel-related thrombosis in their pregnant patients. In most passengers, prevention can be limited to encouraging exercise, avoidance of long sleeping periods, and not using a window seat. Women at high risk for VTE, such as women with a prior history of VTE who are not on anticoagulation or women with known asymptomatic thrombophilia or other risk factors for thrombosis such as obesity, may benefit from a short period (1–3 days) of LMWH starting 2 hours before a long-distance flight.⁹⁵

Activation of the coagulation system has been demonstrated in cigarette smokers.⁹⁶ Heavy smoking was found to be a significant risk factor for VTE in a cross-sectional analysis of 2404 men and women.⁹⁷ An increased risk for thrombosis during pregnancy is seen in cigarette smokers^15,98 and is enhanced with the concomitant use of illicit drugs.⁹⁹ Other obstetric complications associated with smoking and illicit drug use during pregnancy include preterm labor, spontaneous abortion, perinatal death, low birth weight, and abruption placenta. The efficacy of nicotine replacement therapy in pregnancy is uncertain.¹⁰⁰ Recommendations are to advise patients to stop smoking, obtain psychosocial counseling, and utilize adjunctive therapies, which have been shown to have some effect on abstinence rates.¹⁰¹

CONCLUSION

Women are at increased risk for VTE during pregnancy and the postpartum period. Awareness of risk factors and the signs and symptoms of VTE is paramount. Prompt diagnosis and treatment is mandatory to decrease complications of VTE. LMWH is the mainstay treatment of VTE in pregnancy, as it does not cross the placenta. Both LMWH and warfarin are safe during lactation. Close communication among the patient, obstetrician, hematologist, anesthesiologist, and neonatologist is crucial to optimize the care of these patients.

INTRODUCTION

Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a leading nonobstetric cause of maternal death in the United States and in developed countries.^1,2 During pregnancy, the risk for VTE increases four- to six-fold, and although the risk is present throughout pregnancy, the mother is at highest risk immediately postpartum.^3–5

VTE risk is increased due to physiologic and anatomic changes that occur in pregnancy. These changes include hypercoagulability, progesterone-induced venous stasis, decreased venous outflow, compression of the inferior vena cava and pelvic veins by the expanding uterus, and decreased mobility. The hypercoagulability of pregnancy is due to increased levels of coagulation factors I (fibrinogen), VII, VIII, and X, and von Willebrand factor; decreased free protein S, a natural anticoagulant; acquired resistance to activated protein C; and decreased fibrinolysis due to increased levels of plasminogen activator inhibitor-1 and -2.^6,7 These changes confer increased hemostasis to the mother for delivery but also place her at higher risk for thrombosis.

A review of the literature found that more than 70% of pregnancy-associated DVTs are located in the ileofemoral region, as compared with approximately 9% in non-pregnant patients.⁸ The proximal location is associated with a higher risk for post-thrombotic syndrome and embolization as compared with calf DVTs.⁹ Proximal postnatal thrombosis, smoking, and older age are independent predictors of the development of post-thrombotic syndrome.¹⁰

RISK FACTORS

Clinical risk factors that increase the risk for VTE during pregnancy include a prior history of estrogen-related or unprovoked VTE, being a carrier of severe inherited thrombophilia (homozygotes for factor V Leiden or factor II G20210A variants, double heterozygotes, or persons with antithrombin, protein C, or protein S deficiencies), and the presence of antiphospholipid (aPL) antibodies.¹¹ Women with systemic lupus erythematosus, diabetes, sickle cell disease, and heart disease also have a high risk for VTE during pregnancy.¹² Other risk factors predisposing to thrombosis include black ethnicity, smoking, operative procedures, conception after assisted reproductive techniques, high body mass index, antepartum immobilization, severe preeclampsia, advanced age and parity, and a family history of VTE.¹³ A prospective cohort study of 1,297,037 pregnancies and related puerperium identified the following risk factors for thrombosis: hospitalization, infection, hyperemesis, multiple pregnancies, preeclampsia, obesity, cesarean section, major postpartum hemorrhage, intrauterine growth restriction, and fetal death.¹⁴ Risk factors identified in an Agency for Healthcare Research and Quality study include: age 35 or older, black ethnicity, lupus, sickle cell disease, heart disease, postpartum infection, and transfusion.¹⁵ The combination of more than one risk factor increases the risk for VTE. All these factors have to be considered when deciding on prophylactic or therapeutic anticoagulation therapy in pregnancy. In addition, the risks of anticoagulation, including bruising, bleeding, and other side effects (eg, reduced bone mineral density with therapeutic-dose unfractionated heparin), allergic reactions, and rarely thrombocytopenia, must be considered.

EVALUATION AND DIAGNOSIS

CASE PRESENTATION I

A 31-year-old woman G1P0 at 10 weeks’ gestation with no personal or family history of thrombosis presents with acute onset of shortness of breath and left-sided chest pain that awoke her the morning of presentation. Her vital signs are significant for a heart rate of 106 beats/min, respiration rate of 22 breaths/min, blood pressure of 105/76 mm Hg, and pulse oximetry of 98% on room air. The patient denies previous exposure to oral contraceptives. She does not smoke. She reports that she had noticed left calf pain and swelling, which worsened with walking after a 4-hour drive 2 days prior.

• What is the approach to diagnosis of thromboembolism in pregnant patients?

DEEP VEIN THROMBOSIS

Although a clinical diagnosis of DVT in pregnancy is unreliable, a history and physical examination are necessary to exclude other diagnoses and to assess the likelihood of thrombosis. Unfortunately, studies of the accuracy of history and physical examination for detecting DVT and PE have not included pregnant patients. In most pregnant patients with clinically suspected DVT, the diagnosis is not confirmed. Other causes of leg pain and swelling are not uncommon during pregnancy and include cellulitis, ruptured Baker’s cyst, or muscular pain.

A cross-sectional study described the derivation of the LEFt clinical decision rule, which relies on 3 variables in pregnant women with suspected DVT: left leg presentation (L), ≥ 2 cm calf circumference difference (E for edema), and first trimester presentation (Ft). If none of these variables is present, the negative predictive value is 100%.¹⁶ A validation study suggested that a negative LEFt rule accurately identifies pregnant women in whom the risk for confirmed DVT appears to be very low. The rule should not be used as an individual test for excluding DVT during pregnancy, but could be applied in a diagnostic approach in association with D-dimer measurement and compression ultrasonography (CUS); however, it has not been prospectively validated for safety and efficacy.¹⁷ In a study of 149 consecutive pregnant women with suspected DVT, a whole-blood agglutination D-dimer had a sensitivity of 100% and specificity of 60%.¹⁸ A 2006 systematic review found only 4 diagnostic studies of VTE in pregnancy in the literature. One of these studies showed that a combination of a negative CUS and normal D-dimer can accurately exclude DVT.¹⁹

Serial CUS is necessary for pregnant women with a high clinical suspicion of DVT but a negative initial investigation. In a study of 221 pregnant women in whom DVT was clinically suspected, 16 women (7.2%) were diagnosed with DVT by initial CUS, and none were diagnosed with DVT onserial testing.²⁰ During follow-up (≥ 3 months), 6 of the 205 women with normal serial CUS results presented with symptoms of DVT, PE, or both, and 1 of them was diagnosed with DVT and PE. The sensitivity of serial CUS with Doppler imaging was 94.1% (95% confidence interval [CI] 69.2% to 99.7%), and the negative predictive value was 99.5% (95% CI 96.9% to 100%).²⁰ All ultrasounds undertaken for investigation of pregnancy-associated DVT should include imaging of the iliac veins if there is a high index of suspicion and the CUS is negative for femoral DVT. Serial CUS with Doppler imaging of the iliac vein performed over a 7-day period excludes DVT in symptomatic pregnant women.²⁰ Repeat CUS may be done 2 to 4 days and 6 to 8 days after the initial scan.

Ileofemoral vein thrombosis accounts for approximately 90% of proximal thromboses in pregnancy, occurring most often in the left lower extremity.²⁰ The incidence of isolated iliac vein thrombosis in pregnancy is low, but when it does occur, delay in diagnosis can lead to significant morbidity. Therefore, for women with suspected isolated iliac vein thrombosis in whom CUS is negative or nondiagnostic, magnetic resonance direct thrombus imaging (MRDTI) should be performed.²¹ Patients with iliac vein thrombosis may present with unexplained inguinal, pelvic, or abdominal pain, which may be accompanied by back pain, and they usually present with swelling of the entire leg. MRDTI does not require gadolinium contrast and its accuracy appears to be similar to that of venography for iliac vein thrombi in the nonpregnant population.²¹ Exposure to gadolinium during pregnancy is associated with an increased risk for rheumatologic, inflammatory, or infiltrative skin conditions and stillbirth or neonatal death.²²

Ovarian vein thrombosis is a rare but serious diagnosis. It occurs mostly in the postpartum period, mainly after cesarean delivery, and usually affects the right ovarian vein. The diagnosis is confirmed by ultrasound, computed tomography (CT), or magnetic resonance imaging.²³

PULMONARY EMBOLISM

PE is more difficult to diagnose than DVT, particularly because clinical signs of PE are unreliable in the pregnant patient. The mortality rate of untreated PE is high, ranging from 18% to 38%, and approximately one-third of patients with untreated thromboembolic disease develop recurrent embolism.²⁴ Studies have reported a PE prevalence between 1.4% and 4.2% in pregnant women with suspected clinical diagnosis of PE.²⁵

The clinical presentation of PE and associated laboratory testing results may be subtler in pregnant than in nonpregnant patients. Arterial blood gases (ABG) may show hypoxemia or hypocapnia. The ABG in pregnancy has a sensitivity of 76.9%, specificity of 20.2%, and negative and positive predictive values of 80% and 11.5% for PE, respectively.²⁶ The alveolar-arterial oxygen gradient is a poor screening test for PE during pregnancy and postpartum. A retrospective chart review of 17 pregnant women with documented PE showed that 58% had normal alveolar-arterial gradients.²⁷ Therefore, in a pregnant woman with a history suspicious for PE, objective imaging studies should be performed even if the patient has normal ABG.

The 2011 guidelines from the American Thoracic Society (ATS) and the Society of Thoracic Radiology (STR) recommend against using D-dimer to diagnose PE in pregnancy.²⁸ In addition, lower extremity CUS should only be performed as the first diagnostic imaging procedure if the patient has signs or symptoms of DVT. Instead, the ATS/STR guidelines recommend a plain radiograph of the chest as the first imaging test. If the chest radiograph is normal, a ventilation/perfusion scan (V/Q) scan is preferred over CT pulmonary angiography (CTPA). Diagnostic accuracy of the V/Q scan may be superior to CTPA in pregnancy, and it is preferable because of the lower prevalence of indeterminate V/Q scan in pregnant women.²⁹ Moreover, there is lower radiation exposure to the maternal breast and lung tissue with a V/Q scan than with CTPA. CTPA confers lower fetal radiation doses than V/Q scans (0.03–0.66 mGy versus 0.32–0.74 mGy, respectively) but higher total body maternal radiation (4–16 mSv versus 1–2.5 mSv).³⁰ A quantitative approach to lung scan interpretation, based on the distribution histogram of V/Q ratios, may be helpful in categorizing patients with suspected PE.²⁸ A study of 121 suspected episodes of PE in 120 pregnant women showed that 104 women with normal or nondiagnostic scans did not develop subsequent episodes of VTE during a mean follow-up period of 20 months.³¹

If the baseline chest radiograph is abnormal in a pregnant woman with clinical suspicion of PE, a CTPA should be performed. As noted, fetal radiation doses for CTPA examinations in which the fetus is not directly imaged are minimal. If CTPA is recommended for the diagnosis of PE, the patient should be informed that radiation to the breast may increase her baseline risk for breast cancer. The ATS guidelines state that “given the lack of evidence documenting clear superiority of any one diagnostic test, the values and preferences of a patient and her physician likely will and should determine the final choice and sequence of tests performed.”²⁸

CASE I CONTINUED

Upon presentation to the emergency department, the circumference of the patient’s left leg is not significantly greater than that of her right leg, and her leg pain has resolved. Bilateral CUS is negative for proximal or distal DVT. Chest radiograph shows an opacification of her left lower lobe. CTPA shows bilateral segmental and subsegmental lower lobe pulmonary emboli.

• How does risk for VTE change throughout pregnancy?

Women are at increased risk for VTE throughout the entire pregnancy, starting from conception, but mainly during the postpartum period. A Danish historical controlled cohort study of 819,751 pregnant women (ages 15–49 years) over a 10-year period identified 727 women with VTE. The absolute risk for VTE per 10,000 pregnancy-years increased from 4.1 (95% CI 3.2 to 5.2) during weeks 1 to 11 to 59.0 (95% CI 46.1 to 76.4) in week 40 and decreased in the postpartum period from 60 (95% CI 47.2 to 76.4) during the first week after birth to 2.1 during weeks 9–12 after birth (95% CI 1.1 to 4.2).³² This study showed that the risk of VTE increases throughout pregnancy and reaches its maximum during the peripartum period and is not significantly increased after 6 weeks post-delivery. In a retrospective cross-over cohort study of 1,687,930 women in California who delivered their first newborn, an elevated risk of VTE persisted until at least 12 weeks after delivery. However, the absolute increase in risk after 6 weeks postpartum was low.³³

CASE 1 CONCLUSION

The patient is started on anticoagulation therapy and carefully monitored during the remainder of the pregnancy and postpartum period. Anticoagulation is discontinued 6 weeks after delivery.

TREATMENT

ANTICOAGULATION THERAPY

The treatment of VTE can be lifesaving. In a study comparing 35 patients with PE randomly assigned to treatment with anticoagulants versus no treatment, 5 of 19 patients in the untreated group died from PE and an additional 5 had nonfatal recurrences, as compared with none in the treated group.²⁴ Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are both safe and effective anticoagulants during pregnancy as neither crosses the placenta. In a review of 186 reports of fetal and infant outcomes following anticoagulant therapy during pregnancy in 1325 pregnancies, outcomes in UFH-treated patients were similar to those in the normal population after excluding pregnancies with comorbid conditions independently associated with adverse outcomes.³⁴ A 2005 systematic review of LMWH for prophylaxis and treatment of VTE during pregnancy included 64 studies of 277 pregnancies. There were no maternal deaths, live births resulted from 94.7% of the pregnancies, VTE or arterial thrombosis occurred in 0.86%, and significant bleeding occurred in 1.98%.³⁵

The standard UFH regimen is an initial bolus of 5000 units subcutaneously and 17,500 units every 12 hours, with dose adjustment made based on a mid-interval activated partial thromboplastin time (aPTT).³⁶ Although still controversial, it has been suggested that the anti-Xa assay with a mid-dosing interval target of 0.3 to 0.7 U/mL is a more reliable measure of therapeutic UFH activity than the aPTT, as the aPTT response is suppressed due to a pregnancy-related increase in factor VIII. LMWH is dosed based on weight; regimens are enoxaparin 1 mg/kg subcutaneously twice daily or 1.5 mg/kg subcutaneously once daily, and dalteparin 100 units/kg every 12 hours or 150 units/kg daily.

A 2017 Cochrane review of the effect of LMWH compared with UFH for the treatment of VTE in the nonpregnant setting included 23 studies with 9587 patients. Thrombotic complications (odds ratio [OR] 0.70 [CI 0.57 to 0.85]) and major hemorrhage (OR 0.58 [CI 0.40 to 0.83]) were lower in patients receiving LMWH, with a trend toward lower mortality.³⁷ In addition, the incidence of bleeding complications in patients treated with subcutaneous LMWH versus intravenous heparin was compared in a 2012 systematic review of 27 randomized controlled trials with a total of 28,637 patients. In patients treated with LMWH, there was a nonstatistically significant lower incidence of major bleeding events (OR 0.79 [95% CI 0.60 to 1.04]) and a statistically significant reduction in bleeding risk (OR 0.68 [95% CI 0.47 to 1.00]) compared to patients treated with UFH.³⁸ Additionally, a trial comparing the use of standard UFH versus LMWH found a significantly lower incidence of thrombocytopenia in patients treated with LMWH.^39,40 Overall, LMWH is more effective at decreasing both thrombotic and bleeding complications, and the risk for osteoporosis is lower with LMWH. Based on these results, the American College of Chest Physicians (ACCP) recommends LMWH as the first-line treatment for VTE in pregnancy.⁴¹

In specific clinical situations, such as patients with renal dysfunction with creatinine clearance (CrCl) less than 30 mL/min, UFH is indicated. In a study of 103 pregnancies in 93 women given anti-coagulation during pregnancy, 89.3% received UFH. There were no maternal deaths, and fetal demise occurred in 8 pregnancies (7.8%) at a median of 14 weeks’ gestation. There were 2 episodes of PE (1.9%) and 2 major bleeding events requiring transfusion (1.9%).⁴² UFH costs much less than LMWH, and therefore UFH remains an important, inexpensive, and efficacious anticoagulant option for pregnant women who require anticoagulation and cannot afford LMWH.⁴³

Due to the physiologic changes associated with pregnancy, LMWH and UFH dosages may need to be adjusted. An observational study of 20 pregnant women with acute VTE found no recurrent VTE or major bleeding after treatment with dalteparin. Dalteparin doses approximately 10% to 20% higher than those recommended in nonpregnant women were required to reach therapeutic target anti-Xa activity.⁴⁴

Caution Regarding Oral Anticoagulants

Due to its teratogenicity, warfarin is not a first-line anticoagulation option. It is strictly contraindicated during the first trimester during organogenesis, and its use during pregnancy is restricted to women with mechanical heart valves. Warfarin crosses the placenta and has been associated with nasal hypoplasia, stippled epiphyses, and growth restriction, particularly between 6 to 9 weeks’ gestation. Every effort should be made to substitute UFH or LMWH for warfarin between 6 and 12 weeks of gestation. The bridging process should begin as early in the gestational age as possible due to the long half-life of warfarin.⁴⁵ When used later in gestation, warfarin has been associated with fetal hemorrhage and central nervous system abnormalities. Other complications from use during the second and third trimesters include microcephaly, blindness, deafness, and fetal growth restriction.^46,47 Its use also increases the risk for abortion and fetal death in utero.^48–50

The direct oral anticoagulants (DOACs) are not approved for use in pregnancy. Although there are limited anecdotal reports of DOAC use in pregnancy,⁵¹ there is preclinical evidence of placental transfer with the DOACs rivaroxaban and apixaban (direct Xa inhibitors) and the oral thrombin inhibitor dabigatran, thus increasing the risk to the fetus.^52–54 Edoxaban, another direct Xa inhibitor, should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It should be discontinued in nursing mothers.⁵⁵

THROMBOLYSIS

Fetal as well as maternal survival is dependent on adequate maternal perfusion and oxygenation. The risk of death from PE is significant, with a cross-sectional study of 58 patients with acute, massive PE showing a 55% mortality rate.⁵⁶ Thus, pregnancy is not an absolute contraindication to mechanical or systemic (recombinant tissue plasminogen activator or streptokinase) thrombolysis in an unstable patient at high risk for death.^57–59 There are no major studies of this approach, although a small review of 13 cases using systemic thrombolysis showed no increased risk of maternal mortality.⁵⁸ Thrombolysis should be considered for appropriate indications in pregnant patients as it would be in nonpregnant patients. However, caution is required when drawing conclusions regarding maternal and fetal safety, given the lack of controlled clinical trials including pregnant women.

SURGICAL PULMONARY EMBOLECTOMY

Surgical pulmonary embolectomy is an important therapeutic and potentially life-saving option in women presenting with massive PE in the immediate postpartum period. Because of the risk of massive uterine bleeding immediately postpartum, thrombolytic therapy should not be used.⁶⁰

INFERIOR VENA CAVA FILTER

Placement of an inferior vena cava (IVC) filter is indicated in patients who have an acute VTE with absolute contraindications for anticoagulation. In addition, it can be considered in patients with extensive ileofemoral venous thrombosis within 2 weeks prior to expected delivery.⁶¹ In a systematic review of 44 studies of IVC filters placed in pregnant patients, the IVC filter complication rate was 8.87% and the failure-to-retrieve rate was 11.25%.⁶² The complication rate is similar to that found in the nonpregnant population. Thus, IVC filters may be used when appropriately indicated and should be removed as soon as clinically feasible.

RECURRENT THROMBOSIS AND THROMBOPHILIAS

CASE PRESENTATION 2

A 34-year-old pregnant woman G1P0 at 38 weeks’ gestation presents with a painful, swollen left calf that is associated with difficulty on walking; the circumference of the left calf is 2 cm greater than that of the right. She has no shortness of breath or chest pain. She has a prior history of distal right lower extremity DVT while on combined oral contraceptives. Her mother also has a history of DVT while bedbound during a prolonged hospitalization at an older age. CUS is negative, and the patient is discharged home. However, 24 hours later she returns to the hospital with worsening swelling and pain in her left leg. Magnetic resonance venography demonstrates a large left external iliac and common iliac DVT. She is admitted and is started on UFH, and a retrievable IVC filter is placed in anticipation of delivery.

• What is the risk for VTE recurrence during pregnancy?

A personal and family history of VTE should be obtained when evaluating pregnant patients. A retrospective study of 109 women with prior history of VTE showed recurrence rates per patient-year of 10.9% during pregnancy and 3.7% in the nonpregnant period; the relative risk of recurrent VTE during pregnancy was 3.5 (95% CI 1.6 to 7.8).⁶³ Two large European retrospective cohort studies of VTE in pregnancy showed that the recurrence rate of VTE in women with a history of thrombosis is around 6% during pregnancy, equally distributed among trimesters. The highest incidence of recurrence was in the postpartum period, ranging from 8.3% to 10%.⁶⁴ The recurrence risk during pregnancy in women with a history of a single episode of VTE was 2.4% antepartum (95% CI 0.2% to 6.9%).⁶⁵ These risks may be lower in women without thrombophilia or with a temporary risk factor associated with their previous thromboembolic event.⁶⁵ Recurrence risk is higher if the previous VTE was estrogen-related, either due to pregnancy or through hormonal contraception (10%), than if the previous VTE was non-estrogen-related (2.7%).^64,66

The timing of the case patient’s presentation is consistent with reports of increased risk of VTE during the peripartum period. Her prior history of estrogen-related DVT is concerning for a risk of recurrence, particularly during pregnancy. A retrospective cohort study of 1104 women with previous VTE, 88 of whom became pregnant without receiving thromboprophylaxis, showed that the overall rate of VTE recurrence was 5.8% (95% CI 3.0% to 10.6%) and 8.3% (95% CI 4.5% to 14.6%) during pregnancy and postpartum, respectively. The risk of VTE recurrence was absent if the first VTE was related to a transient risk factor other than pregnancy, postpartum period, or hormonal contraception.⁶⁷ However, the recurrence rate of VTE in women with prior unprovoked VTE and/or thrombophilia has been reported as 5.9% (95% CI 1.2% to 16.2%).⁶⁵ The presence of an underlying hypercoagulable state can increase the recurrence risk by 25% to 50%, depending on the disorder.⁶⁸ A retrospective cohort study of 270 pregnancies in 105 carriers of factor V Leiden, identified because of a symptomatic relative with the factor V Leiden mutation, found a VTE risk (mostly in the postpartum period) of 6.4% for heterozygous women, 16.7% for homozygous women, 20% for double heterozygous women, and 1.2% for noncarriers.⁶⁹

• Should the patient be screened for a thrombophilia disorder?

Half of all index thromboses in patients with thrombophilia occur in association with an additional risk factor. In women of child-bearing age, pregnancy, the postpartum period, and the use of combined hormonal contraception are all risk factors for VTE. A 2010 guideline from the British hematology community recommended testing for thrombophilia in women with prior VTE secondary to a minor provoking factor before or during pregnancy, but not testing women with unprovoked VTE (who would receive prophylaxis regardless) or those with VTE secondary to a major provoking factor (who would not require prophylaxis).⁷⁰ Indications to screen for aPL antibodies include: women with (1) 3 unexplained recurrent first-trimester pregnancy losses or 1 second or third trimester fetal loss of morphologically normal fetuses; (2) severe preeclampsia; (3) intrauterine growth restriction; or (4) premature labor (< 34 weeks’ gestation).^71,72

CASE 2 CONCLUSION

The patient is subsequently screened for inherited thrombophilia disorders and is found to be heterozygous for factor V Leiden.

CASE PRESENTATION 3

A 25-year-old woman is diagnosed with antiphospholipid syndrome (APS) during her second pregnancy when she experiences fetal loss during her second trimester. Pathologic examination of the placenta reveals infarcts. Laboratory evaluation reveals positive high-titer anticardiolipin and anti-beta-2 glycoprotein 1 antibodies (IgG isotype) and lupus anticoagulant on 2 separate occasions 12 weeks apart. In a subsequent pregnancy, she is started on prophylactic LMWH and daily low-dose aspirin (81 mg). At 36 weeks’ gestation, she presents with a blood pressure of 210/104 mm Hg and a platelet count of 94,000 cells/µL. She is diagnosed with preeclampsia and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome and is induced for early delivery. About 2 weeks after vaginal delivery, she notices shortness of breath and chest pain. A CTPA demonstrates a right lower lobe lobar defect consistent with a PE. Her anticoagulation is increased to therapeutic dosage LMWH.

• To what extent does thrombophilia increase the risk for VTE in pregnancy?

Approximately 50% of pregnancy-related VTEs are associated with inherited thrombophilia. A systematic review of 79 studies, in which 9 studies (n = 2526 patients) assessed the risk of VTE associated with inherited thrombophilia in pregnancy, revealed that the odds ratio for individuals with thrombophilia to develop VTE ranged from 0.74 to 34.40.⁷³ Although women with thrombophilia have an increased relative risk of developing VTE in pregnancy, the absolute risk of VTE remains low (Table 1).^41,73,74

• How is APS managed in pregnant patients?

Women with history of recurrent early pregnancy loss (< 10 weeks’ gestation) related to the presence of aPL antibodies are managed with low-dose aspirin and prophylactic-dose UFH or LMWH. This treatment increases the rate of subsequent successful pregnancy outcomes and reduces the risk for thrombosis. A 2010 systematic review and meta-analysis of UFH plus low-dose aspirin compared with low-dose aspirin alone in patients with APS and recurrent pregnancy loss included 5 trials and 334 patients. Patients receiving dual therapy had higher rates of live births (74.3%; relative risk [RR] 1.30 [CI 1.04 to 1.63]) compared to the aspirin-only group (55.8%).⁷⁵ A 2009 randomized controlled trial compared low-dose aspirin to low-dose aspirin plus LMWH in women with recurrent pregnancy loss and either aPL antibodies, antinuclear antibody, or inherited thrombophilia. The study was stopped early after 4 years and found no difference in rates of live births between the groups (77.8% versus 79.1%).⁷⁶ However, a randomized case-control trial of women with aPL antibodies and recurrent miscarriage found a 72% live birth rate in 47 women randomly assigned to low-dose aspirin and LMWH.⁷⁷ A 2012 guideline from the American College of Chest Physicians (ACCP) recommends that women with aPL antibodies with a history of 3 or more pregnancy losses receive low-dose aspirin plus prophylactic-dose LMWH or UFH.⁷⁸ A 2014 systematic review and meta-analysis showed that the combination of low-dose aspirin and UFH resulted in a higher live-birth rate than aspirin alone in 803 women with APS (RR 1.54 [95% CI 1.25 to 1.89]).⁷⁹ Further large randomized controlled trials are needed to confirm optimal management of recurrent miscarriage and aPL antibodies.

The addition of prednisone to aspirin, heparin, or both has shown no benefits in pregnant women with aPL antibodies. Indeed, prolonged use of steroids may cause serious pregnancy complications, such as prematurity and hypertension.^80–83 Intravenous infusions of immunoglobulin (IVIG) have not been shown to be superior to heparin and aspirin. This finding was confirmed in a multicenter clinical trial that tested the effects of IVIG compared with LMWH plus low-dose aspirin for the treatment of women with aPL antibodies and recurrent miscarriage. The rate of live-birth was 72.5% in the group treated with heparin plus low-dose aspirin compared with 39.5% in the IVIG group.⁸⁴

Preeclampsia and HELLP syndrome complicated the case patient’s pregnancy even though she was being treated with prophylactic-dose LMWH and low-dose aspirin, the current standard of care for pregnant women with APS (UFH can be used as well). It is important to note that complications may still occur despite standard treatment. Indeed, PE is more common in the postpartum than in the antepartum period. Prompt diagnosis is paramount to initiate the appropriate treatment; in this case the dose of LMWH was increased from prophylactic to therapeutic dose. However, additional therapeutic modalities are necessary to improve outcomes. A randomized controlled trial comparing standard of care with or without hydroxychloroquine is under way to address this issue.

PROPHYLAXIS

CASE PRESENTATION 4

A 34-year-old woman G1P0 at 6 weeks’ gestation with a past medical history of a proximal lower extremity DVT while on oral contraception is treated with warfarin anticoagulation for 6 months. Her obstetrician consults the hematologist to advise regarding antithrombotic management during this pregnancy.

• What is the approach to prophylaxis in women at high risk for pregnancy-associated VTE?

All women at high risk for pregnancy-associated VTE should be counseled about the signs and symptoms of DVT or PE during preconception and pregnancy and have a plan developed should these symptoms arise. The ACCP guidelines on antithrombotic therapy outline recommendations ranging from clinical vigilance to prophylactic and intermediate-dose anticoagulation, depending on the risk for VTE recurrence, based on the personal and family history of VTE and type of thrombophilia (Table 2).⁷⁸ These recommendations range from grade 2B to 2C.

For women with a history of estrogen-related VTE, single unprovoked VTE, or recurrent unprovoked VTE not on chronic anticoagulation, antepartum and postpartum pharmacologic thromboprophylaxis with either prophylactic or intermediate-dose LMWH is recommended (grade 2C). In patients with prior history of provoked VTE (non-estrogen related), antepartum clinical vigilance and postpartum pharmacologic thromboprophylaxis is recommended (grade 2C, 2B).

In asymptomatic pregnant women who are homozygote carriers for factor V Leiden or prothrombin G20210A variants and have a positive family history of thrombosis, antepartum and postpartum pharmacologic thromboprophylaxis is recommended (grade 2B). In asymptomatic homozygote carriers of factor V Leiden or prothrombin G20210A variants with no family history of thrombosis and women with all other thrombophilias with a positive family history of thrombosis, postpartum pharmacologic thromboprophylaxis is indicated (grade 2B and 2C, respectively). For women with confirmed APS and clinical criteria of obstetric APS with recurrent pregnancy loss, antepartum thromboprophylaxis with LMWH and low-dose aspirin is recommended (grade 1B). For pregnant women with all other thrombophilias with no personal or family history of thrombosis, clinical vigilance is suggested (grade 2 C).⁷⁸

As an alternative to LMWH, vitamin K antagonists (VKA) such as warfarin can be used for postpartum thromboprophylaxis; in patients with protein C or S deficiency, due to the risk of warfarin-induced skin necrosis, a rapid-onset anticoagulant must be concomitantly administered. Warfarin and LMWH are safe anticoagulants during lactation, but there are no clinical data on the effects of the DOACs on infants during lactation. Data from animal studies indicate that DOACs are secreted into breast milk.⁸⁵

• What risks are associated with anticoagulant therapy in pregnancy?

VKAs cross the placenta and can cause teratogenicity, pregnancy loss, fetal bleeding, and neurodevelopmental deficits. Therefore, discontinuation of VKAs prior to the sixth week of gestation is necessary to avoid warfarin embryopathy. DOACs have been shown to readily cross the placenta but with unknown human reproductive risks. Fondaparinux, a synthetic pentasaccharide, crosses the placenta in small quantities. Though there are reports of the successful use of fondaparinux in pregnancy, there is limited reported experience of its use in the first trimester.⁸⁶

The risk for bleeding with anticoagulation is notably acceptable. In a case-control study of 88 pregnant women receiving therapeutic-dose anticoagulation, the risk of postpartum hemorrhage (PPH) after vaginal delivery was 30% in those who received LMWH anticoagulation versus 18% in those who did not (OR 1.9 [95% CI 1.1 to 3.5]).⁸⁷ However, the risk for severe PPH (≥ 500 mL) was similar (5.6% versus 5.0%; OR 1.1 [95% CI 0.4 to 3.6]). The risk for PPH after cesarean section was 12% in LMWH users versus 4% in LMWH non-users (OR 2.9 [95% CI 0.5 to 19.4]). The risk for PPH associated with delivery within 24 hours after the last dose of LMWH was 1.2 times higher (95% CI 0.4 to 3.6) compared to a longer interval. Therefore, therapeutic LMWH increases the risk for blood loss after vaginal delivery, but not the risk for severe PPH. The risk for PPH is influenced by the interval between the last dose of LMWH and delivery. Of note in this study, per the institution’s protocol, the anticoagulation was stopped with signs of labor or determination of need for delivery. The risk for blood loss may be mitigated in more planned delivery scenarios.⁸⁷

CASE 4 CONTINUED

The patient is placed on prophylactic-dose LMWH with good tolerance and delivers at 39 weeks' gestation via caesarian section due to nonprogression of labor. Postpartum she is restarted on prophylactic-dose anticoagulation with LMWH. Two weeks after discharge from the hospital, she presents with right calf pain and mild shortness of breath. On physical exam, her leg circumferences are equal. A D-dimer assay is 3375 ng/mL (normal 0–229). CUS of the right leg shows a complete occlusive DVT of the mid-distal superficial femoral and popliteal veins and partially occlusive acute DVT of the right posterior tibial and peroneal veins. CTPA reveals a right lower lobe PE. Because she had developed VTE despite prophylactic LMWH, her anticoagulation is changed to therapeutic dose. She is treated with anticoagulation with LMWH for a total of 3 months, after which a repeat CUS shows no residual thrombosis.

• What is the recommended dosing of heparin and LMWH during pregnancy?

A prospective study of 14 pregnant women receiving UFH prophylaxis found that a prophylactic dose of 5000 units twice a day was inadequate to achieve prophylactic heparin levels in any patient in the second or third trimester.⁸⁸ Similar to treatment dosage, there is no consensus evidence for prophylactic dosing, and dosage recommendations are based on expert opinion. In a retrospective study of 25 pregnant women on intermediate-dose UFH, the mean UFH dose required to achieve a target anti-factor Xa level of 0.1 to 0.3 units/mL was 236.9 units/kg/day.⁸⁹ However, the use of anti-factor Xa levels for monitoring is controversial as there is no data to support a difference in outcomes with its use in prophylactic or therapeutic dosing.

The timing of the previous VTE history is important when deciding on the anticoagulant dose in pregnancy. In pregnant women with a VTE that occurred within the previous 4 to 6 weeks, full-dose anticoagulation with LMWH should be considered; an intermediate dose (three-fourths of a therapeutic dose) may be used if the thrombotic episode occurred more than 6 weeks earlier but still within a year. Prophylactic dosing may be sufficient if the episode occurred more than a year earlier.⁹⁰ A clinical trial (High-Low) is under way to explore the optimal dose of LMWH in pregnant women with prior history of VTE who are not on chronic anticoagulation therapy.⁹¹

• How is anticoagulation therapy managed in the peripartum period?

Neuraxial anesthesia during active labor while on anticoagulation increases the risk for central nervous system bleeding. Therefore, if spontaneous labor occurs in women on therapeutic dose anticoagulation, neuraxial anesthesia cannot be used. However, in the event of elective induction of labor or caesarean section, neuroaxial anesthesia may be performed 12 hours after the administration of the last prophylactic dose of LMWH or 24 hours after the last therapeutic dose of LMWH. Intravenous UFH should be stopped for 6 hours before induction of labor with a confirmed normal aPTT before placement of neuraxial anesthesia. There is no contraindication for using neuraxial anesthesia during subcutaneous standard UFH at total doses of 10,000 units daily. The risk of spinal hematoma with larger daily subcutaneous doses is unclear; therefore, a documented normal aPTT must be obtained before placement of neuroaxial anesthesia.

Postpartum, reinitiation of prophylactic-dose LMWH should be delayed for at least 12 hours after the removal of an epidural catheter. Therapeutic-dose LMWH should be administered no earlier than 24 hours after neuraxial anesthesia, providing that proper hemostasis is achieved. In the absence of persistent bleeding, if no regional anesthesia was used, LMWH may be resumed 12 hours after delivery.⁹² Anticoagulation with either LMWH or warfarin is recommended for at least 6 to 12 weeks postpartum.³³

COUNSELING

Patients should be advised to manage controllable risk factors, including avoiding prolonged immobilization, avoiding excessive weight gain in pregnancy, and stopping smoking. Periods of immobilization tend to cause reduced blood flow (stasis), which predisposes to thrombosis. In a systematic review of records of all patients with confirmed PE after arrival at Charles de Gaulle airport in Paris during a 13-year period, women had a higher risk of PE after a long-distance flight than men, with an estimated incidence of 0.61 per million passengers versus 0.20, respectively; the incidence reached 7.24 and 2.35 cases, respectively, in passengers traveling more than 10,000 kilometers.^93,94

The risk of air travel-related thrombosis in pregnant women is estimated to be between 0.03% and 0.1%. Physicians must decide on an individual basis how to prevent travel-related thrombosis in their pregnant patients. In most passengers, prevention can be limited to encouraging exercise, avoidance of long sleeping periods, and not using a window seat. Women at high risk for VTE, such as women with a prior history of VTE who are not on anticoagulation or women with known asymptomatic thrombophilia or other risk factors for thrombosis such as obesity, may benefit from a short period (1–3 days) of LMWH starting 2 hours before a long-distance flight.⁹⁵

Activation of the coagulation system has been demonstrated in cigarette smokers.⁹⁶ Heavy smoking was found to be a significant risk factor for VTE in a cross-sectional analysis of 2404 men and women.⁹⁷ An increased risk for thrombosis during pregnancy is seen in cigarette smokers^15,98 and is enhanced with the concomitant use of illicit drugs.⁹⁹ Other obstetric complications associated with smoking and illicit drug use during pregnancy include preterm labor, spontaneous abortion, perinatal death, low birth weight, and abruption placenta. The efficacy of nicotine replacement therapy in pregnancy is uncertain.¹⁰⁰ Recommendations are to advise patients to stop smoking, obtain psychosocial counseling, and utilize adjunctive therapies, which have been shown to have some effect on abstinence rates.¹⁰¹

CONCLUSION

Women are at increased risk for VTE during pregnancy and the postpartum period. Awareness of risk factors and the signs and symptoms of VTE is paramount. Prompt diagnosis and treatment is mandatory to decrease complications of VTE. LMWH is the mainstay treatment of VTE in pregnancy, as it does not cross the placenta. Both LMWH and warfarin are safe during lactation. Close communication among the patient, obstetrician, hematologist, anesthesiologist, and neonatologist is crucial to optimize the care of these patients.

INTRODUCTION

Pancreatic cancer is one of the most rapidly rising causes of mortality in the United States. In 2016, the number of deaths from pancreatic cancer exceeded those from breast cancer, making it the third leading cause of cancer-related death in the United States.¹ It is projected that by 2020 pancreatic cancer will overtake colorectal malignancies to become the second most common cause of cancer death in this country.^1,2 The term pancreatic cancer encompasses both exocrine and endocrine tumors. However, since 80% of pancreatic cancers are classified as pancreatic ductal adenocarcinoma (PDA), when speaking about pancreatic cancer most clinicians and scientists are referring to PDA.

Even with advances in chemotherapy and radiotherapy over the past decade, the only curative option for PDA is surgical resection. Unfortunately, only 20% of patients are appropriate surgical candidates at the time of diagnosis.³ Considering the lack of screening options and the ambiguity of symptomatology, roughly 4 out 5 patients with PDA are diagnosed as having locally advanced or metastatic disease that is initially not amenable to surgery.

Locally advanced pancreatic adenocarcinoma presents unique challenges in management and treatment. Treatment options include multi-agent chemotherapy, chemoradiation, or radiotherapy. Some patients can be successfully down-staged with these therapies and be deemed surgical candidates. Other challenges include selecting the appropriate sequence of therapies and stratifying therapies based on comorbidities. In this article, we review the epidemiology, biology, and diagnostic approach to PDA and focus on current treatment strategies for locally advanced pancreatic cancer (LAPC).

EPIDEMIOLOGY

In 2012, GLOBOCAN estimated that PDA caused 331,000 deaths per year, accounting for 4% of all worldwide mortality.^4,5 Despite high incidence rates internationally, PDA is a disease of Western and industrialized nations. In the Unites States, PDA is a malignancy of middle to late adulthood, with a sharp upsurge in incidence after age 50 years.⁶ More than one third of new cases are diagnosed in patients older than 70 years, and more than half of patients diagnosed are older than 60 years of age.² The incidence of pancreatic cancer is fairly equal among men and women, with a slightly higher rate for the male sex. It has an incidence preference for African-Americans by 4.8 cases per 100,000 persons nationally.⁷

Risk factors for the development of exocrine pancreatic cancer include hereditary disposition, underlying medical conditions, and environmental factors. One of the most significant environmental risk factors for the development of PDA is smoking,⁸ which is associated with up to 25% of all cases.⁹ Smoking cessation leads to a rapid reduction in risk for pancreatic cancer, with the risk among former smokers approaching that for never smokers less than 10 years after quitting.⁹ Other environmental factors that contribute to the development of pancreatic cancer include increased body mass index, a high-salt and high-saturated fat diet, heavy alcohol intake, and increased utilization of nonsteroidal inflammatory drugs.^10–13

There is a strong association between new-onset diabetes and increased risk for developing PDA.^14,15 Data also suggest that diabetes may be a risk factor and/or a consequence of tissue destruction that arises during the development or progression of PDA.^16,17 Interestingly, ABO blood grouping is another underlying medical disposition that confers an altered risk profile. Studies have shown that patients with blood group O were less likely than those with type A, B, or AB to develop pancreatic cancer.¹⁸

Genetic predisposition syndromes can elevate an individual patient’s risk for developing PDA. Genetic syndromes and gene alterations that increase the risk for PDA include BRCA1/2, Peutz-Jeghers syndrome, and Lynch syndrome risk.^19–21 Up to 10% to 15% of PDA cases may be due to an inherited familial cancer.²² Having a first-degree relative with PDA increases the odds of developing PDA 1.76-fold compared to those without a family history.²³ The exact biologic and molecular mechanisms of familial pancreatic cancer are unclear. It is estimated that about 10% of patients with familial pancreatic cancer (FPC) carry BRCA2 mutations.²⁴ Individuals at risk for FPC should undergo genetic screening for the presence of the most frequently inherited pancreatic cancer susceptibility genetic defects: BRCA2, PALB2, and ATM germline mutations.²⁵ Carriers of BRCA2, who are also at increased risk for developing breast, ovarian, and prostate cancer, should be monitored closely. Of all hereditary conditions, hereditary pancreatitis confers the highest risk for developing PDA, with an approximate risk elevation of 40% to 50%.^26,27 Although several genetic predisposition syndromes have been identified, most cases of pancreatic adenocarcinoma are thought to be sporadic.

CANCER BIOLOGY AND PATHOLOGY

The pathologic predecessor of PDA is pancreatic intraepithelial neoplasia (PIN). With further dysplastic changes that result from increasing genetic alterations, these precancerous lesions progress from low- to high-grade and finally to adenocarcinoma. More than 90% of all PINs across all grades have oncogenic KRAS mutations.²⁸ Additionally, inactivating mutations in the tumor suppressor genes SMAD4, p53, and CDKN2A are found with increasing frequency in higher grade PINs. The frequency and presence of mutations in both oncogenes and tumor suppressor genes in precursor neoplasias mirror the genetic mutations noted in advanced PDA.²⁹ Among all mutations, KRAS is the most common and most functionally important for pancreatic cancer cell survival. KRAS mutations not only have profound effects on downstream mediators of tumor growth and metastasis, but they are implicated in reprograming of cellular metabolism.^30,31

Pancreatic adenocarcinoma has a unique microenvironment that makes it a difficult target for current therapeutic modalities. First, it is one of the most stroma-rich malignancies. The dense stroma surrounding pancreatic tumor cells leads to increased tumor pressures and alterations in tumor vascular perfusion.³² It also serves as a barrier that prevents chemotherapeutic drugs from reaching the tumor cells. Thus, clinical trials are under way to investigate agents such has hyaluronidase, which may degrade components of the extracellular matrix that supports thestromal environment. Additionally, there is data to suggest that the microenvironment of PDA downregulates immune monitoring, leading to further tumor growth.^27,33 The molecular, cellular, and immunologic complexity of PDA may contribute to its resistance to traditional therapeutics.

EVALUATION AND DIAGNOSIS

CASE PRESENTATION

A 61-year-old man with a history of type 2 diabetes mellitus and chronic tobacco use presents to the emergency department (ED) with a 4-month history of progressively worsening abdominal discomfort and fatigue. He has also noticed darkening of his urine and slight yellow discoloration of his eyes. His weight measured 5 months ago in his primary care physician’s office was 91 kg (200 lb, BMI 29.5) and in the ED is 75 kg (165 lb, BMI 24.4). He has noticed bulky, malodorous, oily stools for about 2 months. Preliminary laboratory studies reveal elevated levels of total bilirubin (2.7 mg/dL) and alkaline phosphatase (204 IU/L). Transabdominal ultrasound (US) is obtained and reveals a 3-cm pancreatic mass with biliary tract dilation.

• Does this patient have pancreatic cancer?

CLINICAL SIGNS AND SYMPTOMS

Establishing the diagnosis of pancreatic cancer in a patient who presents with a high index of suspicion is critical. Patients with pancreatic cancer usually present after a period of nonspecific and vague symptoms, which typically are experienced as abdominal discomfort, weight loss, and weakness. It is estimated that approximately 25% of patients may complain of vague abdominal pain up to 6 months prior to diagnosis. Up to 15% of patients may seek medical attention more than 6 months prior to establishing a diagnosis of PDA.³⁴ The most common symptoms associated with pancreatic cancer in order of decreasing reported frequency are weight loss, anorexia, abdominal/epigastric pain, dark-colored urine, jaundice, nausea, back pain, and diarrhea with associated steatorrhea.³⁵ Upwards of 15% of patients present with painless jaundice, a term that is often associated with pancreatic cancer.³⁶ On exam these patients may have scleral icterus, sublingual jaundice, epigastric pain on palpation, weight loss, hepatomegaly, lymphadenopathy and a nontender, distended, palpable gallbladder (also known as Courvoisier sign).³⁴ Abdominal signs and symptoms arise from tumor growth into surrounding vessels, tissues, and ducts within the abdominal cavity. Compression of the common bile duct accounts for the development of jaundice. Tumor growth around the stomach and duodenum can lead to delayed gastric emptying and subsequently nausea and vomiting. Constriction of the pancreatic duct leads to pancreatic insufficiency, precipitation of weight loss, and steatorrhea. Pancreatic insufficiency can worsen abdominal pain, and lead to increased weight loss and flatulence.

Less common symptoms include pain, erythema, and edema involving the lower extremities, which may be reflective of migratory thrombophlebitis (commonly known as Trousseau syndrome). Thromboembolic disease, including pulmonary embolism, portal vein, and deep vein thromboses are frequently encountered complications of pancreatic cancer. The incidence of thromboembolic events in patients with PDA has been reported to be as high as 54%.³⁷ Of all signs encountered, weight loss is the most common and most profound. Patients with advanced PDA have severe degrees of cachexia. Some patients present with as much as a 5 kg/m² decrease in their BMI from pre-illness baseline BMI, and lose another 3 to 4 kg/m² through disease progression.³⁸ At the time of diagnosis, many patients have already undergone significant weight loss, which can have substantial implications on treatment planning and clinical outcomes.

• What other studies can be done to assist in making the diagnosis?

LABORATORY ABNORMALITIES AND TUMOR MARKERS

Elevations in alkaline phosphatase, γ-glutamyltransferase (GGT), serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), and direct fractions of bilirubin are common in patients with PDA. Patients will usually have an obstructive pattern on their liver panel, with predominant elevations in direct bilirubin, alkaline phosphatase, and GGT, as compared with AST and ALT. Other baseline laboratory studies, including a complete blood count and basic metabolic panel, should be obtained because patients commonly have thrombocytosis, anemia, and electrolyte abnormalities due to the tumor itself and pancreatic insufficiency (Table 1).

Measurement of glycated hemoglobin (HBA1C) is an emerging and important diagnostic test in the diagnosis of pancreatic cancer. Recently, data has emerged to suggest that new-onset diabetes is present in about 50% of patients diagnosed with pancreatic cancer.³⁹ The temporal relationship of pancreatic cancer and diabetes is supported by evidence showing that patients who undergo resection commonly have resolution of their diabetes.¹⁷ This study suggested that hyperglycemia, elevated HBA1C, and symptoms of diabetes in patients older than 50 years may identify patients who have early pancreatic cancer. The entity of pancreatic cancer–associated diabetes needs to be better defined and the algorithmic approach to evaluation and diagnosis, utilizing signs, symptoms, and laboratory values associated with diabetes, needs to be clearly established.

The only serum marker for PDA is carbohydrate antigen 19-9 (CA 19-9), also known as sialylated Lewis antigen or cancer-associated antigen. It was first identified in pancreatic cancer patients in 1981.^40,41 The sensitivity and specificity of CA 19-9 ranges from 70% to approximately 90%.^42,43 Hereditary predispositions and comorbid disease cross-reactivity contribute to the diminished sensitivity and specificity of CA 19-9. In about 5% to 10% of the population, CA 19-9 is not expressed (Lewis antigen A and B negative). Additionally, since CA 19-9 is expressed in the cells that line the biliary tree, diseases that lead to pancreatic or liver inflammation may falsely elevate CA 19-9.⁴⁴ As a result, CA 19-9 is not an ideal screening test. However, data has shown that CA 19-9 may have prognostic value postoperatively and serve as a marker for therapeutic response.^45,46

• Is biopsy needed for this patient and if so, what is the most appropriate technique?

ENDOSCOPIC ULTRASOUND

Generally, diagnosis with tissue is not necessary for patients who clearly have resectable disease and will proceed directly to surgery for management. Nevertheless, it is still commonly obtained in this group of patients. However, in patients with LAPC or with features suggestive of LAPC, such as tumor approximation to critical vessels such as the superior mesenteric artery (SMA) or celiac axis, biopsy is necessary. These patients will receive neoadjuvant therapy, and biopsy is important in establishing a diagnosis. The ideal way to obtain a biopsy is through fine-needle aspiration (FNA) or biopsy (FNB) utilizing endoscopic ultrasound (EUS). Percutaneous and computed tomography (CT)–guided FNB can also be used to obtain a biopsy for diagnosis. In comparison to percutaneous and CT-guided FNB, EUS-FNA/FNB has low rates of complications, a decreased rate of peritoneal seeding, and is cost effective.^47,48

CASE CONTINUED

Abdominal CT obtained following abdominal ultrasound reveals a 3.5-cm mass in the head of the pancreas in close approximation to the SMA and celiac axis.

• Does the patient have borderline resectable or unresectable disease?

IMAGING

Abdominal ultrasound is a reasonable, inexpensive, and safe alternative to abdominal CT as it does not utilize ionizing radiation. It is particularly useful in patients who present with jaundice or have concern for biliary obstruction based on laboratory evaluation. It is particularly sensitive for detecting tumors greater than 3 cm in size.^49,50 In patients whose abdominal ultrasound is unrevealing and whose index of suspicion remains high for PDA, abdominal CT should be the next imaging modality.

Abdominal CT obtained utilizing a pancreatic protocol is ideal for detection and staging of pancreatic tumors. By implementing a triple-phase protocol with arterial, late arterial, and venous phases, tumors, which have a density different from that of the pancreatic parenchyma, are accentuated. Abdominal CT is also able to provide critical information about tumor resectability.⁵¹ By revealing the degree of tumor encasement around the aorta, level of destruction of the superior mesenteric vein, or degree of involvement of the SMA or celiac vessels, abdominal CT determines if a patient should be deemed resectable, borderline resectable, or unresectable (Table 2).^52,53 Resectability is based on thorough imaging evaluation, expert opinion of a multidisciplinary team, and guidelines proposed by American Hepatopancreaticobiliary Association, Society of Surgical Oncology, Society for Surgery of the Alimentary Tract, and the NCCN.⁵⁴

Other imaging modalities have a less clearly established role in the diagnostic approach to PDA. In patients who have contraindications to obtaining CT, magnetic resonance imaging can be utilized as a secondary imaging modality.⁵⁵ The role of positron emission tomography 18F-fluorodeoxyglucose (PET-FDG) is not clearly defined among clinicians, nor reflected in consensus guidelines by the National Comprehensive Cancer Network (NCCN). In clinical practice, it is still often combined with CT to detect metastatic disease, particularly in high-risk patients such has those with LAPC. The role of PET-CT in staging and its impact on clinical outcomes has not been fully established.

Endoscopic retrograde cholangiopancreatography (ERCP) and magnetic resonance cholangiopancreatography (MRCP) can also assist in the diagnosis and management of PDA. In patients with obstructive jaundice, both MRCP and ERCP visualize obstructions and dilations within the biliary tree, with the latter having the ability to intervene. ERCP allows for the collection of tissue to aid in diagnosis, and has the ability to relieve biliary obstruction via stenting.⁵⁶

TREATMENT

CASE CONTINUED

After an abdominal CT is obtained, the patient is referred to an outpatient oncologist because of concern for pancreatic adenocarcinoma. After consultation, the patient is advised to obtain EUS with biopsy and to return immediately afterwards for further treatment planning. The pathology report following EUS confirms that the mass is a poorly differentiated PDA. The patient’s case is discussed at a multidisciplinary meeting with radiation, surgical, and medical oncology. The abdominal CT and PET-CT scan are thoroughly reviewed. After imaging review, the multidisciplinary team concludes that the tumor is in contact with the SMA at 120° and with the common hepatic artery without extension in the celiac axis and without evidence of metastasis.

• What is the appropriate management of borderline resectable pancreatic cancer?

BORDERLINE RESECTABLE CANCER

Patients who have nonmetastatic disease and are deemed resectable and without contraindications to surgery or high-risk features, as defined by NCCN guidelines, should proceed directly to surgery. A large body of evidence suggests that complete surgical resection with negative margins is a significant predictor of survival and currently provides the only option for cure.^57–59 Despite the curative intent of surgery, the rate of recurrence remains high in patients who undergo surgical resection. Even in patients with negative resection margins (R0 resection), the 5-year survival is 20% to 30%, with a median survival ranging from 12 to 25 months, suggesting the presence of regional and distant occult disease at the time of diagnosis.^60–62

Additionally, in half the patients who undergo surgical resection with resultant positive microscopic (R1 resection) or gross (R2 resection) margins, the median survival is no greater than 12 months. In this subset of patients, clinical outcomes are similar to outcomes in patients with locally advanced and metastatic pancreatic cancer, suggesting that upfront surgery and adjuvant therapy may not be the ideal therapeutic option. This raises 2 important points: first, resectability should be assessed carefully in all patients with LAPC, and second, for those patients who are deemed borderline resectable, neoadjuvant therapy should be considered.⁶³ Borderline resectability is defined as tumor abutment ≤ 180° of the celiac artery, and tumor abutment of the superior mesenteric vein /portal vein of > 180° or abutting ≤ 180° with irregularity of the vein with or without thrombosis with anatomical structures that still allows for safe and complete resection and vein reconstruction (Table 2).

Neoadjuvant Therapy

The goal of neoadjuvant therapy is to minimize the negative impact of upfront surgery in patients who have a high likelihood of having microscopic or grossly positive margins. Research has suggested that neoadjuvant therapy may improve resectability, decrease the rate of recurrence, and improve overall survival.^64–66

There is no clear consensus on the ideal management of patients with borderline resectable disease. However, expert guidelines are in agreement that upfront surgery in patients with LAPC is not appropriate, as most patients will not be able to achieve an R0 resection.⁶⁷ As staging and management of patients with LAPC is difficult, expertise of a multidisciplinary team can be helpful.⁶⁸

Several studies and the NCCN guidelines support the use of neoadjuvant therapy in patients deemed borderline resectable.^69,70 Treatment of borderline resectable disease is similar to unresectable LAPC and generally involves 2 chemotherapy treatment backbones: FOLFIRINOX (folinic acid [leucovorin], fluorouracil [5-FU], irinotecan, and oxaliplatin) or gemcitabine-based therapy.

Phase 1 to 2/3 clinical trials conducted by Conroy et al from 2005 to 2011, including the landmark ACCORD-11 trial, established the safety and role of FOLFIRINOX in metastatic pancreatic cancer and also demonstrated an improved overall survival with the use of this therapy in these patients.^71,72 These findings led to interest in FOLFIRINOX as a neoadjuvant therapy for patients with LAPC. Since then, multiple prospective and retrospective studies have shown that 54% to 100% of patients with borderline resectable LAPC who were treated with FOLFIRINOX were down-staged significantly enough to undergo resection. Of those patients, more than 90% had a R0 resection following surgery (Table 3).^73–79

Data over the past 7 years suggests that neoadjuvant FOLFIRINOX improves overall survival and resectability in patients with borderline disease. However, treatment with FOLFIRINOX is not without limitations. FOLFIRINOX is associated with higher rates of febrile neutropenia, thrombocytopenia, diarrhea, and sensory neuropathy as compared with gemcitabine-based therapy.⁷² Other less commonly observed toxicities associated with FOLFIRINOX include mucositis, hand-foot syndrome, pulmonary toxicity, and alopecia. Dose-attenuated FOLFIRINOX-based regimens, including those that exclude the bolus fluorouracil dose and augment upfront filgrastim, have demonstrated improved safety and comparable efficacy as compared to standard FOLFIRINOX.⁸⁰

Gemcitabine has been the fundamental treatment backbone for PDA since the results of the phase 3 CONKO-001 trial were published.⁸¹ Gemcitabine is a pyrimidine antimetabolite and potent inhibitor of DNA polymerase and ribonucleotide reductase.⁸² In recent years, multiple combination therapies with gemcitabine have been investigated, including regimens with nab-paclitaxel, oxaliplatin, or docetaxel. Resection rates and negative margin outcomes have been shown to be comparable to patients who received FOLFIRINOX in the neoadjuvant setting with borderline locally advanced disease.^83–85 In addition to having a more tolerable side effect profile in comparison to fluorouracil-based regimens, gemcitabine is considered to be a potent radiosensitizer.⁸⁶ For this reason, studies have also investigated the role of radiotherapy in conjunction with gemcitabine, revealing negative margin resection rates above 80% in patients with borderline resectable disease.^87,88

Because very few studies directly comparing FOLFIRINOX with gemcitabine-based combination regimens have been completed, there is no clear consensus on the preferred treatment regimen, in both borderline and unresectable LAPC. Decisions to treat are influenced predominantly by comorbidities, adverse effect profiles, and performance status of patients, as FOLFIRINOX is the more toxic of the 2 treatment backbones. Therefore, FOLFIRINOX has mostly been utilized in patients with relatively good functional status (Eastern Cooperative Oncology Group [ECOG] performance status 0 to 1).⁸⁹ In elderly patients and those with poor functional status, ECOG 2 to 4, gemcitabine as a single agent is a reasonable alternative in the neoadjuvant setting of borderline resectable disease.

The exact role of radiation therapy in addition to induction chemotherapy in borderline resectable pancreatic cancer has not been clearly established because of the lack of prospective studies in this area. Multiple large retrospective series have identified high rates of conversion to margin-negative resection with neoadjuvant chemoradiation alone.⁹⁰ Based on available data, it is reasonable for patients with borderline resectable disease to proceed with any of the following treatment options: chemotherapy, chemoradiation, or induction chemotherapy followed by chemoradiation (Figure). Chemotherapy and chemoradiation are generally more appropriate with patients with high CA 19-9 levels or those at an elevated risk of having positive margins or occult metastatic disease.⁹¹ Obtaining negative margin resections is the predominant goal of neoadjuvant radiotherapy.⁸⁹ Many studies have identified margin status to be one of the most significant prognostic factors in PDA.^57,59,92,93 Additionally, several studies have highlighted that radiotherapy in the neoadjuvant setting could improve negative margin resection rates, local control, and clinical outcomes in patients with borderline resectable locally advanced disease.^94–97 A common multimodal regimen utilized in the neoadjuvant setting combines capecitabine, an oral prodrug that is converted to fluorouracil, with radiation therapy. This combination has also been shown to improve resectability rates and long-term clinical outcomes in patients with borderline resectable disease.⁹⁸ Additionally, neoadjuvant radiation therapy can potentially downstage patients with unresectable disease at the time of diagnosis to become surgical candidates.⁹⁹ Despite the paucity of data, interval scans utilizing CT following neoadjuvant therapy should be obtained 2 to 4 months after completion of therapy to determine therapeutic response, evaluate for disease progression, and, most important, reassess surgical stage/resectability. It is clinically acceptable to proceed to resection with radiographically stable disease post-neoadjuvant therapy.

Many patients classified as borderline resectable are able to proceed with surgery following neoadjuvant therapy. Unfortunately, specific data on adjuvant therapy following neoadjuvant chemotherapy or chemoradiotherapy and surgical resection in borderline resectable patients is scarce. Clinical practice guidelines are extrapolated from studies where upfront resection in clearly resectable patients was followed by adjuvant therapy. Based on these data, approximately 6 months of perioperative chemotherapy with or without chemoradiotherapy is a reasonable consideration. Nevertheless, about 80% of patients at the time of diagnosis are deemed to be unresectable, and a smaller number do not proceed to surgery despite an initial classification as borderline resectable. Of the 80% of patients with advanced disease, about half are metastatic at presentation and the remaining 30% to 40% are defined as having unresectable LAPC.¹⁰⁰

CASE CONTINUED

The patient is deemed borderline resectable. He receives neoadjuvant therapy with gemcitabine and nab-paclitaxel. Two months after therapy, interval imaging with abdominal CT does not show improvement in tumor size and there is now evidence that the tumor has invaded the celiac axis and is abutting more than 180° of the SMA. The patient presents to the oncologist to discuss further management. He has lost about 15 lb since his last evaluation, is capable of self-care, but is unable to carry on with any work activities.

• What is the appropriate management of unresectable nonmetastatic LAPC?

UNRESECTABLE LOCALLY ADVANCED CANCER

As in the case of borderline resectable disease, there are many treatment options for patients with unresectable LAPC. Timing, optimal chemotherapy regimen, and the addition of regularly and hypofractionated radiotherapy are issues currently under investigation. However, there are some general considerations and principles that are followed as reflected in the NCCN guidelines and recent studies. The primary therapeutic aims in patients with unresectable locally advanced disease are to increase survival and improve palliation.

The elderly comprise a large percentage of the patients diagnosed with unresectable locally advanced disease. Pharmacokinetics and toxicity profiles are altered in the elderly population.^101,102 Therefore, it is important to assess functional status and comorbidities as these are critical factors in determining treatment regimens, similar to patients with borderline resectable disease. Currently, the most common first-line therapies in advanced pancreatic cancer are gemcitabine alone, gemcitabine and nab-paclitaxel, FOLFIRINOX, gemcitabine/capecitabine, and gemcitabine/oxaliplatin.¹⁰³ The overall treatment approach to unresectable locally advanced pancreatic adenocarcinoma closely mirrors that of patients with borderline resectable disease and metastatic disease. Much of the data supporting treatment regimens in unresectable LAPC is extrapolated from clinical trials looking at advanced or metastatic pancreatic cancer.

Consensus opinions domestically and from Europe recommend that patients with locally advanced unresectable disease undergo upfront chemotherapy (Figure).¹⁰⁴ This is based on the premise that initial chemotherapy may destroy occult metastatic cells and increase the efficacy of consolidative chemotherapy, particularly with radiation in the future. Upfront chemoradiotherapy has only been investigated in a small series of trials in which no clear survival benefit was observed and has the added consequence of treatment-related toxicity.¹⁰⁵ However, data is limited in this regard, with variations in treatment protocols and cohort compositions contributing to the inconclusive findings.

No head-to-head studies investigating FOLFIRINOX versus nab-paclitaxel and gemcitabine in patients with locally advanced disease have been published, but clinical trials are under way. Other combination therapies have been looked at through small retrospective or prospective studies, but no robust, large-scale clinical trials have been completed. For this reason, NCCN guidelines recommend enrollment of patients with LAPC into active clinical trials.

• What is the role of radiation therapy in unresectable LAPC?

Despite the reported advantages of neoadjuvant radiation in patients with potentially resectable disease, there is significant debate regarding the timing and role of neoadjuvant radiation in patients with unresectable disease. Numerous comprehensive analyses and studiest indicate that chemoradiotherapy leads to significantly better overall survival compared to no therapy or radiation therapy alone in LAPC.^68,110,111 However, conflicting data support the use of upfront chemoradiotherapy in unresectable LAPC when compared to chemotherapy alone. Unfortunately, most prospective studies investigating the role of radiotherapy were performed following administration of single-agent gemcitabine, which is no longer considered standard of care for patients with LAPC. In spite of this, ECOG 4201 identified a statistically significant improvement in median overall survival following the addition of gemcitabine-based radiotherapy. Huguet et al in his review pointed out that upfront chemoradiotherapy was not superior to chemotherapy only and was associated with increased treatment toxicity.¹⁰⁵ Additionally, a recent phase 3 study looking at chemoradiotherapy versus chemotherapy alone in patients treated with gemcitabine found no difference in overall survival.¹¹² This can potentially be attributed to the fact that about 30% of patients with LAPC develop metastatic disease in the early phases of treatment due to poor control of local and systemically occult disease.¹¹³ Given the propensity for high rates of occult metastatic disease in LAPC, treatment paradigms and consensus guidelines recommend multi-agent systemic chemotherapy followed by chemoradiotherapy in select patients.

Based on current studies and until further clinical investigations are completed, consensus opinion indicates that the most appropriate approach in unresectable LAPC is to begin with induction chemotherapy (with either gemcitabine plus nab-paclitaxel, FOLFIRINOX, capecitabine, or other treatment combinations), followed by chemoradiation in the absence of disease progression when the first repeat imaging evaluation is completed (Figure). One important caveat regarding reimaging with CT in the neoadjuvant setting is that radiologic response may not correlate with pathologic response.¹¹⁴ PET-CT may have a role in predicting response to neoadjuvant therapy. Overall, induction chemotherapy followed by consolidative chemoradiation may confer numerous benefits: it removes the unnecessary burden and toxicity associated with radiotherapy in the nearly one third of patients who have pervasive disease progression during initial treatment; it allows testing and increases the chances of tolerating full-dose systemic chemotherapy; and it raises the likelihood of converting patients who do not progress to metastasis during the initial phase of treatment from unresectable to resectable status.^103,115 Despite the lack of strong conclusive data, the general agreement is that neoadjuvant chemoradiotherapy converts about one third of borderline and unresectable LAPC to an R0 resection.^95,103 There are very specific rationales for the addition of radiotherapy in LAPC, and these functions need to be better defined through further clinical trials.

CASE CONTINUED

The patient is unable to tolerate his first round of second-line therapy with modified FOLFIRINOX. His overall treatment plan is transitioned to palliation. He continues to have pain, despite increasing doses of narcotics.

• What is the next step for patients in whom second-line therapy fails and who have intractable pain while on high-dose narcotics?

A subset of patients with unresectable LAPC may not be amenable to chemotherapy with or without radiation due to significant comorbidities or because they present with or progress to ECOG scores 3 or 4. The goal in these patients should be palliation. Pain is one of the most predominant and difficult to manage symptoms in progressive LAPC. Opioid-based medications are the primary treatment for pain in LAPC. However, patients sometimes become refractory to opioid medications. In this group of patients, it is reasonable to consider palliative radiation as an alternative method for pain control.¹¹⁶

An alternative to palliative radiation in the setting of progressive pain in PDA is celiac plexus block or neurolysis. By injecting an anesthetic or alcohol into the celiac plexus, neural signaling pathways involved in the propagation of pain are inhibited without leading to significant nerve destruction. Additionally, chemical splanchnicectomy allows for reduced opioid medication use and associated side effects.¹¹⁷

In general patients with LAPC have profound weight loss prior to and during treatment. This has significant implications prognostically and on treatment options. The underlying etiology is multifactorial, but one of the primary driving factors is pancreatic insufficiency. An estimated 65% of pancreatic cancer patients have fat malabsorption, and 50% have protein malabsorption, leading to steatorrhea and weight loss.¹¹⁸ Patients diagnosed with pancreatic cancer should be given enzyme replacement with formulations that include lipase, amylase, and protease. A minimum dose of enzyme replacement should include 40,000 to 50,000 U of lipase during meals and 25,000 U during snack intake. If maldigestion, symptoms, or nutritional endpoints (BMI, albumin, prealbumin, cholesterol) do not improve, the pancreatic enzyme dose should be escalated and a proton-pump inhibitor (PPI) added. In patients with pancreatic insufficiency, PPIs have been shown to improve fat absorption.¹¹⁹ Enzyme replacement therapy has been shown to prevent weight loss in patients with unresectable pancreatic cancer.¹²⁰

As most patients with LAPC go on to develop progressive disease, palliative care becomes an integral aspect of the therapeutic paradigm. Palliation in LAPC has a significant role in determining quality of life and ensuring patient’s goals of care have been meet. Studies have suggested that pancreatic cancer is second only to lung cancer in terms of the number of emergency department visits in the later stages of disease.¹²⁰ Additionally, aggressive care in the setting of incurable diseases such as LAPC has been associated with poor quality of life.¹²¹ More recently it has been shown that involvement of palliative care in patients with advanced pancreatic is associated with less aggressive care near death.¹²² Therefore, the incorporation of palliative or supportive care teams in the treatment of patients with progressive LAPC can improve quality of life and alleviate suffering associated with increasing symptom burden.

CONCLUSION

LAPC is a difficult disease for both provider and patient. There is a paucity of robust clinical trials in the neoadjuvant setting for LAPC. Current research is complicated by varying consensus definitions of resectability and the varying treatment configurations across studies. The optimal type, timing, and sequence of treatment and whether to add radiation therapy in LAPC have not been clearly defined. However, based on the available studies and consensus guidelines, patients who are deemed to have LAPC should have neoadjuvant therapy. FOLFIRINOX or gemcitabine with nab-paclitaxel should be considered first-line treatments. Patients with LAPC who respond to chemotherapy or are ineligible for multi-drug chemotherapy may benefit from chemoradiotherapy. In patients with unresectable disease, chemoradiotherapy has been shown to enhance survival as compared to best supportive care or radiation alone. For borderline resectable disease, it is reasonable to treat patients with either chemoradiotherapy, chemotherapy alone, or chemotherapy followed by chemoradiotherapy.

Considering the invasive nature of LAPC and the controversy around neoadjuvant treatment protocols, enrollment of patients with LAPC into clinical trials is important and will help determine the optimal treatment regimen for future patients.

INTRODUCTION

Pancreatic cancer is one of the most rapidly rising causes of mortality in the United States. In 2016, the number of deaths from pancreatic cancer exceeded those from breast cancer, making it the third leading cause of cancer-related death in the United States.¹ It is projected that by 2020 pancreatic cancer will overtake colorectal malignancies to become the second most common cause of cancer death in this country.^1,2 The term pancreatic cancer encompasses both exocrine and endocrine tumors. However, since 80% of pancreatic cancers are classified as pancreatic ductal adenocarcinoma (PDA), when speaking about pancreatic cancer most clinicians and scientists are referring to PDA.

Even with advances in chemotherapy and radiotherapy over the past decade, the only curative option for PDA is surgical resection. Unfortunately, only 20% of patients are appropriate surgical candidates at the time of diagnosis.³ Considering the lack of screening options and the ambiguity of symptomatology, roughly 4 out 5 patients with PDA are diagnosed as having locally advanced or metastatic disease that is initially not amenable to surgery.

Locally advanced pancreatic adenocarcinoma presents unique challenges in management and treatment. Treatment options include multi-agent chemotherapy, chemoradiation, or radiotherapy. Some patients can be successfully down-staged with these therapies and be deemed surgical candidates. Other challenges include selecting the appropriate sequence of therapies and stratifying therapies based on comorbidities. In this article, we review the epidemiology, biology, and diagnostic approach to PDA and focus on current treatment strategies for locally advanced pancreatic cancer (LAPC).

EPIDEMIOLOGY

In 2012, GLOBOCAN estimated that PDA caused 331,000 deaths per year, accounting for 4% of all worldwide mortality.^4,5 Despite high incidence rates internationally, PDA is a disease of Western and industrialized nations. In the Unites States, PDA is a malignancy of middle to late adulthood, with a sharp upsurge in incidence after age 50 years.⁶ More than one third of new cases are diagnosed in patients older than 70 years, and more than half of patients diagnosed are older than 60 years of age.² The incidence of pancreatic cancer is fairly equal among men and women, with a slightly higher rate for the male sex. It has an incidence preference for African-Americans by 4.8 cases per 100,000 persons nationally.⁷

Risk factors for the development of exocrine pancreatic cancer include hereditary disposition, underlying medical conditions, and environmental factors. One of the most significant environmental risk factors for the development of PDA is smoking,⁸ which is associated with up to 25% of all cases.⁹ Smoking cessation leads to a rapid reduction in risk for pancreatic cancer, with the risk among former smokers approaching that for never smokers less than 10 years after quitting.⁹ Other environmental factors that contribute to the development of pancreatic cancer include increased body mass index, a high-salt and high-saturated fat diet, heavy alcohol intake, and increased utilization of nonsteroidal inflammatory drugs.^10–13

There is a strong association between new-onset diabetes and increased risk for developing PDA.^14,15 Data also suggest that diabetes may be a risk factor and/or a consequence of tissue destruction that arises during the development or progression of PDA.^16,17 Interestingly, ABO blood grouping is another underlying medical disposition that confers an altered risk profile. Studies have shown that patients with blood group O were less likely than those with type A, B, or AB to develop pancreatic cancer.¹⁸

Genetic predisposition syndromes can elevate an individual patient’s risk for developing PDA. Genetic syndromes and gene alterations that increase the risk for PDA include BRCA1/2, Peutz-Jeghers syndrome, and Lynch syndrome risk.^19–21 Up to 10% to 15% of PDA cases may be due to an inherited familial cancer.²² Having a first-degree relative with PDA increases the odds of developing PDA 1.76-fold compared to those without a family history.²³ The exact biologic and molecular mechanisms of familial pancreatic cancer are unclear. It is estimated that about 10% of patients with familial pancreatic cancer (FPC) carry BRCA2 mutations.²⁴ Individuals at risk for FPC should undergo genetic screening for the presence of the most frequently inherited pancreatic cancer susceptibility genetic defects: BRCA2, PALB2, and ATM germline mutations.²⁵ Carriers of BRCA2, who are also at increased risk for developing breast, ovarian, and prostate cancer, should be monitored closely. Of all hereditary conditions, hereditary pancreatitis confers the highest risk for developing PDA, with an approximate risk elevation of 40% to 50%.^26,27 Although several genetic predisposition syndromes have been identified, most cases of pancreatic adenocarcinoma are thought to be sporadic.

CANCER BIOLOGY AND PATHOLOGY

The pathologic predecessor of PDA is pancreatic intraepithelial neoplasia (PIN). With further dysplastic changes that result from increasing genetic alterations, these precancerous lesions progress from low- to high-grade and finally to adenocarcinoma. More than 90% of all PINs across all grades have oncogenic KRAS mutations.²⁸ Additionally, inactivating mutations in the tumor suppressor genes SMAD4, p53, and CDKN2A are found with increasing frequency in higher grade PINs. The frequency and presence of mutations in both oncogenes and tumor suppressor genes in precursor neoplasias mirror the genetic mutations noted in advanced PDA.²⁹ Among all mutations, KRAS is the most common and most functionally important for pancreatic cancer cell survival. KRAS mutations not only have profound effects on downstream mediators of tumor growth and metastasis, but they are implicated in reprograming of cellular metabolism.^30,31

Pancreatic adenocarcinoma has a unique microenvironment that makes it a difficult target for current therapeutic modalities. First, it is one of the most stroma-rich malignancies. The dense stroma surrounding pancreatic tumor cells leads to increased tumor pressures and alterations in tumor vascular perfusion.³² It also serves as a barrier that prevents chemotherapeutic drugs from reaching the tumor cells. Thus, clinical trials are under way to investigate agents such has hyaluronidase, which may degrade components of the extracellular matrix that supports thestromal environment. Additionally, there is data to suggest that the microenvironment of PDA downregulates immune monitoring, leading to further tumor growth.^27,33 The molecular, cellular, and immunologic complexity of PDA may contribute to its resistance to traditional therapeutics.

EVALUATION AND DIAGNOSIS

CASE PRESENTATION

A 61-year-old man with a history of type 2 diabetes mellitus and chronic tobacco use presents to the emergency department (ED) with a 4-month history of progressively worsening abdominal discomfort and fatigue. He has also noticed darkening of his urine and slight yellow discoloration of his eyes. His weight measured 5 months ago in his primary care physician’s office was 91 kg (200 lb, BMI 29.5) and in the ED is 75 kg (165 lb, BMI 24.4). He has noticed bulky, malodorous, oily stools for about 2 months. Preliminary laboratory studies reveal elevated levels of total bilirubin (2.7 mg/dL) and alkaline phosphatase (204 IU/L). Transabdominal ultrasound (US) is obtained and reveals a 3-cm pancreatic mass with biliary tract dilation.

• Does this patient have pancreatic cancer?

CLINICAL SIGNS AND SYMPTOMS

Establishing the diagnosis of pancreatic cancer in a patient who presents with a high index of suspicion is critical. Patients with pancreatic cancer usually present after a period of nonspecific and vague symptoms, which typically are experienced as abdominal discomfort, weight loss, and weakness. It is estimated that approximately 25% of patients may complain of vague abdominal pain up to 6 months prior to diagnosis. Up to 15% of patients may seek medical attention more than 6 months prior to establishing a diagnosis of PDA.³⁴ The most common symptoms associated with pancreatic cancer in order of decreasing reported frequency are weight loss, anorexia, abdominal/epigastric pain, dark-colored urine, jaundice, nausea, back pain, and diarrhea with associated steatorrhea.³⁵ Upwards of 15% of patients present with painless jaundice, a term that is often associated with pancreatic cancer.³⁶ On exam these patients may have scleral icterus, sublingual jaundice, epigastric pain on palpation, weight loss, hepatomegaly, lymphadenopathy and a nontender, distended, palpable gallbladder (also known as Courvoisier sign).³⁴ Abdominal signs and symptoms arise from tumor growth into surrounding vessels, tissues, and ducts within the abdominal cavity. Compression of the common bile duct accounts for the development of jaundice. Tumor growth around the stomach and duodenum can lead to delayed gastric emptying and subsequently nausea and vomiting. Constriction of the pancreatic duct leads to pancreatic insufficiency, precipitation of weight loss, and steatorrhea. Pancreatic insufficiency can worsen abdominal pain, and lead to increased weight loss and flatulence.

Less common symptoms include pain, erythema, and edema involving the lower extremities, which may be reflective of migratory thrombophlebitis (commonly known as Trousseau syndrome). Thromboembolic disease, including pulmonary embolism, portal vein, and deep vein thromboses are frequently encountered complications of pancreatic cancer. The incidence of thromboembolic events in patients with PDA has been reported to be as high as 54%.³⁷ Of all signs encountered, weight loss is the most common and most profound. Patients with advanced PDA have severe degrees of cachexia. Some patients present with as much as a 5 kg/m² decrease in their BMI from pre-illness baseline BMI, and lose another 3 to 4 kg/m² through disease progression.³⁸ At the time of diagnosis, many patients have already undergone significant weight loss, which can have substantial implications on treatment planning and clinical outcomes.

• What other studies can be done to assist in making the diagnosis?

LABORATORY ABNORMALITIES AND TUMOR MARKERS

Elevations in alkaline phosphatase, γ-glutamyltransferase (GGT), serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), and direct fractions of bilirubin are common in patients with PDA. Patients will usually have an obstructive pattern on their liver panel, with predominant elevations in direct bilirubin, alkaline phosphatase, and GGT, as compared with AST and ALT. Other baseline laboratory studies, including a complete blood count and basic metabolic panel, should be obtained because patients commonly have thrombocytosis, anemia, and electrolyte abnormalities due to the tumor itself and pancreatic insufficiency (Table 1).

Measurement of glycated hemoglobin (HBA1C) is an emerging and important diagnostic test in the diagnosis of pancreatic cancer. Recently, data has emerged to suggest that new-onset diabetes is present in about 50% of patients diagnosed with pancreatic cancer.³⁹ The temporal relationship of pancreatic cancer and diabetes is supported by evidence showing that patients who undergo resection commonly have resolution of their diabetes.¹⁷ This study suggested that hyperglycemia, elevated HBA1C, and symptoms of diabetes in patients older than 50 years may identify patients who have early pancreatic cancer. The entity of pancreatic cancer–associated diabetes needs to be better defined and the algorithmic approach to evaluation and diagnosis, utilizing signs, symptoms, and laboratory values associated with diabetes, needs to be clearly established.

The only serum marker for PDA is carbohydrate antigen 19-9 (CA 19-9), also known as sialylated Lewis antigen or cancer-associated antigen. It was first identified in pancreatic cancer patients in 1981.^40,41 The sensitivity and specificity of CA 19-9 ranges from 70% to approximately 90%.^42,43 Hereditary predispositions and comorbid disease cross-reactivity contribute to the diminished sensitivity and specificity of CA 19-9. In about 5% to 10% of the population, CA 19-9 is not expressed (Lewis antigen A and B negative). Additionally, since CA 19-9 is expressed in the cells that line the biliary tree, diseases that lead to pancreatic or liver inflammation may falsely elevate CA 19-9.⁴⁴ As a result, CA 19-9 is not an ideal screening test. However, data has shown that CA 19-9 may have prognostic value postoperatively and serve as a marker for therapeutic response.^45,46

• Is biopsy needed for this patient and if so, what is the most appropriate technique?

ENDOSCOPIC ULTRASOUND

Generally, diagnosis with tissue is not necessary for patients who clearly have resectable disease and will proceed directly to surgery for management. Nevertheless, it is still commonly obtained in this group of patients. However, in patients with LAPC or with features suggestive of LAPC, such as tumor approximation to critical vessels such as the superior mesenteric artery (SMA) or celiac axis, biopsy is necessary. These patients will receive neoadjuvant therapy, and biopsy is important in establishing a diagnosis. The ideal way to obtain a biopsy is through fine-needle aspiration (FNA) or biopsy (FNB) utilizing endoscopic ultrasound (EUS). Percutaneous and computed tomography (CT)–guided FNB can also be used to obtain a biopsy for diagnosis. In comparison to percutaneous and CT-guided FNB, EUS-FNA/FNB has low rates of complications, a decreased rate of peritoneal seeding, and is cost effective.^47,48

CASE CONTINUED

Abdominal CT obtained following abdominal ultrasound reveals a 3.5-cm mass in the head of the pancreas in close approximation to the SMA and celiac axis.

• Does the patient have borderline resectable or unresectable disease?

IMAGING

Abdominal ultrasound is a reasonable, inexpensive, and safe alternative to abdominal CT as it does not utilize ionizing radiation. It is particularly useful in patients who present with jaundice or have concern for biliary obstruction based on laboratory evaluation. It is particularly sensitive for detecting tumors greater than 3 cm in size.^49,50 In patients whose abdominal ultrasound is unrevealing and whose index of suspicion remains high for PDA, abdominal CT should be the next imaging modality.

Abdominal CT obtained utilizing a pancreatic protocol is ideal for detection and staging of pancreatic tumors. By implementing a triple-phase protocol with arterial, late arterial, and venous phases, tumors, which have a density different from that of the pancreatic parenchyma, are accentuated. Abdominal CT is also able to provide critical information about tumor resectability.⁵¹ By revealing the degree of tumor encasement around the aorta, level of destruction of the superior mesenteric vein, or degree of involvement of the SMA or celiac vessels, abdominal CT determines if a patient should be deemed resectable, borderline resectable, or unresectable (Table 2).^52,53 Resectability is based on thorough imaging evaluation, expert opinion of a multidisciplinary team, and guidelines proposed by American Hepatopancreaticobiliary Association, Society of Surgical Oncology, Society for Surgery of the Alimentary Tract, and the NCCN.⁵⁴

Other imaging modalities have a less clearly established role in the diagnostic approach to PDA. In patients who have contraindications to obtaining CT, magnetic resonance imaging can be utilized as a secondary imaging modality.⁵⁵ The role of positron emission tomography 18F-fluorodeoxyglucose (PET-FDG) is not clearly defined among clinicians, nor reflected in consensus guidelines by the National Comprehensive Cancer Network (NCCN). In clinical practice, it is still often combined with CT to detect metastatic disease, particularly in high-risk patients such has those with LAPC. The role of PET-CT in staging and its impact on clinical outcomes has not been fully established.

Endoscopic retrograde cholangiopancreatography (ERCP) and magnetic resonance cholangiopancreatography (MRCP) can also assist in the diagnosis and management of PDA. In patients with obstructive jaundice, both MRCP and ERCP visualize obstructions and dilations within the biliary tree, with the latter having the ability to intervene. ERCP allows for the collection of tissue to aid in diagnosis, and has the ability to relieve biliary obstruction via stenting.⁵⁶

TREATMENT

CASE CONTINUED

After an abdominal CT is obtained, the patient is referred to an outpatient oncologist because of concern for pancreatic adenocarcinoma. After consultation, the patient is advised to obtain EUS with biopsy and to return immediately afterwards for further treatment planning. The pathology report following EUS confirms that the mass is a poorly differentiated PDA. The patient’s case is discussed at a multidisciplinary meeting with radiation, surgical, and medical oncology. The abdominal CT and PET-CT scan are thoroughly reviewed. After imaging review, the multidisciplinary team concludes that the tumor is in contact with the SMA at 120° and with the common hepatic artery without extension in the celiac axis and without evidence of metastasis.

• What is the appropriate management of borderline resectable pancreatic cancer?

BORDERLINE RESECTABLE CANCER

Patients who have nonmetastatic disease and are deemed resectable and without contraindications to surgery or high-risk features, as defined by NCCN guidelines, should proceed directly to surgery. A large body of evidence suggests that complete surgical resection with negative margins is a significant predictor of survival and currently provides the only option for cure.^57–59 Despite the curative intent of surgery, the rate of recurrence remains high in patients who undergo surgical resection. Even in patients with negative resection margins (R0 resection), the 5-year survival is 20% to 30%, with a median survival ranging from 12 to 25 months, suggesting the presence of regional and distant occult disease at the time of diagnosis.^60–62

Additionally, in half the patients who undergo surgical resection with resultant positive microscopic (R1 resection) or gross (R2 resection) margins, the median survival is no greater than 12 months. In this subset of patients, clinical outcomes are similar to outcomes in patients with locally advanced and metastatic pancreatic cancer, suggesting that upfront surgery and adjuvant therapy may not be the ideal therapeutic option. This raises 2 important points: first, resectability should be assessed carefully in all patients with LAPC, and second, for those patients who are deemed borderline resectable, neoadjuvant therapy should be considered.⁶³ Borderline resectability is defined as tumor abutment ≤ 180° of the celiac artery, and tumor abutment of the superior mesenteric vein /portal vein of > 180° or abutting ≤ 180° with irregularity of the vein with or without thrombosis with anatomical structures that still allows for safe and complete resection and vein reconstruction (Table 2).

Neoadjuvant Therapy

The goal of neoadjuvant therapy is to minimize the negative impact of upfront surgery in patients who have a high likelihood of having microscopic or grossly positive margins. Research has suggested that neoadjuvant therapy may improve resectability, decrease the rate of recurrence, and improve overall survival.^64–66

There is no clear consensus on the ideal management of patients with borderline resectable disease. However, expert guidelines are in agreement that upfront surgery in patients with LAPC is not appropriate, as most patients will not be able to achieve an R0 resection.⁶⁷ As staging and management of patients with LAPC is difficult, expertise of a multidisciplinary team can be helpful.⁶⁸

Several studies and the NCCN guidelines support the use of neoadjuvant therapy in patients deemed borderline resectable.^69,70 Treatment of borderline resectable disease is similar to unresectable LAPC and generally involves 2 chemotherapy treatment backbones: FOLFIRINOX (folinic acid [leucovorin], fluorouracil [5-FU], irinotecan, and oxaliplatin) or gemcitabine-based therapy.

Phase 1 to 2/3 clinical trials conducted by Conroy et al from 2005 to 2011, including the landmark ACCORD-11 trial, established the safety and role of FOLFIRINOX in metastatic pancreatic cancer and also demonstrated an improved overall survival with the use of this therapy in these patients.^71,72 These findings led to interest in FOLFIRINOX as a neoadjuvant therapy for patients with LAPC. Since then, multiple prospective and retrospective studies have shown that 54% to 100% of patients with borderline resectable LAPC who were treated with FOLFIRINOX were down-staged significantly enough to undergo resection. Of those patients, more than 90% had a R0 resection following surgery (Table 3).^73–79

Data over the past 7 years suggests that neoadjuvant FOLFIRINOX improves overall survival and resectability in patients with borderline disease. However, treatment with FOLFIRINOX is not without limitations. FOLFIRINOX is associated with higher rates of febrile neutropenia, thrombocytopenia, diarrhea, and sensory neuropathy as compared with gemcitabine-based therapy.⁷² Other less commonly observed toxicities associated with FOLFIRINOX include mucositis, hand-foot syndrome, pulmonary toxicity, and alopecia. Dose-attenuated FOLFIRINOX-based regimens, including those that exclude the bolus fluorouracil dose and augment upfront filgrastim, have demonstrated improved safety and comparable efficacy as compared to standard FOLFIRINOX.⁸⁰

Gemcitabine has been the fundamental treatment backbone for PDA since the results of the phase 3 CONKO-001 trial were published.⁸¹ Gemcitabine is a pyrimidine antimetabolite and potent inhibitor of DNA polymerase and ribonucleotide reductase.⁸² In recent years, multiple combination therapies with gemcitabine have been investigated, including regimens with nab-paclitaxel, oxaliplatin, or docetaxel. Resection rates and negative margin outcomes have been shown to be comparable to patients who received FOLFIRINOX in the neoadjuvant setting with borderline locally advanced disease.^83–85 In addition to having a more tolerable side effect profile in comparison to fluorouracil-based regimens, gemcitabine is considered to be a potent radiosensitizer.⁸⁶ For this reason, studies have also investigated the role of radiotherapy in conjunction with gemcitabine, revealing negative margin resection rates above 80% in patients with borderline resectable disease.^87,88

Because very few studies directly comparing FOLFIRINOX with gemcitabine-based combination regimens have been completed, there is no clear consensus on the preferred treatment regimen, in both borderline and unresectable LAPC. Decisions to treat are influenced predominantly by comorbidities, adverse effect profiles, and performance status of patients, as FOLFIRINOX is the more toxic of the 2 treatment backbones. Therefore, FOLFIRINOX has mostly been utilized in patients with relatively good functional status (Eastern Cooperative Oncology Group [ECOG] performance status 0 to 1).⁸⁹ In elderly patients and those with poor functional status, ECOG 2 to 4, gemcitabine as a single agent is a reasonable alternative in the neoadjuvant setting of borderline resectable disease.

The exact role of radiation therapy in addition to induction chemotherapy in borderline resectable pancreatic cancer has not been clearly established because of the lack of prospective studies in this area. Multiple large retrospective series have identified high rates of conversion to margin-negative resection with neoadjuvant chemoradiation alone.⁹⁰ Based on available data, it is reasonable for patients with borderline resectable disease to proceed with any of the following treatment options: chemotherapy, chemoradiation, or induction chemotherapy followed by chemoradiation (Figure). Chemotherapy and chemoradiation are generally more appropriate with patients with high CA 19-9 levels or those at an elevated risk of having positive margins or occult metastatic disease.⁹¹ Obtaining negative margin resections is the predominant goal of neoadjuvant radiotherapy.⁸⁹ Many studies have identified margin status to be one of the most significant prognostic factors in PDA.^57,59,92,93 Additionally, several studies have highlighted that radiotherapy in the neoadjuvant setting could improve negative margin resection rates, local control, and clinical outcomes in patients with borderline resectable locally advanced disease.^94–97 A common multimodal regimen utilized in the neoadjuvant setting combines capecitabine, an oral prodrug that is converted to fluorouracil, with radiation therapy. This combination has also been shown to improve resectability rates and long-term clinical outcomes in patients with borderline resectable disease.⁹⁸ Additionally, neoadjuvant radiation therapy can potentially downstage patients with unresectable disease at the time of diagnosis to become surgical candidates.⁹⁹ Despite the paucity of data, interval scans utilizing CT following neoadjuvant therapy should be obtained 2 to 4 months after completion of therapy to determine therapeutic response, evaluate for disease progression, and, most important, reassess surgical stage/resectability. It is clinically acceptable to proceed to resection with radiographically stable disease post-neoadjuvant therapy.

Many patients classified as borderline resectable are able to proceed with surgery following neoadjuvant therapy. Unfortunately, specific data on adjuvant therapy following neoadjuvant chemotherapy or chemoradiotherapy and surgical resection in borderline resectable patients is scarce. Clinical practice guidelines are extrapolated from studies where upfront resection in clearly resectable patients was followed by adjuvant therapy. Based on these data, approximately 6 months of perioperative chemotherapy with or without chemoradiotherapy is a reasonable consideration. Nevertheless, about 80% of patients at the time of diagnosis are deemed to be unresectable, and a smaller number do not proceed to surgery despite an initial classification as borderline resectable. Of the 80% of patients with advanced disease, about half are metastatic at presentation and the remaining 30% to 40% are defined as having unresectable LAPC.¹⁰⁰

CASE CONTINUED

The patient is deemed borderline resectable. He receives neoadjuvant therapy with gemcitabine and nab-paclitaxel. Two months after therapy, interval imaging with abdominal CT does not show improvement in tumor size and there is now evidence that the tumor has invaded the celiac axis and is abutting more than 180° of the SMA. The patient presents to the oncologist to discuss further management. He has lost about 15 lb since his last evaluation, is capable of self-care, but is unable to carry on with any work activities.

• What is the appropriate management of unresectable nonmetastatic LAPC?

UNRESECTABLE LOCALLY ADVANCED CANCER

As in the case of borderline resectable disease, there are many treatment options for patients with unresectable LAPC. Timing, optimal chemotherapy regimen, and the addition of regularly and hypofractionated radiotherapy are issues currently under investigation. However, there are some general considerations and principles that are followed as reflected in the NCCN guidelines and recent studies. The primary therapeutic aims in patients with unresectable locally advanced disease are to increase survival and improve palliation.

The elderly comprise a large percentage of the patients diagnosed with unresectable locally advanced disease. Pharmacokinetics and toxicity profiles are altered in the elderly population.^101,102 Therefore, it is important to assess functional status and comorbidities as these are critical factors in determining treatment regimens, similar to patients with borderline resectable disease. Currently, the most common first-line therapies in advanced pancreatic cancer are gemcitabine alone, gemcitabine and nab-paclitaxel, FOLFIRINOX, gemcitabine/capecitabine, and gemcitabine/oxaliplatin.¹⁰³ The overall treatment approach to unresectable locally advanced pancreatic adenocarcinoma closely mirrors that of patients with borderline resectable disease and metastatic disease. Much of the data supporting treatment regimens in unresectable LAPC is extrapolated from clinical trials looking at advanced or metastatic pancreatic cancer.

Consensus opinions domestically and from Europe recommend that patients with locally advanced unresectable disease undergo upfront chemotherapy (Figure).¹⁰⁴ This is based on the premise that initial chemotherapy may destroy occult metastatic cells and increase the efficacy of consolidative chemotherapy, particularly with radiation in the future. Upfront chemoradiotherapy has only been investigated in a small series of trials in which no clear survival benefit was observed and has the added consequence of treatment-related toxicity.¹⁰⁵ However, data is limited in this regard, with variations in treatment protocols and cohort compositions contributing to the inconclusive findings.

No head-to-head studies investigating FOLFIRINOX versus nab-paclitaxel and gemcitabine in patients with locally advanced disease have been published, but clinical trials are under way. Other combination therapies have been looked at through small retrospective or prospective studies, but no robust, large-scale clinical trials have been completed. For this reason, NCCN guidelines recommend enrollment of patients with LAPC into active clinical trials.

• What is the role of radiation therapy in unresectable LAPC?

Despite the reported advantages of neoadjuvant radiation in patients with potentially resectable disease, there is significant debate regarding the timing and role of neoadjuvant radiation in patients with unresectable disease. Numerous comprehensive analyses and studiest indicate that chemoradiotherapy leads to significantly better overall survival compared to no therapy or radiation therapy alone in LAPC.^68,110,111 However, conflicting data support the use of upfront chemoradiotherapy in unresectable LAPC when compared to chemotherapy alone. Unfortunately, most prospective studies investigating the role of radiotherapy were performed following administration of single-agent gemcitabine, which is no longer considered standard of care for patients with LAPC. In spite of this, ECOG 4201 identified a statistically significant improvement in median overall survival following the addition of gemcitabine-based radiotherapy. Huguet et al in his review pointed out that upfront chemoradiotherapy was not superior to chemotherapy only and was associated with increased treatment toxicity.¹⁰⁵ Additionally, a recent phase 3 study looking at chemoradiotherapy versus chemotherapy alone in patients treated with gemcitabine found no difference in overall survival.¹¹² This can potentially be attributed to the fact that about 30% of patients with LAPC develop metastatic disease in the early phases of treatment due to poor control of local and systemically occult disease.¹¹³ Given the propensity for high rates of occult metastatic disease in LAPC, treatment paradigms and consensus guidelines recommend multi-agent systemic chemotherapy followed by chemoradiotherapy in select patients.

Based on current studies and until further clinical investigations are completed, consensus opinion indicates that the most appropriate approach in unresectable LAPC is to begin with induction chemotherapy (with either gemcitabine plus nab-paclitaxel, FOLFIRINOX, capecitabine, or other treatment combinations), followed by chemoradiation in the absence of disease progression when the first repeat imaging evaluation is completed (Figure). One important caveat regarding reimaging with CT in the neoadjuvant setting is that radiologic response may not correlate with pathologic response.¹¹⁴ PET-CT may have a role in predicting response to neoadjuvant therapy. Overall, induction chemotherapy followed by consolidative chemoradiation may confer numerous benefits: it removes the unnecessary burden and toxicity associated with radiotherapy in the nearly one third of patients who have pervasive disease progression during initial treatment; it allows testing and increases the chances of tolerating full-dose systemic chemotherapy; and it raises the likelihood of converting patients who do not progress to metastasis during the initial phase of treatment from unresectable to resectable status.^103,115 Despite the lack of strong conclusive data, the general agreement is that neoadjuvant chemoradiotherapy converts about one third of borderline and unresectable LAPC to an R0 resection.^95,103 There are very specific rationales for the addition of radiotherapy in LAPC, and these functions need to be better defined through further clinical trials.

CASE CONTINUED

The patient is unable to tolerate his first round of second-line therapy with modified FOLFIRINOX. His overall treatment plan is transitioned to palliation. He continues to have pain, despite increasing doses of narcotics.

• What is the next step for patients in whom second-line therapy fails and who have intractable pain while on high-dose narcotics?

A subset of patients with unresectable LAPC may not be amenable to chemotherapy with or without radiation due to significant comorbidities or because they present with or progress to ECOG scores 3 or 4. The goal in these patients should be palliation. Pain is one of the most predominant and difficult to manage symptoms in progressive LAPC. Opioid-based medications are the primary treatment for pain in LAPC. However, patients sometimes become refractory to opioid medications. In this group of patients, it is reasonable to consider palliative radiation as an alternative method for pain control.¹¹⁶

An alternative to palliative radiation in the setting of progressive pain in PDA is celiac plexus block or neurolysis. By injecting an anesthetic or alcohol into the celiac plexus, neural signaling pathways involved in the propagation of pain are inhibited without leading to significant nerve destruction. Additionally, chemical splanchnicectomy allows for reduced opioid medication use and associated side effects.¹¹⁷

In general patients with LAPC have profound weight loss prior to and during treatment. This has significant implications prognostically and on treatment options. The underlying etiology is multifactorial, but one of the primary driving factors is pancreatic insufficiency. An estimated 65% of pancreatic cancer patients have fat malabsorption, and 50% have protein malabsorption, leading to steatorrhea and weight loss.¹¹⁸ Patients diagnosed with pancreatic cancer should be given enzyme replacement with formulations that include lipase, amylase, and protease. A minimum dose of enzyme replacement should include 40,000 to 50,000 U of lipase during meals and 25,000 U during snack intake. If maldigestion, symptoms, or nutritional endpoints (BMI, albumin, prealbumin, cholesterol) do not improve, the pancreatic enzyme dose should be escalated and a proton-pump inhibitor (PPI) added. In patients with pancreatic insufficiency, PPIs have been shown to improve fat absorption.¹¹⁹ Enzyme replacement therapy has been shown to prevent weight loss in patients with unresectable pancreatic cancer.¹²⁰

As most patients with LAPC go on to develop progressive disease, palliative care becomes an integral aspect of the therapeutic paradigm. Palliation in LAPC has a significant role in determining quality of life and ensuring patient’s goals of care have been meet. Studies have suggested that pancreatic cancer is second only to lung cancer in terms of the number of emergency department visits in the later stages of disease.¹²⁰ Additionally, aggressive care in the setting of incurable diseases such as LAPC has been associated with poor quality of life.¹²¹ More recently it has been shown that involvement of palliative care in patients with advanced pancreatic is associated with less aggressive care near death.¹²² Therefore, the incorporation of palliative or supportive care teams in the treatment of patients with progressive LAPC can improve quality of life and alleviate suffering associated with increasing symptom burden.

CONCLUSION

LAPC is a difficult disease for both provider and patient. There is a paucity of robust clinical trials in the neoadjuvant setting for LAPC. Current research is complicated by varying consensus definitions of resectability and the varying treatment configurations across studies. The optimal type, timing, and sequence of treatment and whether to add radiation therapy in LAPC have not been clearly defined. However, based on the available studies and consensus guidelines, patients who are deemed to have LAPC should have neoadjuvant therapy. FOLFIRINOX or gemcitabine with nab-paclitaxel should be considered first-line treatments. Patients with LAPC who respond to chemotherapy or are ineligible for multi-drug chemotherapy may benefit from chemoradiotherapy. In patients with unresectable disease, chemoradiotherapy has been shown to enhance survival as compared to best supportive care or radiation alone. For borderline resectable disease, it is reasonable to treat patients with either chemoradiotherapy, chemotherapy alone, or chemotherapy followed by chemoradiotherapy.

Considering the invasive nature of LAPC and the controversy around neoadjuvant treatment protocols, enrollment of patients with LAPC into clinical trials is important and will help determine the optimal treatment regimen for future patients.

INTRODUCTION

Pancreatic cancer is one of the most rapidly rising causes of mortality in the United States. In 2016, the number of deaths from pancreatic cancer exceeded those from breast cancer, making it the third leading cause of cancer-related death in the United States.¹ It is projected that by 2020 pancreatic cancer will overtake colorectal malignancies to become the second most common cause of cancer death in this country.^1,2 The term pancreatic cancer encompasses both exocrine and endocrine tumors. However, since 80% of pancreatic cancers are classified as pancreatic ductal adenocarcinoma (PDA), when speaking about pancreatic cancer most clinicians and scientists are referring to PDA.

Even with advances in chemotherapy and radiotherapy over the past decade, the only curative option for PDA is surgical resection. Unfortunately, only 20% of patients are appropriate surgical candidates at the time of diagnosis.³ Considering the lack of screening options and the ambiguity of symptomatology, roughly 4 out 5 patients with PDA are diagnosed as having locally advanced or metastatic disease that is initially not amenable to surgery.

Locally advanced pancreatic adenocarcinoma presents unique challenges in management and treatment. Treatment options include multi-agent chemotherapy, chemoradiation, or radiotherapy. Some patients can be successfully down-staged with these therapies and be deemed surgical candidates. Other challenges include selecting the appropriate sequence of therapies and stratifying therapies based on comorbidities. In this article, we review the epidemiology, biology, and diagnostic approach to PDA and focus on current treatment strategies for locally advanced pancreatic cancer (LAPC).

EPIDEMIOLOGY

In 2012, GLOBOCAN estimated that PDA caused 331,000 deaths per year, accounting for 4% of all worldwide mortality.^4,5 Despite high incidence rates internationally, PDA is a disease of Western and industrialized nations. In the Unites States, PDA is a malignancy of middle to late adulthood, with a sharp upsurge in incidence after age 50 years.⁶ More than one third of new cases are diagnosed in patients older than 70 years, and more than half of patients diagnosed are older than 60 years of age.² The incidence of pancreatic cancer is fairly equal among men and women, with a slightly higher rate for the male sex. It has an incidence preference for African-Americans by 4.8 cases per 100,000 persons nationally.⁷

Risk factors for the development of exocrine pancreatic cancer include hereditary disposition, underlying medical conditions, and environmental factors. One of the most significant environmental risk factors for the development of PDA is smoking,⁸ which is associated with up to 25% of all cases.⁹ Smoking cessation leads to a rapid reduction in risk for pancreatic cancer, with the risk among former smokers approaching that for never smokers less than 10 years after quitting.⁹ Other environmental factors that contribute to the development of pancreatic cancer include increased body mass index, a high-salt and high-saturated fat diet, heavy alcohol intake, and increased utilization of nonsteroidal inflammatory drugs.^10–13

There is a strong association between new-onset diabetes and increased risk for developing PDA.^14,15 Data also suggest that diabetes may be a risk factor and/or a consequence of tissue destruction that arises during the development or progression of PDA.^16,17 Interestingly, ABO blood grouping is another underlying medical disposition that confers an altered risk profile. Studies have shown that patients with blood group O were less likely than those with type A, B, or AB to develop pancreatic cancer.¹⁸

Genetic predisposition syndromes can elevate an individual patient’s risk for developing PDA. Genetic syndromes and gene alterations that increase the risk for PDA include BRCA1/2, Peutz-Jeghers syndrome, and Lynch syndrome risk.^19–21 Up to 10% to 15% of PDA cases may be due to an inherited familial cancer.²² Having a first-degree relative with PDA increases the odds of developing PDA 1.76-fold compared to those without a family history.²³ The exact biologic and molecular mechanisms of familial pancreatic cancer are unclear. It is estimated that about 10% of patients with familial pancreatic cancer (FPC) carry BRCA2 mutations.²⁴ Individuals at risk for FPC should undergo genetic screening for the presence of the most frequently inherited pancreatic cancer susceptibility genetic defects: BRCA2, PALB2, and ATM germline mutations.²⁵ Carriers of BRCA2, who are also at increased risk for developing breast, ovarian, and prostate cancer, should be monitored closely. Of all hereditary conditions, hereditary pancreatitis confers the highest risk for developing PDA, with an approximate risk elevation of 40% to 50%.^26,27 Although several genetic predisposition syndromes have been identified, most cases of pancreatic adenocarcinoma are thought to be sporadic.

CANCER BIOLOGY AND PATHOLOGY

The pathologic predecessor of PDA is pancreatic intraepithelial neoplasia (PIN). With further dysplastic changes that result from increasing genetic alterations, these precancerous lesions progress from low- to high-grade and finally to adenocarcinoma. More than 90% of all PINs across all grades have oncogenic KRAS mutations.²⁸ Additionally, inactivating mutations in the tumor suppressor genes SMAD4, p53, and CDKN2A are found with increasing frequency in higher grade PINs. The frequency and presence of mutations in both oncogenes and tumor suppressor genes in precursor neoplasias mirror the genetic mutations noted in advanced PDA.²⁹ Among all mutations, KRAS is the most common and most functionally important for pancreatic cancer cell survival. KRAS mutations not only have profound effects on downstream mediators of tumor growth and metastasis, but they are implicated in reprograming of cellular metabolism.^30,31

Pancreatic adenocarcinoma has a unique microenvironment that makes it a difficult target for current therapeutic modalities. First, it is one of the most stroma-rich malignancies. The dense stroma surrounding pancreatic tumor cells leads to increased tumor pressures and alterations in tumor vascular perfusion.³² It also serves as a barrier that prevents chemotherapeutic drugs from reaching the tumor cells. Thus, clinical trials are under way to investigate agents such has hyaluronidase, which may degrade components of the extracellular matrix that supports thestromal environment. Additionally, there is data to suggest that the microenvironment of PDA downregulates immune monitoring, leading to further tumor growth.^27,33 The molecular, cellular, and immunologic complexity of PDA may contribute to its resistance to traditional therapeutics.

EVALUATION AND DIAGNOSIS

CASE PRESENTATION

A 61-year-old man with a history of type 2 diabetes mellitus and chronic tobacco use presents to the emergency department (ED) with a 4-month history of progressively worsening abdominal discomfort and fatigue. He has also noticed darkening of his urine and slight yellow discoloration of his eyes. His weight measured 5 months ago in his primary care physician’s office was 91 kg (200 lb, BMI 29.5) and in the ED is 75 kg (165 lb, BMI 24.4). He has noticed bulky, malodorous, oily stools for about 2 months. Preliminary laboratory studies reveal elevated levels of total bilirubin (2.7 mg/dL) and alkaline phosphatase (204 IU/L). Transabdominal ultrasound (US) is obtained and reveals a 3-cm pancreatic mass with biliary tract dilation.

• Does this patient have pancreatic cancer?

CLINICAL SIGNS AND SYMPTOMS

Establishing the diagnosis of pancreatic cancer in a patient who presents with a high index of suspicion is critical. Patients with pancreatic cancer usually present after a period of nonspecific and vague symptoms, which typically are experienced as abdominal discomfort, weight loss, and weakness. It is estimated that approximately 25% of patients may complain of vague abdominal pain up to 6 months prior to diagnosis. Up to 15% of patients may seek medical attention more than 6 months prior to establishing a diagnosis of PDA.³⁴ The most common symptoms associated with pancreatic cancer in order of decreasing reported frequency are weight loss, anorexia, abdominal/epigastric pain, dark-colored urine, jaundice, nausea, back pain, and diarrhea with associated steatorrhea.³⁵ Upwards of 15% of patients present with painless jaundice, a term that is often associated with pancreatic cancer.³⁶ On exam these patients may have scleral icterus, sublingual jaundice, epigastric pain on palpation, weight loss, hepatomegaly, lymphadenopathy and a nontender, distended, palpable gallbladder (also known as Courvoisier sign).³⁴ Abdominal signs and symptoms arise from tumor growth into surrounding vessels, tissues, and ducts within the abdominal cavity. Compression of the common bile duct accounts for the development of jaundice. Tumor growth around the stomach and duodenum can lead to delayed gastric emptying and subsequently nausea and vomiting. Constriction of the pancreatic duct leads to pancreatic insufficiency, precipitation of weight loss, and steatorrhea. Pancreatic insufficiency can worsen abdominal pain, and lead to increased weight loss and flatulence.

Less common symptoms include pain, erythema, and edema involving the lower extremities, which may be reflective of migratory thrombophlebitis (commonly known as Trousseau syndrome). Thromboembolic disease, including pulmonary embolism, portal vein, and deep vein thromboses are frequently encountered complications of pancreatic cancer. The incidence of thromboembolic events in patients with PDA has been reported to be as high as 54%.³⁷ Of all signs encountered, weight loss is the most common and most profound. Patients with advanced PDA have severe degrees of cachexia. Some patients present with as much as a 5 kg/m² decrease in their BMI from pre-illness baseline BMI, and lose another 3 to 4 kg/m² through disease progression.³⁸ At the time of diagnosis, many patients have already undergone significant weight loss, which can have substantial implications on treatment planning and clinical outcomes.

• What other studies can be done to assist in making the diagnosis?

LABORATORY ABNORMALITIES AND TUMOR MARKERS

Elevations in alkaline phosphatase, γ-glutamyltransferase (GGT), serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), and direct fractions of bilirubin are common in patients with PDA. Patients will usually have an obstructive pattern on their liver panel, with predominant elevations in direct bilirubin, alkaline phosphatase, and GGT, as compared with AST and ALT. Other baseline laboratory studies, including a complete blood count and basic metabolic panel, should be obtained because patients commonly have thrombocytosis, anemia, and electrolyte abnormalities due to the tumor itself and pancreatic insufficiency (Table 1).

Measurement of glycated hemoglobin (HBA1C) is an emerging and important diagnostic test in the diagnosis of pancreatic cancer. Recently, data has emerged to suggest that new-onset diabetes is present in about 50% of patients diagnosed with pancreatic cancer.³⁹ The temporal relationship of pancreatic cancer and diabetes is supported by evidence showing that patients who undergo resection commonly have resolution of their diabetes.¹⁷ This study suggested that hyperglycemia, elevated HBA1C, and symptoms of diabetes in patients older than 50 years may identify patients who have early pancreatic cancer. The entity of pancreatic cancer–associated diabetes needs to be better defined and the algorithmic approach to evaluation and diagnosis, utilizing signs, symptoms, and laboratory values associated with diabetes, needs to be clearly established.

The only serum marker for PDA is carbohydrate antigen 19-9 (CA 19-9), also known as sialylated Lewis antigen or cancer-associated antigen. It was first identified in pancreatic cancer patients in 1981.^40,41 The sensitivity and specificity of CA 19-9 ranges from 70% to approximately 90%.^42,43 Hereditary predispositions and comorbid disease cross-reactivity contribute to the diminished sensitivity and specificity of CA 19-9. In about 5% to 10% of the population, CA 19-9 is not expressed (Lewis antigen A and B negative). Additionally, since CA 19-9 is expressed in the cells that line the biliary tree, diseases that lead to pancreatic or liver inflammation may falsely elevate CA 19-9.⁴⁴ As a result, CA 19-9 is not an ideal screening test. However, data has shown that CA 19-9 may have prognostic value postoperatively and serve as a marker for therapeutic response.^45,46

• Is biopsy needed for this patient and if so, what is the most appropriate technique?

ENDOSCOPIC ULTRASOUND

Generally, diagnosis with tissue is not necessary for patients who clearly have resectable disease and will proceed directly to surgery for management. Nevertheless, it is still commonly obtained in this group of patients. However, in patients with LAPC or with features suggestive of LAPC, such as tumor approximation to critical vessels such as the superior mesenteric artery (SMA) or celiac axis, biopsy is necessary. These patients will receive neoadjuvant therapy, and biopsy is important in establishing a diagnosis. The ideal way to obtain a biopsy is through fine-needle aspiration (FNA) or biopsy (FNB) utilizing endoscopic ultrasound (EUS). Percutaneous and computed tomography (CT)–guided FNB can also be used to obtain a biopsy for diagnosis. In comparison to percutaneous and CT-guided FNB, EUS-FNA/FNB has low rates of complications, a decreased rate of peritoneal seeding, and is cost effective.^47,48

CASE CONTINUED

Abdominal CT obtained following abdominal ultrasound reveals a 3.5-cm mass in the head of the pancreas in close approximation to the SMA and celiac axis.

• Does the patient have borderline resectable or unresectable disease?

IMAGING

Abdominal ultrasound is a reasonable, inexpensive, and safe alternative to abdominal CT as it does not utilize ionizing radiation. It is particularly useful in patients who present with jaundice or have concern for biliary obstruction based on laboratory evaluation. It is particularly sensitive for detecting tumors greater than 3 cm in size.^49,50 In patients whose abdominal ultrasound is unrevealing and whose index of suspicion remains high for PDA, abdominal CT should be the next imaging modality.

Abdominal CT obtained utilizing a pancreatic protocol is ideal for detection and staging of pancreatic tumors. By implementing a triple-phase protocol with arterial, late arterial, and venous phases, tumors, which have a density different from that of the pancreatic parenchyma, are accentuated. Abdominal CT is also able to provide critical information about tumor resectability.⁵¹ By revealing the degree of tumor encasement around the aorta, level of destruction of the superior mesenteric vein, or degree of involvement of the SMA or celiac vessels, abdominal CT determines if a patient should be deemed resectable, borderline resectable, or unresectable (Table 2).^52,53 Resectability is based on thorough imaging evaluation, expert opinion of a multidisciplinary team, and guidelines proposed by American Hepatopancreaticobiliary Association, Society of Surgical Oncology, Society for Surgery of the Alimentary Tract, and the NCCN.⁵⁴

Other imaging modalities have a less clearly established role in the diagnostic approach to PDA. In patients who have contraindications to obtaining CT, magnetic resonance imaging can be utilized as a secondary imaging modality.⁵⁵ The role of positron emission tomography 18F-fluorodeoxyglucose (PET-FDG) is not clearly defined among clinicians, nor reflected in consensus guidelines by the National Comprehensive Cancer Network (NCCN). In clinical practice, it is still often combined with CT to detect metastatic disease, particularly in high-risk patients such has those with LAPC. The role of PET-CT in staging and its impact on clinical outcomes has not been fully established.

Endoscopic retrograde cholangiopancreatography (ERCP) and magnetic resonance cholangiopancreatography (MRCP) can also assist in the diagnosis and management of PDA. In patients with obstructive jaundice, both MRCP and ERCP visualize obstructions and dilations within the biliary tree, with the latter having the ability to intervene. ERCP allows for the collection of tissue to aid in diagnosis, and has the ability to relieve biliary obstruction via stenting.⁵⁶

TREATMENT

CASE CONTINUED

After an abdominal CT is obtained, the patient is referred to an outpatient oncologist because of concern for pancreatic adenocarcinoma. After consultation, the patient is advised to obtain EUS with biopsy and to return immediately afterwards for further treatment planning. The pathology report following EUS confirms that the mass is a poorly differentiated PDA. The patient’s case is discussed at a multidisciplinary meeting with radiation, surgical, and medical oncology. The abdominal CT and PET-CT scan are thoroughly reviewed. After imaging review, the multidisciplinary team concludes that the tumor is in contact with the SMA at 120° and with the common hepatic artery without extension in the celiac axis and without evidence of metastasis.

• What is the appropriate management of borderline resectable pancreatic cancer?

BORDERLINE RESECTABLE CANCER

Patients who have nonmetastatic disease and are deemed resectable and without contraindications to surgery or high-risk features, as defined by NCCN guidelines, should proceed directly to surgery. A large body of evidence suggests that complete surgical resection with negative margins is a significant predictor of survival and currently provides the only option for cure.^57–59 Despite the curative intent of surgery, the rate of recurrence remains high in patients who undergo surgical resection. Even in patients with negative resection margins (R0 resection), the 5-year survival is 20% to 30%, with a median survival ranging from 12 to 25 months, suggesting the presence of regional and distant occult disease at the time of diagnosis.^60–62

Additionally, in half the patients who undergo surgical resection with resultant positive microscopic (R1 resection) or gross (R2 resection) margins, the median survival is no greater than 12 months. In this subset of patients, clinical outcomes are similar to outcomes in patients with locally advanced and metastatic pancreatic cancer, suggesting that upfront surgery and adjuvant therapy may not be the ideal therapeutic option. This raises 2 important points: first, resectability should be assessed carefully in all patients with LAPC, and second, for those patients who are deemed borderline resectable, neoadjuvant therapy should be considered.⁶³ Borderline resectability is defined as tumor abutment ≤ 180° of the celiac artery, and tumor abutment of the superior mesenteric vein /portal vein of > 180° or abutting ≤ 180° with irregularity of the vein with or without thrombosis with anatomical structures that still allows for safe and complete resection and vein reconstruction (Table 2).

Neoadjuvant Therapy

The goal of neoadjuvant therapy is to minimize the negative impact of upfront surgery in patients who have a high likelihood of having microscopic or grossly positive margins. Research has suggested that neoadjuvant therapy may improve resectability, decrease the rate of recurrence, and improve overall survival.^64–66

There is no clear consensus on the ideal management of patients with borderline resectable disease. However, expert guidelines are in agreement that upfront surgery in patients with LAPC is not appropriate, as most patients will not be able to achieve an R0 resection.⁶⁷ As staging and management of patients with LAPC is difficult, expertise of a multidisciplinary team can be helpful.⁶⁸

Several studies and the NCCN guidelines support the use of neoadjuvant therapy in patients deemed borderline resectable.^69,70 Treatment of borderline resectable disease is similar to unresectable LAPC and generally involves 2 chemotherapy treatment backbones: FOLFIRINOX (folinic acid [leucovorin], fluorouracil [5-FU], irinotecan, and oxaliplatin) or gemcitabine-based therapy.

Phase 1 to 2/3 clinical trials conducted by Conroy et al from 2005 to 2011, including the landmark ACCORD-11 trial, established the safety and role of FOLFIRINOX in metastatic pancreatic cancer and also demonstrated an improved overall survival with the use of this therapy in these patients.^71,72 These findings led to interest in FOLFIRINOX as a neoadjuvant therapy for patients with LAPC. Since then, multiple prospective and retrospective studies have shown that 54% to 100% of patients with borderline resectable LAPC who were treated with FOLFIRINOX were down-staged significantly enough to undergo resection. Of those patients, more than 90% had a R0 resection following surgery (Table 3).^73–79

Data over the past 7 years suggests that neoadjuvant FOLFIRINOX improves overall survival and resectability in patients with borderline disease. However, treatment with FOLFIRINOX is not without limitations. FOLFIRINOX is associated with higher rates of febrile neutropenia, thrombocytopenia, diarrhea, and sensory neuropathy as compared with gemcitabine-based therapy.⁷² Other less commonly observed toxicities associated with FOLFIRINOX include mucositis, hand-foot syndrome, pulmonary toxicity, and alopecia. Dose-attenuated FOLFIRINOX-based regimens, including those that exclude the bolus fluorouracil dose and augment upfront filgrastim, have demonstrated improved safety and comparable efficacy as compared to standard FOLFIRINOX.⁸⁰

Gemcitabine has been the fundamental treatment backbone for PDA since the results of the phase 3 CONKO-001 trial were published.⁸¹ Gemcitabine is a pyrimidine antimetabolite and potent inhibitor of DNA polymerase and ribonucleotide reductase.⁸² In recent years, multiple combination therapies with gemcitabine have been investigated, including regimens with nab-paclitaxel, oxaliplatin, or docetaxel. Resection rates and negative margin outcomes have been shown to be comparable to patients who received FOLFIRINOX in the neoadjuvant setting with borderline locally advanced disease.^83–85 In addition to having a more tolerable side effect profile in comparison to fluorouracil-based regimens, gemcitabine is considered to be a potent radiosensitizer.⁸⁶ For this reason, studies have also investigated the role of radiotherapy in conjunction with gemcitabine, revealing negative margin resection rates above 80% in patients with borderline resectable disease.^87,88

Because very few studies directly comparing FOLFIRINOX with gemcitabine-based combination regimens have been completed, there is no clear consensus on the preferred treatment regimen, in both borderline and unresectable LAPC. Decisions to treat are influenced predominantly by comorbidities, adverse effect profiles, and performance status of patients, as FOLFIRINOX is the more toxic of the 2 treatment backbones. Therefore, FOLFIRINOX has mostly been utilized in patients with relatively good functional status (Eastern Cooperative Oncology Group [ECOG] performance status 0 to 1).⁸⁹ In elderly patients and those with poor functional status, ECOG 2 to 4, gemcitabine as a single agent is a reasonable alternative in the neoadjuvant setting of borderline resectable disease.

The exact role of radiation therapy in addition to induction chemotherapy in borderline resectable pancreatic cancer has not been clearly established because of the lack of prospective studies in this area. Multiple large retrospective series have identified high rates of conversion to margin-negative resection with neoadjuvant chemoradiation alone.⁹⁰ Based on available data, it is reasonable for patients with borderline resectable disease to proceed with any of the following treatment options: chemotherapy, chemoradiation, or induction chemotherapy followed by chemoradiation (Figure). Chemotherapy and chemoradiation are generally more appropriate with patients with high CA 19-9 levels or those at an elevated risk of having positive margins or occult metastatic disease.⁹¹ Obtaining negative margin resections is the predominant goal of neoadjuvant radiotherapy.⁸⁹ Many studies have identified margin status to be one of the most significant prognostic factors in PDA.^57,59,92,93 Additionally, several studies have highlighted that radiotherapy in the neoadjuvant setting could improve negative margin resection rates, local control, and clinical outcomes in patients with borderline resectable locally advanced disease.^94–97 A common multimodal regimen utilized in the neoadjuvant setting combines capecitabine, an oral prodrug that is converted to fluorouracil, with radiation therapy. This combination has also been shown to improve resectability rates and long-term clinical outcomes in patients with borderline resectable disease.⁹⁸ Additionally, neoadjuvant radiation therapy can potentially downstage patients with unresectable disease at the time of diagnosis to become surgical candidates.⁹⁹ Despite the paucity of data, interval scans utilizing CT following neoadjuvant therapy should be obtained 2 to 4 months after completion of therapy to determine therapeutic response, evaluate for disease progression, and, most important, reassess surgical stage/resectability. It is clinically acceptable to proceed to resection with radiographically stable disease post-neoadjuvant therapy.

Many patients classified as borderline resectable are able to proceed with surgery following neoadjuvant therapy. Unfortunately, specific data on adjuvant therapy following neoadjuvant chemotherapy or chemoradiotherapy and surgical resection in borderline resectable patients is scarce. Clinical practice guidelines are extrapolated from studies where upfront resection in clearly resectable patients was followed by adjuvant therapy. Based on these data, approximately 6 months of perioperative chemotherapy with or without chemoradiotherapy is a reasonable consideration. Nevertheless, about 80% of patients at the time of diagnosis are deemed to be unresectable, and a smaller number do not proceed to surgery despite an initial classification as borderline resectable. Of the 80% of patients with advanced disease, about half are metastatic at presentation and the remaining 30% to 40% are defined as having unresectable LAPC.¹⁰⁰

CASE CONTINUED

The patient is deemed borderline resectable. He receives neoadjuvant therapy with gemcitabine and nab-paclitaxel. Two months after therapy, interval imaging with abdominal CT does not show improvement in tumor size and there is now evidence that the tumor has invaded the celiac axis and is abutting more than 180° of the SMA. The patient presents to the oncologist to discuss further management. He has lost about 15 lb since his last evaluation, is capable of self-care, but is unable to carry on with any work activities.

• What is the appropriate management of unresectable nonmetastatic LAPC?

UNRESECTABLE LOCALLY ADVANCED CANCER

As in the case of borderline resectable disease, there are many treatment options for patients with unresectable LAPC. Timing, optimal chemotherapy regimen, and the addition of regularly and hypofractionated radiotherapy are issues currently under investigation. However, there are some general considerations and principles that are followed as reflected in the NCCN guidelines and recent studies. The primary therapeutic aims in patients with unresectable locally advanced disease are to increase survival and improve palliation.

The elderly comprise a large percentage of the patients diagnosed with unresectable locally advanced disease. Pharmacokinetics and toxicity profiles are altered in the elderly population.^101,102 Therefore, it is important to assess functional status and comorbidities as these are critical factors in determining treatment regimens, similar to patients with borderline resectable disease. Currently, the most common first-line therapies in advanced pancreatic cancer are gemcitabine alone, gemcitabine and nab-paclitaxel, FOLFIRINOX, gemcitabine/capecitabine, and gemcitabine/oxaliplatin.¹⁰³ The overall treatment approach to unresectable locally advanced pancreatic adenocarcinoma closely mirrors that of patients with borderline resectable disease and metastatic disease. Much of the data supporting treatment regimens in unresectable LAPC is extrapolated from clinical trials looking at advanced or metastatic pancreatic cancer.

Consensus opinions domestically and from Europe recommend that patients with locally advanced unresectable disease undergo upfront chemotherapy (Figure).¹⁰⁴ This is based on the premise that initial chemotherapy may destroy occult metastatic cells and increase the efficacy of consolidative chemotherapy, particularly with radiation in the future. Upfront chemoradiotherapy has only been investigated in a small series of trials in which no clear survival benefit was observed and has the added consequence of treatment-related toxicity.¹⁰⁵ However, data is limited in this regard, with variations in treatment protocols and cohort compositions contributing to the inconclusive findings.

No head-to-head studies investigating FOLFIRINOX versus nab-paclitaxel and gemcitabine in patients with locally advanced disease have been published, but clinical trials are under way. Other combination therapies have been looked at through small retrospective or prospective studies, but no robust, large-scale clinical trials have been completed. For this reason, NCCN guidelines recommend enrollment of patients with LAPC into active clinical trials.

• What is the role of radiation therapy in unresectable LAPC?

Despite the reported advantages of neoadjuvant radiation in patients with potentially resectable disease, there is significant debate regarding the timing and role of neoadjuvant radiation in patients with unresectable disease. Numerous comprehensive analyses and studiest indicate that chemoradiotherapy leads to significantly better overall survival compared to no therapy or radiation therapy alone in LAPC.^68,110,111 However, conflicting data support the use of upfront chemoradiotherapy in unresectable LAPC when compared to chemotherapy alone. Unfortunately, most prospective studies investigating the role of radiotherapy were performed following administration of single-agent gemcitabine, which is no longer considered standard of care for patients with LAPC. In spite of this, ECOG 4201 identified a statistically significant improvement in median overall survival following the addition of gemcitabine-based radiotherapy. Huguet et al in his review pointed out that upfront chemoradiotherapy was not superior to chemotherapy only and was associated with increased treatment toxicity.¹⁰⁵ Additionally, a recent phase 3 study looking at chemoradiotherapy versus chemotherapy alone in patients treated with gemcitabine found no difference in overall survival.¹¹² This can potentially be attributed to the fact that about 30% of patients with LAPC develop metastatic disease in the early phases of treatment due to poor control of local and systemically occult disease.¹¹³ Given the propensity for high rates of occult metastatic disease in LAPC, treatment paradigms and consensus guidelines recommend multi-agent systemic chemotherapy followed by chemoradiotherapy in select patients.

Based on current studies and until further clinical investigations are completed, consensus opinion indicates that the most appropriate approach in unresectable LAPC is to begin with induction chemotherapy (with either gemcitabine plus nab-paclitaxel, FOLFIRINOX, capecitabine, or other treatment combinations), followed by chemoradiation in the absence of disease progression when the first repeat imaging evaluation is completed (Figure). One important caveat regarding reimaging with CT in the neoadjuvant setting is that radiologic response may not correlate with pathologic response.¹¹⁴ PET-CT may have a role in predicting response to neoadjuvant therapy. Overall, induction chemotherapy followed by consolidative chemoradiation may confer numerous benefits: it removes the unnecessary burden and toxicity associated with radiotherapy in the nearly one third of patients who have pervasive disease progression during initial treatment; it allows testing and increases the chances of tolerating full-dose systemic chemotherapy; and it raises the likelihood of converting patients who do not progress to metastasis during the initial phase of treatment from unresectable to resectable status.^103,115 Despite the lack of strong conclusive data, the general agreement is that neoadjuvant chemoradiotherapy converts about one third of borderline and unresectable LAPC to an R0 resection.^95,103 There are very specific rationales for the addition of radiotherapy in LAPC, and these functions need to be better defined through further clinical trials.

CASE CONTINUED

The patient is unable to tolerate his first round of second-line therapy with modified FOLFIRINOX. His overall treatment plan is transitioned to palliation. He continues to have pain, despite increasing doses of narcotics.

• What is the next step for patients in whom second-line therapy fails and who have intractable pain while on high-dose narcotics?

A subset of patients with unresectable LAPC may not be amenable to chemotherapy with or without radiation due to significant comorbidities or because they present with or progress to ECOG scores 3 or 4. The goal in these patients should be palliation. Pain is one of the most predominant and difficult to manage symptoms in progressive LAPC. Opioid-based medications are the primary treatment for pain in LAPC. However, patients sometimes become refractory to opioid medications. In this group of patients, it is reasonable to consider palliative radiation as an alternative method for pain control.¹¹⁶

An alternative to palliative radiation in the setting of progressive pain in PDA is celiac plexus block or neurolysis. By injecting an anesthetic or alcohol into the celiac plexus, neural signaling pathways involved in the propagation of pain are inhibited without leading to significant nerve destruction. Additionally, chemical splanchnicectomy allows for reduced opioid medication use and associated side effects.¹¹⁷

In general patients with LAPC have profound weight loss prior to and during treatment. This has significant implications prognostically and on treatment options. The underlying etiology is multifactorial, but one of the primary driving factors is pancreatic insufficiency. An estimated 65% of pancreatic cancer patients have fat malabsorption, and 50% have protein malabsorption, leading to steatorrhea and weight loss.¹¹⁸ Patients diagnosed with pancreatic cancer should be given enzyme replacement with formulations that include lipase, amylase, and protease. A minimum dose of enzyme replacement should include 40,000 to 50,000 U of lipase during meals and 25,000 U during snack intake. If maldigestion, symptoms, or nutritional endpoints (BMI, albumin, prealbumin, cholesterol) do not improve, the pancreatic enzyme dose should be escalated and a proton-pump inhibitor (PPI) added. In patients with pancreatic insufficiency, PPIs have been shown to improve fat absorption.¹¹⁹ Enzyme replacement therapy has been shown to prevent weight loss in patients with unresectable pancreatic cancer.¹²⁰

As most patients with LAPC go on to develop progressive disease, palliative care becomes an integral aspect of the therapeutic paradigm. Palliation in LAPC has a significant role in determining quality of life and ensuring patient’s goals of care have been meet. Studies have suggested that pancreatic cancer is second only to lung cancer in terms of the number of emergency department visits in the later stages of disease.¹²⁰ Additionally, aggressive care in the setting of incurable diseases such as LAPC has been associated with poor quality of life.¹²¹ More recently it has been shown that involvement of palliative care in patients with advanced pancreatic is associated with less aggressive care near death.¹²² Therefore, the incorporation of palliative or supportive care teams in the treatment of patients with progressive LAPC can improve quality of life and alleviate suffering associated with increasing symptom burden.

CONCLUSION

LAPC is a difficult disease for both provider and patient. There is a paucity of robust clinical trials in the neoadjuvant setting for LAPC. Current research is complicated by varying consensus definitions of resectability and the varying treatment configurations across studies. The optimal type, timing, and sequence of treatment and whether to add radiation therapy in LAPC have not been clearly defined. However, based on the available studies and consensus guidelines, patients who are deemed to have LAPC should have neoadjuvant therapy. FOLFIRINOX or gemcitabine with nab-paclitaxel should be considered first-line treatments. Patients with LAPC who respond to chemotherapy or are ineligible for multi-drug chemotherapy may benefit from chemoradiotherapy. In patients with unresectable disease, chemoradiotherapy has been shown to enhance survival as compared to best supportive care or radiation alone. For borderline resectable disease, it is reasonable to treat patients with either chemoradiotherapy, chemotherapy alone, or chemotherapy followed by chemoradiotherapy.

Considering the invasive nature of LAPC and the controversy around neoadjuvant treatment protocols, enrollment of patients with LAPC into clinical trials is important and will help determine the optimal treatment regimen for future patients.

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.

A Tuesday morning session at 10:35–11:15 a.m. called “Hospitalist Careers: So Many Options” will highlight the wide range of job possibilities for young hospitalists and provide a framework for advancing your career.

“Especially early in their careers, hospitalists can sometimes be overwhelmed by the possibilities of where their career can go and how to get to the position that they want, whether it’s leadership or another ultimate goal,” said copresenter Brian Markoff, MD, FACP, SFHM, chief of the division of hospital medicine at Mount Sinai St. Luke’s Hospital in New York. “This session is designed to help young physicians figure out where they are, where they want to be, and how they might be able to get there.”

The session – aimed at medical students, residents, fellows, and new hospitalists – will review different careers in hospital medicine, including academics and clinical work; share some individual success stories of currently practicing hospitalists; discuss the importance of mentorship; and note how you can use the Society of Hospital Medicine to advance your career status. “This is to help you take a step back and think about the big picture,” said copresenter Alfred Burger, MD, FACP, SFHM, associate program director of the internal medicine residency at Mount Sinai Beth Israel Hospital in New York.

Hospitalist careers today are quite varied, Dr. Burger said. Some physicians have a career that is primarily clinical while others have moved into a wide variety of leadership roles. “Hospitalists have ascended to some of the highest levels of leadership, whether it’s surgeon general or a chief medical officer or chief operating officer of a government agency or hospital group,” he said.

Some hospitalists have had success moving into the business and consulting range after practicing in a hospital setting, advising organizations how to do things more efficiently, while others have taken on health services research or patient safety and quality improvement work, he added.

Young hospitalists lately have been concerned with how much job advancement depends on gaining an extra degree like an MBA, versus being a really good hospitalist and working your way up, Dr. Markoff said. “We tell them, ‘You can do both,’ ” he said. “Depending on your career choice, you may or may not need an advanced degree.” In the past, Dr. Burger added, most hospitalists started a career and then gained additional degrees as needed. Today more hospitalists are starting their careers as a dual or sometimes triple degree holder.

“Hopefully, the session will help young hospitalists reflect on their own practice and help them sort out what they are doing that will get them to their ultimate career goal,” Dr. Markoff said. “The main take-home message is ‘There’s no one right way to get the career you want, but it’s going to take some active management on your part to get on the right path.’ ”

Dr. Burger thinks that the career pathways in hospital medicine are limited only by your own imagination. “Our talk is meant to inspire you to see the wide possibilities,” he said.

Attendees of the session, now in its third year, can serve as resources to peers and others who are more junior, Dr. Burger noted. “You may be able to inspire somebody based on something you heard” or share advice learned with a friend or colleague, he said, noting that some hospitalists have attended more than once.

“Hospitalist Careers: So Many Options”Tuesday, 10:35 a.m.–11:15 a.m.

A Tuesday morning session at 10:35–11:15 a.m. called “Hospitalist Careers: So Many Options” will highlight the wide range of job possibilities for young hospitalists and provide a framework for advancing your career.

“Especially early in their careers, hospitalists can sometimes be overwhelmed by the possibilities of where their career can go and how to get to the position that they want, whether it’s leadership or another ultimate goal,” said copresenter Brian Markoff, MD, FACP, SFHM, chief of the division of hospital medicine at Mount Sinai St. Luke’s Hospital in New York. “This session is designed to help young physicians figure out where they are, where they want to be, and how they might be able to get there.”

The session – aimed at medical students, residents, fellows, and new hospitalists – will review different careers in hospital medicine, including academics and clinical work; share some individual success stories of currently practicing hospitalists; discuss the importance of mentorship; and note how you can use the Society of Hospital Medicine to advance your career status. “This is to help you take a step back and think about the big picture,” said copresenter Alfred Burger, MD, FACP, SFHM, associate program director of the internal medicine residency at Mount Sinai Beth Israel Hospital in New York.

Hospitalist careers today are quite varied, Dr. Burger said. Some physicians have a career that is primarily clinical while others have moved into a wide variety of leadership roles. “Hospitalists have ascended to some of the highest levels of leadership, whether it’s surgeon general or a chief medical officer or chief operating officer of a government agency or hospital group,” he said.

Some hospitalists have had success moving into the business and consulting range after practicing in a hospital setting, advising organizations how to do things more efficiently, while others have taken on health services research or patient safety and quality improvement work, he added.

Young hospitalists lately have been concerned with how much job advancement depends on gaining an extra degree like an MBA, versus being a really good hospitalist and working your way up, Dr. Markoff said. “We tell them, ‘You can do both,’ ” he said. “Depending on your career choice, you may or may not need an advanced degree.” In the past, Dr. Burger added, most hospitalists started a career and then gained additional degrees as needed. Today more hospitalists are starting their careers as a dual or sometimes triple degree holder.

“Hopefully, the session will help young hospitalists reflect on their own practice and help them sort out what they are doing that will get them to their ultimate career goal,” Dr. Markoff said. “The main take-home message is ‘There’s no one right way to get the career you want, but it’s going to take some active management on your part to get on the right path.’ ”

Dr. Burger thinks that the career pathways in hospital medicine are limited only by your own imagination. “Our talk is meant to inspire you to see the wide possibilities,” he said.

Attendees of the session, now in its third year, can serve as resources to peers and others who are more junior, Dr. Burger noted. “You may be able to inspire somebody based on something you heard” or share advice learned with a friend or colleague, he said, noting that some hospitalists have attended more than once.

“Hospitalist Careers: So Many Options”Tuesday, 10:35 a.m.–11:15 a.m.

A Tuesday morning session at 10:35–11:15 a.m. called “Hospitalist Careers: So Many Options” will highlight the wide range of job possibilities for young hospitalists and provide a framework for advancing your career.

“Especially early in their careers, hospitalists can sometimes be overwhelmed by the possibilities of where their career can go and how to get to the position that they want, whether it’s leadership or another ultimate goal,” said copresenter Brian Markoff, MD, FACP, SFHM, chief of the division of hospital medicine at Mount Sinai St. Luke’s Hospital in New York. “This session is designed to help young physicians figure out where they are, where they want to be, and how they might be able to get there.”

The session – aimed at medical students, residents, fellows, and new hospitalists – will review different careers in hospital medicine, including academics and clinical work; share some individual success stories of currently practicing hospitalists; discuss the importance of mentorship; and note how you can use the Society of Hospital Medicine to advance your career status. “This is to help you take a step back and think about the big picture,” said copresenter Alfred Burger, MD, FACP, SFHM, associate program director of the internal medicine residency at Mount Sinai Beth Israel Hospital in New York.

Hospitalist careers today are quite varied, Dr. Burger said. Some physicians have a career that is primarily clinical while others have moved into a wide variety of leadership roles. “Hospitalists have ascended to some of the highest levels of leadership, whether it’s surgeon general or a chief medical officer or chief operating officer of a government agency or hospital group,” he said.

Some hospitalists have had success moving into the business and consulting range after practicing in a hospital setting, advising organizations how to do things more efficiently, while others have taken on health services research or patient safety and quality improvement work, he added.

Young hospitalists lately have been concerned with how much job advancement depends on gaining an extra degree like an MBA, versus being a really good hospitalist and working your way up, Dr. Markoff said. “We tell them, ‘You can do both,’ ” he said. “Depending on your career choice, you may or may not need an advanced degree.” In the past, Dr. Burger added, most hospitalists started a career and then gained additional degrees as needed. Today more hospitalists are starting their careers as a dual or sometimes triple degree holder.

“Hopefully, the session will help young hospitalists reflect on their own practice and help them sort out what they are doing that will get them to their ultimate career goal,” Dr. Markoff said. “The main take-home message is ‘There’s no one right way to get the career you want, but it’s going to take some active management on your part to get on the right path.’ ”

Dr. Burger thinks that the career pathways in hospital medicine are limited only by your own imagination. “Our talk is meant to inspire you to see the wide possibilities,” he said.

Attendees of the session, now in its third year, can serve as resources to peers and others who are more junior, Dr. Burger noted. “You may be able to inspire somebody based on something you heard” or share advice learned with a friend or colleague, he said, noting that some hospitalists have attended more than once.

“Hospitalist Careers: So Many Options”Tuesday, 10:35 a.m.–11:15 a.m.

Societal trends – and ills – don’t stop at the hospital door, and opioid use is no exception. Hospitalists are frequently presented with difficult cases involving patients who have been using opioids for long periods of time, including some who show signs of opioid addiction. These cases present challenges for treatment and sometimes tense situations in which patients request delivery of pain medication that a hospitalist might consider excessive or potentially harmful.

Two experienced hospitalists will guide HM17 attendees through this dicey terrain in “The Hospitalist’s Role in the Opioid Epidemic” session, scheduled for Tuesday, May 2, 1:35–2:35 p.m., as part of the Quality Track.

The Hospitalist’s Role in the Opioid Epidemic
Tuesday, May 2, 1:35–2:35 p.m.

Societal trends – and ills – don’t stop at the hospital door, and opioid use is no exception. Hospitalists are frequently presented with difficult cases involving patients who have been using opioids for long periods of time, including some who show signs of opioid addiction. These cases present challenges for treatment and sometimes tense situations in which patients request delivery of pain medication that a hospitalist might consider excessive or potentially harmful.

Two experienced hospitalists will guide HM17 attendees through this dicey terrain in “The Hospitalist’s Role in the Opioid Epidemic” session, scheduled for Tuesday, May 2, 1:35–2:35 p.m., as part of the Quality Track.

The Hospitalist’s Role in the Opioid Epidemic
Tuesday, May 2, 1:35–2:35 p.m.

Societal trends – and ills – don’t stop at the hospital door, and opioid use is no exception. Hospitalists are frequently presented with difficult cases involving patients who have been using opioids for long periods of time, including some who show signs of opioid addiction. These cases present challenges for treatment and sometimes tense situations in which patients request delivery of pain medication that a hospitalist might consider excessive or potentially harmful.

Two experienced hospitalists will guide HM17 attendees through this dicey terrain in “The Hospitalist’s Role in the Opioid Epidemic” session, scheduled for Tuesday, May 2, 1:35–2:35 p.m., as part of the Quality Track.

The Hospitalist’s Role in the Opioid Epidemic
Tuesday, May 2, 1:35–2:35 p.m.

In adults with acute myeloid leukemia who achieve complete remission with one to two cycles of induction therapy, a slightly longer course of idarubicin during consolidation therapy increases leukemia-free survival without increasing nonhematologic toxicity, according to new findings.

The optimal dose of anthracyclines, such as idarubicin, during consolidation therapy in this patient population has not been explored to date. Researchers performed a randomized phase III clinical trial, comparing standard (2-day) idarubicin with increased (3-day) idarubicin during consolidation therapy with cytarabine and etoposide.

The 7-year trial involved 293 patients, aged 15-60 years (median age, 45 years), who were treated at 23 Australian hospitals after achieving complete remission with one to two courses of intensive cytarabine-based induction therapy. Study participants were randomly assigned to receive either standard or intensive idarubicin, said Kenneth F. Bradstock, MB, PhD, of the University of Sydney, Australia, and his associates.

More patients who were receiving the higher cumulative dose of idarubicin had leukemia-free survival at 3 years (47%), compared with the standard-dose group (35%), for a hazard ratio of 0.74 favoring intensive idarubicin. The estimated median leukemia-free survival was 2.13 years for intensified idarubicin, compared with 0.93 years for standard idarubicin (J Clin Oncol. 2017 Apr 3. doi: 10.1200/JCO.2016.70.6374).

Additionally, the time to relapse was significantly longer for intensive idarubicin (17 months) than for standard idarubicin (10 months). This study was not powered to detect a difference between the two groups in overall survival.

There was no significant difference between the two study groups in the incidence of serious nonhematologic toxicities or in the rate of treatment-related death, even though the patients receiving intensive idarubicin showed a clear increase in myelotoxicity, as expected.

In exploratory analyses, the researchers could not detect a specific benefit of increased idarubicin dose in any patient subgroups, in particular, younger versus older ages, adverse versus intermediate karyotypes, and mutations in the FLT3 and NPM1 genes. However, they were limited because of the low number of cases in some subgroups.

The trial was supported by the National Health and Medical Research Council of Australia, Pfizer Australia, and Amgen Australia. Dr. Bradstock reported ties to Amgen Australia. His is associates reported ties to numerous industry sources.

In adults with acute myeloid leukemia who achieve complete remission with one to two cycles of induction therapy, a slightly longer course of idarubicin during consolidation therapy increases leukemia-free survival without increasing nonhematologic toxicity, according to new findings.

The optimal dose of anthracyclines, such as idarubicin, during consolidation therapy in this patient population has not been explored to date. Researchers performed a randomized phase III clinical trial, comparing standard (2-day) idarubicin with increased (3-day) idarubicin during consolidation therapy with cytarabine and etoposide.

The 7-year trial involved 293 patients, aged 15-60 years (median age, 45 years), who were treated at 23 Australian hospitals after achieving complete remission with one to two courses of intensive cytarabine-based induction therapy. Study participants were randomly assigned to receive either standard or intensive idarubicin, said Kenneth F. Bradstock, MB, PhD, of the University of Sydney, Australia, and his associates.

More patients who were receiving the higher cumulative dose of idarubicin had leukemia-free survival at 3 years (47%), compared with the standard-dose group (35%), for a hazard ratio of 0.74 favoring intensive idarubicin. The estimated median leukemia-free survival was 2.13 years for intensified idarubicin, compared with 0.93 years for standard idarubicin (J Clin Oncol. 2017 Apr 3. doi: 10.1200/JCO.2016.70.6374).

Additionally, the time to relapse was significantly longer for intensive idarubicin (17 months) than for standard idarubicin (10 months). This study was not powered to detect a difference between the two groups in overall survival.

There was no significant difference between the two study groups in the incidence of serious nonhematologic toxicities or in the rate of treatment-related death, even though the patients receiving intensive idarubicin showed a clear increase in myelotoxicity, as expected.

In exploratory analyses, the researchers could not detect a specific benefit of increased idarubicin dose in any patient subgroups, in particular, younger versus older ages, adverse versus intermediate karyotypes, and mutations in the FLT3 and NPM1 genes. However, they were limited because of the low number of cases in some subgroups.

The trial was supported by the National Health and Medical Research Council of Australia, Pfizer Australia, and Amgen Australia. Dr. Bradstock reported ties to Amgen Australia. His is associates reported ties to numerous industry sources.

In adults with acute myeloid leukemia who achieve complete remission with one to two cycles of induction therapy, a slightly longer course of idarubicin during consolidation therapy increases leukemia-free survival without increasing nonhematologic toxicity, according to new findings.

The optimal dose of anthracyclines, such as idarubicin, during consolidation therapy in this patient population has not been explored to date. Researchers performed a randomized phase III clinical trial, comparing standard (2-day) idarubicin with increased (3-day) idarubicin during consolidation therapy with cytarabine and etoposide.

The 7-year trial involved 293 patients, aged 15-60 years (median age, 45 years), who were treated at 23 Australian hospitals after achieving complete remission with one to two courses of intensive cytarabine-based induction therapy. Study participants were randomly assigned to receive either standard or intensive idarubicin, said Kenneth F. Bradstock, MB, PhD, of the University of Sydney, Australia, and his associates.

More patients who were receiving the higher cumulative dose of idarubicin had leukemia-free survival at 3 years (47%), compared with the standard-dose group (35%), for a hazard ratio of 0.74 favoring intensive idarubicin. The estimated median leukemia-free survival was 2.13 years for intensified idarubicin, compared with 0.93 years for standard idarubicin (J Clin Oncol. 2017 Apr 3. doi: 10.1200/JCO.2016.70.6374).

Additionally, the time to relapse was significantly longer for intensive idarubicin (17 months) than for standard idarubicin (10 months). This study was not powered to detect a difference between the two groups in overall survival.

There was no significant difference between the two study groups in the incidence of serious nonhematologic toxicities or in the rate of treatment-related death, even though the patients receiving intensive idarubicin showed a clear increase in myelotoxicity, as expected.

In exploratory analyses, the researchers could not detect a specific benefit of increased idarubicin dose in any patient subgroups, in particular, younger versus older ages, adverse versus intermediate karyotypes, and mutations in the FLT3 and NPM1 genes. However, they were limited because of the low number of cases in some subgroups.

The trial was supported by the National Health and Medical Research Council of Australia, Pfizer Australia, and Amgen Australia. Dr. Bradstock reported ties to Amgen Australia. His is associates reported ties to numerous industry sources.

Maintenance therapy with lenalidomide significantly prolongs progression-free survival (PFS) in elderly patients with diffuse large B-cell lymphoma (DLBCL), according to findings from a phase III trial.

None of the previous trials assessing a maintenance drug in this patient population – including bevacizumab, rituximab, enzastaurin, or everolimus – have reported such a benefit, Catherine Thieblemont, MD, PhD, of the department of hematology-oncology, Hôpital Saint-Louis, Paris, and her associates, reported.

The standard regimen for newly diagnosed DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), but 30%-40% of patients have disease progression or relapse, usually during the first 2 years after diagnosis. Lenalidomide is an immunomodulator with antineoplastic activity and has shown activity in relapsed DLBCL. The investigators compared 24 months of lenalidomide maintenance therapy against a matching placebo in an international, randomized double-blind phase III trial involving 650 patients aged 60-80 years who showed either partial or complete responses to first-line R-CHOP.

After a median follow-up of 39 months (range, 0-74 months), median PFS was not yet reached in the lenalidomide group and was estimated to be 58.9 months in the placebo group, for a hazard ratio of 0.708 favoring lenalidomide. This represents a statistically significant and clinically meaningful improvement in PFS, Dr. Thieblemont and her associates noted (J Clin Oncol. 2017 Apr 20. doi: 10.1200/JCO.2017.72.6984).

This survival benefit was consistent across all subgroups of patients. Most important, PFS was significantly prolonged regardless of whether patients had shown only a partial response or a complete response to R-CHOP, the investigators said.

The maintenance therapy did not appear to prolong overall survival, which was 87% for lenalidomide and 89% for placebo.

“We do not yet fully understand the basis for lack of an [overall survival] benefit despite the positive PFS data. Other than that, this is not due to excessive toxicity in the experimental arm,” they said. “We speculate the reason may be differences in the outcomes after progression or some other unrecognized reason.”

The study was sponsored by the Lymphoma Academic Research Organisation of France and Celgene. Dr. Thieblemont reported ties to Celgene, Bayer, AbbVie, Janssen, and Roche. Her associates reported ties to numerous industry sources.

[email protected]

Maintenance therapy with lenalidomide significantly prolongs progression-free survival (PFS) in elderly patients with diffuse large B-cell lymphoma (DLBCL), according to findings from a phase III trial.

None of the previous trials assessing a maintenance drug in this patient population – including bevacizumab, rituximab, enzastaurin, or everolimus – have reported such a benefit, Catherine Thieblemont, MD, PhD, of the department of hematology-oncology, Hôpital Saint-Louis, Paris, and her associates, reported.

The standard regimen for newly diagnosed DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), but 30%-40% of patients have disease progression or relapse, usually during the first 2 years after diagnosis. Lenalidomide is an immunomodulator with antineoplastic activity and has shown activity in relapsed DLBCL. The investigators compared 24 months of lenalidomide maintenance therapy against a matching placebo in an international, randomized double-blind phase III trial involving 650 patients aged 60-80 years who showed either partial or complete responses to first-line R-CHOP.

After a median follow-up of 39 months (range, 0-74 months), median PFS was not yet reached in the lenalidomide group and was estimated to be 58.9 months in the placebo group, for a hazard ratio of 0.708 favoring lenalidomide. This represents a statistically significant and clinically meaningful improvement in PFS, Dr. Thieblemont and her associates noted (J Clin Oncol. 2017 Apr 20. doi: 10.1200/JCO.2017.72.6984).

This survival benefit was consistent across all subgroups of patients. Most important, PFS was significantly prolonged regardless of whether patients had shown only a partial response or a complete response to R-CHOP, the investigators said.

The maintenance therapy did not appear to prolong overall survival, which was 87% for lenalidomide and 89% for placebo.

“We do not yet fully understand the basis for lack of an [overall survival] benefit despite the positive PFS data. Other than that, this is not due to excessive toxicity in the experimental arm,” they said. “We speculate the reason may be differences in the outcomes after progression or some other unrecognized reason.”

The study was sponsored by the Lymphoma Academic Research Organisation of France and Celgene. Dr. Thieblemont reported ties to Celgene, Bayer, AbbVie, Janssen, and Roche. Her associates reported ties to numerous industry sources.

[email protected]

Maintenance therapy with lenalidomide significantly prolongs progression-free survival (PFS) in elderly patients with diffuse large B-cell lymphoma (DLBCL), according to findings from a phase III trial.

None of the previous trials assessing a maintenance drug in this patient population – including bevacizumab, rituximab, enzastaurin, or everolimus – have reported such a benefit, Catherine Thieblemont, MD, PhD, of the department of hematology-oncology, Hôpital Saint-Louis, Paris, and her associates, reported.

The standard regimen for newly diagnosed DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), but 30%-40% of patients have disease progression or relapse, usually during the first 2 years after diagnosis. Lenalidomide is an immunomodulator with antineoplastic activity and has shown activity in relapsed DLBCL. The investigators compared 24 months of lenalidomide maintenance therapy against a matching placebo in an international, randomized double-blind phase III trial involving 650 patients aged 60-80 years who showed either partial or complete responses to first-line R-CHOP.

After a median follow-up of 39 months (range, 0-74 months), median PFS was not yet reached in the lenalidomide group and was estimated to be 58.9 months in the placebo group, for a hazard ratio of 0.708 favoring lenalidomide. This represents a statistically significant and clinically meaningful improvement in PFS, Dr. Thieblemont and her associates noted (J Clin Oncol. 2017 Apr 20. doi: 10.1200/JCO.2017.72.6984).

This survival benefit was consistent across all subgroups of patients. Most important, PFS was significantly prolonged regardless of whether patients had shown only a partial response or a complete response to R-CHOP, the investigators said.

The maintenance therapy did not appear to prolong overall survival, which was 87% for lenalidomide and 89% for placebo.

“We do not yet fully understand the basis for lack of an [overall survival] benefit despite the positive PFS data. Other than that, this is not due to excessive toxicity in the experimental arm,” they said. “We speculate the reason may be differences in the outcomes after progression or some other unrecognized reason.”

The study was sponsored by the Lymphoma Academic Research Organisation of France and Celgene. Dr. Thieblemont reported ties to Celgene, Bayer, AbbVie, Janssen, and Roche. Her associates reported ties to numerous industry sources.

[email protected]

Being underweight or experiencing rapid weight loss are both independently associated with an increased risk of cause-specific mortality in individuals with rheumatoid arthritis, according to new research.

In a cohort of 1,600 U.S. veterans with rheumatoid arthritis who were followed for a median of 3.2 years, researchers found that being overweight (BMI 25-30 kg/m²) was associated with a 41% lower risk of cardiovascular mortality. Cumulative weight loss of greater than 10% and weight loss greater than 3 kg/m2 per year were both significantly associated with a twofold higher risk of cardiovascular mortality.

Similarly, more rapid weight loss of more than 3 kg/m² per year was also associated with a greater than twofold increase in the risk of cancer mortality, while less rapid weight loss did not show a significant impact (Arthritis Care Res. 2017 Apr 20. doi: 10.1002/acr.23258).

Individuals who were underweight (BMI less than 20 kg/m²) had nearly a threefold greater risk of respiratory mortality, compared with individuals with a normal BMI. Researchers saw a dose-dependent association between respiratory mortality and percent of weight loss: 5%-10% weight loss was associated with an 86% higher risk of respiratory mortality, and greater than 10% weight loss showed a more than twofold greater risk.

This appears to be the first study to examine the impact of both BMI and weight loss on cause-specific mortality in rheumatoid arthritis, according to Bryant R. England, MD, of the VA Nebraska-Western Iowa Healthcare System of Nebraska, Omaha, and his coauthors.

“In this study of cause-specific mortality, we again demonstrate that underweight BMI and weight loss both drive mortality risk, but, importantly, this risk may differ across causes,” they wrote. “In cardiovascular and cancer mortality, we identified rapid and cumulative weight loss as the weight parameters most predictive of death, while in respiratory mortality underweight BMI was the weight parameter most predictive.”

Weight loss most likely reflects a systematic process, such as inflammation, that is a well-known risk factor for cardiovascular disease and mortality in people with rheumatoid arthritis, the authors suggested. Weight loss may also reflect comorbidities, chronic illness, disease phenotype, aging, smoking, and other factors, they said.

“Overall, these data illustrate the importance of considering the dynamic nature of body composition when assessing mortality risk in RA,” they said.

The authors noted that, while the study population was predominantly composed of older men, their findings were largely in agreement with those from studies with a higher proportion of women.

The researchers received grant support from the Department of Veterans’ Affairs and the National Institutes of Health. They reported having no conflicts of interest.

Being underweight or experiencing rapid weight loss are both independently associated with an increased risk of cause-specific mortality in individuals with rheumatoid arthritis, according to new research.

In a cohort of 1,600 U.S. veterans with rheumatoid arthritis who were followed for a median of 3.2 years, researchers found that being overweight (BMI 25-30 kg/m²) was associated with a 41% lower risk of cardiovascular mortality. Cumulative weight loss of greater than 10% and weight loss greater than 3 kg/m2 per year were both significantly associated with a twofold higher risk of cardiovascular mortality.

Similarly, more rapid weight loss of more than 3 kg/m² per year was also associated with a greater than twofold increase in the risk of cancer mortality, while less rapid weight loss did not show a significant impact (Arthritis Care Res. 2017 Apr 20. doi: 10.1002/acr.23258).

Individuals who were underweight (BMI less than 20 kg/m²) had nearly a threefold greater risk of respiratory mortality, compared with individuals with a normal BMI. Researchers saw a dose-dependent association between respiratory mortality and percent of weight loss: 5%-10% weight loss was associated with an 86% higher risk of respiratory mortality, and greater than 10% weight loss showed a more than twofold greater risk.

This appears to be the first study to examine the impact of both BMI and weight loss on cause-specific mortality in rheumatoid arthritis, according to Bryant R. England, MD, of the VA Nebraska-Western Iowa Healthcare System of Nebraska, Omaha, and his coauthors.

“In this study of cause-specific mortality, we again demonstrate that underweight BMI and weight loss both drive mortality risk, but, importantly, this risk may differ across causes,” they wrote. “In cardiovascular and cancer mortality, we identified rapid and cumulative weight loss as the weight parameters most predictive of death, while in respiratory mortality underweight BMI was the weight parameter most predictive.”

Weight loss most likely reflects a systematic process, such as inflammation, that is a well-known risk factor for cardiovascular disease and mortality in people with rheumatoid arthritis, the authors suggested. Weight loss may also reflect comorbidities, chronic illness, disease phenotype, aging, smoking, and other factors, they said.

“Overall, these data illustrate the importance of considering the dynamic nature of body composition when assessing mortality risk in RA,” they said.

The authors noted that, while the study population was predominantly composed of older men, their findings were largely in agreement with those from studies with a higher proportion of women.

The researchers received grant support from the Department of Veterans’ Affairs and the National Institutes of Health. They reported having no conflicts of interest.

Being underweight or experiencing rapid weight loss are both independently associated with an increased risk of cause-specific mortality in individuals with rheumatoid arthritis, according to new research.

In a cohort of 1,600 U.S. veterans with rheumatoid arthritis who were followed for a median of 3.2 years, researchers found that being overweight (BMI 25-30 kg/m²) was associated with a 41% lower risk of cardiovascular mortality. Cumulative weight loss of greater than 10% and weight loss greater than 3 kg/m2 per year were both significantly associated with a twofold higher risk of cardiovascular mortality.

Similarly, more rapid weight loss of more than 3 kg/m² per year was also associated with a greater than twofold increase in the risk of cancer mortality, while less rapid weight loss did not show a significant impact (Arthritis Care Res. 2017 Apr 20. doi: 10.1002/acr.23258).

Individuals who were underweight (BMI less than 20 kg/m²) had nearly a threefold greater risk of respiratory mortality, compared with individuals with a normal BMI. Researchers saw a dose-dependent association between respiratory mortality and percent of weight loss: 5%-10% weight loss was associated with an 86% higher risk of respiratory mortality, and greater than 10% weight loss showed a more than twofold greater risk.

This appears to be the first study to examine the impact of both BMI and weight loss on cause-specific mortality in rheumatoid arthritis, according to Bryant R. England, MD, of the VA Nebraska-Western Iowa Healthcare System of Nebraska, Omaha, and his coauthors.

“In this study of cause-specific mortality, we again demonstrate that underweight BMI and weight loss both drive mortality risk, but, importantly, this risk may differ across causes,” they wrote. “In cardiovascular and cancer mortality, we identified rapid and cumulative weight loss as the weight parameters most predictive of death, while in respiratory mortality underweight BMI was the weight parameter most predictive.”

Weight loss most likely reflects a systematic process, such as inflammation, that is a well-known risk factor for cardiovascular disease and mortality in people with rheumatoid arthritis, the authors suggested. Weight loss may also reflect comorbidities, chronic illness, disease phenotype, aging, smoking, and other factors, they said.

“Overall, these data illustrate the importance of considering the dynamic nature of body composition when assessing mortality risk in RA,” they said.

The authors noted that, while the study population was predominantly composed of older men, their findings were largely in agreement with those from studies with a higher proportion of women.

The researchers received grant support from the Department of Veterans’ Affairs and the National Institutes of Health. They reported having no conflicts of interest.