Patient & Survivor Care

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious side effect that can be dose limiting and affect patient quality of life for prolonged time,¹ with an overall incidence of about 38% in patients who are treated with multiple chemotherapeutic agents. ² CIPN has various clinical presentations – affecting the motor, sensory, and autonomic nerves – but the most common manifestations are numbness, tingling, and burning pain affecting the upper and lower extremities (the stocking-and-glove distribution).^3-5 It can also lead to numerous negative effects on activities of daily living, functioning,⁶ leisure activities, dressing, household and work activities, going barefoot or wearing shoes, and driving. The incidence of CIPN is variable, depending on many factors such as type of chemotherapy, total dose, dose per cycle, infusion duration, and comorbidities as diabetes mellitus. ^5-7

The most common antineoplastic agents causing peripheral neuropathy are oxaliplatin, cisplatin, taxanes, Vinca alkaloids, bortezomib, and thalidomide.^3,8,9

Different components of the nervous system are targets of various chemotherapeutic agents, from dorsal root ganglion (DRG) cells to the distal axon. The DRG is the most vulnerable to neurotoxicity because it is less protected by the nervous system blood barrier, hence the predominance of sensory symptoms in CIPN.¹⁰ The pathogenesis of CIPN is not fully understood, and it is most probably multifaceted and not always related to the antineoplastic mechanism. Findings from experimental studies have shown an accumulation of chemotherapeutic compounds in the cell bodies of the DRG, resulting in decreased cellular metabolism and axoplasmic transport. Another proposed mechanism is the induction of apoptosis in sensory neuron of the posterior spinal ganglion after binding to DNA strands.^7,11

Opioids had been used for managing pain in patients with cancer, but their addictive side effects limit use in the treatment of chronic pain,¹² so several drugs called coanalgesics have been introduced as a treatment for CIPN, including antidepressants (tricyclic antidepressants, serotonin [5HT], and norepinephrine [NE] reuptake inhibitors), anti-convulsants (carbamazepine, and gabapentin), topical lidocaine patch, and topical gel.¹³ Duloxetine has been shown to be effective as a treatment option for painful diabetic neuropathy,^14-16 but there is a lack of data on its effectiveness in patients with CIPN.^17,18 To date, the therapeutic options for CIPN remain limited.^12,13,19

The imbalance of 5HT and NE in the pain inhibitory pathways may contribute to the peripheral neuropathic pain.²⁰ Duloxetine hydrochloride is a 5HT–NE reuptake inhibitor used to treat depression and generalized anxiety disorder.²¹ Duloxetine effect in decreasing pain transmission through increasing synaptic concentrations of NE and 5HT, which results in blocking input signals to the dorsal horn neurons in the spinal cord.¹²
 

Methods

We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA statement) guidelines during the preparation of this systematic review.²²

Inclusion criteria

Trial or study type. Articles publishing findings from randomized controlled trials, nonrandomized controlled trials, retrospective studies, and single-arm studies of duloxetine in the treatment of CIPN were included in our review.



Intervention. The intervention was duloxetine with all doses, either administered alone or with other antineuropathic drugs.



Comparator. The comparator was placebo (control group) or other antineuropathic drugs or no control group.



Population. The population included cancer patients with painful CIPN.



Outcome. At least one of the following outcomes was used for pain assessment: visual analog scale (VAS) score; Brief Pain Inventory-Short Form (BPI-SF), neuropathic pain score using National Cancer Institute’s Common Toxicity Criteria for Adverse Events, version 3 or version 4 (NCI-CTCAE v3.0, v4.0), or Functional Assessment of Cancer Therapy-Taxane (FACT-Tax) Scales.
 

Exclusion criteria

Studies in a non-English language, animal studies, studies whose full-text article was not available, and thesis and conference papers were not included.
 

Objective and study design

The objective of this systematic review was to systematically assess the effectiveness of duloxetine in the treatment of pain in patients with CIPN.
 

Information sources and search

Medical electronic databases. PubMed and Scopus, from inception to January 2018, were searched using the following search queries: (((duloxetine) AND chemotherapy induced peripheral neuropathy)) OR ((((chemotherapy) AND (neuropathic pain OR peripheral neuropathy))) AND duloxetine).



Selection of studies. The authors selected eligible studies. The screening of search results was performed in the following 2 steps:

n Screen title and abstracts against the selection criteria. Articles that were unclear from their title or abstract were reviewed against the selection criteria through the full text.

n Retrieve and screen full-text articles of eligible abstracts for eligibility to systematic review.
 

Data extraction

Two authors extracted the following data independently: sample size, mean age, chemotherapeutic drug, duloxetine dosage, and outcomes for pain assessment using at least one score from VAS, BPI-SF, neuropathic pain score using the NCI-CTCAE v3.0 and v4.0, or FACT-Tax, and other secondary outcomes. The data was exported from the online forms as a Microsoft Excel sheet.
 

Statistical analysis

We calculated the mean age and associated standard deviations (SDs) for all patients by using the pooled mean and pooled SD equation, according to Cochrane handbook of systematic reviews of interventions 5.1.0 (updated March 2011).²³ When data are expressed as median and interquartile range, we used Hozo and colleagues’ BMC Research Methodology equation to calculate or estimate the mean and SD.²⁴

Data are expressed as means with SD (unless stated otherwise); statistical results were considered significant when the P-value was less than .05. Data analysis was performed using the SPSS Statistical Package, version 23 (IBM Corp., Armonk, NY).
 

Synthesis of data and analysis

Because of heterogeneity and low sample size of studies, no statistically justified analyses could be performed on the provided data. Instead, a descriptive analysis of published studies was performed.
 

Summary measures

The search strings, the list of relevant reviews, the data coding, and the quality criteria that were used can be requested from the corresponding author.
 

Results

Selection of articles

The systematic literature search and subsequent selection are summarized in a flow diagram (Figure). The PubMed database online search identified 41 publications, and a second database search through Scopus identified 29 publications. After 27 duplicate publications were removed, a total of 43 publications were screened for title and abstract. All articles with animal instead of human patients, review articles as well as articles not written in the English language were excluded (n = 33 articles). A total of 10 full-text articles were assessed for eligibility, with 5 being excluded for the following reasons: full text not available (n = 1), review article (n = 2), secondary analysis (n = 1), and primary outcome not met (n = 1).

Study characteristics

Characteristics of the included studies and patient outcome are summarized in Table 1 and Table 2. A total of 5 studies from 2012 through 2017 were included in the descriptive analysis and systematic review. In all, 4 trials were prospective studies, and 1 trial was retrospective; among all trials, 2 studies were single arm and 3 were placebo-controlled and/or crossover.

Baseline characteristics of included studies

There were 431 participants in the total 5 studies included in this systematic review. The number of patients per study ranged from 25 to 231. Patients were mostly older, with mean sample ages ranging from 47.9 to 63 years, and the pooled mean age for all participants in the total 5 studies was 57.7 years.

In all included studies, duloxetine was given in varying doses of 20 mg, 30 mg, 40 mg, or 60 mg. Also, different therapeutic regimens of duloxetine were used, including placebo control or crossover with vitamin B12; 80% of the studies used escalation of doses over time (only 1 trial used fixed doses for each group of patients in the study). Escalation of duloxetine by doubling the dose was done in all 4 studies, with duloxetine doses of 30 mg and 60 mg used in 75% of those studies (3 out of 4 studies).

Comparator drug was used in 4 studies (1 was single arm) in our review analysis. The comparator drug was placebo in 1 study only, and the remaining 3 studies used other antineurotoxicity or antineuropathic pain therapy, mainly vitamin B12 (as only comparator in 1 study), fish oil, pregabalin, selective 5HT reuptake inhibitors, and nonsteroidal anti-inflammatory agents.

Regarding CIPN, the chemotherapeutic agents used in the studies were as follows (after exclusion of 11 patients who never received treatment in 1 study): 224 patients (52.9%) were on paclitaxel, 168 (39.7%) on oxaliplatin, 14 (3.30%) on R-CHOP, 8 (1.89%) on combined bortezomib–dexamethasone, 5 (1.18%) on FOLFOX, and 4 (0.94%) on other taxanes.

Improvement in pain scores was the primary and/or secondary endpoint in the included studies (Table 2). Pain was assessed by 6 different scores, including the VAS, BPI-SF, neuropathic pain score using NCI-CTCAE v3.0 and v4.0, and FACT-Tax, with all reported once except the VAS score, which was reported in 2 studies. Only 1 study, by Yang and colleagues,²⁵ measured pain by 2 scores (the VAS and NCI-CTCAE v3.0), with the rest of the studies assessing pain by just 1 of the aforementioned scores. The pretreatment pain score was reported in only 2 studies, by Smith and colleagues and Wang and colleagues, using BPI-SF and FACT-Tax scores, respectively, with total respective mean scores of 5.8 (SD, 1.7) and 11.77 (SD, 1.73).^17,26

Secondary endpoints were related mainly to pain score, drug adverse effect, and assessment of quality of life (Table 2). In the study by Yang and colleagues,²⁵ 9 patients (28.1%) discontinued duloxetine because of intolerable adverse events, with dizziness or giddiness as the most common cause (44.4% of patients who discontinued treatment). Studies by Otake and colleagues¹² and Hirayama and colleagues² reported duloxetine adverse events that were very mild and usually well tolerated in collectively 22 patients, with fatigue (n = 6) and somnolence (n = 5) as the most reported adverse effects. Wang and colleagues¹⁷ reported nonneuropathic adverse events that were attributed to chemotherapy and were mild and similar in both study groups.
 

Discussion

To our knowledge, this is the first systematic review to discuss the effectiveness of duloxetine specifically in treatment of pain in CIPN. The administration of chemotherapeutic agents such as paclitaxel, cisplatin, oxaliplatin, and vincristine was accompanied by CIPN. The currently available treatment options for CIPN are limited. To date, no drug has been approved specifically for treatment of pain in CIPN.¹²

In our review, we included cancer patients with CIPN and associated pain. Several previous studies^8,27,28 discussed tingling and numbness as a common adverse effect in CIPN, and usually about 20% to 42% of patients develop chronic pain.

Six different pain assessment scores were reported in the total 5 studies in our review, with VAS and NCI-CTCAE scores reported in more than 1 study. This reflects the major challenges facing the assessment of CIPN, as various scales and tools are available for pain assessment but without a standardized approach for CIPN that can be precisely implemented.⁸ Several other challenges regarding pain scores were observed, with Smith and colleagues as the only authors to report both pretreatment pain score and grade, while the rest of the studies failed to report either pain score or grade, or even both.

Another difficulty observed in our review was the variability in study participants in both population size and type of cancer treated. The population size in largest study included in our review was 231 patients and the smallest was 25 patients; collectively, there were only 431 patients in the included studies. Although the type of primary cancer varied in between studies, gynecologic malignancies comprised most cases (215 patients), followed by gastrointestinal tumors, and few cases of hematologic and genitourinary malignancies were reported. Similar results were observed by Geber and colleagues in their large study screening pain in cancer patients, in which gynecologic malignancies were diagnosed in 28 patients out of 61 with CIPN, representing the highest percentage (45.9%) of malignancy type in that study.²⁶

In the study by Otake and colleagues¹² examining duloxetine for CIPN in patients with gynecologic cancer, the authors concluded that duloxetine dosage either 20 mg/day or 40 mg/day was not associated with the effectiveness of duloxetine treatment by either univariate or multivariate analysis. Previous authors have provided an explanation for the difference in duloxetine response among CIPN patients and attributed those differences to the underlying pain mechanisms.^14,29 In other words, pain in those patients is both peripheral nociceptive and central neuropathic, and it is likely to be caused by mixed mechanisms.

Another variation observed among CIPN patients in our review was the chemotherapeutic agents used. That was noted by Smith and colleagues,²⁶ who reported that patients with cancer who received platinum therapies (oxaliplatin) experienced more benefit from duloxetine in terms of pain improvement than those who received taxanes (P = .13). We found no other published studies on the response to duloxetine among different chemotherapeutic agents used. However, 2 studies of duloxetine response in patients with other pain-related disorders (painful diabetic peripheral neuropathy and fibromyalgia) showed significant improvement in pain symptoms compared with placebo. In a study of pain in chemotherapy-induced neuropathy (CIN) by Geber and colleagues,²⁹ the preexisting pain medication was not reported, but the authors concluded that treatment for CIN-related neuropathic pain differs from that for nonneuropathic (ie, musculoskeletal) pain, with the former being treated mainly with pharmacotherapy and the latter with physiotherapy and behavioral exercises. They asserted that different pain patterns could help flag neuropathic or musculoskeletal pain so that the selected treatments would be more specific. Differences in pain improvement related to duloxetine may be attributed to the underlying pain mechanism, and whether it is mixed or centrally or peripherally related was also discussed by Geber and colleagues.²⁹

In the study by Geber and colleagues, the chemotherapeutic protocols comprised a combination of chemotherapeutic agents so that the symptoms and signs of CIPN could not be attributed to a single agent.²⁹ By contrast, all the studies included in our review used a chemotherapeutic protocol with single agent so that specific symptoms and signs of CIPN could be attributed to an individual chemotherapeutic agent.

Findings from studies on the effect of duloxetine in treatment of pain in diabetic peripheral neuropathy have shown that duloxetine at a dose of 60 mg/day effectively improves pain in 43% to 68% of patients.^15,16,30 Similarly, in our review, the study by Yang and colleagues²⁵ showed a 63% subjective reduction in pain severity by VAS score in CIPN patients but lower improvement of 47.4% by NCI-CTCAE v3.0; this can be attributed to the simplistic 4-grade rating scale of the latter.

During our analysis of studies, we noticed that no diagnostic criteria were implemented for diagnosis or inclusion of CIPN patients in any of the included studies, and this represents a major challenge in any analysis of studies with neuropathic pain patients. In 2016, Finnerup and colleagues updated the previous 2008 grading system for diagnosis of neuropathic pain, which is intended to determine the level of certainty with which the pain in question is neuropathic.³¹ The system defines the diagnostic certainty into 3 levels: Possible, Probable, and Definite. Although the number of studies used the grading system during the inclusion of neuropathic pain patients increased from 5% in 2009 to 30% in 2014, still more than two-thirds of studies do not use a standardized system for diagnosis and/or inclusion of neuropathic pain in patients.
 

Strength and limitations

The first strength of this review is that it identifies gaps in our current knowledge about duloxetine in the treatment of pain in cancer patients with CIPN. Second, we collected all available articles from inception until January 2018. Third, this review can serve as a model for future studies investigating the effectiveness of duloxetine in treatment of CIPN.

There are also limitations to this review that should be discussed. First, the studies vary greatly in samples, methodologies, and outcomes measured. Second, the diagnostic criteria for CIPN and the pain assessment tools vary among the studies. Third, there is also variability in the duloxetine doses and administration regimens among the studies, and some articles did not report the precise outcome in pain scores. Furthermore, the articles reviewed included retrospective, single-arm, or nonrandomized controlled studies with relatively small numbers of participants.

To improve the results, more placebo-controlled or head-to-head trials (with other agents used in treatment of CIPN) with large sample sizes would be needed.
 

Conclusions

Our purpose was to describe the effectiveness of duloxetine in improving pain scores among CIPN patients, but because of heterogeneity, the low sample size of available studies, and lack of high-quality evidence, we were only able to perform a descriptive analysis of published studies. From the descriptive analyses and from the available data of relatively small sample sized studies, it can be concluded that despite the aforementioned limitations, duloxetine remains a useful therapeutic option for pain in CIPN patients, regardless of the type of chemotherapeutic agent used.

Acknowledgments

That authors express their sincere gratitude to Nahla A Merghany and Sarah M Abd Elfadel for helping them retrieve all the relevant articles for this review.

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious side effect that can be dose limiting and affect patient quality of life for prolonged time,¹ with an overall incidence of about 38% in patients who are treated with multiple chemotherapeutic agents. ² CIPN has various clinical presentations – affecting the motor, sensory, and autonomic nerves – but the most common manifestations are numbness, tingling, and burning pain affecting the upper and lower extremities (the stocking-and-glove distribution).^3-5 It can also lead to numerous negative effects on activities of daily living, functioning,⁶ leisure activities, dressing, household and work activities, going barefoot or wearing shoes, and driving. The incidence of CIPN is variable, depending on many factors such as type of chemotherapy, total dose, dose per cycle, infusion duration, and comorbidities as diabetes mellitus. ^5-7

The most common antineoplastic agents causing peripheral neuropathy are oxaliplatin, cisplatin, taxanes, Vinca alkaloids, bortezomib, and thalidomide.^3,8,9

Different components of the nervous system are targets of various chemotherapeutic agents, from dorsal root ganglion (DRG) cells to the distal axon. The DRG is the most vulnerable to neurotoxicity because it is less protected by the nervous system blood barrier, hence the predominance of sensory symptoms in CIPN.¹⁰ The pathogenesis of CIPN is not fully understood, and it is most probably multifaceted and not always related to the antineoplastic mechanism. Findings from experimental studies have shown an accumulation of chemotherapeutic compounds in the cell bodies of the DRG, resulting in decreased cellular metabolism and axoplasmic transport. Another proposed mechanism is the induction of apoptosis in sensory neuron of the posterior spinal ganglion after binding to DNA strands.^7,11

Opioids had been used for managing pain in patients with cancer, but their addictive side effects limit use in the treatment of chronic pain,¹² so several drugs called coanalgesics have been introduced as a treatment for CIPN, including antidepressants (tricyclic antidepressants, serotonin [5HT], and norepinephrine [NE] reuptake inhibitors), anti-convulsants (carbamazepine, and gabapentin), topical lidocaine patch, and topical gel.¹³ Duloxetine has been shown to be effective as a treatment option for painful diabetic neuropathy,^14-16 but there is a lack of data on its effectiveness in patients with CIPN.^17,18 To date, the therapeutic options for CIPN remain limited.^12,13,19

The imbalance of 5HT and NE in the pain inhibitory pathways may contribute to the peripheral neuropathic pain.²⁰ Duloxetine hydrochloride is a 5HT–NE reuptake inhibitor used to treat depression and generalized anxiety disorder.²¹ Duloxetine effect in decreasing pain transmission through increasing synaptic concentrations of NE and 5HT, which results in blocking input signals to the dorsal horn neurons in the spinal cord.¹²
 

Methods

We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA statement) guidelines during the preparation of this systematic review.²²

Inclusion criteria

Trial or study type. Articles publishing findings from randomized controlled trials, nonrandomized controlled trials, retrospective studies, and single-arm studies of duloxetine in the treatment of CIPN were included in our review.



Intervention. The intervention was duloxetine with all doses, either administered alone or with other antineuropathic drugs.



Comparator. The comparator was placebo (control group) or other antineuropathic drugs or no control group.



Population. The population included cancer patients with painful CIPN.



Outcome. At least one of the following outcomes was used for pain assessment: visual analog scale (VAS) score; Brief Pain Inventory-Short Form (BPI-SF), neuropathic pain score using National Cancer Institute’s Common Toxicity Criteria for Adverse Events, version 3 or version 4 (NCI-CTCAE v3.0, v4.0), or Functional Assessment of Cancer Therapy-Taxane (FACT-Tax) Scales.
 

Exclusion criteria

Studies in a non-English language, animal studies, studies whose full-text article was not available, and thesis and conference papers were not included.
 

Objective and study design

The objective of this systematic review was to systematically assess the effectiveness of duloxetine in the treatment of pain in patients with CIPN.
 

Information sources and search

Medical electronic databases. PubMed and Scopus, from inception to January 2018, were searched using the following search queries: (((duloxetine) AND chemotherapy induced peripheral neuropathy)) OR ((((chemotherapy) AND (neuropathic pain OR peripheral neuropathy))) AND duloxetine).



Selection of studies. The authors selected eligible studies. The screening of search results was performed in the following 2 steps:

n Screen title and abstracts against the selection criteria. Articles that were unclear from their title or abstract were reviewed against the selection criteria through the full text.

n Retrieve and screen full-text articles of eligible abstracts for eligibility to systematic review.
 

Data extraction

Two authors extracted the following data independently: sample size, mean age, chemotherapeutic drug, duloxetine dosage, and outcomes for pain assessment using at least one score from VAS, BPI-SF, neuropathic pain score using the NCI-CTCAE v3.0 and v4.0, or FACT-Tax, and other secondary outcomes. The data was exported from the online forms as a Microsoft Excel sheet.
 

Statistical analysis

We calculated the mean age and associated standard deviations (SDs) for all patients by using the pooled mean and pooled SD equation, according to Cochrane handbook of systematic reviews of interventions 5.1.0 (updated March 2011).²³ When data are expressed as median and interquartile range, we used Hozo and colleagues’ BMC Research Methodology equation to calculate or estimate the mean and SD.²⁴

Data are expressed as means with SD (unless stated otherwise); statistical results were considered significant when the P-value was less than .05. Data analysis was performed using the SPSS Statistical Package, version 23 (IBM Corp., Armonk, NY).
 

Synthesis of data and analysis

Because of heterogeneity and low sample size of studies, no statistically justified analyses could be performed on the provided data. Instead, a descriptive analysis of published studies was performed.
 

Summary measures

The search strings, the list of relevant reviews, the data coding, and the quality criteria that were used can be requested from the corresponding author.
 

Results

Selection of articles

The systematic literature search and subsequent selection are summarized in a flow diagram (Figure). The PubMed database online search identified 41 publications, and a second database search through Scopus identified 29 publications. After 27 duplicate publications were removed, a total of 43 publications were screened for title and abstract. All articles with animal instead of human patients, review articles as well as articles not written in the English language were excluded (n = 33 articles). A total of 10 full-text articles were assessed for eligibility, with 5 being excluded for the following reasons: full text not available (n = 1), review article (n = 2), secondary analysis (n = 1), and primary outcome not met (n = 1).

Study characteristics

Characteristics of the included studies and patient outcome are summarized in Table 1 and Table 2. A total of 5 studies from 2012 through 2017 were included in the descriptive analysis and systematic review. In all, 4 trials were prospective studies, and 1 trial was retrospective; among all trials, 2 studies were single arm and 3 were placebo-controlled and/or crossover.

Baseline characteristics of included studies

There were 431 participants in the total 5 studies included in this systematic review. The number of patients per study ranged from 25 to 231. Patients were mostly older, with mean sample ages ranging from 47.9 to 63 years, and the pooled mean age for all participants in the total 5 studies was 57.7 years.

In all included studies, duloxetine was given in varying doses of 20 mg, 30 mg, 40 mg, or 60 mg. Also, different therapeutic regimens of duloxetine were used, including placebo control or crossover with vitamin B12; 80% of the studies used escalation of doses over time (only 1 trial used fixed doses for each group of patients in the study). Escalation of duloxetine by doubling the dose was done in all 4 studies, with duloxetine doses of 30 mg and 60 mg used in 75% of those studies (3 out of 4 studies).

Comparator drug was used in 4 studies (1 was single arm) in our review analysis. The comparator drug was placebo in 1 study only, and the remaining 3 studies used other antineurotoxicity or antineuropathic pain therapy, mainly vitamin B12 (as only comparator in 1 study), fish oil, pregabalin, selective 5HT reuptake inhibitors, and nonsteroidal anti-inflammatory agents.

Regarding CIPN, the chemotherapeutic agents used in the studies were as follows (after exclusion of 11 patients who never received treatment in 1 study): 224 patients (52.9%) were on paclitaxel, 168 (39.7%) on oxaliplatin, 14 (3.30%) on R-CHOP, 8 (1.89%) on combined bortezomib–dexamethasone, 5 (1.18%) on FOLFOX, and 4 (0.94%) on other taxanes.

Improvement in pain scores was the primary and/or secondary endpoint in the included studies (Table 2). Pain was assessed by 6 different scores, including the VAS, BPI-SF, neuropathic pain score using NCI-CTCAE v3.0 and v4.0, and FACT-Tax, with all reported once except the VAS score, which was reported in 2 studies. Only 1 study, by Yang and colleagues,²⁵ measured pain by 2 scores (the VAS and NCI-CTCAE v3.0), with the rest of the studies assessing pain by just 1 of the aforementioned scores. The pretreatment pain score was reported in only 2 studies, by Smith and colleagues and Wang and colleagues, using BPI-SF and FACT-Tax scores, respectively, with total respective mean scores of 5.8 (SD, 1.7) and 11.77 (SD, 1.73).^17,26

Secondary endpoints were related mainly to pain score, drug adverse effect, and assessment of quality of life (Table 2). In the study by Yang and colleagues,²⁵ 9 patients (28.1%) discontinued duloxetine because of intolerable adverse events, with dizziness or giddiness as the most common cause (44.4% of patients who discontinued treatment). Studies by Otake and colleagues¹² and Hirayama and colleagues² reported duloxetine adverse events that were very mild and usually well tolerated in collectively 22 patients, with fatigue (n = 6) and somnolence (n = 5) as the most reported adverse effects. Wang and colleagues¹⁷ reported nonneuropathic adverse events that were attributed to chemotherapy and were mild and similar in both study groups.
 

Discussion

To our knowledge, this is the first systematic review to discuss the effectiveness of duloxetine specifically in treatment of pain in CIPN. The administration of chemotherapeutic agents such as paclitaxel, cisplatin, oxaliplatin, and vincristine was accompanied by CIPN. The currently available treatment options for CIPN are limited. To date, no drug has been approved specifically for treatment of pain in CIPN.¹²

In our review, we included cancer patients with CIPN and associated pain. Several previous studies^8,27,28 discussed tingling and numbness as a common adverse effect in CIPN, and usually about 20% to 42% of patients develop chronic pain.

Six different pain assessment scores were reported in the total 5 studies in our review, with VAS and NCI-CTCAE scores reported in more than 1 study. This reflects the major challenges facing the assessment of CIPN, as various scales and tools are available for pain assessment but without a standardized approach for CIPN that can be precisely implemented.⁸ Several other challenges regarding pain scores were observed, with Smith and colleagues as the only authors to report both pretreatment pain score and grade, while the rest of the studies failed to report either pain score or grade, or even both.

Another difficulty observed in our review was the variability in study participants in both population size and type of cancer treated. The population size in largest study included in our review was 231 patients and the smallest was 25 patients; collectively, there were only 431 patients in the included studies. Although the type of primary cancer varied in between studies, gynecologic malignancies comprised most cases (215 patients), followed by gastrointestinal tumors, and few cases of hematologic and genitourinary malignancies were reported. Similar results were observed by Geber and colleagues in their large study screening pain in cancer patients, in which gynecologic malignancies were diagnosed in 28 patients out of 61 with CIPN, representing the highest percentage (45.9%) of malignancy type in that study.²⁶

In the study by Otake and colleagues¹² examining duloxetine for CIPN in patients with gynecologic cancer, the authors concluded that duloxetine dosage either 20 mg/day or 40 mg/day was not associated with the effectiveness of duloxetine treatment by either univariate or multivariate analysis. Previous authors have provided an explanation for the difference in duloxetine response among CIPN patients and attributed those differences to the underlying pain mechanisms.^14,29 In other words, pain in those patients is both peripheral nociceptive and central neuropathic, and it is likely to be caused by mixed mechanisms.

Another variation observed among CIPN patients in our review was the chemotherapeutic agents used. That was noted by Smith and colleagues,²⁶ who reported that patients with cancer who received platinum therapies (oxaliplatin) experienced more benefit from duloxetine in terms of pain improvement than those who received taxanes (P = .13). We found no other published studies on the response to duloxetine among different chemotherapeutic agents used. However, 2 studies of duloxetine response in patients with other pain-related disorders (painful diabetic peripheral neuropathy and fibromyalgia) showed significant improvement in pain symptoms compared with placebo. In a study of pain in chemotherapy-induced neuropathy (CIN) by Geber and colleagues,²⁹ the preexisting pain medication was not reported, but the authors concluded that treatment for CIN-related neuropathic pain differs from that for nonneuropathic (ie, musculoskeletal) pain, with the former being treated mainly with pharmacotherapy and the latter with physiotherapy and behavioral exercises. They asserted that different pain patterns could help flag neuropathic or musculoskeletal pain so that the selected treatments would be more specific. Differences in pain improvement related to duloxetine may be attributed to the underlying pain mechanism, and whether it is mixed or centrally or peripherally related was also discussed by Geber and colleagues.²⁹

In the study by Geber and colleagues, the chemotherapeutic protocols comprised a combination of chemotherapeutic agents so that the symptoms and signs of CIPN could not be attributed to a single agent.²⁹ By contrast, all the studies included in our review used a chemotherapeutic protocol with single agent so that specific symptoms and signs of CIPN could be attributed to an individual chemotherapeutic agent.

Findings from studies on the effect of duloxetine in treatment of pain in diabetic peripheral neuropathy have shown that duloxetine at a dose of 60 mg/day effectively improves pain in 43% to 68% of patients.^15,16,30 Similarly, in our review, the study by Yang and colleagues²⁵ showed a 63% subjective reduction in pain severity by VAS score in CIPN patients but lower improvement of 47.4% by NCI-CTCAE v3.0; this can be attributed to the simplistic 4-grade rating scale of the latter.

During our analysis of studies, we noticed that no diagnostic criteria were implemented for diagnosis or inclusion of CIPN patients in any of the included studies, and this represents a major challenge in any analysis of studies with neuropathic pain patients. In 2016, Finnerup and colleagues updated the previous 2008 grading system for diagnosis of neuropathic pain, which is intended to determine the level of certainty with which the pain in question is neuropathic.³¹ The system defines the diagnostic certainty into 3 levels: Possible, Probable, and Definite. Although the number of studies used the grading system during the inclusion of neuropathic pain patients increased from 5% in 2009 to 30% in 2014, still more than two-thirds of studies do not use a standardized system for diagnosis and/or inclusion of neuropathic pain in patients.
 

Strength and limitations

The first strength of this review is that it identifies gaps in our current knowledge about duloxetine in the treatment of pain in cancer patients with CIPN. Second, we collected all available articles from inception until January 2018. Third, this review can serve as a model for future studies investigating the effectiveness of duloxetine in treatment of CIPN.

There are also limitations to this review that should be discussed. First, the studies vary greatly in samples, methodologies, and outcomes measured. Second, the diagnostic criteria for CIPN and the pain assessment tools vary among the studies. Third, there is also variability in the duloxetine doses and administration regimens among the studies, and some articles did not report the precise outcome in pain scores. Furthermore, the articles reviewed included retrospective, single-arm, or nonrandomized controlled studies with relatively small numbers of participants.

To improve the results, more placebo-controlled or head-to-head trials (with other agents used in treatment of CIPN) with large sample sizes would be needed.
 

Conclusions

Our purpose was to describe the effectiveness of duloxetine in improving pain scores among CIPN patients, but because of heterogeneity, the low sample size of available studies, and lack of high-quality evidence, we were only able to perform a descriptive analysis of published studies. From the descriptive analyses and from the available data of relatively small sample sized studies, it can be concluded that despite the aforementioned limitations, duloxetine remains a useful therapeutic option for pain in CIPN patients, regardless of the type of chemotherapeutic agent used.

Acknowledgments

That authors express their sincere gratitude to Nahla A Merghany and Sarah M Abd Elfadel for helping them retrieve all the relevant articles for this review.

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious side effect that can be dose limiting and affect patient quality of life for prolonged time,¹ with an overall incidence of about 38% in patients who are treated with multiple chemotherapeutic agents. ² CIPN has various clinical presentations – affecting the motor, sensory, and autonomic nerves – but the most common manifestations are numbness, tingling, and burning pain affecting the upper and lower extremities (the stocking-and-glove distribution).^3-5 It can also lead to numerous negative effects on activities of daily living, functioning,⁶ leisure activities, dressing, household and work activities, going barefoot or wearing shoes, and driving. The incidence of CIPN is variable, depending on many factors such as type of chemotherapy, total dose, dose per cycle, infusion duration, and comorbidities as diabetes mellitus. ^5-7

The most common antineoplastic agents causing peripheral neuropathy are oxaliplatin, cisplatin, taxanes, Vinca alkaloids, bortezomib, and thalidomide.^3,8,9

Different components of the nervous system are targets of various chemotherapeutic agents, from dorsal root ganglion (DRG) cells to the distal axon. The DRG is the most vulnerable to neurotoxicity because it is less protected by the nervous system blood barrier, hence the predominance of sensory symptoms in CIPN.¹⁰ The pathogenesis of CIPN is not fully understood, and it is most probably multifaceted and not always related to the antineoplastic mechanism. Findings from experimental studies have shown an accumulation of chemotherapeutic compounds in the cell bodies of the DRG, resulting in decreased cellular metabolism and axoplasmic transport. Another proposed mechanism is the induction of apoptosis in sensory neuron of the posterior spinal ganglion after binding to DNA strands.^7,11

Opioids had been used for managing pain in patients with cancer, but their addictive side effects limit use in the treatment of chronic pain,¹² so several drugs called coanalgesics have been introduced as a treatment for CIPN, including antidepressants (tricyclic antidepressants, serotonin [5HT], and norepinephrine [NE] reuptake inhibitors), anti-convulsants (carbamazepine, and gabapentin), topical lidocaine patch, and topical gel.¹³ Duloxetine has been shown to be effective as a treatment option for painful diabetic neuropathy,^14-16 but there is a lack of data on its effectiveness in patients with CIPN.^17,18 To date, the therapeutic options for CIPN remain limited.^12,13,19

The imbalance of 5HT and NE in the pain inhibitory pathways may contribute to the peripheral neuropathic pain.²⁰ Duloxetine hydrochloride is a 5HT–NE reuptake inhibitor used to treat depression and generalized anxiety disorder.²¹ Duloxetine effect in decreasing pain transmission through increasing synaptic concentrations of NE and 5HT, which results in blocking input signals to the dorsal horn neurons in the spinal cord.¹²
 

Methods

We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA statement) guidelines during the preparation of this systematic review.²²

Inclusion criteria

Trial or study type. Articles publishing findings from randomized controlled trials, nonrandomized controlled trials, retrospective studies, and single-arm studies of duloxetine in the treatment of CIPN were included in our review.



Intervention. The intervention was duloxetine with all doses, either administered alone or with other antineuropathic drugs.



Comparator. The comparator was placebo (control group) or other antineuropathic drugs or no control group.



Population. The population included cancer patients with painful CIPN.



Outcome. At least one of the following outcomes was used for pain assessment: visual analog scale (VAS) score; Brief Pain Inventory-Short Form (BPI-SF), neuropathic pain score using National Cancer Institute’s Common Toxicity Criteria for Adverse Events, version 3 or version 4 (NCI-CTCAE v3.0, v4.0), or Functional Assessment of Cancer Therapy-Taxane (FACT-Tax) Scales.
 

Exclusion criteria

Studies in a non-English language, animal studies, studies whose full-text article was not available, and thesis and conference papers were not included.
 

Objective and study design

The objective of this systematic review was to systematically assess the effectiveness of duloxetine in the treatment of pain in patients with CIPN.
 

Information sources and search

Medical electronic databases. PubMed and Scopus, from inception to January 2018, were searched using the following search queries: (((duloxetine) AND chemotherapy induced peripheral neuropathy)) OR ((((chemotherapy) AND (neuropathic pain OR peripheral neuropathy))) AND duloxetine).



Selection of studies. The authors selected eligible studies. The screening of search results was performed in the following 2 steps:

n Screen title and abstracts against the selection criteria. Articles that were unclear from their title or abstract were reviewed against the selection criteria through the full text.

n Retrieve and screen full-text articles of eligible abstracts for eligibility to systematic review.
 

Data extraction

Two authors extracted the following data independently: sample size, mean age, chemotherapeutic drug, duloxetine dosage, and outcomes for pain assessment using at least one score from VAS, BPI-SF, neuropathic pain score using the NCI-CTCAE v3.0 and v4.0, or FACT-Tax, and other secondary outcomes. The data was exported from the online forms as a Microsoft Excel sheet.
 

Statistical analysis

We calculated the mean age and associated standard deviations (SDs) for all patients by using the pooled mean and pooled SD equation, according to Cochrane handbook of systematic reviews of interventions 5.1.0 (updated March 2011).²³ When data are expressed as median and interquartile range, we used Hozo and colleagues’ BMC Research Methodology equation to calculate or estimate the mean and SD.²⁴

Data are expressed as means with SD (unless stated otherwise); statistical results were considered significant when the P-value was less than .05. Data analysis was performed using the SPSS Statistical Package, version 23 (IBM Corp., Armonk, NY).
 

Synthesis of data and analysis

Because of heterogeneity and low sample size of studies, no statistically justified analyses could be performed on the provided data. Instead, a descriptive analysis of published studies was performed.
 

Summary measures

The search strings, the list of relevant reviews, the data coding, and the quality criteria that were used can be requested from the corresponding author.
 

Results

Selection of articles

The systematic literature search and subsequent selection are summarized in a flow diagram (Figure). The PubMed database online search identified 41 publications, and a second database search through Scopus identified 29 publications. After 27 duplicate publications were removed, a total of 43 publications were screened for title and abstract. All articles with animal instead of human patients, review articles as well as articles not written in the English language were excluded (n = 33 articles). A total of 10 full-text articles were assessed for eligibility, with 5 being excluded for the following reasons: full text not available (n = 1), review article (n = 2), secondary analysis (n = 1), and primary outcome not met (n = 1).

Study characteristics

Characteristics of the included studies and patient outcome are summarized in Table 1 and Table 2. A total of 5 studies from 2012 through 2017 were included in the descriptive analysis and systematic review. In all, 4 trials were prospective studies, and 1 trial was retrospective; among all trials, 2 studies were single arm and 3 were placebo-controlled and/or crossover.

Baseline characteristics of included studies

There were 431 participants in the total 5 studies included in this systematic review. The number of patients per study ranged from 25 to 231. Patients were mostly older, with mean sample ages ranging from 47.9 to 63 years, and the pooled mean age for all participants in the total 5 studies was 57.7 years.

In all included studies, duloxetine was given in varying doses of 20 mg, 30 mg, 40 mg, or 60 mg. Also, different therapeutic regimens of duloxetine were used, including placebo control or crossover with vitamin B12; 80% of the studies used escalation of doses over time (only 1 trial used fixed doses for each group of patients in the study). Escalation of duloxetine by doubling the dose was done in all 4 studies, with duloxetine doses of 30 mg and 60 mg used in 75% of those studies (3 out of 4 studies).

Comparator drug was used in 4 studies (1 was single arm) in our review analysis. The comparator drug was placebo in 1 study only, and the remaining 3 studies used other antineurotoxicity or antineuropathic pain therapy, mainly vitamin B12 (as only comparator in 1 study), fish oil, pregabalin, selective 5HT reuptake inhibitors, and nonsteroidal anti-inflammatory agents.

Regarding CIPN, the chemotherapeutic agents used in the studies were as follows (after exclusion of 11 patients who never received treatment in 1 study): 224 patients (52.9%) were on paclitaxel, 168 (39.7%) on oxaliplatin, 14 (3.30%) on R-CHOP, 8 (1.89%) on combined bortezomib–dexamethasone, 5 (1.18%) on FOLFOX, and 4 (0.94%) on other taxanes.

Improvement in pain scores was the primary and/or secondary endpoint in the included studies (Table 2). Pain was assessed by 6 different scores, including the VAS, BPI-SF, neuropathic pain score using NCI-CTCAE v3.0 and v4.0, and FACT-Tax, with all reported once except the VAS score, which was reported in 2 studies. Only 1 study, by Yang and colleagues,²⁵ measured pain by 2 scores (the VAS and NCI-CTCAE v3.0), with the rest of the studies assessing pain by just 1 of the aforementioned scores. The pretreatment pain score was reported in only 2 studies, by Smith and colleagues and Wang and colleagues, using BPI-SF and FACT-Tax scores, respectively, with total respective mean scores of 5.8 (SD, 1.7) and 11.77 (SD, 1.73).^17,26

Secondary endpoints were related mainly to pain score, drug adverse effect, and assessment of quality of life (Table 2). In the study by Yang and colleagues,²⁵ 9 patients (28.1%) discontinued duloxetine because of intolerable adverse events, with dizziness or giddiness as the most common cause (44.4% of patients who discontinued treatment). Studies by Otake and colleagues¹² and Hirayama and colleagues² reported duloxetine adverse events that were very mild and usually well tolerated in collectively 22 patients, with fatigue (n = 6) and somnolence (n = 5) as the most reported adverse effects. Wang and colleagues¹⁷ reported nonneuropathic adverse events that were attributed to chemotherapy and were mild and similar in both study groups.
 

Discussion

To our knowledge, this is the first systematic review to discuss the effectiveness of duloxetine specifically in treatment of pain in CIPN. The administration of chemotherapeutic agents such as paclitaxel, cisplatin, oxaliplatin, and vincristine was accompanied by CIPN. The currently available treatment options for CIPN are limited. To date, no drug has been approved specifically for treatment of pain in CIPN.¹²

In our review, we included cancer patients with CIPN and associated pain. Several previous studies^8,27,28 discussed tingling and numbness as a common adverse effect in CIPN, and usually about 20% to 42% of patients develop chronic pain.

Six different pain assessment scores were reported in the total 5 studies in our review, with VAS and NCI-CTCAE scores reported in more than 1 study. This reflects the major challenges facing the assessment of CIPN, as various scales and tools are available for pain assessment but without a standardized approach for CIPN that can be precisely implemented.⁸ Several other challenges regarding pain scores were observed, with Smith and colleagues as the only authors to report both pretreatment pain score and grade, while the rest of the studies failed to report either pain score or grade, or even both.

Another difficulty observed in our review was the variability in study participants in both population size and type of cancer treated. The population size in largest study included in our review was 231 patients and the smallest was 25 patients; collectively, there were only 431 patients in the included studies. Although the type of primary cancer varied in between studies, gynecologic malignancies comprised most cases (215 patients), followed by gastrointestinal tumors, and few cases of hematologic and genitourinary malignancies were reported. Similar results were observed by Geber and colleagues in their large study screening pain in cancer patients, in which gynecologic malignancies were diagnosed in 28 patients out of 61 with CIPN, representing the highest percentage (45.9%) of malignancy type in that study.²⁶

In the study by Otake and colleagues¹² examining duloxetine for CIPN in patients with gynecologic cancer, the authors concluded that duloxetine dosage either 20 mg/day or 40 mg/day was not associated with the effectiveness of duloxetine treatment by either univariate or multivariate analysis. Previous authors have provided an explanation for the difference in duloxetine response among CIPN patients and attributed those differences to the underlying pain mechanisms.^14,29 In other words, pain in those patients is both peripheral nociceptive and central neuropathic, and it is likely to be caused by mixed mechanisms.

Another variation observed among CIPN patients in our review was the chemotherapeutic agents used. That was noted by Smith and colleagues,²⁶ who reported that patients with cancer who received platinum therapies (oxaliplatin) experienced more benefit from duloxetine in terms of pain improvement than those who received taxanes (P = .13). We found no other published studies on the response to duloxetine among different chemotherapeutic agents used. However, 2 studies of duloxetine response in patients with other pain-related disorders (painful diabetic peripheral neuropathy and fibromyalgia) showed significant improvement in pain symptoms compared with placebo. In a study of pain in chemotherapy-induced neuropathy (CIN) by Geber and colleagues,²⁹ the preexisting pain medication was not reported, but the authors concluded that treatment for CIN-related neuropathic pain differs from that for nonneuropathic (ie, musculoskeletal) pain, with the former being treated mainly with pharmacotherapy and the latter with physiotherapy and behavioral exercises. They asserted that different pain patterns could help flag neuropathic or musculoskeletal pain so that the selected treatments would be more specific. Differences in pain improvement related to duloxetine may be attributed to the underlying pain mechanism, and whether it is mixed or centrally or peripherally related was also discussed by Geber and colleagues.²⁹

In the study by Geber and colleagues, the chemotherapeutic protocols comprised a combination of chemotherapeutic agents so that the symptoms and signs of CIPN could not be attributed to a single agent.²⁹ By contrast, all the studies included in our review used a chemotherapeutic protocol with single agent so that specific symptoms and signs of CIPN could be attributed to an individual chemotherapeutic agent.

Findings from studies on the effect of duloxetine in treatment of pain in diabetic peripheral neuropathy have shown that duloxetine at a dose of 60 mg/day effectively improves pain in 43% to 68% of patients.^15,16,30 Similarly, in our review, the study by Yang and colleagues²⁵ showed a 63% subjective reduction in pain severity by VAS score in CIPN patients but lower improvement of 47.4% by NCI-CTCAE v3.0; this can be attributed to the simplistic 4-grade rating scale of the latter.

During our analysis of studies, we noticed that no diagnostic criteria were implemented for diagnosis or inclusion of CIPN patients in any of the included studies, and this represents a major challenge in any analysis of studies with neuropathic pain patients. In 2016, Finnerup and colleagues updated the previous 2008 grading system for diagnosis of neuropathic pain, which is intended to determine the level of certainty with which the pain in question is neuropathic.³¹ The system defines the diagnostic certainty into 3 levels: Possible, Probable, and Definite. Although the number of studies used the grading system during the inclusion of neuropathic pain patients increased from 5% in 2009 to 30% in 2014, still more than two-thirds of studies do not use a standardized system for diagnosis and/or inclusion of neuropathic pain in patients.
 

Strength and limitations

The first strength of this review is that it identifies gaps in our current knowledge about duloxetine in the treatment of pain in cancer patients with CIPN. Second, we collected all available articles from inception until January 2018. Third, this review can serve as a model for future studies investigating the effectiveness of duloxetine in treatment of CIPN.

There are also limitations to this review that should be discussed. First, the studies vary greatly in samples, methodologies, and outcomes measured. Second, the diagnostic criteria for CIPN and the pain assessment tools vary among the studies. Third, there is also variability in the duloxetine doses and administration regimens among the studies, and some articles did not report the precise outcome in pain scores. Furthermore, the articles reviewed included retrospective, single-arm, or nonrandomized controlled studies with relatively small numbers of participants.

To improve the results, more placebo-controlled or head-to-head trials (with other agents used in treatment of CIPN) with large sample sizes would be needed.
 

Conclusions

Our purpose was to describe the effectiveness of duloxetine in improving pain scores among CIPN patients, but because of heterogeneity, the low sample size of available studies, and lack of high-quality evidence, we were only able to perform a descriptive analysis of published studies. From the descriptive analyses and from the available data of relatively small sample sized studies, it can be concluded that despite the aforementioned limitations, duloxetine remains a useful therapeutic option for pain in CIPN patients, regardless of the type of chemotherapeutic agent used.

Acknowledgments

That authors express their sincere gratitude to Nahla A Merghany and Sarah M Abd Elfadel for helping them retrieve all the relevant articles for this review.

Anemia is a common complication of cancer treatment as well as of cancer itself. Most cancer patients undergoing chemotherapy experience anemia sometime during their treatment course.^1,2 Moderate to severe anemia is associated with an array of symptoms that are known to compromise the physical functioning and quality of life of cancer patients. Common anemia-related symptoms include fatigue, drowsiness, depression, dyspnea, tachycardia, and dizziness.^1,3-7

Symptoms produced by cancer itself or the disease treatment (ie, side effects such as anemia) collectively compose a patient’s symptom burden.⁸ Although the occurrence of anemia-related fatigue has been described more systematically, other clinical presentations of chemotherapy-induced anemia (CIA) are not well characterized. Furthermore, the overall symptom burdens associated with different ranges of hemoglobin (Hb) concentrations have also not been well reported. Although various tools have been developed to facilitate the reporting of fatigue and other symptoms experienced by patients with CIA, such as the Functional Assessment of Cancer Therapy-Anemia (FACT-An) questionnaire and the MD Anderson Symptom Inventory (MDASI),^9-11 these questionnaires have not been extensively used outside of the research context. As such, knowledge on symptom burdens associated with CIA in real-world patient populations remains lacking.

Given the common occurrence of CIA, management of CIA and associated symptoms plays an important role to patients’ quality of life during cancer treatment. Symptom control is often the main goal for patients with stage IV cancers, as treatment for disease is most likely palliative or noncurative. To facilitate supportive care planning, it is important to understand patient symptom burdens as chemotherapy progresses over cycles and Hb levels decline. We conducted a comprehensive medical record review study in patients diagnosed with stage IV non-Hodgkin lymphoma (NHL), breast cancer, and lung cancers at Kaiser Permanente Southern California (KPSC), a large community-based health care delivery system. The objective of this study was to report the occurrence of CIA-related symptoms throughout the course of chemotherapy and by Hb levels.
 

Methods

Study setting and population

KPSC is an integrated managed-care organization that provides comprehensive health services for 4 million racially, ethnically, and socioeconomically diverse members who broadly represent the population in Southern California.¹² The organization maintains electronic records of health care received by its members, including physician record notes and clinical databases such as laboratory test results, diagnosis codes, medical procedures, medication dispenses, and disease registries. KPSC’s cancer registry is Surveillance, Epidemiology, and End Results, which is affiliated and routinely collects information on age, sex, race and/or ethnicity, cancer type, histology, and stage at diagnosis.

Patients who met the following inclusion criteria were included in this study: diagnosed with stage IV NHL, breast cancer, or lung cancer at age 18 years or older at KPSC between March 25, 2010 and December 31, 2012; initiated myelosuppressive chemotherapy at KPSC before June 30, 2013 (only the first chemotherapy course was included in this evaluation); and had at least 1 Hb measurement during the course of chemotherapy. Of those who met the inclusion criteria, patients who met the following criteria were excluded if they had less than 12 months KPSC membership before start of chemotherapy, missing information on cancer stage or chemotherapy regimen/agents, a diagnosis of myelodysplastic syndrome before chemotherapy initiation, a diagnosis of inherited anemia, an Hb concentration <10 g/L within 3 months before chemotherapy initiation, a transfusion within 2 weeks before chemotherapy initiation, radiation within 4 months before chemotherapy initiation, or bone marrow transplantation within 12 months before chemotherapy initiation or during the chemotherapy course. These exclusion criteria were applied to evaluate symptom burdens most likely related to CIA as opposed to other cancer treatment or pre-existing anemia.

CIA in this study was defined as moderate to severe anemia with Hb <10 g/dL after chemotherapy initiation. Based on this definition for CIA, all patients who developed CIA between the first chemotherapy administration to 60 days after the last dose of chemotherapy were included for the record review. In addition, a random sample of 100 patients who did not develop CIA (ie, did not reach an Hb <10 g/dL during chemotherapy) but otherwise met study eligibility criteria was also reviewed to serve as a comparison group. Of those, 2 patients were subsequently excluded after record review because of findings of ineligibility, so only 98 patients were presented. The large number of patients (ie, >4,000) who did not develop CIA made record review of all patients infeasible.
 

Data collection

Data on anemia-related symptoms or signs and anemia-related comorbidities (Table 1) were collected by standardized review of physician record notes in the electronic medical records. A set of 24 anemia-related symptoms were identified based on the literature and clinical expertise and included abdominal pain, blurred vision/double vision/loss of vision, cold intolerance/coldness in hands or feet, depression/anxiety, diarrhea, dizziness/lightheadedness, dyspnea/shortness of breath/tachypnea, edema, fatigue, headache, heart failure, heat intolerance, hypotension, insomnia, leg pain, loss of appetite, nausea/vomiting, pale skin, palpitations/tachycardia, paralysis/ataxia/numbness or tingling in extremities, pectoral angina/chest pain, sweating/diaphoresis, syncope, and vertigo. Record review period was defined as 1 month before chemotherapy to 60 days after the last dose of chemotherapy in the first course. To understand the development of new symptoms during chemotherapy treatment, pre-existing symptoms documented within 1 month before chemotherapy initiation were recorded. The entire record review process was standardized between 2 trained abstractors, including the training, instruction manual, ongoing feedback, abstraction form/database, and coding.

The data elements extracted included the date the symptom was documented, date the symptom started, symptom duration (when available), and any relevant comments regarding the symptom (ie, if dyspnea was at rest or on exertion, whether the symptom was a side effect caused by chemotherapy, or change in symptom severity). Ten percent of the records were reviewed independently by 2 abstractors to ensure quality control. Additional quality control measures included SAS algorithms (SAS Institute, Inc., Cary, North Carolina) to check reasonability and logical consistency in the abstracted data.

Patient demographic characteristics, cancer stage, additional selected comorbidities (Table 1), chemotherapy information, Hb test results, and anemia treatment, including erythrocyte stimulating agent (ESA) use and red blood cell transfusion, were collected using KPSC’s cancer registry and clinical databases. Anemia was defined by severity as grade 1 (10 g/dL to lower limit of normal, ie, 14 g/dL for men and 12 g/dL for women), grade 2 (8.0-9.9 g/dL), grade 3 (6.5-7.9 g/dL), and grade 4 (<6.5 g/dL) following the National Cancer Institute’s Common Terminology Criteria for Adverse Events.¹³

Statistical analysis

Distributions of demographic, cancer, and treatment characteristics were calculated by CIA status, overall and by cancer type. Differences between patients who did and did not develop CIA were assessed using chi-square test and Kruskal-Wallis test. For those who developed CIA, the distribution of the worst anemia grade was also calculated for each cycle of chemotherapy.

Next, the distributions for the following symptom categories were calculated in the 2 study samples defined by CIA status: pre-existing symptoms that occurred before chemotherapy, any symptoms during chemotherapy (ie, whether they started before chemotherapy), and incident symptoms during chemotherapy (ie, new symptoms that only started after chemotherapy). Specifically, the proportion of patients with each individual symptom and the distribution of the number of symptoms per patient were calculated. Differences in symptom distribution by CIA status were assessed using chi-square test.

The distribution of symptoms in each chemotherapy cycle was calculated up to 6 chemotherapy cycles (as >80% of the patients only had treatment up to 6 cycles) in the 2 study samples defined by CIA status. For this analysis, a symptom was “mapped” to a cycle if the date (or date range) of the symptom fell within the date range of that chemotherapy cycle. In patients who developed CIA, the distribution of symptoms was also calculated by anemia grade. This was again done on the chemotherapy cycle level. For each chemotherapy cycle, an anemia grade was assigned (no anemia or anemia grade 1, 2, 3, and 4) using the lowest Hb measurement in that cycle. Symptoms that occurred in a chemotherapy cycle were then “mapped” to the anemia grade of that cycle. Some patients had more than 1 anemia event of the same grade (eg, if a patient’s grade 2 anemia persist across cycles). For these patients, we randomly selected only 1 anemia event of the same grade from each patient to be included in this analysis. Patients could still contribute multiple events of different grades to this analysis. We calculated the mean number of symptoms per patient for each anemia grade (ie, 1-4) separately. Because of the small number of patients who developed grade 4 anemia (n = 11), they were combined with the grade 3 patients when the distributions of individual symptoms were evaluated.

All analyses were repeated stratified by gender. P values for differences between men and women were calculated using chi-square test or t test. All analyses were conducted using SAS version 9.3.
 

Results

A total of 402 stage IV NHL, breast, and lung cancer patients who developed CIA and 98 patients who did not develop CIA during the first course of chemotherapy were included (Figure 1).

Table 3 shows the number and proportion of study patients with each of the symptoms documented before and after chemotherapy initiation for the 2 study samples. Patients who developed CIA had statistically significantly more pre-existing symptoms, incident symptoms, or any symptoms that occurred during chemotherapy compared with patients who did not develop CIA. The mean number of pre-existing symptoms was 1.7 (standard deviation [SD], 2.0) for those with CIA and 1.2 (SD, 1.5) for those without CIA (P = .04). The mean number of symptoms that occurred during chemotherapy was 6.8 (SD, 3.4) and 4.1 (SD, 2.7), respectively (P < .01). Of individual symptoms, fatigue was the most commonly documented symptom during chemotherapy in patients who developed CIA, noted in 90% of the study sample (Table 3). Dyspnea/shortness of breath (58%), nausea/vomiting (56%), and loss of appetite (56%) were documented in 50% or more of these patients. Abdominal pain (35%), depression/anxiety (43%), dizziness/lightheadedness (30%), edema (39%), palpitations/tachycardia (34%), and pectoral angina/chest pain (34%) were documented in 30% or more of these patients. In patients who did not develop CIA, fatigue remained the most prevalent symptom (77% of the patients). Other than fatigue, only dyspnea/shortness of breath (41%), nausea/vomiting (43%) and paralysis/ataxia/tingling in extremities (33%) were noted in 30% or more of this study sample.

Discussion

In this study, we described the number and type of symptoms documented in the medical record notes among stage IV NHL, breast cancer, and lung cancer patients who did or did not develop CIA during chemotherapy. Patients who developed CIA had significantly greater numbers of different symptoms documented during chemotherapy than those who did not develop CIA (6.8 vs 4.1). This difference is clinically significant because most symptoms described in this study can be expected to have a negative impact on a patient’s quality of life. In patients who developed CIA, fatigue was the most commonly documented symptom, noted for 90% of the study population. In addition to fatigue, many other symptoms were noted in a large proportion of patients. In contrast, in patients who did not develop CIA, only a few symptoms (including fatigue) were more commonly noted in this sample. We observed more symptoms in chemotherapy cycles with higher grades of anemia. Of the symptoms examined, abdominal pain, depression, diarrhea, dizziness/lightheadedness, dyspnea, edema, fatigue, heart failure, headache, hypotension, insomnia, leg pain, loss of appetite, nausea/vomiting, pale skin, pectoral angina, sweating, and syncope particularly demonstrated a clearly increasing prevalence with declining Hb level. We also reported that patients who developed severe anemia (grades 3 and 4) experienced an average of 5 to 6 different symptoms at the time of the anemia episode. These data demonstrated a significant symptom burden in cancer patients with CIA seen in community-based oncology practices. Findings on the types of symptoms most commonly noted in various grades of CIA episodes provided some guidance for supportive care planning. As previous studies have shown a reduction in symptom burden after anemia treatment in patients with CIA,^14-16 our results support the idea of early lab draws and active management of CIA in maintaining quality of life in cancer patients undergoing chemotherapy.

Our findings on the prevalence of fatigue are in line with other studies in the literature. Maxwell reported that the prevalence of fatigue was 80% to 96% in cancer patients.¹⁷ Cella and colleagues found that using FACT-General questionnaire, 75% of cancer patients reported fatigue.¹¹ The comparability of our estimate and those found in studies based on patient self-report offered some assurance of the validity of assessing symptom prevalence through physician record notes. In addition to fatigue, we described prevalence of 23 additional symptoms, most of which have not been extensively studied in the literature. Gabrilove and colleagues found that a substantial proportion of patients with CIA had moderate to severe score for lack of appetite (36%) and disturbed sleep (41%) using the MDASI.¹⁰ The prevalence of loss of appetite and insomnia was around 50% and 25%, respectively, in our study samples. A 2013 systematic review of 21 multinational studies reported the pooled prevalence of several nonfatigue symptoms in cancer patients including headache (23%), sleep disturbance/insomnia (49%), appetite changes (45%), nausea/vomiting (26%), diarrhea (15%), depression (34%), dyspnea (44%), dizziness (26%), numbness/tingling (42%), edema (14%), and sweating (28%).¹⁸ Our prevalence estimates in patients with CIA for most of these symptoms were higher, likely because Reilly and colleagues used source studies that included any cancer patients undergoing treatment and not just those with CIA. Our findings on the increased symptom burden in patients who experienced episodes of advanced anemia compared with patients with mild anemia were also consistent with the literature. To this end, several studies using MDASI or the FACT-An reported differential symptom burdens by Hb level based on patient self-report,^10,11,19 including data on improvement in symptom burden and quality of life after anemia was amended with the use of ESA.^20,21

We found that the number of pre-existing symptoms was significantly higher in patients who went on to develop CIA than in patients who did not develop CIA. Specifically, fatigue, loss of appetite, and pale skin before chemotherapy seemed to be significantly more common in patients who went on to develop CIA. This finding suggested that presentation of these symptoms before chemotherapy initiation may be a predictor for developing moderate or severe anemia during treatment. This is a novel hypothesis, as no studies have evaluated the relationship between pretreatment symptom and risk of CIA. However, our study was not designed to address this specific question. Additional investigation is needed to further shed light on whether the occurrence of anemia-related symptoms in nonanemic patients can be used to effectively risk-stratify patients for subsequent CIA.

Contrary to our expectation, the prevalence of most symptoms did not clearly increase as chemotherapy progressed. There are several possible explanations to this phenomenon, with the most likely being related to reporting of anemia-related symptoms. For example, patients might stop reporting the same symptom repeatedly or become adjusted to the new Hb levels, leading to less symptom manifestation. Clinicians may also be less likely to ask about symptoms in later treatment cycles and/or to document chronic symptoms. Several symptoms were rarely documented altogether, such as cold intolerance, heat intolerance, heart failure, and vertigo. Symptoms reported in earlier cycles could also be managed successfully. Another possible explanation is differential loss of follow-up. Patients who experienced severe adverse events or symptoms may terminate treatment prematurely. Thus, symptom burden found toward later cycles may not represent the true symptom burden should everyone who initiated the chemotherapy treatment complete all planned cycles.
 

Limitations

In addition to the limitations already discussed, there are several others that should be considered when interpreting our results. We did not have a consistent measure of symptom severity in the medical records. Duration of symptoms was also often poorly documented by physicians. Therefore, our results are not directly comparable with studies such as the MDASI that incorporate severity or duration in their prevalence measure. There may also be “reporting bias” by the clinicians owing to different perceived levels of severity or clinical relevance of the different symptoms. As a result, some symptoms may be underdocumented, leading to undercounting.

We also did not distinguish the exact cause of the symptoms (ie, owing to anemia, cancer, chemotherapy itself, or other chemotherapy-induced complications), as it was not possible to reliably ascertain the cause from record review. Furthermore, symptom assessment was not separately performed for grade 4 anemia because of the small number of events in the study population. We also did not plan to evaluate the impact of anemia treatment on symptom burden, as our goal was to comprehensively describe a wide spectrum of symptoms experienced by patients with different Hb levels. However, previous studies have shown the benefit of treatments that correct CIA in symptom management.^14-16 Finally, this study does not inform about the relative importance of these symptoms to patients’ quality of life. To this end, a qualitative study found fatigue, shortness of breath, and lightheadedness/dizziness to be the most important symptoms ranked by patients with CIA.²²

Despite the potential limitations, our study has several important strengths. In addition to fatigue, patients with CIA suffer from a wide range of other anemia-related symptoms, but data on the prevalence of these symptoms have been lacking. To our knowledge, this is among the first studies that collected data on a comprehensive list of symptoms and provided detailed analysis by chemotherapy cycle and anemia grade. The combined use of KPSC’s clinical databases and medical record review allowed us to provide detailed characterization of the study population in terms of their treatment history, history of comorbidities, and laboratory data.
 

Conclusions

Our data provide physicians a comprehensive picture of prevalence of various types of symptoms and how symptom burden evolves as chemotherapy cycle and anemia severity progress. High-grade CIA correlates with an increased symptom burden. Such an understanding can be crucial in facilitating supportive care planning by helping physicians anticipate the timing and proactively determine the management approach of chemotherapy-related anemia and its symptoms.

Anemia is a common complication of cancer treatment as well as of cancer itself. Most cancer patients undergoing chemotherapy experience anemia sometime during their treatment course.^1,2 Moderate to severe anemia is associated with an array of symptoms that are known to compromise the physical functioning and quality of life of cancer patients. Common anemia-related symptoms include fatigue, drowsiness, depression, dyspnea, tachycardia, and dizziness.^1,3-7

Symptoms produced by cancer itself or the disease treatment (ie, side effects such as anemia) collectively compose a patient’s symptom burden.⁸ Although the occurrence of anemia-related fatigue has been described more systematically, other clinical presentations of chemotherapy-induced anemia (CIA) are not well characterized. Furthermore, the overall symptom burdens associated with different ranges of hemoglobin (Hb) concentrations have also not been well reported. Although various tools have been developed to facilitate the reporting of fatigue and other symptoms experienced by patients with CIA, such as the Functional Assessment of Cancer Therapy-Anemia (FACT-An) questionnaire and the MD Anderson Symptom Inventory (MDASI),^9-11 these questionnaires have not been extensively used outside of the research context. As such, knowledge on symptom burdens associated with CIA in real-world patient populations remains lacking.

Given the common occurrence of CIA, management of CIA and associated symptoms plays an important role to patients’ quality of life during cancer treatment. Symptom control is often the main goal for patients with stage IV cancers, as treatment for disease is most likely palliative or noncurative. To facilitate supportive care planning, it is important to understand patient symptom burdens as chemotherapy progresses over cycles and Hb levels decline. We conducted a comprehensive medical record review study in patients diagnosed with stage IV non-Hodgkin lymphoma (NHL), breast cancer, and lung cancers at Kaiser Permanente Southern California (KPSC), a large community-based health care delivery system. The objective of this study was to report the occurrence of CIA-related symptoms throughout the course of chemotherapy and by Hb levels.
 

Methods

Study setting and population

KPSC is an integrated managed-care organization that provides comprehensive health services for 4 million racially, ethnically, and socioeconomically diverse members who broadly represent the population in Southern California.¹² The organization maintains electronic records of health care received by its members, including physician record notes and clinical databases such as laboratory test results, diagnosis codes, medical procedures, medication dispenses, and disease registries. KPSC’s cancer registry is Surveillance, Epidemiology, and End Results, which is affiliated and routinely collects information on age, sex, race and/or ethnicity, cancer type, histology, and stage at diagnosis.

Patients who met the following inclusion criteria were included in this study: diagnosed with stage IV NHL, breast cancer, or lung cancer at age 18 years or older at KPSC between March 25, 2010 and December 31, 2012; initiated myelosuppressive chemotherapy at KPSC before June 30, 2013 (only the first chemotherapy course was included in this evaluation); and had at least 1 Hb measurement during the course of chemotherapy. Of those who met the inclusion criteria, patients who met the following criteria were excluded if they had less than 12 months KPSC membership before start of chemotherapy, missing information on cancer stage or chemotherapy regimen/agents, a diagnosis of myelodysplastic syndrome before chemotherapy initiation, a diagnosis of inherited anemia, an Hb concentration <10 g/L within 3 months before chemotherapy initiation, a transfusion within 2 weeks before chemotherapy initiation, radiation within 4 months before chemotherapy initiation, or bone marrow transplantation within 12 months before chemotherapy initiation or during the chemotherapy course. These exclusion criteria were applied to evaluate symptom burdens most likely related to CIA as opposed to other cancer treatment or pre-existing anemia.

CIA in this study was defined as moderate to severe anemia with Hb <10 g/dL after chemotherapy initiation. Based on this definition for CIA, all patients who developed CIA between the first chemotherapy administration to 60 days after the last dose of chemotherapy were included for the record review. In addition, a random sample of 100 patients who did not develop CIA (ie, did not reach an Hb <10 g/dL during chemotherapy) but otherwise met study eligibility criteria was also reviewed to serve as a comparison group. Of those, 2 patients were subsequently excluded after record review because of findings of ineligibility, so only 98 patients were presented. The large number of patients (ie, >4,000) who did not develop CIA made record review of all patients infeasible.
 

Data collection

Data on anemia-related symptoms or signs and anemia-related comorbidities (Table 1) were collected by standardized review of physician record notes in the electronic medical records. A set of 24 anemia-related symptoms were identified based on the literature and clinical expertise and included abdominal pain, blurred vision/double vision/loss of vision, cold intolerance/coldness in hands or feet, depression/anxiety, diarrhea, dizziness/lightheadedness, dyspnea/shortness of breath/tachypnea, edema, fatigue, headache, heart failure, heat intolerance, hypotension, insomnia, leg pain, loss of appetite, nausea/vomiting, pale skin, palpitations/tachycardia, paralysis/ataxia/numbness or tingling in extremities, pectoral angina/chest pain, sweating/diaphoresis, syncope, and vertigo. Record review period was defined as 1 month before chemotherapy to 60 days after the last dose of chemotherapy in the first course. To understand the development of new symptoms during chemotherapy treatment, pre-existing symptoms documented within 1 month before chemotherapy initiation were recorded. The entire record review process was standardized between 2 trained abstractors, including the training, instruction manual, ongoing feedback, abstraction form/database, and coding.

The data elements extracted included the date the symptom was documented, date the symptom started, symptom duration (when available), and any relevant comments regarding the symptom (ie, if dyspnea was at rest or on exertion, whether the symptom was a side effect caused by chemotherapy, or change in symptom severity). Ten percent of the records were reviewed independently by 2 abstractors to ensure quality control. Additional quality control measures included SAS algorithms (SAS Institute, Inc., Cary, North Carolina) to check reasonability and logical consistency in the abstracted data.

Patient demographic characteristics, cancer stage, additional selected comorbidities (Table 1), chemotherapy information, Hb test results, and anemia treatment, including erythrocyte stimulating agent (ESA) use and red blood cell transfusion, were collected using KPSC’s cancer registry and clinical databases. Anemia was defined by severity as grade 1 (10 g/dL to lower limit of normal, ie, 14 g/dL for men and 12 g/dL for women), grade 2 (8.0-9.9 g/dL), grade 3 (6.5-7.9 g/dL), and grade 4 (<6.5 g/dL) following the National Cancer Institute’s Common Terminology Criteria for Adverse Events.¹³

Statistical analysis

Distributions of demographic, cancer, and treatment characteristics were calculated by CIA status, overall and by cancer type. Differences between patients who did and did not develop CIA were assessed using chi-square test and Kruskal-Wallis test. For those who developed CIA, the distribution of the worst anemia grade was also calculated for each cycle of chemotherapy.

Next, the distributions for the following symptom categories were calculated in the 2 study samples defined by CIA status: pre-existing symptoms that occurred before chemotherapy, any symptoms during chemotherapy (ie, whether they started before chemotherapy), and incident symptoms during chemotherapy (ie, new symptoms that only started after chemotherapy). Specifically, the proportion of patients with each individual symptom and the distribution of the number of symptoms per patient were calculated. Differences in symptom distribution by CIA status were assessed using chi-square test.

The distribution of symptoms in each chemotherapy cycle was calculated up to 6 chemotherapy cycles (as >80% of the patients only had treatment up to 6 cycles) in the 2 study samples defined by CIA status. For this analysis, a symptom was “mapped” to a cycle if the date (or date range) of the symptom fell within the date range of that chemotherapy cycle. In patients who developed CIA, the distribution of symptoms was also calculated by anemia grade. This was again done on the chemotherapy cycle level. For each chemotherapy cycle, an anemia grade was assigned (no anemia or anemia grade 1, 2, 3, and 4) using the lowest Hb measurement in that cycle. Symptoms that occurred in a chemotherapy cycle were then “mapped” to the anemia grade of that cycle. Some patients had more than 1 anemia event of the same grade (eg, if a patient’s grade 2 anemia persist across cycles). For these patients, we randomly selected only 1 anemia event of the same grade from each patient to be included in this analysis. Patients could still contribute multiple events of different grades to this analysis. We calculated the mean number of symptoms per patient for each anemia grade (ie, 1-4) separately. Because of the small number of patients who developed grade 4 anemia (n = 11), they were combined with the grade 3 patients when the distributions of individual symptoms were evaluated.

All analyses were repeated stratified by gender. P values for differences between men and women were calculated using chi-square test or t test. All analyses were conducted using SAS version 9.3.
 

Results

A total of 402 stage IV NHL, breast, and lung cancer patients who developed CIA and 98 patients who did not develop CIA during the first course of chemotherapy were included (Figure 1).

Table 3 shows the number and proportion of study patients with each of the symptoms documented before and after chemotherapy initiation for the 2 study samples. Patients who developed CIA had statistically significantly more pre-existing symptoms, incident symptoms, or any symptoms that occurred during chemotherapy compared with patients who did not develop CIA. The mean number of pre-existing symptoms was 1.7 (standard deviation [SD], 2.0) for those with CIA and 1.2 (SD, 1.5) for those without CIA (P = .04). The mean number of symptoms that occurred during chemotherapy was 6.8 (SD, 3.4) and 4.1 (SD, 2.7), respectively (P < .01). Of individual symptoms, fatigue was the most commonly documented symptom during chemotherapy in patients who developed CIA, noted in 90% of the study sample (Table 3). Dyspnea/shortness of breath (58%), nausea/vomiting (56%), and loss of appetite (56%) were documented in 50% or more of these patients. Abdominal pain (35%), depression/anxiety (43%), dizziness/lightheadedness (30%), edema (39%), palpitations/tachycardia (34%), and pectoral angina/chest pain (34%) were documented in 30% or more of these patients. In patients who did not develop CIA, fatigue remained the most prevalent symptom (77% of the patients). Other than fatigue, only dyspnea/shortness of breath (41%), nausea/vomiting (43%) and paralysis/ataxia/tingling in extremities (33%) were noted in 30% or more of this study sample.

Discussion

In this study, we described the number and type of symptoms documented in the medical record notes among stage IV NHL, breast cancer, and lung cancer patients who did or did not develop CIA during chemotherapy. Patients who developed CIA had significantly greater numbers of different symptoms documented during chemotherapy than those who did not develop CIA (6.8 vs 4.1). This difference is clinically significant because most symptoms described in this study can be expected to have a negative impact on a patient’s quality of life. In patients who developed CIA, fatigue was the most commonly documented symptom, noted for 90% of the study population. In addition to fatigue, many other symptoms were noted in a large proportion of patients. In contrast, in patients who did not develop CIA, only a few symptoms (including fatigue) were more commonly noted in this sample. We observed more symptoms in chemotherapy cycles with higher grades of anemia. Of the symptoms examined, abdominal pain, depression, diarrhea, dizziness/lightheadedness, dyspnea, edema, fatigue, heart failure, headache, hypotension, insomnia, leg pain, loss of appetite, nausea/vomiting, pale skin, pectoral angina, sweating, and syncope particularly demonstrated a clearly increasing prevalence with declining Hb level. We also reported that patients who developed severe anemia (grades 3 and 4) experienced an average of 5 to 6 different symptoms at the time of the anemia episode. These data demonstrated a significant symptom burden in cancer patients with CIA seen in community-based oncology practices. Findings on the types of symptoms most commonly noted in various grades of CIA episodes provided some guidance for supportive care planning. As previous studies have shown a reduction in symptom burden after anemia treatment in patients with CIA,^14-16 our results support the idea of early lab draws and active management of CIA in maintaining quality of life in cancer patients undergoing chemotherapy.

Our findings on the prevalence of fatigue are in line with other studies in the literature. Maxwell reported that the prevalence of fatigue was 80% to 96% in cancer patients.¹⁷ Cella and colleagues found that using FACT-General questionnaire, 75% of cancer patients reported fatigue.¹¹ The comparability of our estimate and those found in studies based on patient self-report offered some assurance of the validity of assessing symptom prevalence through physician record notes. In addition to fatigue, we described prevalence of 23 additional symptoms, most of which have not been extensively studied in the literature. Gabrilove and colleagues found that a substantial proportion of patients with CIA had moderate to severe score for lack of appetite (36%) and disturbed sleep (41%) using the MDASI.¹⁰ The prevalence of loss of appetite and insomnia was around 50% and 25%, respectively, in our study samples. A 2013 systematic review of 21 multinational studies reported the pooled prevalence of several nonfatigue symptoms in cancer patients including headache (23%), sleep disturbance/insomnia (49%), appetite changes (45%), nausea/vomiting (26%), diarrhea (15%), depression (34%), dyspnea (44%), dizziness (26%), numbness/tingling (42%), edema (14%), and sweating (28%).¹⁸ Our prevalence estimates in patients with CIA for most of these symptoms were higher, likely because Reilly and colleagues used source studies that included any cancer patients undergoing treatment and not just those with CIA. Our findings on the increased symptom burden in patients who experienced episodes of advanced anemia compared with patients with mild anemia were also consistent with the literature. To this end, several studies using MDASI or the FACT-An reported differential symptom burdens by Hb level based on patient self-report,^10,11,19 including data on improvement in symptom burden and quality of life after anemia was amended with the use of ESA.^20,21

We found that the number of pre-existing symptoms was significantly higher in patients who went on to develop CIA than in patients who did not develop CIA. Specifically, fatigue, loss of appetite, and pale skin before chemotherapy seemed to be significantly more common in patients who went on to develop CIA. This finding suggested that presentation of these symptoms before chemotherapy initiation may be a predictor for developing moderate or severe anemia during treatment. This is a novel hypothesis, as no studies have evaluated the relationship between pretreatment symptom and risk of CIA. However, our study was not designed to address this specific question. Additional investigation is needed to further shed light on whether the occurrence of anemia-related symptoms in nonanemic patients can be used to effectively risk-stratify patients for subsequent CIA.

Contrary to our expectation, the prevalence of most symptoms did not clearly increase as chemotherapy progressed. There are several possible explanations to this phenomenon, with the most likely being related to reporting of anemia-related symptoms. For example, patients might stop reporting the same symptom repeatedly or become adjusted to the new Hb levels, leading to less symptom manifestation. Clinicians may also be less likely to ask about symptoms in later treatment cycles and/or to document chronic symptoms. Several symptoms were rarely documented altogether, such as cold intolerance, heat intolerance, heart failure, and vertigo. Symptoms reported in earlier cycles could also be managed successfully. Another possible explanation is differential loss of follow-up. Patients who experienced severe adverse events or symptoms may terminate treatment prematurely. Thus, symptom burden found toward later cycles may not represent the true symptom burden should everyone who initiated the chemotherapy treatment complete all planned cycles.
 

Limitations

In addition to the limitations already discussed, there are several others that should be considered when interpreting our results. We did not have a consistent measure of symptom severity in the medical records. Duration of symptoms was also often poorly documented by physicians. Therefore, our results are not directly comparable with studies such as the MDASI that incorporate severity or duration in their prevalence measure. There may also be “reporting bias” by the clinicians owing to different perceived levels of severity or clinical relevance of the different symptoms. As a result, some symptoms may be underdocumented, leading to undercounting.

We also did not distinguish the exact cause of the symptoms (ie, owing to anemia, cancer, chemotherapy itself, or other chemotherapy-induced complications), as it was not possible to reliably ascertain the cause from record review. Furthermore, symptom assessment was not separately performed for grade 4 anemia because of the small number of events in the study population. We also did not plan to evaluate the impact of anemia treatment on symptom burden, as our goal was to comprehensively describe a wide spectrum of symptoms experienced by patients with different Hb levels. However, previous studies have shown the benefit of treatments that correct CIA in symptom management.^14-16 Finally, this study does not inform about the relative importance of these symptoms to patients’ quality of life. To this end, a qualitative study found fatigue, shortness of breath, and lightheadedness/dizziness to be the most important symptoms ranked by patients with CIA.²²

Despite the potential limitations, our study has several important strengths. In addition to fatigue, patients with CIA suffer from a wide range of other anemia-related symptoms, but data on the prevalence of these symptoms have been lacking. To our knowledge, this is among the first studies that collected data on a comprehensive list of symptoms and provided detailed analysis by chemotherapy cycle and anemia grade. The combined use of KPSC’s clinical databases and medical record review allowed us to provide detailed characterization of the study population in terms of their treatment history, history of comorbidities, and laboratory data.
 

Conclusions

Our data provide physicians a comprehensive picture of prevalence of various types of symptoms and how symptom burden evolves as chemotherapy cycle and anemia severity progress. High-grade CIA correlates with an increased symptom burden. Such an understanding can be crucial in facilitating supportive care planning by helping physicians anticipate the timing and proactively determine the management approach of chemotherapy-related anemia and its symptoms.

Anemia is a common complication of cancer treatment as well as of cancer itself. Most cancer patients undergoing chemotherapy experience anemia sometime during their treatment course.^1,2 Moderate to severe anemia is associated with an array of symptoms that are known to compromise the physical functioning and quality of life of cancer patients. Common anemia-related symptoms include fatigue, drowsiness, depression, dyspnea, tachycardia, and dizziness.^1,3-7

Symptoms produced by cancer itself or the disease treatment (ie, side effects such as anemia) collectively compose a patient’s symptom burden.⁸ Although the occurrence of anemia-related fatigue has been described more systematically, other clinical presentations of chemotherapy-induced anemia (CIA) are not well characterized. Furthermore, the overall symptom burdens associated with different ranges of hemoglobin (Hb) concentrations have also not been well reported. Although various tools have been developed to facilitate the reporting of fatigue and other symptoms experienced by patients with CIA, such as the Functional Assessment of Cancer Therapy-Anemia (FACT-An) questionnaire and the MD Anderson Symptom Inventory (MDASI),^9-11 these questionnaires have not been extensively used outside of the research context. As such, knowledge on symptom burdens associated with CIA in real-world patient populations remains lacking.

Given the common occurrence of CIA, management of CIA and associated symptoms plays an important role to patients’ quality of life during cancer treatment. Symptom control is often the main goal for patients with stage IV cancers, as treatment for disease is most likely palliative or noncurative. To facilitate supportive care planning, it is important to understand patient symptom burdens as chemotherapy progresses over cycles and Hb levels decline. We conducted a comprehensive medical record review study in patients diagnosed with stage IV non-Hodgkin lymphoma (NHL), breast cancer, and lung cancers at Kaiser Permanente Southern California (KPSC), a large community-based health care delivery system. The objective of this study was to report the occurrence of CIA-related symptoms throughout the course of chemotherapy and by Hb levels.
 

Methods

Study setting and population

KPSC is an integrated managed-care organization that provides comprehensive health services for 4 million racially, ethnically, and socioeconomically diverse members who broadly represent the population in Southern California.¹² The organization maintains electronic records of health care received by its members, including physician record notes and clinical databases such as laboratory test results, diagnosis codes, medical procedures, medication dispenses, and disease registries. KPSC’s cancer registry is Surveillance, Epidemiology, and End Results, which is affiliated and routinely collects information on age, sex, race and/or ethnicity, cancer type, histology, and stage at diagnosis.

Patients who met the following inclusion criteria were included in this study: diagnosed with stage IV NHL, breast cancer, or lung cancer at age 18 years or older at KPSC between March 25, 2010 and December 31, 2012; initiated myelosuppressive chemotherapy at KPSC before June 30, 2013 (only the first chemotherapy course was included in this evaluation); and had at least 1 Hb measurement during the course of chemotherapy. Of those who met the inclusion criteria, patients who met the following criteria were excluded if they had less than 12 months KPSC membership before start of chemotherapy, missing information on cancer stage or chemotherapy regimen/agents, a diagnosis of myelodysplastic syndrome before chemotherapy initiation, a diagnosis of inherited anemia, an Hb concentration <10 g/L within 3 months before chemotherapy initiation, a transfusion within 2 weeks before chemotherapy initiation, radiation within 4 months before chemotherapy initiation, or bone marrow transplantation within 12 months before chemotherapy initiation or during the chemotherapy course. These exclusion criteria were applied to evaluate symptom burdens most likely related to CIA as opposed to other cancer treatment or pre-existing anemia.

CIA in this study was defined as moderate to severe anemia with Hb <10 g/dL after chemotherapy initiation. Based on this definition for CIA, all patients who developed CIA between the first chemotherapy administration to 60 days after the last dose of chemotherapy were included for the record review. In addition, a random sample of 100 patients who did not develop CIA (ie, did not reach an Hb <10 g/dL during chemotherapy) but otherwise met study eligibility criteria was also reviewed to serve as a comparison group. Of those, 2 patients were subsequently excluded after record review because of findings of ineligibility, so only 98 patients were presented. The large number of patients (ie, >4,000) who did not develop CIA made record review of all patients infeasible.
 

Data collection

Data on anemia-related symptoms or signs and anemia-related comorbidities (Table 1) were collected by standardized review of physician record notes in the electronic medical records. A set of 24 anemia-related symptoms were identified based on the literature and clinical expertise and included abdominal pain, blurred vision/double vision/loss of vision, cold intolerance/coldness in hands or feet, depression/anxiety, diarrhea, dizziness/lightheadedness, dyspnea/shortness of breath/tachypnea, edema, fatigue, headache, heart failure, heat intolerance, hypotension, insomnia, leg pain, loss of appetite, nausea/vomiting, pale skin, palpitations/tachycardia, paralysis/ataxia/numbness or tingling in extremities, pectoral angina/chest pain, sweating/diaphoresis, syncope, and vertigo. Record review period was defined as 1 month before chemotherapy to 60 days after the last dose of chemotherapy in the first course. To understand the development of new symptoms during chemotherapy treatment, pre-existing symptoms documented within 1 month before chemotherapy initiation were recorded. The entire record review process was standardized between 2 trained abstractors, including the training, instruction manual, ongoing feedback, abstraction form/database, and coding.

The data elements extracted included the date the symptom was documented, date the symptom started, symptom duration (when available), and any relevant comments regarding the symptom (ie, if dyspnea was at rest or on exertion, whether the symptom was a side effect caused by chemotherapy, or change in symptom severity). Ten percent of the records were reviewed independently by 2 abstractors to ensure quality control. Additional quality control measures included SAS algorithms (SAS Institute, Inc., Cary, North Carolina) to check reasonability and logical consistency in the abstracted data.

Patient demographic characteristics, cancer stage, additional selected comorbidities (Table 1), chemotherapy information, Hb test results, and anemia treatment, including erythrocyte stimulating agent (ESA) use and red blood cell transfusion, were collected using KPSC’s cancer registry and clinical databases. Anemia was defined by severity as grade 1 (10 g/dL to lower limit of normal, ie, 14 g/dL for men and 12 g/dL for women), grade 2 (8.0-9.9 g/dL), grade 3 (6.5-7.9 g/dL), and grade 4 (<6.5 g/dL) following the National Cancer Institute’s Common Terminology Criteria for Adverse Events.¹³

Statistical analysis

Distributions of demographic, cancer, and treatment characteristics were calculated by CIA status, overall and by cancer type. Differences between patients who did and did not develop CIA were assessed using chi-square test and Kruskal-Wallis test. For those who developed CIA, the distribution of the worst anemia grade was also calculated for each cycle of chemotherapy.

Next, the distributions for the following symptom categories were calculated in the 2 study samples defined by CIA status: pre-existing symptoms that occurred before chemotherapy, any symptoms during chemotherapy (ie, whether they started before chemotherapy), and incident symptoms during chemotherapy (ie, new symptoms that only started after chemotherapy). Specifically, the proportion of patients with each individual symptom and the distribution of the number of symptoms per patient were calculated. Differences in symptom distribution by CIA status were assessed using chi-square test.

The distribution of symptoms in each chemotherapy cycle was calculated up to 6 chemotherapy cycles (as >80% of the patients only had treatment up to 6 cycles) in the 2 study samples defined by CIA status. For this analysis, a symptom was “mapped” to a cycle if the date (or date range) of the symptom fell within the date range of that chemotherapy cycle. In patients who developed CIA, the distribution of symptoms was also calculated by anemia grade. This was again done on the chemotherapy cycle level. For each chemotherapy cycle, an anemia grade was assigned (no anemia or anemia grade 1, 2, 3, and 4) using the lowest Hb measurement in that cycle. Symptoms that occurred in a chemotherapy cycle were then “mapped” to the anemia grade of that cycle. Some patients had more than 1 anemia event of the same grade (eg, if a patient’s grade 2 anemia persist across cycles). For these patients, we randomly selected only 1 anemia event of the same grade from each patient to be included in this analysis. Patients could still contribute multiple events of different grades to this analysis. We calculated the mean number of symptoms per patient for each anemia grade (ie, 1-4) separately. Because of the small number of patients who developed grade 4 anemia (n = 11), they were combined with the grade 3 patients when the distributions of individual symptoms were evaluated.

All analyses were repeated stratified by gender. P values for differences between men and women were calculated using chi-square test or t test. All analyses were conducted using SAS version 9.3.
 

Results

A total of 402 stage IV NHL, breast, and lung cancer patients who developed CIA and 98 patients who did not develop CIA during the first course of chemotherapy were included (Figure 1).

Table 3 shows the number and proportion of study patients with each of the symptoms documented before and after chemotherapy initiation for the 2 study samples. Patients who developed CIA had statistically significantly more pre-existing symptoms, incident symptoms, or any symptoms that occurred during chemotherapy compared with patients who did not develop CIA. The mean number of pre-existing symptoms was 1.7 (standard deviation [SD], 2.0) for those with CIA and 1.2 (SD, 1.5) for those without CIA (P = .04). The mean number of symptoms that occurred during chemotherapy was 6.8 (SD, 3.4) and 4.1 (SD, 2.7), respectively (P < .01). Of individual symptoms, fatigue was the most commonly documented symptom during chemotherapy in patients who developed CIA, noted in 90% of the study sample (Table 3). Dyspnea/shortness of breath (58%), nausea/vomiting (56%), and loss of appetite (56%) were documented in 50% or more of these patients. Abdominal pain (35%), depression/anxiety (43%), dizziness/lightheadedness (30%), edema (39%), palpitations/tachycardia (34%), and pectoral angina/chest pain (34%) were documented in 30% or more of these patients. In patients who did not develop CIA, fatigue remained the most prevalent symptom (77% of the patients). Other than fatigue, only dyspnea/shortness of breath (41%), nausea/vomiting (43%) and paralysis/ataxia/tingling in extremities (33%) were noted in 30% or more of this study sample.

Discussion

In this study, we described the number and type of symptoms documented in the medical record notes among stage IV NHL, breast cancer, and lung cancer patients who did or did not develop CIA during chemotherapy. Patients who developed CIA had significantly greater numbers of different symptoms documented during chemotherapy than those who did not develop CIA (6.8 vs 4.1). This difference is clinically significant because most symptoms described in this study can be expected to have a negative impact on a patient’s quality of life. In patients who developed CIA, fatigue was the most commonly documented symptom, noted for 90% of the study population. In addition to fatigue, many other symptoms were noted in a large proportion of patients. In contrast, in patients who did not develop CIA, only a few symptoms (including fatigue) were more commonly noted in this sample. We observed more symptoms in chemotherapy cycles with higher grades of anemia. Of the symptoms examined, abdominal pain, depression, diarrhea, dizziness/lightheadedness, dyspnea, edema, fatigue, heart failure, headache, hypotension, insomnia, leg pain, loss of appetite, nausea/vomiting, pale skin, pectoral angina, sweating, and syncope particularly demonstrated a clearly increasing prevalence with declining Hb level. We also reported that patients who developed severe anemia (grades 3 and 4) experienced an average of 5 to 6 different symptoms at the time of the anemia episode. These data demonstrated a significant symptom burden in cancer patients with CIA seen in community-based oncology practices. Findings on the types of symptoms most commonly noted in various grades of CIA episodes provided some guidance for supportive care planning. As previous studies have shown a reduction in symptom burden after anemia treatment in patients with CIA,^14-16 our results support the idea of early lab draws and active management of CIA in maintaining quality of life in cancer patients undergoing chemotherapy.

Our findings on the prevalence of fatigue are in line with other studies in the literature. Maxwell reported that the prevalence of fatigue was 80% to 96% in cancer patients.¹⁷ Cella and colleagues found that using FACT-General questionnaire, 75% of cancer patients reported fatigue.¹¹ The comparability of our estimate and those found in studies based on patient self-report offered some assurance of the validity of assessing symptom prevalence through physician record notes. In addition to fatigue, we described prevalence of 23 additional symptoms, most of which have not been extensively studied in the literature. Gabrilove and colleagues found that a substantial proportion of patients with CIA had moderate to severe score for lack of appetite (36%) and disturbed sleep (41%) using the MDASI.¹⁰ The prevalence of loss of appetite and insomnia was around 50% and 25%, respectively, in our study samples. A 2013 systematic review of 21 multinational studies reported the pooled prevalence of several nonfatigue symptoms in cancer patients including headache (23%), sleep disturbance/insomnia (49%), appetite changes (45%), nausea/vomiting (26%), diarrhea (15%), depression (34%), dyspnea (44%), dizziness (26%), numbness/tingling (42%), edema (14%), and sweating (28%).¹⁸ Our prevalence estimates in patients with CIA for most of these symptoms were higher, likely because Reilly and colleagues used source studies that included any cancer patients undergoing treatment and not just those with CIA. Our findings on the increased symptom burden in patients who experienced episodes of advanced anemia compared with patients with mild anemia were also consistent with the literature. To this end, several studies using MDASI or the FACT-An reported differential symptom burdens by Hb level based on patient self-report,^10,11,19 including data on improvement in symptom burden and quality of life after anemia was amended with the use of ESA.^20,21

We found that the number of pre-existing symptoms was significantly higher in patients who went on to develop CIA than in patients who did not develop CIA. Specifically, fatigue, loss of appetite, and pale skin before chemotherapy seemed to be significantly more common in patients who went on to develop CIA. This finding suggested that presentation of these symptoms before chemotherapy initiation may be a predictor for developing moderate or severe anemia during treatment. This is a novel hypothesis, as no studies have evaluated the relationship between pretreatment symptom and risk of CIA. However, our study was not designed to address this specific question. Additional investigation is needed to further shed light on whether the occurrence of anemia-related symptoms in nonanemic patients can be used to effectively risk-stratify patients for subsequent CIA.

Contrary to our expectation, the prevalence of most symptoms did not clearly increase as chemotherapy progressed. There are several possible explanations to this phenomenon, with the most likely being related to reporting of anemia-related symptoms. For example, patients might stop reporting the same symptom repeatedly or become adjusted to the new Hb levels, leading to less symptom manifestation. Clinicians may also be less likely to ask about symptoms in later treatment cycles and/or to document chronic symptoms. Several symptoms were rarely documented altogether, such as cold intolerance, heat intolerance, heart failure, and vertigo. Symptoms reported in earlier cycles could also be managed successfully. Another possible explanation is differential loss of follow-up. Patients who experienced severe adverse events or symptoms may terminate treatment prematurely. Thus, symptom burden found toward later cycles may not represent the true symptom burden should everyone who initiated the chemotherapy treatment complete all planned cycles.
 

Limitations

In addition to the limitations already discussed, there are several others that should be considered when interpreting our results. We did not have a consistent measure of symptom severity in the medical records. Duration of symptoms was also often poorly documented by physicians. Therefore, our results are not directly comparable with studies such as the MDASI that incorporate severity or duration in their prevalence measure. There may also be “reporting bias” by the clinicians owing to different perceived levels of severity or clinical relevance of the different symptoms. As a result, some symptoms may be underdocumented, leading to undercounting.

We also did not distinguish the exact cause of the symptoms (ie, owing to anemia, cancer, chemotherapy itself, or other chemotherapy-induced complications), as it was not possible to reliably ascertain the cause from record review. Furthermore, symptom assessment was not separately performed for grade 4 anemia because of the small number of events in the study population. We also did not plan to evaluate the impact of anemia treatment on symptom burden, as our goal was to comprehensively describe a wide spectrum of symptoms experienced by patients with different Hb levels. However, previous studies have shown the benefit of treatments that correct CIA in symptom management.^14-16 Finally, this study does not inform about the relative importance of these symptoms to patients’ quality of life. To this end, a qualitative study found fatigue, shortness of breath, and lightheadedness/dizziness to be the most important symptoms ranked by patients with CIA.²²

Despite the potential limitations, our study has several important strengths. In addition to fatigue, patients with CIA suffer from a wide range of other anemia-related symptoms, but data on the prevalence of these symptoms have been lacking. To our knowledge, this is among the first studies that collected data on a comprehensive list of symptoms and provided detailed analysis by chemotherapy cycle and anemia grade. The combined use of KPSC’s clinical databases and medical record review allowed us to provide detailed characterization of the study population in terms of their treatment history, history of comorbidities, and laboratory data.
 

Conclusions

Our data provide physicians a comprehensive picture of prevalence of various types of symptoms and how symptom burden evolves as chemotherapy cycle and anemia severity progress. High-grade CIA correlates with an increased symptom burden. Such an understanding can be crucial in facilitating supportive care planning by helping physicians anticipate the timing and proactively determine the management approach of chemotherapy-related anemia and its symptoms.

Cancer patients treated with the oral anticoagulant apixaban (Eliquis) had a lower rate of venous thromboembolism but a higher rate of major bleeding, according to data from the AVERT study.

In the placebo-controlled, double-blind trial, 574 ambulatory cancer patients who were at moderate to high risk of thromboembolism (Khorana risk score of 2 or more) and were starting chemotherapy were randomized to either apixaban 2.5 mg twice daily or to placebo for 180 days. Over the 210-day study period, 12 patients (4.2%) in the apixaban group experienced a venous thromboembolism as did 28 patients (10.2%) in the placebo group, an adjusted 61% reduction in risk associated with anticoagulant therapy. The number needed to treat to prevent one venous thromboembolism was 17, Marc Carrier, MD, of the University of Ottawa, and his coauthors reported in the Dec. 4 edition of the New England Journal of Medicine.

“The treatment of venous thromboembolism with therapeutic anticoagulation is challenging in patients with cancer, because it often involves daily injections of low-molecular-weight heparin and is associated with a high risk of thromboembolism recurrence and serious bleeding complications,” they wrote. As an oral agent, apixaban offers a more convenient alternative.

The authors added that their study found more favorable benefits from anticoagulant therapy than had been seen in previous studies and suggested that this may be the result of using a different agent and a twice-daily dosing regimen.

In the AVERT study, the lower incidence of thromboembolism in the treatment arm was largely because of a reduction in pulmonary embolisms; there were 5 cases in the apixaban group, compared with 16 in the placebo group. The apixaban group experienced 7 cases of deep-vein thrombosis, and the placebo group experienced 12 cases.

During the treatment period, the placebo group had 20 venous thrombembolisms and the apixaban group had 3.

However the incidence of major bleeding was twice as high in the apixaban group: 10 patients (3.5%), compared with 5 (1.8%) in the placebo group (P = .046). The difference between the two groups was mostly based on an increased incidence of gastrointestinal bleeding, hematuria, and gynecologic bleeding among patients treated with apixaban.

None of the major bleeds affected critical organs in any patients. Most were category 2 bleeds, and three cases were judged to be clinical emergencies.

There were 62 deaths overall in the study – 35 in the apixaban group and 27 in the placebo group – and 87% of these deaths were related to the cancer.

Many patients in the study had advanced cancer, which was also the most common cause of death, the authors said. However, there was one death from pulmonary embolism in the placebo group. The dominant cancer types in the study participants were lymphoma, gynecologic, pancreatic, and lung cancers. Two-thirds of the patients in each group had a Khorana risk score of 2, and one patient in each group had a score of 5.

A different trial design and larger study would be needed to examine the impact of treatment on mortality and outcomes related to specific tumor types and chemotherapy regimens, the authors said.

They stressed that only 5.9% of patients in the study had renal dysfunction, so the study results cannot necessarily be applied to these patients more generally, especially as they are known to be at higher risk of bleeding.

The study was supported by the Canadian Institutes of Health Research and Bristol-Myers Squibb–Pfizer Alliance. Thirteen authors declared honoraria, grants or personal fees from the pharmaceutical industry unrelated to the study. Two declared grants from the study funders for the study; ten authors had no conflicts of interest to declare.
 

SOURCE: Carrier M et al. N Engl J Med. 2018 Dec 4. doi: 10.1056/NEJMoa1814468
 

Cancer patients treated with the oral anticoagulant apixaban (Eliquis) had a lower rate of venous thromboembolism but a higher rate of major bleeding, according to data from the AVERT study.

In the placebo-controlled, double-blind trial, 574 ambulatory cancer patients who were at moderate to high risk of thromboembolism (Khorana risk score of 2 or more) and were starting chemotherapy were randomized to either apixaban 2.5 mg twice daily or to placebo for 180 days. Over the 210-day study period, 12 patients (4.2%) in the apixaban group experienced a venous thromboembolism as did 28 patients (10.2%) in the placebo group, an adjusted 61% reduction in risk associated with anticoagulant therapy. The number needed to treat to prevent one venous thromboembolism was 17, Marc Carrier, MD, of the University of Ottawa, and his coauthors reported in the Dec. 4 edition of the New England Journal of Medicine.

“The treatment of venous thromboembolism with therapeutic anticoagulation is challenging in patients with cancer, because it often involves daily injections of low-molecular-weight heparin and is associated with a high risk of thromboembolism recurrence and serious bleeding complications,” they wrote. As an oral agent, apixaban offers a more convenient alternative.

The authors added that their study found more favorable benefits from anticoagulant therapy than had been seen in previous studies and suggested that this may be the result of using a different agent and a twice-daily dosing regimen.

In the AVERT study, the lower incidence of thromboembolism in the treatment arm was largely because of a reduction in pulmonary embolisms; there were 5 cases in the apixaban group, compared with 16 in the placebo group. The apixaban group experienced 7 cases of deep-vein thrombosis, and the placebo group experienced 12 cases.

During the treatment period, the placebo group had 20 venous thrombembolisms and the apixaban group had 3.

However the incidence of major bleeding was twice as high in the apixaban group: 10 patients (3.5%), compared with 5 (1.8%) in the placebo group (P = .046). The difference between the two groups was mostly based on an increased incidence of gastrointestinal bleeding, hematuria, and gynecologic bleeding among patients treated with apixaban.

None of the major bleeds affected critical organs in any patients. Most were category 2 bleeds, and three cases were judged to be clinical emergencies.

There were 62 deaths overall in the study – 35 in the apixaban group and 27 in the placebo group – and 87% of these deaths were related to the cancer.

Many patients in the study had advanced cancer, which was also the most common cause of death, the authors said. However, there was one death from pulmonary embolism in the placebo group. The dominant cancer types in the study participants were lymphoma, gynecologic, pancreatic, and lung cancers. Two-thirds of the patients in each group had a Khorana risk score of 2, and one patient in each group had a score of 5.

A different trial design and larger study would be needed to examine the impact of treatment on mortality and outcomes related to specific tumor types and chemotherapy regimens, the authors said.

They stressed that only 5.9% of patients in the study had renal dysfunction, so the study results cannot necessarily be applied to these patients more generally, especially as they are known to be at higher risk of bleeding.

The study was supported by the Canadian Institutes of Health Research and Bristol-Myers Squibb–Pfizer Alliance. Thirteen authors declared honoraria, grants or personal fees from the pharmaceutical industry unrelated to the study. Two declared grants from the study funders for the study; ten authors had no conflicts of interest to declare.
 

SOURCE: Carrier M et al. N Engl J Med. 2018 Dec 4. doi: 10.1056/NEJMoa1814468
 

Cancer patients treated with the oral anticoagulant apixaban (Eliquis) had a lower rate of venous thromboembolism but a higher rate of major bleeding, according to data from the AVERT study.

In the placebo-controlled, double-blind trial, 574 ambulatory cancer patients who were at moderate to high risk of thromboembolism (Khorana risk score of 2 or more) and were starting chemotherapy were randomized to either apixaban 2.5 mg twice daily or to placebo for 180 days. Over the 210-day study period, 12 patients (4.2%) in the apixaban group experienced a venous thromboembolism as did 28 patients (10.2%) in the placebo group, an adjusted 61% reduction in risk associated with anticoagulant therapy. The number needed to treat to prevent one venous thromboembolism was 17, Marc Carrier, MD, of the University of Ottawa, and his coauthors reported in the Dec. 4 edition of the New England Journal of Medicine.

“The treatment of venous thromboembolism with therapeutic anticoagulation is challenging in patients with cancer, because it often involves daily injections of low-molecular-weight heparin and is associated with a high risk of thromboembolism recurrence and serious bleeding complications,” they wrote. As an oral agent, apixaban offers a more convenient alternative.

The authors added that their study found more favorable benefits from anticoagulant therapy than had been seen in previous studies and suggested that this may be the result of using a different agent and a twice-daily dosing regimen.

In the AVERT study, the lower incidence of thromboembolism in the treatment arm was largely because of a reduction in pulmonary embolisms; there were 5 cases in the apixaban group, compared with 16 in the placebo group. The apixaban group experienced 7 cases of deep-vein thrombosis, and the placebo group experienced 12 cases.

During the treatment period, the placebo group had 20 venous thrombembolisms and the apixaban group had 3.

However the incidence of major bleeding was twice as high in the apixaban group: 10 patients (3.5%), compared with 5 (1.8%) in the placebo group (P = .046). The difference between the two groups was mostly based on an increased incidence of gastrointestinal bleeding, hematuria, and gynecologic bleeding among patients treated with apixaban.

None of the major bleeds affected critical organs in any patients. Most were category 2 bleeds, and three cases were judged to be clinical emergencies.

There were 62 deaths overall in the study – 35 in the apixaban group and 27 in the placebo group – and 87% of these deaths were related to the cancer.

Many patients in the study had advanced cancer, which was also the most common cause of death, the authors said. However, there was one death from pulmonary embolism in the placebo group. The dominant cancer types in the study participants were lymphoma, gynecologic, pancreatic, and lung cancers. Two-thirds of the patients in each group had a Khorana risk score of 2, and one patient in each group had a score of 5.

A different trial design and larger study would be needed to examine the impact of treatment on mortality and outcomes related to specific tumor types and chemotherapy regimens, the authors said.

They stressed that only 5.9% of patients in the study had renal dysfunction, so the study results cannot necessarily be applied to these patients more generally, especially as they are known to be at higher risk of bleeding.

The study was supported by the Canadian Institutes of Health Research and Bristol-Myers Squibb–Pfizer Alliance. Thirteen authors declared honoraria, grants or personal fees from the pharmaceutical industry unrelated to the study. Two declared grants from the study funders for the study; ten authors had no conflicts of interest to declare.
 

SOURCE: Carrier M et al. N Engl J Med. 2018 Dec 4. doi: 10.1056/NEJMoa1814468
 

One evening as the oncology fellow on call, I received a phone call from the ICU fellow.

“Can you meet me in the emergency room?” he asked. “I want to make sure we’re on the same page.”

A patient we had discharged from the hospital 2 days before was back. He had metastatic stomach cancer that had spread into his lungs and the lymph nodes in his chest. While he was in the hospital, he had required several liters of oxygen to maintain a normal work of breathing.

But now, he was in the emergency room, he was requiring a full face mask to help him breathe – and his oxygen levels were still dropping.

The ICU had been called. The next step along the algorithm of worsening breathing would be intubation. They would have to sedate him, put a breathing tube down his throat, and connect him to a ventilator to keep him alive.

But they didn’t want to do that if he was dying from his cancer.

Hence the call to me. My job, as the oncologist on call, was to answer the question: Is he dying?

Specifically, that meant weigh in on his cancer prognosis. Put his disease into context. Does he have any more options, chemotherapy or otherwise?

As an oncology fellow, I’ve found this to be one of the most common calls I get. Someone is critically ill and they need something to survive – maybe it’s intubation; maybe it’s surgery. The patient also happens to have metastatic cancer. The question posed to me is: Should we proceed?

It’s also one of the most difficult calls. Because doctors are historically bad at prognosticating. Because often I’m meeting the patient for the first time. Because the decision is huge and often final, and because both options are bad.

Suppose I say he has a good year or 2 ahead of him, and we intubate him – and then he never comes off the ventilator. We are eventually forced to withdraw care, and to the family it’s as though they are killing their father. It’s traumatic; it’s painful; and it deprives someone of a comfortable passing. Suppose I say he is dying from his cancer and we decide against a breathing tube. If I am wrong in that direction, a person’s life is cut short. It’s a perfect storm of high risk and low certainty.

Many people with metastatic cancer say they wouldn’t want invasive treatment near the end of life. But how do we know when it’s the end? There is still a moment when you must determine: Is this it? The truth is it’s not always clear.

Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford (Calif.) University. Follow her on Twitter @ilanayurkiewicz.

One evening as the oncology fellow on call, I received a phone call from the ICU fellow.

“Can you meet me in the emergency room?” he asked. “I want to make sure we’re on the same page.”

A patient we had discharged from the hospital 2 days before was back. He had metastatic stomach cancer that had spread into his lungs and the lymph nodes in his chest. While he was in the hospital, he had required several liters of oxygen to maintain a normal work of breathing.

But now, he was in the emergency room, he was requiring a full face mask to help him breathe – and his oxygen levels were still dropping.

The ICU had been called. The next step along the algorithm of worsening breathing would be intubation. They would have to sedate him, put a breathing tube down his throat, and connect him to a ventilator to keep him alive.

But they didn’t want to do that if he was dying from his cancer.

Hence the call to me. My job, as the oncologist on call, was to answer the question: Is he dying?

Specifically, that meant weigh in on his cancer prognosis. Put his disease into context. Does he have any more options, chemotherapy or otherwise?

As an oncology fellow, I’ve found this to be one of the most common calls I get. Someone is critically ill and they need something to survive – maybe it’s intubation; maybe it’s surgery. The patient also happens to have metastatic cancer. The question posed to me is: Should we proceed?

It’s also one of the most difficult calls. Because doctors are historically bad at prognosticating. Because often I’m meeting the patient for the first time. Because the decision is huge and often final, and because both options are bad.

Suppose I say he has a good year or 2 ahead of him, and we intubate him – and then he never comes off the ventilator. We are eventually forced to withdraw care, and to the family it’s as though they are killing their father. It’s traumatic; it’s painful; and it deprives someone of a comfortable passing. Suppose I say he is dying from his cancer and we decide against a breathing tube. If I am wrong in that direction, a person’s life is cut short. It’s a perfect storm of high risk and low certainty.

Many people with metastatic cancer say they wouldn’t want invasive treatment near the end of life. But how do we know when it’s the end? There is still a moment when you must determine: Is this it? The truth is it’s not always clear.

Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford (Calif.) University. Follow her on Twitter @ilanayurkiewicz.

One evening as the oncology fellow on call, I received a phone call from the ICU fellow.

“Can you meet me in the emergency room?” he asked. “I want to make sure we’re on the same page.”

A patient we had discharged from the hospital 2 days before was back. He had metastatic stomach cancer that had spread into his lungs and the lymph nodes in his chest. While he was in the hospital, he had required several liters of oxygen to maintain a normal work of breathing.

But now, he was in the emergency room, he was requiring a full face mask to help him breathe – and his oxygen levels were still dropping.

The ICU had been called. The next step along the algorithm of worsening breathing would be intubation. They would have to sedate him, put a breathing tube down his throat, and connect him to a ventilator to keep him alive.

But they didn’t want to do that if he was dying from his cancer.

Hence the call to me. My job, as the oncologist on call, was to answer the question: Is he dying?

Specifically, that meant weigh in on his cancer prognosis. Put his disease into context. Does he have any more options, chemotherapy or otherwise?

As an oncology fellow, I’ve found this to be one of the most common calls I get. Someone is critically ill and they need something to survive – maybe it’s intubation; maybe it’s surgery. The patient also happens to have metastatic cancer. The question posed to me is: Should we proceed?

It’s also one of the most difficult calls. Because doctors are historically bad at prognosticating. Because often I’m meeting the patient for the first time. Because the decision is huge and often final, and because both options are bad.

Suppose I say he has a good year or 2 ahead of him, and we intubate him – and then he never comes off the ventilator. We are eventually forced to withdraw care, and to the family it’s as though they are killing their father. It’s traumatic; it’s painful; and it deprives someone of a comfortable passing. Suppose I say he is dying from his cancer and we decide against a breathing tube. If I am wrong in that direction, a person’s life is cut short. It’s a perfect storm of high risk and low certainty.

Many people with metastatic cancer say they wouldn’t want invasive treatment near the end of life. But how do we know when it’s the end? There is still a moment when you must determine: Is this it? The truth is it’s not always clear.

Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford (Calif.) University. Follow her on Twitter @ilanayurkiewicz.

India has the third largest HIV epidemic in the world because of its large population size, with 0.3% of the adult population infected with HIV. That translates to 2.1 million infected people, posing a significant challenge in the management of these individuals.¹ In all, 43% of the infected are currently on highly active antiretroviral therapy (HAART).¹ There has been a significant decrease in the number of HIV-AIDS–related deaths in recent years because of the remarkable increase in the use of antiretroviral therapy.² However, the prolonged life expectancy in these patients has resulted in an increase in the risk of various new diseases such as cancers. With the complex interactions between altered immunity and infections, the risk of cancers is markedly increased in patients with HIV-AIDS.³ The spectrum of malignancies in this group of patients differs from that in the general population. In addition, the pattern and the magnitude of malignancies differ in different parts of the world.⁴ In this study, we have analyzed the pattern of malignancies in patients with HIV-AIDS in a regional cancer center in India. The aim of the study was to analyze the pattern of malignancies in patients with HIV-AIDS based on their age and sex and to document the CD4 counts at the time the malignancy was diagnosed.

Methods

We retrieved data from our institution’s medical records department on all patients who had HIV-AIDS and had been diagnosed with a malignancy. Data of all patients presenting with a malignancy and coexisting HIV-AIDS from January 2013 through December 2016 were analyzed initially. Only patients for whom there was a documented CD4 count were included in the final retrospective analysis. We analyzed the correlation between the patients’ CD4 counts and malignancies subclassified as AIDS-defining malignancies (ADMs; aggressive B-cell non-Hodgkin lymphoma [NHL] and cervical cancer) or non–AIDS-defining malignancies (NADMs; all other malignancies other than aggressive NHL and carcinoma cervix were defined as NADM). We also analyzed the correlation between the CD4 count and NHL and other malignancies. A statistical analysis was performed using SPSS Statistics for Windows, version 23 (IBM Corp, Armonk, NY). The independent sample Mann-Whitney U or Kruskal-Wallis tests were used for comparing the CD4 counts between the various subgroups of malignancies. The study was carried out in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines.
 

Results

A total of 370 patients who were diagnosed with malignancy and have coexisting HIV-AIDS were identified. In all, 85 patients were excluded because there were no CD4 counts available for them, and the remaining 285 patients were included in the final analysis. Of that total, 136 patients (48%) were men, and 149 (52%) were women.

The median age of the population was 44.8 years (5-80 years) at the time of diagnosis with malignancy. The mean CD4 count of the entire population was 235.4 cells/mm³ (50-734 cells/mm³). There were 104 patients with CD4 counts of ≤200 cells/mm³, and 181 patients had CD4 counts of >200 cells/mm³ (Table 1). All patients received the HAART regimen, efavirenz-lamuvidine-tenofovir (600 mg/300 mg/300 mg Telura).

Discussion

In 2015, a report from the Indian government estimated the prevalence of HIV in the country as 0.26% (0.22%-0.32%).⁵ The report also noted a decreasing trend in the number of new cases of HIV diagnosed and a decrease in the number of AIDS-related deaths.⁵ The decrease in deaths from AIDS is primarily attributed to the widespread use of HAART. With the introduction of HAART therapy, the survival of patients diagnosed with HIV-AIDS has increased markedly.⁶ However, newer challenges have emerged with improved survival, such as an increasing number of patients being diagnosed with malignancies. In the current HAART era, the pattern of malignancies in people living with HIV-AIDS has changed compared with the pre-HAART era.⁷ The literature suggests that worldwide, malignancies are encountered in about 30% patients with HIV-AIDS, but that percentage differs sharply from that encountered in India, where it is less than 5%.⁸ This may partly be explained by opportunistic infections such as tuberculosis in Indian patients, which remains the leading cause of death in the HIV-AIDS population. In our study, we retrospectively analyzed the pattern of malignancies in patients with HIV-AIDS.

Although few studies have quoted NHL as the predominant malignancy in their patients with HIV-AIDS, the predominant malignancy was cervical cancer in our patient population, as seen in few other studies.^8-10 Head and neck malignancies also continue to be common malignancies in men with HIV-AIDS.¹⁰ Thus, an increase in malignancies induced by the human papillomavirus (HPV) can be seen in this group of patients. Only a few pediatric malignancies were noted in our study, and all of those patients had a vertical transmission of HIV.

Kaposi sarcoma is quite rare in the Indian population, and no case of Kaposi sarcoma was diagnosed in our study population. A similar finding was seen in several earlier publications from India. In the largest published series from India by Dhir and colleagues, evaluating 251 patients with HIV-AIDS and malignancy, no case of Kaposi sarcoma was reported.¹⁰ The authors mentioned that this finding might be because of the low seroprevalence of Kaposi sarcoma-associated herpesvirus in the Asian population.¹⁰ Three different studies from southern India have also not reported the incidence of Kaposi Sarcoma in their series of HIV-AIDS patients with malignancies,^11-13 and similar findings were also reported in a study from northern India.⁹ The incidence of other immunodeficiency-related malignancies was identical to those reported in other studies in the literature.^10,14

As seen in other studies, the CD4 counts in patients with ADM were significantly lower compared with those of patients with NADM, and that difference was not seen when CD4 counts of patients with cervical cancer were compared with patients in the NADM subgroup. The risk of NHL increases proportionally to the degree of immune suppression. The increased susceptibility to various infections in patients with low CD4 counts may also contribute to the occurrence of NHL in patients with low CD4 counts. The occurrence of various other rare cancers in patients with HIV-AIDS may be because of confounding rather than a direct HIV or immunosuppression effect.

An increasing incidence of NADMs has been noted in the Western literature.^7,14 ADMs remain the most common malignancies in the HIV-AIDS population, accounting for about 48% of all malignancies.⁸ This is in concordance with previous publications from India.^8,10 With the widespread availability of generic HAART, the incidence of ADMs may decrease even more in the future. In developing countries where the screening procedures for malignancies in both the general population and patients with HIV-AIDS have not yet been implemented at a national level, premalignant lesions of the cervix are not detected.¹⁰ Cervical cancer is the most common malignancy in our study population, which underscores the importance of cervical cancer screening in patients with HIV-AIDS.

In the developed countries, following the introduction of HAART in HIV-AIDS management, the incidence of Kaposi sarcoma decreased by 60% to 70%, and the incidence of NHL decreased by 30% to 50%, whereas the rates of cervical cancer remained either stable or declined.^15,16 Despite the declining trend, the incidence of these malignancies continues to be high among patients with HIV-AIDS compared with the general population.¹⁷ A study from the United States showed increasing trends in various NADMs (such as anal, lung, and liver cancers and Hodgkin lymphoma) from 2006 to 2010.¹⁷ In 2003, the number of patients with NADM were higher than the number of patients with ADM in the United States.¹⁴ In a population-based study from Brazil, ADMs were the most common malignancies diagnosed in patients with HIV-AIDS. A declining trend was noted in the incidence of ADMs in the population and an increasing trend in the incidence of NADMs. This increase in NADM incidence was contributed by anal and lung cancers.¹⁸ Studies from developing countries such as Uganda and Botswana have also shown a decrease in the incidence of Kaposi sarcoma after the introduction of HAART.^19-21

Kaposi sarcoma, cervical cancer, NHL (including Burkitt lymphoma, immunoblastic lymphoma, and primary CNS lymphoma [PCNSL]) comprise ADMs. All 3 ADMs have an underlying viral infection as the causative agent.²² Kaposi sarcoma is caused by the Kaposi sarcoma herpes virus, for which seroprevalence varies worldwide.²³ As already noted in this article, the incidence of Kaposi sarcoma among the HIV-AIDS population has decreased worldwide since the introduction of HAART. The preinvasive uterine cervix lesions and carcinoma cervix are caused by HPV. NHL in patients with HIV-AIDS is a predominantly aggressive B-cell neoplasm. Epstein-Barr virus is implicated for most of the ADM NHLs.²⁴ PCNSL occurs in patients with low CD4 counts and poses a diagnostic challenge. The treatment outcomes for patients with PCNSL before the HAART era were dismal. With the widespread use of HAART, the treatment outcomes of patients with HIV-AIDS and NHL improved, and, currently, these patients are managed the same way as other patients with NHL.²²

The increasing incidence of the NADM is partly attributed to the increasing incidence of these malignancies in the general population. An elevated risk of certain NADMs is also attributable to viral infections. The common NADMs in the United States are lung, anal, oropharyngeal, and hepatocellular cancers and Hodgkin lymphoma.¹⁴ The common NADMs in our study population were oral, oropharyngeal, colon, and breast cancers and Hodgkin lymphoma. One-third of head and neck cancers, including most oropharyngeal cancers, and cervical and anal cancers in patients with HIV-AIDS are related to HPV.²⁵ Patients with HIV-AIDS are at increased risk for chronic HPV infection from immunosuppression. Chronic HPV infections and prolonged immunosuppression cause premalignant high-grade squamous intraepithelial lesions and invasive cancers.²² The initiation of and adherence to HAART leads to immune recovery and reduces high-risk HPV-associated morbidity.²⁶ Findings from previous studies have demonstrated the benefits of screening for cervical cancer in patients with HIV-AIDS.²⁷ The HPV vaccine is immunogenic in patients with HIV-AIDS and might help prevent HPV-associated malignancies.²⁸

Conclusions

With the wide use of HAART by patients with HIV-AIDS, we can expect an increase in the survival of that population. The incidence of malignancies may also increase significantly in these patients, and further longitudinal studies are needed, as malignancies may emerge as the most common cause of death in patients with HIV-AIDS. In addition, the extensive use of HAART therapy and implementation of screening programs for cervical cancer in patients with HIV-AIDS could result in a decrease in the incidence of ADMs.

India has the third largest HIV epidemic in the world because of its large population size, with 0.3% of the adult population infected with HIV. That translates to 2.1 million infected people, posing a significant challenge in the management of these individuals.¹ In all, 43% of the infected are currently on highly active antiretroviral therapy (HAART).¹ There has been a significant decrease in the number of HIV-AIDS–related deaths in recent years because of the remarkable increase in the use of antiretroviral therapy.² However, the prolonged life expectancy in these patients has resulted in an increase in the risk of various new diseases such as cancers. With the complex interactions between altered immunity and infections, the risk of cancers is markedly increased in patients with HIV-AIDS.³ The spectrum of malignancies in this group of patients differs from that in the general population. In addition, the pattern and the magnitude of malignancies differ in different parts of the world.⁴ In this study, we have analyzed the pattern of malignancies in patients with HIV-AIDS in a regional cancer center in India. The aim of the study was to analyze the pattern of malignancies in patients with HIV-AIDS based on their age and sex and to document the CD4 counts at the time the malignancy was diagnosed.

Methods

We retrieved data from our institution’s medical records department on all patients who had HIV-AIDS and had been diagnosed with a malignancy. Data of all patients presenting with a malignancy and coexisting HIV-AIDS from January 2013 through December 2016 were analyzed initially. Only patients for whom there was a documented CD4 count were included in the final retrospective analysis. We analyzed the correlation between the patients’ CD4 counts and malignancies subclassified as AIDS-defining malignancies (ADMs; aggressive B-cell non-Hodgkin lymphoma [NHL] and cervical cancer) or non–AIDS-defining malignancies (NADMs; all other malignancies other than aggressive NHL and carcinoma cervix were defined as NADM). We also analyzed the correlation between the CD4 count and NHL and other malignancies. A statistical analysis was performed using SPSS Statistics for Windows, version 23 (IBM Corp, Armonk, NY). The independent sample Mann-Whitney U or Kruskal-Wallis tests were used for comparing the CD4 counts between the various subgroups of malignancies. The study was carried out in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines.
 

Results

A total of 370 patients who were diagnosed with malignancy and have coexisting HIV-AIDS were identified. In all, 85 patients were excluded because there were no CD4 counts available for them, and the remaining 285 patients were included in the final analysis. Of that total, 136 patients (48%) were men, and 149 (52%) were women.

The median age of the population was 44.8 years (5-80 years) at the time of diagnosis with malignancy. The mean CD4 count of the entire population was 235.4 cells/mm³ (50-734 cells/mm³). There were 104 patients with CD4 counts of ≤200 cells/mm³, and 181 patients had CD4 counts of >200 cells/mm³ (Table 1). All patients received the HAART regimen, efavirenz-lamuvidine-tenofovir (600 mg/300 mg/300 mg Telura).

Discussion

In 2015, a report from the Indian government estimated the prevalence of HIV in the country as 0.26% (0.22%-0.32%).⁵ The report also noted a decreasing trend in the number of new cases of HIV diagnosed and a decrease in the number of AIDS-related deaths.⁵ The decrease in deaths from AIDS is primarily attributed to the widespread use of HAART. With the introduction of HAART therapy, the survival of patients diagnosed with HIV-AIDS has increased markedly.⁶ However, newer challenges have emerged with improved survival, such as an increasing number of patients being diagnosed with malignancies. In the current HAART era, the pattern of malignancies in people living with HIV-AIDS has changed compared with the pre-HAART era.⁷ The literature suggests that worldwide, malignancies are encountered in about 30% patients with HIV-AIDS, but that percentage differs sharply from that encountered in India, where it is less than 5%.⁸ This may partly be explained by opportunistic infections such as tuberculosis in Indian patients, which remains the leading cause of death in the HIV-AIDS population. In our study, we retrospectively analyzed the pattern of malignancies in patients with HIV-AIDS.

Although few studies have quoted NHL as the predominant malignancy in their patients with HIV-AIDS, the predominant malignancy was cervical cancer in our patient population, as seen in few other studies.^8-10 Head and neck malignancies also continue to be common malignancies in men with HIV-AIDS.¹⁰ Thus, an increase in malignancies induced by the human papillomavirus (HPV) can be seen in this group of patients. Only a few pediatric malignancies were noted in our study, and all of those patients had a vertical transmission of HIV.

Kaposi sarcoma is quite rare in the Indian population, and no case of Kaposi sarcoma was diagnosed in our study population. A similar finding was seen in several earlier publications from India. In the largest published series from India by Dhir and colleagues, evaluating 251 patients with HIV-AIDS and malignancy, no case of Kaposi sarcoma was reported.¹⁰ The authors mentioned that this finding might be because of the low seroprevalence of Kaposi sarcoma-associated herpesvirus in the Asian population.¹⁰ Three different studies from southern India have also not reported the incidence of Kaposi Sarcoma in their series of HIV-AIDS patients with malignancies,^11-13 and similar findings were also reported in a study from northern India.⁹ The incidence of other immunodeficiency-related malignancies was identical to those reported in other studies in the literature.^10,14

As seen in other studies, the CD4 counts in patients with ADM were significantly lower compared with those of patients with NADM, and that difference was not seen when CD4 counts of patients with cervical cancer were compared with patients in the NADM subgroup. The risk of NHL increases proportionally to the degree of immune suppression. The increased susceptibility to various infections in patients with low CD4 counts may also contribute to the occurrence of NHL in patients with low CD4 counts. The occurrence of various other rare cancers in patients with HIV-AIDS may be because of confounding rather than a direct HIV or immunosuppression effect.

An increasing incidence of NADMs has been noted in the Western literature.^7,14 ADMs remain the most common malignancies in the HIV-AIDS population, accounting for about 48% of all malignancies.⁸ This is in concordance with previous publications from India.^8,10 With the widespread availability of generic HAART, the incidence of ADMs may decrease even more in the future. In developing countries where the screening procedures for malignancies in both the general population and patients with HIV-AIDS have not yet been implemented at a national level, premalignant lesions of the cervix are not detected.¹⁰ Cervical cancer is the most common malignancy in our study population, which underscores the importance of cervical cancer screening in patients with HIV-AIDS.

In the developed countries, following the introduction of HAART in HIV-AIDS management, the incidence of Kaposi sarcoma decreased by 60% to 70%, and the incidence of NHL decreased by 30% to 50%, whereas the rates of cervical cancer remained either stable or declined.^15,16 Despite the declining trend, the incidence of these malignancies continues to be high among patients with HIV-AIDS compared with the general population.¹⁷ A study from the United States showed increasing trends in various NADMs (such as anal, lung, and liver cancers and Hodgkin lymphoma) from 2006 to 2010.¹⁷ In 2003, the number of patients with NADM were higher than the number of patients with ADM in the United States.¹⁴ In a population-based study from Brazil, ADMs were the most common malignancies diagnosed in patients with HIV-AIDS. A declining trend was noted in the incidence of ADMs in the population and an increasing trend in the incidence of NADMs. This increase in NADM incidence was contributed by anal and lung cancers.¹⁸ Studies from developing countries such as Uganda and Botswana have also shown a decrease in the incidence of Kaposi sarcoma after the introduction of HAART.^19-21

Kaposi sarcoma, cervical cancer, NHL (including Burkitt lymphoma, immunoblastic lymphoma, and primary CNS lymphoma [PCNSL]) comprise ADMs. All 3 ADMs have an underlying viral infection as the causative agent.²² Kaposi sarcoma is caused by the Kaposi sarcoma herpes virus, for which seroprevalence varies worldwide.²³ As already noted in this article, the incidence of Kaposi sarcoma among the HIV-AIDS population has decreased worldwide since the introduction of HAART. The preinvasive uterine cervix lesions and carcinoma cervix are caused by HPV. NHL in patients with HIV-AIDS is a predominantly aggressive B-cell neoplasm. Epstein-Barr virus is implicated for most of the ADM NHLs.²⁴ PCNSL occurs in patients with low CD4 counts and poses a diagnostic challenge. The treatment outcomes for patients with PCNSL before the HAART era were dismal. With the widespread use of HAART, the treatment outcomes of patients with HIV-AIDS and NHL improved, and, currently, these patients are managed the same way as other patients with NHL.²²

The increasing incidence of the NADM is partly attributed to the increasing incidence of these malignancies in the general population. An elevated risk of certain NADMs is also attributable to viral infections. The common NADMs in the United States are lung, anal, oropharyngeal, and hepatocellular cancers and Hodgkin lymphoma.¹⁴ The common NADMs in our study population were oral, oropharyngeal, colon, and breast cancers and Hodgkin lymphoma. One-third of head and neck cancers, including most oropharyngeal cancers, and cervical and anal cancers in patients with HIV-AIDS are related to HPV.²⁵ Patients with HIV-AIDS are at increased risk for chronic HPV infection from immunosuppression. Chronic HPV infections and prolonged immunosuppression cause premalignant high-grade squamous intraepithelial lesions and invasive cancers.²² The initiation of and adherence to HAART leads to immune recovery and reduces high-risk HPV-associated morbidity.²⁶ Findings from previous studies have demonstrated the benefits of screening for cervical cancer in patients with HIV-AIDS.²⁷ The HPV vaccine is immunogenic in patients with HIV-AIDS and might help prevent HPV-associated malignancies.²⁸

Conclusions

With the wide use of HAART by patients with HIV-AIDS, we can expect an increase in the survival of that population. The incidence of malignancies may also increase significantly in these patients, and further longitudinal studies are needed, as malignancies may emerge as the most common cause of death in patients with HIV-AIDS. In addition, the extensive use of HAART therapy and implementation of screening programs for cervical cancer in patients with HIV-AIDS could result in a decrease in the incidence of ADMs.

India has the third largest HIV epidemic in the world because of its large population size, with 0.3% of the adult population infected with HIV. That translates to 2.1 million infected people, posing a significant challenge in the management of these individuals.¹ In all, 43% of the infected are currently on highly active antiretroviral therapy (HAART).¹ There has been a significant decrease in the number of HIV-AIDS–related deaths in recent years because of the remarkable increase in the use of antiretroviral therapy.² However, the prolonged life expectancy in these patients has resulted in an increase in the risk of various new diseases such as cancers. With the complex interactions between altered immunity and infections, the risk of cancers is markedly increased in patients with HIV-AIDS.³ The spectrum of malignancies in this group of patients differs from that in the general population. In addition, the pattern and the magnitude of malignancies differ in different parts of the world.⁴ In this study, we have analyzed the pattern of malignancies in patients with HIV-AIDS in a regional cancer center in India. The aim of the study was to analyze the pattern of malignancies in patients with HIV-AIDS based on their age and sex and to document the CD4 counts at the time the malignancy was diagnosed.

Methods

We retrieved data from our institution’s medical records department on all patients who had HIV-AIDS and had been diagnosed with a malignancy. Data of all patients presenting with a malignancy and coexisting HIV-AIDS from January 2013 through December 2016 were analyzed initially. Only patients for whom there was a documented CD4 count were included in the final retrospective analysis. We analyzed the correlation between the patients’ CD4 counts and malignancies subclassified as AIDS-defining malignancies (ADMs; aggressive B-cell non-Hodgkin lymphoma [NHL] and cervical cancer) or non–AIDS-defining malignancies (NADMs; all other malignancies other than aggressive NHL and carcinoma cervix were defined as NADM). We also analyzed the correlation between the CD4 count and NHL and other malignancies. A statistical analysis was performed using SPSS Statistics for Windows, version 23 (IBM Corp, Armonk, NY). The independent sample Mann-Whitney U or Kruskal-Wallis tests were used for comparing the CD4 counts between the various subgroups of malignancies. The study was carried out in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines.
 

Results

A total of 370 patients who were diagnosed with malignancy and have coexisting HIV-AIDS were identified. In all, 85 patients were excluded because there were no CD4 counts available for them, and the remaining 285 patients were included in the final analysis. Of that total, 136 patients (48%) were men, and 149 (52%) were women.

The median age of the population was 44.8 years (5-80 years) at the time of diagnosis with malignancy. The mean CD4 count of the entire population was 235.4 cells/mm³ (50-734 cells/mm³). There were 104 patients with CD4 counts of ≤200 cells/mm³, and 181 patients had CD4 counts of >200 cells/mm³ (Table 1). All patients received the HAART regimen, efavirenz-lamuvidine-tenofovir (600 mg/300 mg/300 mg Telura).

Discussion

In 2015, a report from the Indian government estimated the prevalence of HIV in the country as 0.26% (0.22%-0.32%).⁵ The report also noted a decreasing trend in the number of new cases of HIV diagnosed and a decrease in the number of AIDS-related deaths.⁵ The decrease in deaths from AIDS is primarily attributed to the widespread use of HAART. With the introduction of HAART therapy, the survival of patients diagnosed with HIV-AIDS has increased markedly.⁶ However, newer challenges have emerged with improved survival, such as an increasing number of patients being diagnosed with malignancies. In the current HAART era, the pattern of malignancies in people living with HIV-AIDS has changed compared with the pre-HAART era.⁷ The literature suggests that worldwide, malignancies are encountered in about 30% patients with HIV-AIDS, but that percentage differs sharply from that encountered in India, where it is less than 5%.⁸ This may partly be explained by opportunistic infections such as tuberculosis in Indian patients, which remains the leading cause of death in the HIV-AIDS population. In our study, we retrospectively analyzed the pattern of malignancies in patients with HIV-AIDS.

Although few studies have quoted NHL as the predominant malignancy in their patients with HIV-AIDS, the predominant malignancy was cervical cancer in our patient population, as seen in few other studies.^8-10 Head and neck malignancies also continue to be common malignancies in men with HIV-AIDS.¹⁰ Thus, an increase in malignancies induced by the human papillomavirus (HPV) can be seen in this group of patients. Only a few pediatric malignancies were noted in our study, and all of those patients had a vertical transmission of HIV.

Kaposi sarcoma is quite rare in the Indian population, and no case of Kaposi sarcoma was diagnosed in our study population. A similar finding was seen in several earlier publications from India. In the largest published series from India by Dhir and colleagues, evaluating 251 patients with HIV-AIDS and malignancy, no case of Kaposi sarcoma was reported.¹⁰ The authors mentioned that this finding might be because of the low seroprevalence of Kaposi sarcoma-associated herpesvirus in the Asian population.¹⁰ Three different studies from southern India have also not reported the incidence of Kaposi Sarcoma in their series of HIV-AIDS patients with malignancies,^11-13 and similar findings were also reported in a study from northern India.⁹ The incidence of other immunodeficiency-related malignancies was identical to those reported in other studies in the literature.^10,14

As seen in other studies, the CD4 counts in patients with ADM were significantly lower compared with those of patients with NADM, and that difference was not seen when CD4 counts of patients with cervical cancer were compared with patients in the NADM subgroup. The risk of NHL increases proportionally to the degree of immune suppression. The increased susceptibility to various infections in patients with low CD4 counts may also contribute to the occurrence of NHL in patients with low CD4 counts. The occurrence of various other rare cancers in patients with HIV-AIDS may be because of confounding rather than a direct HIV or immunosuppression effect.

An increasing incidence of NADMs has been noted in the Western literature.^7,14 ADMs remain the most common malignancies in the HIV-AIDS population, accounting for about 48% of all malignancies.⁸ This is in concordance with previous publications from India.^8,10 With the widespread availability of generic HAART, the incidence of ADMs may decrease even more in the future. In developing countries where the screening procedures for malignancies in both the general population and patients with HIV-AIDS have not yet been implemented at a national level, premalignant lesions of the cervix are not detected.¹⁰ Cervical cancer is the most common malignancy in our study population, which underscores the importance of cervical cancer screening in patients with HIV-AIDS.

In the developed countries, following the introduction of HAART in HIV-AIDS management, the incidence of Kaposi sarcoma decreased by 60% to 70%, and the incidence of NHL decreased by 30% to 50%, whereas the rates of cervical cancer remained either stable or declined.^15,16 Despite the declining trend, the incidence of these malignancies continues to be high among patients with HIV-AIDS compared with the general population.¹⁷ A study from the United States showed increasing trends in various NADMs (such as anal, lung, and liver cancers and Hodgkin lymphoma) from 2006 to 2010.¹⁷ In 2003, the number of patients with NADM were higher than the number of patients with ADM in the United States.¹⁴ In a population-based study from Brazil, ADMs were the most common malignancies diagnosed in patients with HIV-AIDS. A declining trend was noted in the incidence of ADMs in the population and an increasing trend in the incidence of NADMs. This increase in NADM incidence was contributed by anal and lung cancers.¹⁸ Studies from developing countries such as Uganda and Botswana have also shown a decrease in the incidence of Kaposi sarcoma after the introduction of HAART.^19-21

Kaposi sarcoma, cervical cancer, NHL (including Burkitt lymphoma, immunoblastic lymphoma, and primary CNS lymphoma [PCNSL]) comprise ADMs. All 3 ADMs have an underlying viral infection as the causative agent.²² Kaposi sarcoma is caused by the Kaposi sarcoma herpes virus, for which seroprevalence varies worldwide.²³ As already noted in this article, the incidence of Kaposi sarcoma among the HIV-AIDS population has decreased worldwide since the introduction of HAART. The preinvasive uterine cervix lesions and carcinoma cervix are caused by HPV. NHL in patients with HIV-AIDS is a predominantly aggressive B-cell neoplasm. Epstein-Barr virus is implicated for most of the ADM NHLs.²⁴ PCNSL occurs in patients with low CD4 counts and poses a diagnostic challenge. The treatment outcomes for patients with PCNSL before the HAART era were dismal. With the widespread use of HAART, the treatment outcomes of patients with HIV-AIDS and NHL improved, and, currently, these patients are managed the same way as other patients with NHL.²²

The increasing incidence of the NADM is partly attributed to the increasing incidence of these malignancies in the general population. An elevated risk of certain NADMs is also attributable to viral infections. The common NADMs in the United States are lung, anal, oropharyngeal, and hepatocellular cancers and Hodgkin lymphoma.¹⁴ The common NADMs in our study population were oral, oropharyngeal, colon, and breast cancers and Hodgkin lymphoma. One-third of head and neck cancers, including most oropharyngeal cancers, and cervical and anal cancers in patients with HIV-AIDS are related to HPV.²⁵ Patients with HIV-AIDS are at increased risk for chronic HPV infection from immunosuppression. Chronic HPV infections and prolonged immunosuppression cause premalignant high-grade squamous intraepithelial lesions and invasive cancers.²² The initiation of and adherence to HAART leads to immune recovery and reduces high-risk HPV-associated morbidity.²⁶ Findings from previous studies have demonstrated the benefits of screening for cervical cancer in patients with HIV-AIDS.²⁷ The HPV vaccine is immunogenic in patients with HIV-AIDS and might help prevent HPV-associated malignancies.²⁸

Conclusions

With the wide use of HAART by patients with HIV-AIDS, we can expect an increase in the survival of that population. The incidence of malignancies may also increase significantly in these patients, and further longitudinal studies are needed, as malignancies may emerge as the most common cause of death in patients with HIV-AIDS. In addition, the extensive use of HAART therapy and implementation of screening programs for cervical cancer in patients with HIV-AIDS could result in a decrease in the incidence of ADMs.

SAN DIEGO – A smartphone app that included artificial intelligence elements was associated with improved pain outcomes and reduced hospital admissions in patients with advanced cancers.

Pain severity significantly decreased among patients randomized to use the app versus control patients who received only palliative care, researchers reported at the Palliative and Supportive Care in Oncology Symposium.

The risk of pain-related hospital admissions was significantly lower for those who used the pain tracking app, called ePAL, though anxiety scores were higher in the app users, the investigators said, and no difference between arms was noted in quality of life or global symptom scores.

The ePAL app prompts patients three times per week to track their pain levels and, depending on the severity of pain, will use an algorithm to guide patients through their symptoms, or, in patients with persistent or worsening pain, connect them directly with the palliative care service for additional assessment.

The app also includes pain management tips, among other educational content, provides the ability to request pain prescription refills, and creates a summary of the patient’s pain condition for the provider, said Mihir M. Kamdar, MD, associate director of palliative care at Massachusetts General Hospital in Boston.

“The provider can actually start the visit with that information, instead of having to spend several minutes trying to recap what might or might not have happened since the last clinic visit,” Dr. Kamdar said.

The study included 112 English-speaking adult patients with stage IV solid cancers and moderate to severe pain who were being followed in a palliative care clinic. They were randomly assigned to receive the ePAL app plus standard of care or standard of care alone; 39 patients in the app group and 40 in the control arm completed the 8-week evaluation.

Pain severity, the primary study endpoint, decreased over time in the intervention group, from a composite Brief Pain Inventory score of 3.74 at enrollment to 2.99 at 8 weeks, while in the control group, the scores were 4.02 at enrollment and 4.05 at 8 weeks (P = .017 for intervention versus control), Dr. Kamdar reported.

Risk of pain-related hospital admissions was significantly lower in the intervention group, according to Dr. Kamdar. The per-patient risk of an inpatient admission was 0.071 and 0.232 for the intervention and controls groups, respectively, with a risk ratio of 0.31 (95% CI, 0.11-0.89; P = .018).

Anxiety was increased in the app users, as measured by the Generalized Anxiety Disorder 7-item scale, with a significant difference between the app and control groups at 8 weeks (P = .015). However, the change was in a range considered mild and was not seen in patients who used the app more than two times per week.

Negative attitudes toward cancer pain treatment decreased significantly in the app group, as shown by a lower score on the Barriers Questionnaire II at 8 weeks (P = .042), Dr. Kamdar reported.

The app and study were supported by the McKesson Foundation’s Mobilizing for Health Initiative. Dr. Kamdar reported stock/ownership and consulting/advisory role disclosures related to Amorsa Therapeutics.

SOURCE: Kamdar MM et al. PallOnc 2018, Abstract 76.

SAN DIEGO – A smartphone app that included artificial intelligence elements was associated with improved pain outcomes and reduced hospital admissions in patients with advanced cancers.

Pain severity significantly decreased among patients randomized to use the app versus control patients who received only palliative care, researchers reported at the Palliative and Supportive Care in Oncology Symposium.

The risk of pain-related hospital admissions was significantly lower for those who used the pain tracking app, called ePAL, though anxiety scores were higher in the app users, the investigators said, and no difference between arms was noted in quality of life or global symptom scores.

The ePAL app prompts patients three times per week to track their pain levels and, depending on the severity of pain, will use an algorithm to guide patients through their symptoms, or, in patients with persistent or worsening pain, connect them directly with the palliative care service for additional assessment.

The app also includes pain management tips, among other educational content, provides the ability to request pain prescription refills, and creates a summary of the patient’s pain condition for the provider, said Mihir M. Kamdar, MD, associate director of palliative care at Massachusetts General Hospital in Boston.

“The provider can actually start the visit with that information, instead of having to spend several minutes trying to recap what might or might not have happened since the last clinic visit,” Dr. Kamdar said.

The study included 112 English-speaking adult patients with stage IV solid cancers and moderate to severe pain who were being followed in a palliative care clinic. They were randomly assigned to receive the ePAL app plus standard of care or standard of care alone; 39 patients in the app group and 40 in the control arm completed the 8-week evaluation.

Pain severity, the primary study endpoint, decreased over time in the intervention group, from a composite Brief Pain Inventory score of 3.74 at enrollment to 2.99 at 8 weeks, while in the control group, the scores were 4.02 at enrollment and 4.05 at 8 weeks (P = .017 for intervention versus control), Dr. Kamdar reported.

Risk of pain-related hospital admissions was significantly lower in the intervention group, according to Dr. Kamdar. The per-patient risk of an inpatient admission was 0.071 and 0.232 for the intervention and controls groups, respectively, with a risk ratio of 0.31 (95% CI, 0.11-0.89; P = .018).

Anxiety was increased in the app users, as measured by the Generalized Anxiety Disorder 7-item scale, with a significant difference between the app and control groups at 8 weeks (P = .015). However, the change was in a range considered mild and was not seen in patients who used the app more than two times per week.

Negative attitudes toward cancer pain treatment decreased significantly in the app group, as shown by a lower score on the Barriers Questionnaire II at 8 weeks (P = .042), Dr. Kamdar reported.

The app and study were supported by the McKesson Foundation’s Mobilizing for Health Initiative. Dr. Kamdar reported stock/ownership and consulting/advisory role disclosures related to Amorsa Therapeutics.

SOURCE: Kamdar MM et al. PallOnc 2018, Abstract 76.

SAN DIEGO – A smartphone app that included artificial intelligence elements was associated with improved pain outcomes and reduced hospital admissions in patients with advanced cancers.

Pain severity significantly decreased among patients randomized to use the app versus control patients who received only palliative care, researchers reported at the Palliative and Supportive Care in Oncology Symposium.

The risk of pain-related hospital admissions was significantly lower for those who used the pain tracking app, called ePAL, though anxiety scores were higher in the app users, the investigators said, and no difference between arms was noted in quality of life or global symptom scores.

The ePAL app prompts patients three times per week to track their pain levels and, depending on the severity of pain, will use an algorithm to guide patients through their symptoms, or, in patients with persistent or worsening pain, connect them directly with the palliative care service for additional assessment.

The app also includes pain management tips, among other educational content, provides the ability to request pain prescription refills, and creates a summary of the patient’s pain condition for the provider, said Mihir M. Kamdar, MD, associate director of palliative care at Massachusetts General Hospital in Boston.

“The provider can actually start the visit with that information, instead of having to spend several minutes trying to recap what might or might not have happened since the last clinic visit,” Dr. Kamdar said.

The study included 112 English-speaking adult patients with stage IV solid cancers and moderate to severe pain who were being followed in a palliative care clinic. They were randomly assigned to receive the ePAL app plus standard of care or standard of care alone; 39 patients in the app group and 40 in the control arm completed the 8-week evaluation.

Pain severity, the primary study endpoint, decreased over time in the intervention group, from a composite Brief Pain Inventory score of 3.74 at enrollment to 2.99 at 8 weeks, while in the control group, the scores were 4.02 at enrollment and 4.05 at 8 weeks (P = .017 for intervention versus control), Dr. Kamdar reported.

Risk of pain-related hospital admissions was significantly lower in the intervention group, according to Dr. Kamdar. The per-patient risk of an inpatient admission was 0.071 and 0.232 for the intervention and controls groups, respectively, with a risk ratio of 0.31 (95% CI, 0.11-0.89; P = .018).

Anxiety was increased in the app users, as measured by the Generalized Anxiety Disorder 7-item scale, with a significant difference between the app and control groups at 8 weeks (P = .015). However, the change was in a range considered mild and was not seen in patients who used the app more than two times per week.

Negative attitudes toward cancer pain treatment decreased significantly in the app group, as shown by a lower score on the Barriers Questionnaire II at 8 weeks (P = .042), Dr. Kamdar reported.

The app and study were supported by the McKesson Foundation’s Mobilizing for Health Initiative. Dr. Kamdar reported stock/ownership and consulting/advisory role disclosures related to Amorsa Therapeutics.

SOURCE: Kamdar MM et al. PallOnc 2018, Abstract 76.

Multiple myeloma is the most common plasma cell neoplasm, with an estimated 24,000 cases occurring annually.¹ Symptomatic multiple myeloma most commonly presents with one or more of the cardinal CRAB phenomena of hypercalcemia, renal dysfunction, anemia, or lytic bone lesions.² Less commonly, patients may present with plasmacytomas (focal lesions of malignant plasma cells), which may involve bony or soft tissues.¹

Plasma cell neoplasms occasionally involve the joints, including the elbows, typically as plasmacytomas. The elbow is an unusual but reported location of plasmacytomas.^3,4 A case of multiple myeloma and amyloid light-chain (AL) amyloidosis has been reported, with manifestations including pseudomyopathy, bone marrow plasmacytosis, and bilateral trochanteric bursitis.⁵Bursitis is defined as inflammation of the synovial-fluid–containing sacs that lubricate joints. The olecranon bursa is commonly affected. Etiologies include infection, inflammatory disease, trauma, and malignancy. Furthermore, there is an association between bursitis and immunosuppression.^6,7 The most common modes of therapy used to treat bursitis are nonsteroidal anti-inflammatory drugs, corticosteroid injections, and surgical management.

Trochanteric bursitis has been attributed to multiple myeloma in one previous case report, but we are not aware of any previous cases of olecranon bursitis caused by multiple myeloma. Here, we present the case of a 46-year-old man with heavily pretreated multiple myeloma and amyloidosis who developed left olecranon bursitis contemporaneously with disease relapse; flow cytometric analysis of the bursal fluid demonstrated an abnormal plasma cell population, establishing the etiology.

Case presentation and summary

A 46-year-old man with a longstanding history of multiple myeloma developed swelling of the left elbow that was initially painless in September 2016. He had been diagnosed with IgA kappa multiple myeloma and AL deposition in 2011. Over the course of his disease, he was treated with the following sequence of therapies: cyclophosphamide, bortezomib, and dexamethasone, followed by melphalan-conditioned autologous peripheral blood stem cell transplant; lenalidomide and dexamethasone; carfilzomib and dexamethasone; pomalidomide, bortezomib, and dexamethasone; and bortezomib, lenalidomide, dexamethasone, doxorubicin, cyclophosphamide, and etoposide, followed by second melphalan-conditioned autologous peripheral blood stem cell transplant. In addition to treatment with numerous novel and chemotherapeutic agents, his disease course was notable for amyloid deposition in the liver, bone marrow, and kidneys, which resulted in dialysis dependence.

After the second autologous transplant, he achieved a very good partial response and experienced about 9 months of remission, after which laboratory evaluation indicated recurrence of IgA kappa monoclonal protein and free kappa light-chains, which increased slowly over several months without focal symptoms, cytopenias, or decline in organ function (Figure 1).

Discussion

Our patient experienced left olecranon bursitis simultaneously with relapse of multiple myeloma and AL amyloidosis. Evaluation for infectious causes was negative, and the bursal fluid did not have strongly inflammatory characteristics. Furthermore, a small plasma cell population was isolated from the fluid. Imaging did not reveal an underlying dominant lytic lesion. Although we do not have direct pathologic confirmation, the clinical scenario and flow cytometry findings support our interpretation that the patient’s bursitis was caused by or at least related to underlying multiple myeloma. While reactive plasma cells are also CD38 positive and CD138 positive, they maintain the expression of CD19 and CD45 without aberrant expression of CD56 or CD117 and do not show loss of expression of CD81 or CD27. In this situation, we suspect that either a plasmacytoma involving the soft tissue of the bursa or amyloid infiltration of the synovium may have occurred. Anti-myeloma therapies and radiation therapy did not result in control of the bursitis, though it should be noted that the patient’s highly refractory disease progressed despite treatment with a combination of later-generation immunomodulatory imide and proteasome inhibitor therapies.

Cases of malignant bursitis have been reported several times in the literature, though nearly all of the instances involved connective tissue or metastatic tumors. Tumor histologies include osteochondroma,^8,9 malignant fibrous histiocytoma,¹⁰ synovial sarcoma,¹¹ and metastatic breast cancer.¹²

Hematologic malignancies are more rare causes of bursitis; our literature search identified a report of 2 cases of non-Hodgkin lymphoma mimicking rheumatoid arthritis. The joints were the knee and elbow. Synovial fluid from one case was clear and yellow, with leukocytosis with a neutrophilic predominance (similar to our case). In both cases, pathology confirmed lymphomatous infiltration of the synovium.¹³ Notably, we identified a case of a previously healthy 35-year-old woman with bilateral trochanteric bursitis. Biopsy of tissue from the right trochanteric bursa demonstrated positive birefringence, diagnostic of AL amyloidosis. The patient also had a biclonal paraprotein accompanied by calvarial lytic lesions. She was treated with a corticosteroid pulse and bisphosphonates, followed by autologous hematopoietic stem cell transplant. ⁵ Our case shares features with the above case, including the relatively young age of the patient and the presence of AL amyloidosis.

Our patient wished to avoid a surgical biopsy procedure, and therefore we utilized flow cytometry of the bursal fluid to establish that the etiology of fluid collection was consistent with his concurrent relapse of multiple myeloma. We believe that we are reporting the second case of multiple myeloma-associated bursitis and the first case associated with multiple myeloma relapse; to our knowledge, it is the first to be diagnosed with the aid of flow cytometry.

Because of our patient’s reliance on hemodialysis beginning one year prior to his presentation with olecranon bursitis, we entertain “dialysis elbow” within the differential diagnosis. Dialysis elbow is a relatively uncommon complication of dialysis, in which patients develop olecranon bursitis on the same side as the hemodialysis access after a prolonged (months to years) duration of hemodialysis. Serositis and mechanical forces are the hypothesized etiologies¹⁴; infectious and rheumatologic causes were excluded from the reported cases. Nevertheless, we favor a malignant cause based upon the flow cytometry findings indicating involvement by immunophenotypically abnormal plasma cells.

Our patient was treated initially with serial drainage and nonsteroidals, which had little impact. After diagnosis of a plasma cell population in the fluid, we offered local treatment with radiation and systemic treatment of multiple myeloma, which offered better but suboptimal control. Possible treatments for olecranon bursitis include surgery, corticosteroid injections, anti-inflammatories, and serial drainage. Nonsurgical management may be more effective than surgical management, and corticosteroid injection carries significant risks. On the other hand, serial drainage does not confer additional infection risk in cases with aseptic etiology.¹⁵ We combined conservative measures as well as treatment of the underlying disease, but we believe that our patient did not derive significant benefit because of the refractory nature of his disease; he also expressed a preference to avoid surgical intervention.
 

Conclusion

Bursitis is a rare but thought-provoking potential manifestation of multiple myeloma and AL amyloidosis; we believe that our patient’s bursitis was related to plasma cell neoplasia based upon co-occurrence with disease relapse. His bursitis turned out to be an early indicator of impending systemic relapse. In this particular case, in which the patient wished to avoid surgical intervention, flow cytometry was of great value, and we believe that our case is the first report of malignant bursitis being diagnosed by flow cytometry. Our patient’s case shares similarities with other biopsy-confirmed cases of malignant bursitis, but we were able to avoid the need for surgical biopsy or bursal stripping.

The authors thank Jennifer Wilham MT (ASCP), Pat Byrd MT (ASCP), and Darlene Mann MT (ASCP) for their technical support.

Multiple myeloma is the most common plasma cell neoplasm, with an estimated 24,000 cases occurring annually.¹ Symptomatic multiple myeloma most commonly presents with one or more of the cardinal CRAB phenomena of hypercalcemia, renal dysfunction, anemia, or lytic bone lesions.² Less commonly, patients may present with plasmacytomas (focal lesions of malignant plasma cells), which may involve bony or soft tissues.¹

Plasma cell neoplasms occasionally involve the joints, including the elbows, typically as plasmacytomas. The elbow is an unusual but reported location of plasmacytomas.^3,4 A case of multiple myeloma and amyloid light-chain (AL) amyloidosis has been reported, with manifestations including pseudomyopathy, bone marrow plasmacytosis, and bilateral trochanteric bursitis.⁵Bursitis is defined as inflammation of the synovial-fluid–containing sacs that lubricate joints. The olecranon bursa is commonly affected. Etiologies include infection, inflammatory disease, trauma, and malignancy. Furthermore, there is an association between bursitis and immunosuppression.^6,7 The most common modes of therapy used to treat bursitis are nonsteroidal anti-inflammatory drugs, corticosteroid injections, and surgical management.

Trochanteric bursitis has been attributed to multiple myeloma in one previous case report, but we are not aware of any previous cases of olecranon bursitis caused by multiple myeloma. Here, we present the case of a 46-year-old man with heavily pretreated multiple myeloma and amyloidosis who developed left olecranon bursitis contemporaneously with disease relapse; flow cytometric analysis of the bursal fluid demonstrated an abnormal plasma cell population, establishing the etiology.

Case presentation and summary

A 46-year-old man with a longstanding history of multiple myeloma developed swelling of the left elbow that was initially painless in September 2016. He had been diagnosed with IgA kappa multiple myeloma and AL deposition in 2011. Over the course of his disease, he was treated with the following sequence of therapies: cyclophosphamide, bortezomib, and dexamethasone, followed by melphalan-conditioned autologous peripheral blood stem cell transplant; lenalidomide and dexamethasone; carfilzomib and dexamethasone; pomalidomide, bortezomib, and dexamethasone; and bortezomib, lenalidomide, dexamethasone, doxorubicin, cyclophosphamide, and etoposide, followed by second melphalan-conditioned autologous peripheral blood stem cell transplant. In addition to treatment with numerous novel and chemotherapeutic agents, his disease course was notable for amyloid deposition in the liver, bone marrow, and kidneys, which resulted in dialysis dependence.

After the second autologous transplant, he achieved a very good partial response and experienced about 9 months of remission, after which laboratory evaluation indicated recurrence of IgA kappa monoclonal protein and free kappa light-chains, which increased slowly over several months without focal symptoms, cytopenias, or decline in organ function (Figure 1).

Discussion

Our patient experienced left olecranon bursitis simultaneously with relapse of multiple myeloma and AL amyloidosis. Evaluation for infectious causes was negative, and the bursal fluid did not have strongly inflammatory characteristics. Furthermore, a small plasma cell population was isolated from the fluid. Imaging did not reveal an underlying dominant lytic lesion. Although we do not have direct pathologic confirmation, the clinical scenario and flow cytometry findings support our interpretation that the patient’s bursitis was caused by or at least related to underlying multiple myeloma. While reactive plasma cells are also CD38 positive and CD138 positive, they maintain the expression of CD19 and CD45 without aberrant expression of CD56 or CD117 and do not show loss of expression of CD81 or CD27. In this situation, we suspect that either a plasmacytoma involving the soft tissue of the bursa or amyloid infiltration of the synovium may have occurred. Anti-myeloma therapies and radiation therapy did not result in control of the bursitis, though it should be noted that the patient’s highly refractory disease progressed despite treatment with a combination of later-generation immunomodulatory imide and proteasome inhibitor therapies.

Cases of malignant bursitis have been reported several times in the literature, though nearly all of the instances involved connective tissue or metastatic tumors. Tumor histologies include osteochondroma,^8,9 malignant fibrous histiocytoma,¹⁰ synovial sarcoma,¹¹ and metastatic breast cancer.¹²

Hematologic malignancies are more rare causes of bursitis; our literature search identified a report of 2 cases of non-Hodgkin lymphoma mimicking rheumatoid arthritis. The joints were the knee and elbow. Synovial fluid from one case was clear and yellow, with leukocytosis with a neutrophilic predominance (similar to our case). In both cases, pathology confirmed lymphomatous infiltration of the synovium.¹³ Notably, we identified a case of a previously healthy 35-year-old woman with bilateral trochanteric bursitis. Biopsy of tissue from the right trochanteric bursa demonstrated positive birefringence, diagnostic of AL amyloidosis. The patient also had a biclonal paraprotein accompanied by calvarial lytic lesions. She was treated with a corticosteroid pulse and bisphosphonates, followed by autologous hematopoietic stem cell transplant. ⁵ Our case shares features with the above case, including the relatively young age of the patient and the presence of AL amyloidosis.

Our patient wished to avoid a surgical biopsy procedure, and therefore we utilized flow cytometry of the bursal fluid to establish that the etiology of fluid collection was consistent with his concurrent relapse of multiple myeloma. We believe that we are reporting the second case of multiple myeloma-associated bursitis and the first case associated with multiple myeloma relapse; to our knowledge, it is the first to be diagnosed with the aid of flow cytometry.

Because of our patient’s reliance on hemodialysis beginning one year prior to his presentation with olecranon bursitis, we entertain “dialysis elbow” within the differential diagnosis. Dialysis elbow is a relatively uncommon complication of dialysis, in which patients develop olecranon bursitis on the same side as the hemodialysis access after a prolonged (months to years) duration of hemodialysis. Serositis and mechanical forces are the hypothesized etiologies¹⁴; infectious and rheumatologic causes were excluded from the reported cases. Nevertheless, we favor a malignant cause based upon the flow cytometry findings indicating involvement by immunophenotypically abnormal plasma cells.

Our patient was treated initially with serial drainage and nonsteroidals, which had little impact. After diagnosis of a plasma cell population in the fluid, we offered local treatment with radiation and systemic treatment of multiple myeloma, which offered better but suboptimal control. Possible treatments for olecranon bursitis include surgery, corticosteroid injections, anti-inflammatories, and serial drainage. Nonsurgical management may be more effective than surgical management, and corticosteroid injection carries significant risks. On the other hand, serial drainage does not confer additional infection risk in cases with aseptic etiology.¹⁵ We combined conservative measures as well as treatment of the underlying disease, but we believe that our patient did not derive significant benefit because of the refractory nature of his disease; he also expressed a preference to avoid surgical intervention.
 

Conclusion

Bursitis is a rare but thought-provoking potential manifestation of multiple myeloma and AL amyloidosis; we believe that our patient’s bursitis was related to plasma cell neoplasia based upon co-occurrence with disease relapse. His bursitis turned out to be an early indicator of impending systemic relapse. In this particular case, in which the patient wished to avoid surgical intervention, flow cytometry was of great value, and we believe that our case is the first report of malignant bursitis being diagnosed by flow cytometry. Our patient’s case shares similarities with other biopsy-confirmed cases of malignant bursitis, but we were able to avoid the need for surgical biopsy or bursal stripping.

The authors thank Jennifer Wilham MT (ASCP), Pat Byrd MT (ASCP), and Darlene Mann MT (ASCP) for their technical support.

Multiple myeloma is the most common plasma cell neoplasm, with an estimated 24,000 cases occurring annually.¹ Symptomatic multiple myeloma most commonly presents with one or more of the cardinal CRAB phenomena of hypercalcemia, renal dysfunction, anemia, or lytic bone lesions.² Less commonly, patients may present with plasmacytomas (focal lesions of malignant plasma cells), which may involve bony or soft tissues.¹

Plasma cell neoplasms occasionally involve the joints, including the elbows, typically as plasmacytomas. The elbow is an unusual but reported location of plasmacytomas.^3,4 A case of multiple myeloma and amyloid light-chain (AL) amyloidosis has been reported, with manifestations including pseudomyopathy, bone marrow plasmacytosis, and bilateral trochanteric bursitis.⁵Bursitis is defined as inflammation of the synovial-fluid–containing sacs that lubricate joints. The olecranon bursa is commonly affected. Etiologies include infection, inflammatory disease, trauma, and malignancy. Furthermore, there is an association between bursitis and immunosuppression.^6,7 The most common modes of therapy used to treat bursitis are nonsteroidal anti-inflammatory drugs, corticosteroid injections, and surgical management.

Trochanteric bursitis has been attributed to multiple myeloma in one previous case report, but we are not aware of any previous cases of olecranon bursitis caused by multiple myeloma. Here, we present the case of a 46-year-old man with heavily pretreated multiple myeloma and amyloidosis who developed left olecranon bursitis contemporaneously with disease relapse; flow cytometric analysis of the bursal fluid demonstrated an abnormal plasma cell population, establishing the etiology.

Case presentation and summary

A 46-year-old man with a longstanding history of multiple myeloma developed swelling of the left elbow that was initially painless in September 2016. He had been diagnosed with IgA kappa multiple myeloma and AL deposition in 2011. Over the course of his disease, he was treated with the following sequence of therapies: cyclophosphamide, bortezomib, and dexamethasone, followed by melphalan-conditioned autologous peripheral blood stem cell transplant; lenalidomide and dexamethasone; carfilzomib and dexamethasone; pomalidomide, bortezomib, and dexamethasone; and bortezomib, lenalidomide, dexamethasone, doxorubicin, cyclophosphamide, and etoposide, followed by second melphalan-conditioned autologous peripheral blood stem cell transplant. In addition to treatment with numerous novel and chemotherapeutic agents, his disease course was notable for amyloid deposition in the liver, bone marrow, and kidneys, which resulted in dialysis dependence.

After the second autologous transplant, he achieved a very good partial response and experienced about 9 months of remission, after which laboratory evaluation indicated recurrence of IgA kappa monoclonal protein and free kappa light-chains, which increased slowly over several months without focal symptoms, cytopenias, or decline in organ function (Figure 1).

Discussion

Our patient experienced left olecranon bursitis simultaneously with relapse of multiple myeloma and AL amyloidosis. Evaluation for infectious causes was negative, and the bursal fluid did not have strongly inflammatory characteristics. Furthermore, a small plasma cell population was isolated from the fluid. Imaging did not reveal an underlying dominant lytic lesion. Although we do not have direct pathologic confirmation, the clinical scenario and flow cytometry findings support our interpretation that the patient’s bursitis was caused by or at least related to underlying multiple myeloma. While reactive plasma cells are also CD38 positive and CD138 positive, they maintain the expression of CD19 and CD45 without aberrant expression of CD56 or CD117 and do not show loss of expression of CD81 or CD27. In this situation, we suspect that either a plasmacytoma involving the soft tissue of the bursa or amyloid infiltration of the synovium may have occurred. Anti-myeloma therapies and radiation therapy did not result in control of the bursitis, though it should be noted that the patient’s highly refractory disease progressed despite treatment with a combination of later-generation immunomodulatory imide and proteasome inhibitor therapies.

Cases of malignant bursitis have been reported several times in the literature, though nearly all of the instances involved connective tissue or metastatic tumors. Tumor histologies include osteochondroma,^8,9 malignant fibrous histiocytoma,¹⁰ synovial sarcoma,¹¹ and metastatic breast cancer.¹²

Hematologic malignancies are more rare causes of bursitis; our literature search identified a report of 2 cases of non-Hodgkin lymphoma mimicking rheumatoid arthritis. The joints were the knee and elbow. Synovial fluid from one case was clear and yellow, with leukocytosis with a neutrophilic predominance (similar to our case). In both cases, pathology confirmed lymphomatous infiltration of the synovium.¹³ Notably, we identified a case of a previously healthy 35-year-old woman with bilateral trochanteric bursitis. Biopsy of tissue from the right trochanteric bursa demonstrated positive birefringence, diagnostic of AL amyloidosis. The patient also had a biclonal paraprotein accompanied by calvarial lytic lesions. She was treated with a corticosteroid pulse and bisphosphonates, followed by autologous hematopoietic stem cell transplant. ⁵ Our case shares features with the above case, including the relatively young age of the patient and the presence of AL amyloidosis.

Our patient wished to avoid a surgical biopsy procedure, and therefore we utilized flow cytometry of the bursal fluid to establish that the etiology of fluid collection was consistent with his concurrent relapse of multiple myeloma. We believe that we are reporting the second case of multiple myeloma-associated bursitis and the first case associated with multiple myeloma relapse; to our knowledge, it is the first to be diagnosed with the aid of flow cytometry.

Because of our patient’s reliance on hemodialysis beginning one year prior to his presentation with olecranon bursitis, we entertain “dialysis elbow” within the differential diagnosis. Dialysis elbow is a relatively uncommon complication of dialysis, in which patients develop olecranon bursitis on the same side as the hemodialysis access after a prolonged (months to years) duration of hemodialysis. Serositis and mechanical forces are the hypothesized etiologies¹⁴; infectious and rheumatologic causes were excluded from the reported cases. Nevertheless, we favor a malignant cause based upon the flow cytometry findings indicating involvement by immunophenotypically abnormal plasma cells.

Our patient was treated initially with serial drainage and nonsteroidals, which had little impact. After diagnosis of a plasma cell population in the fluid, we offered local treatment with radiation and systemic treatment of multiple myeloma, which offered better but suboptimal control. Possible treatments for olecranon bursitis include surgery, corticosteroid injections, anti-inflammatories, and serial drainage. Nonsurgical management may be more effective than surgical management, and corticosteroid injection carries significant risks. On the other hand, serial drainage does not confer additional infection risk in cases with aseptic etiology.¹⁵ We combined conservative measures as well as treatment of the underlying disease, but we believe that our patient did not derive significant benefit because of the refractory nature of his disease; he also expressed a preference to avoid surgical intervention.
 

Conclusion

Bursitis is a rare but thought-provoking potential manifestation of multiple myeloma and AL amyloidosis; we believe that our patient’s bursitis was related to plasma cell neoplasia based upon co-occurrence with disease relapse. His bursitis turned out to be an early indicator of impending systemic relapse. In this particular case, in which the patient wished to avoid surgical intervention, flow cytometry was of great value, and we believe that our case is the first report of malignant bursitis being diagnosed by flow cytometry. Our patient’s case shares similarities with other biopsy-confirmed cases of malignant bursitis, but we were able to avoid the need for surgical biopsy or bursal stripping.

The authors thank Jennifer Wilham MT (ASCP), Pat Byrd MT (ASCP), and Darlene Mann MT (ASCP) for their technical support.

Researchers have identified biomarkers that might eventually be used to flag cancer patients with severe cutaneous adverse reactions (SCARs) at an increased risk of mortality.

In a retrospective study, elevated elafin, interleukin (IL)-6, and tumor necrosis factor (TNF)–alpha levels were significantly associated with a greater risk of all-cause mortality among hospitalized cancer patients who developed SCARs, which includes Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug-induced hypersensitivity syndrome.

In the study, published in the Journal of the American Academy of Dermatology, Shoko Mori of the dermatology service at Memorial Sloan Kettering Cancer Center, New York, and coauthors looked at 49 cancer patients hospitalized (41) or treated at an urgent care center (8), between August 2016 and July 2017 who experienced a morbilliform rash. Overall, 27 patients had a simple morbilliform rash, without systemic involvement; 22 had a complex morbilliform rash with systemic involvement, including 9 with cutaneous manifestations of graft versus host disease (GVHD) and 13 with rashes secondary to drug exposure.

The majority of the patients had a hematologic malignancy (18 with a simple rash, and 16 with a complex rash); the rest had a solid organ malignancy (9 with a simple rash and 6 with a complex rash).

Nearly one-third (30.6%) of patients died within 6 months of having a dermatologic consultation. These patients showed significantly higher levels of serum elafin – a protein that is not detectable in normal skin but is overexpressed in wound healing and inflammatory disorders – as well as IL-6 and TNF-alpha, compared with patients who were alive at 6 months.

“While GVHD and drug-related SCARs are difficult to distinguish clinically, our results suggest that elafin may be a useful biomarker to identify patients with a suspected diagnosis of SCARs or GVHD who are at increased risk of death within 6 months,” the investigators wrote. “Given its broad anti-inflammatory activity, elafin’s potential as a therapeutic agent for SCARs should be further explored.”

They noted that elevated TNF-alpha levels pointed to another potential therapeutic target for SCARs among patients undergoing treatment for cancer. Patients who died were also less likely to have elevated bilirubin level relative to baseline than patients who survived past 6 months.

The patients with a complex morbilliform rash caused by drug exposure had significantly higher median levels of IL-10 and IL-6, compared with those with a complex rash related to GVHD or with a simple rash. “Thought to originate from activated keratinocytes in TEN [toxic epidermal necrolysis], elevated IL-10 may reflect a defense mechanism against drug-specific cytotoxic T cells that are activated during the disease process,” the authors wrote.

Patients with complex rash also had a significantly higher median white blood cell count and higher median values for all cytokines, compared with the simple rash group, although only differences in TNF-alpha levels were statistically significant.

“A larger, prospective study examining the association of cytokines with SCARs is needed, as well as longitudinal assessment of cytokine levels to assess their prognostic significance,” the authors wrote. “This exploratory analysis presents potential therapeutic targets in a high-risk patient population, for whom a ‘complex’ rash can disrupt and delay treatment of underlying disease.”

The study was partly funded by the National Cancer Institute/National Institutes of Health via a grant to the Memorial Sloan Kettering Cancer Center. One author declared support from a Dermatology Foundation Career Development Award.

SOURCE: Mori S et al. J Am Acad Dermatol, 2018 October 26. doi: 10.1016/j.jaad.2018.10.039.

Researchers have identified biomarkers that might eventually be used to flag cancer patients with severe cutaneous adverse reactions (SCARs) at an increased risk of mortality.

In a retrospective study, elevated elafin, interleukin (IL)-6, and tumor necrosis factor (TNF)–alpha levels were significantly associated with a greater risk of all-cause mortality among hospitalized cancer patients who developed SCARs, which includes Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug-induced hypersensitivity syndrome.

In the study, published in the Journal of the American Academy of Dermatology, Shoko Mori of the dermatology service at Memorial Sloan Kettering Cancer Center, New York, and coauthors looked at 49 cancer patients hospitalized (41) or treated at an urgent care center (8), between August 2016 and July 2017 who experienced a morbilliform rash. Overall, 27 patients had a simple morbilliform rash, without systemic involvement; 22 had a complex morbilliform rash with systemic involvement, including 9 with cutaneous manifestations of graft versus host disease (GVHD) and 13 with rashes secondary to drug exposure.

The majority of the patients had a hematologic malignancy (18 with a simple rash, and 16 with a complex rash); the rest had a solid organ malignancy (9 with a simple rash and 6 with a complex rash).

Nearly one-third (30.6%) of patients died within 6 months of having a dermatologic consultation. These patients showed significantly higher levels of serum elafin – a protein that is not detectable in normal skin but is overexpressed in wound healing and inflammatory disorders – as well as IL-6 and TNF-alpha, compared with patients who were alive at 6 months.

“While GVHD and drug-related SCARs are difficult to distinguish clinically, our results suggest that elafin may be a useful biomarker to identify patients with a suspected diagnosis of SCARs or GVHD who are at increased risk of death within 6 months,” the investigators wrote. “Given its broad anti-inflammatory activity, elafin’s potential as a therapeutic agent for SCARs should be further explored.”

They noted that elevated TNF-alpha levels pointed to another potential therapeutic target for SCARs among patients undergoing treatment for cancer. Patients who died were also less likely to have elevated bilirubin level relative to baseline than patients who survived past 6 months.

The patients with a complex morbilliform rash caused by drug exposure had significantly higher median levels of IL-10 and IL-6, compared with those with a complex rash related to GVHD or with a simple rash. “Thought to originate from activated keratinocytes in TEN [toxic epidermal necrolysis], elevated IL-10 may reflect a defense mechanism against drug-specific cytotoxic T cells that are activated during the disease process,” the authors wrote.

Patients with complex rash also had a significantly higher median white blood cell count and higher median values for all cytokines, compared with the simple rash group, although only differences in TNF-alpha levels were statistically significant.

“A larger, prospective study examining the association of cytokines with SCARs is needed, as well as longitudinal assessment of cytokine levels to assess their prognostic significance,” the authors wrote. “This exploratory analysis presents potential therapeutic targets in a high-risk patient population, for whom a ‘complex’ rash can disrupt and delay treatment of underlying disease.”

The study was partly funded by the National Cancer Institute/National Institutes of Health via a grant to the Memorial Sloan Kettering Cancer Center. One author declared support from a Dermatology Foundation Career Development Award.

SOURCE: Mori S et al. J Am Acad Dermatol, 2018 October 26. doi: 10.1016/j.jaad.2018.10.039.

Researchers have identified biomarkers that might eventually be used to flag cancer patients with severe cutaneous adverse reactions (SCARs) at an increased risk of mortality.

In a retrospective study, elevated elafin, interleukin (IL)-6, and tumor necrosis factor (TNF)–alpha levels were significantly associated with a greater risk of all-cause mortality among hospitalized cancer patients who developed SCARs, which includes Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug-induced hypersensitivity syndrome.

In the study, published in the Journal of the American Academy of Dermatology, Shoko Mori of the dermatology service at Memorial Sloan Kettering Cancer Center, New York, and coauthors looked at 49 cancer patients hospitalized (41) or treated at an urgent care center (8), between August 2016 and July 2017 who experienced a morbilliform rash. Overall, 27 patients had a simple morbilliform rash, without systemic involvement; 22 had a complex morbilliform rash with systemic involvement, including 9 with cutaneous manifestations of graft versus host disease (GVHD) and 13 with rashes secondary to drug exposure.

The majority of the patients had a hematologic malignancy (18 with a simple rash, and 16 with a complex rash); the rest had a solid organ malignancy (9 with a simple rash and 6 with a complex rash).

Nearly one-third (30.6%) of patients died within 6 months of having a dermatologic consultation. These patients showed significantly higher levels of serum elafin – a protein that is not detectable in normal skin but is overexpressed in wound healing and inflammatory disorders – as well as IL-6 and TNF-alpha, compared with patients who were alive at 6 months.

“While GVHD and drug-related SCARs are difficult to distinguish clinically, our results suggest that elafin may be a useful biomarker to identify patients with a suspected diagnosis of SCARs or GVHD who are at increased risk of death within 6 months,” the investigators wrote. “Given its broad anti-inflammatory activity, elafin’s potential as a therapeutic agent for SCARs should be further explored.”

They noted that elevated TNF-alpha levels pointed to another potential therapeutic target for SCARs among patients undergoing treatment for cancer. Patients who died were also less likely to have elevated bilirubin level relative to baseline than patients who survived past 6 months.

The patients with a complex morbilliform rash caused by drug exposure had significantly higher median levels of IL-10 and IL-6, compared with those with a complex rash related to GVHD or with a simple rash. “Thought to originate from activated keratinocytes in TEN [toxic epidermal necrolysis], elevated IL-10 may reflect a defense mechanism against drug-specific cytotoxic T cells that are activated during the disease process,” the authors wrote.

Patients with complex rash also had a significantly higher median white blood cell count and higher median values for all cytokines, compared with the simple rash group, although only differences in TNF-alpha levels were statistically significant.

“A larger, prospective study examining the association of cytokines with SCARs is needed, as well as longitudinal assessment of cytokine levels to assess their prognostic significance,” the authors wrote. “This exploratory analysis presents potential therapeutic targets in a high-risk patient population, for whom a ‘complex’ rash can disrupt and delay treatment of underlying disease.”

The study was partly funded by the National Cancer Institute/National Institutes of Health via a grant to the Memorial Sloan Kettering Cancer Center. One author declared support from a Dermatology Foundation Career Development Award.

SOURCE: Mori S et al. J Am Acad Dermatol, 2018 October 26. doi: 10.1016/j.jaad.2018.10.039.

Recurrence risk is significant among all patients with venous thromboembolism (VTE), though recurrence is most frequent in patients with cancer-related VTE, according to a nationwide Danish study.

Ida Ehlers Albertsen, MD, of Aalborg (Denmark) University Hospital and her coauthors followed 73,993 patients who were diagnosed with incident VTE during January 2000–December 2015. The patients’ VTEs were classified as either cancer-related, unprovoked (occurring in patients without any provoking factors), or provoked (occurring in patients with one or more provoking factors, such as recent major surgery, recent fracture/trauma, obesity, or hormone replacement therapy).

The researchers found similar risks of recurrence among patients with unprovoked and provoked VTE at 6-month follow-up, with rates per 100 person-years of 6.80 and 6.92, respectively. By comparison, the recurrence rate for cancer-related VTE at 6 months was 9.06. The findings were reported in the American Journal of Medicine.

However, at 10-year follow-up the rates were 3.70 for cancer-related VTE, 2.84 for unprovoked VTE, and 2.22 for provoked VTE, which reinforces the belief that “unprovoked venous thromboembolism is associated with long-term higher risk of recurrence than provoked venous thromboembolism.”

Additionally, at 10-year follow-up, the absolute recurrence risk of cancer-related VTE and unprovoked VTE were both at approximately 20%, with recurrence risk of provoked VTE at just above 15%. Compared with the recurrence risk of provoked VTE at 10-year follow-up, the hazard ratios of cancer-related VTE and unprovoked VTE recurrence risk were 1.23 (95% confidence interval, 1.13-1.33) and 1.18 (95% CI, 1.13-1.24), respectively.

The coauthors observed several challenges in comparing their study to previous analyses on recurrent risk, noting that the definition of provoked VTE “varies throughout the literature” and that the majority of VTE studies “provide cumulative incidence proportions and not the actual rates.” They also stated that indefinite or extended therapy for all VTE patients comes with its own potential complications, even with the improved safety of non–vitamin K antagonist oral anticoagulants, writing that “treatment should be given to patients where the benefits outweigh the risks.”

Despite the differences in recurrence rates at 6-month and 10-year follow-up, the coauthors suggested that enough risk was present in all types to warrant additional studies and reconsider how VTE patients are categorized.

“A high recurrence risk in all types of venous thromboembolism indicates that further research is needed to optimize risk stratification for venous thromboembolism patients,” they wrote.

The study was partially funded by a grant from the Obel Family Foundation. Some authors reported financial disclosures related to Janssen, Bayer, Roche, and others.

SOURCE: Albertsen IE et al. Am J Med. 2018 Sep;131(9):1067-74.e4.

Recurrence risk is significant among all patients with venous thromboembolism (VTE), though recurrence is most frequent in patients with cancer-related VTE, according to a nationwide Danish study.

Ida Ehlers Albertsen, MD, of Aalborg (Denmark) University Hospital and her coauthors followed 73,993 patients who were diagnosed with incident VTE during January 2000–December 2015. The patients’ VTEs were classified as either cancer-related, unprovoked (occurring in patients without any provoking factors), or provoked (occurring in patients with one or more provoking factors, such as recent major surgery, recent fracture/trauma, obesity, or hormone replacement therapy).

The researchers found similar risks of recurrence among patients with unprovoked and provoked VTE at 6-month follow-up, with rates per 100 person-years of 6.80 and 6.92, respectively. By comparison, the recurrence rate for cancer-related VTE at 6 months was 9.06. The findings were reported in the American Journal of Medicine.

However, at 10-year follow-up the rates were 3.70 for cancer-related VTE, 2.84 for unprovoked VTE, and 2.22 for provoked VTE, which reinforces the belief that “unprovoked venous thromboembolism is associated with long-term higher risk of recurrence than provoked venous thromboembolism.”

Additionally, at 10-year follow-up, the absolute recurrence risk of cancer-related VTE and unprovoked VTE were both at approximately 20%, with recurrence risk of provoked VTE at just above 15%. Compared with the recurrence risk of provoked VTE at 10-year follow-up, the hazard ratios of cancer-related VTE and unprovoked VTE recurrence risk were 1.23 (95% confidence interval, 1.13-1.33) and 1.18 (95% CI, 1.13-1.24), respectively.

The coauthors observed several challenges in comparing their study to previous analyses on recurrent risk, noting that the definition of provoked VTE “varies throughout the literature” and that the majority of VTE studies “provide cumulative incidence proportions and not the actual rates.” They also stated that indefinite or extended therapy for all VTE patients comes with its own potential complications, even with the improved safety of non–vitamin K antagonist oral anticoagulants, writing that “treatment should be given to patients where the benefits outweigh the risks.”

Despite the differences in recurrence rates at 6-month and 10-year follow-up, the coauthors suggested that enough risk was present in all types to warrant additional studies and reconsider how VTE patients are categorized.

“A high recurrence risk in all types of venous thromboembolism indicates that further research is needed to optimize risk stratification for venous thromboembolism patients,” they wrote.

The study was partially funded by a grant from the Obel Family Foundation. Some authors reported financial disclosures related to Janssen, Bayer, Roche, and others.

SOURCE: Albertsen IE et al. Am J Med. 2018 Sep;131(9):1067-74.e4.

Recurrence risk is significant among all patients with venous thromboembolism (VTE), though recurrence is most frequent in patients with cancer-related VTE, according to a nationwide Danish study.

Ida Ehlers Albertsen, MD, of Aalborg (Denmark) University Hospital and her coauthors followed 73,993 patients who were diagnosed with incident VTE during January 2000–December 2015. The patients’ VTEs were classified as either cancer-related, unprovoked (occurring in patients without any provoking factors), or provoked (occurring in patients with one or more provoking factors, such as recent major surgery, recent fracture/trauma, obesity, or hormone replacement therapy).

The researchers found similar risks of recurrence among patients with unprovoked and provoked VTE at 6-month follow-up, with rates per 100 person-years of 6.80 and 6.92, respectively. By comparison, the recurrence rate for cancer-related VTE at 6 months was 9.06. The findings were reported in the American Journal of Medicine.

However, at 10-year follow-up the rates were 3.70 for cancer-related VTE, 2.84 for unprovoked VTE, and 2.22 for provoked VTE, which reinforces the belief that “unprovoked venous thromboembolism is associated with long-term higher risk of recurrence than provoked venous thromboembolism.”

Additionally, at 10-year follow-up, the absolute recurrence risk of cancer-related VTE and unprovoked VTE were both at approximately 20%, with recurrence risk of provoked VTE at just above 15%. Compared with the recurrence risk of provoked VTE at 10-year follow-up, the hazard ratios of cancer-related VTE and unprovoked VTE recurrence risk were 1.23 (95% confidence interval, 1.13-1.33) and 1.18 (95% CI, 1.13-1.24), respectively.

The coauthors observed several challenges in comparing their study to previous analyses on recurrent risk, noting that the definition of provoked VTE “varies throughout the literature” and that the majority of VTE studies “provide cumulative incidence proportions and not the actual rates.” They also stated that indefinite or extended therapy for all VTE patients comes with its own potential complications, even with the improved safety of non–vitamin K antagonist oral anticoagulants, writing that “treatment should be given to patients where the benefits outweigh the risks.”

Despite the differences in recurrence rates at 6-month and 10-year follow-up, the coauthors suggested that enough risk was present in all types to warrant additional studies and reconsider how VTE patients are categorized.

“A high recurrence risk in all types of venous thromboembolism indicates that further research is needed to optimize risk stratification for venous thromboembolism patients,” they wrote.

The study was partially funded by a grant from the Obel Family Foundation. Some authors reported financial disclosures related to Janssen, Bayer, Roche, and others.

SOURCE: Albertsen IE et al. Am J Med. 2018 Sep;131(9):1067-74.e4.

SAN DIEGO – Oncologists spent on average 3 minutes less with minority patients than with nonminority patients at a critical transition visit to talk about a scan result related to advanced cancer, a study investigator reported.

The gap was most pronounced for visits where a negative scan result was communicated, said investigator Cardinale B. Smith, MD, PhD, director of Quality for Cancer Services, Mount Sinai Health System, New York.

Future work is needed to look at the content of these conversations to determine to what extent physician- or patient-specific factors may have contributed to this difference, according to Dr. Smith.

“This will be critically important to ensure that we provide high-quality care to our minority patients,” Dr. Smith said at the 2018 Palliative and Supportive Care in Oncology Symposium.

The study included 22 oncologists from four hospitals randomized to either a usual-care group or an intervention group that included several interventions designed to improve communication techniques related to goals-of-care conversations

Sixty-nine percent of the physicians were white, while 23% were Asian, 8% were Hispanic, and 5% were black, Dr. Smith said.

Postimaging encounters were audio recorded for 142 patients, more than half of whom were minorities; 32% were black and 26% were Hispanic, according to the investigator, while 38% were white and 4% were Asian.

Overall, time spent with minorities at the scan results visit was 11.5 minutes versus 16.5 minutes for nonminorities (P = .0007), Dr. Smith reported.

When the scan was positive, there was actually no significant difference in time spent on minority versus nonminority visits, (16 versus 18 minutes; P = .59), a finding that Dr. Smith said was “encouraging” in an interview. However, there was a marked difference in length of time spent on minority versus nonminority visits when the scans showed no progression (10 versus 15 minutes; P = .0003).

“There’s something about regular, routine visits, which are still just as important as [positive] scan visits, in which there is a difference in the time spent,” Dr. Smith said in an interview. “We’re really interested in doing a more in-depth analysis of those conversations to see what’s contributing to those differences.”

After adjusting for patient insurance, education, income progression, status, and hospital, investigators found that oncologists spent 13.5 minutes (interquartile range, 12-16) with minority patients versus 16.5 minutes (IQR, 16-19) for nonminority patients (P less than .0001).

In terms of the communications intervention, investigators found no difference in time spent with minorities versus nonminorities among the intervention or control physicians. However, the intervention was aimed at improving the rate of goals of care conversations rather than improving communication based on race or ethnicity, Dr. Smith said.

By contrast, the finding of decreased time spent in communication encounters with minority patients merits further study to see how much of the disparity is mediated by differences in patients versus oncologists, she added.

In literature on communication disparities in other care settings outside of oncology, care conversations with minorities tend to be more closed ended, as opposed to open ended – so instead of asking if a patient is doing well, a physician might start out with a declarative statement that the patient’s findings are positive, she said.

On the other hand, some literature suggests that minority patients may not question the physician as much as nonminorities, or may not spend as much time asking directed questions during the visit. “That may also contribute to decreased time spent during those encounters,” Dr. Smith added.

The research was supported by the Patient Centered Outcomes Research Institute. Dr. Smith reported honoraria and a consulting or advisory role with Teva.

SOURCE: Smith CB et al. PallOnc 2018, Abstract 19.

SAN DIEGO – Oncologists spent on average 3 minutes less with minority patients than with nonminority patients at a critical transition visit to talk about a scan result related to advanced cancer, a study investigator reported.

The gap was most pronounced for visits where a negative scan result was communicated, said investigator Cardinale B. Smith, MD, PhD, director of Quality for Cancer Services, Mount Sinai Health System, New York.

Future work is needed to look at the content of these conversations to determine to what extent physician- or patient-specific factors may have contributed to this difference, according to Dr. Smith.

“This will be critically important to ensure that we provide high-quality care to our minority patients,” Dr. Smith said at the 2018 Palliative and Supportive Care in Oncology Symposium.

The study included 22 oncologists from four hospitals randomized to either a usual-care group or an intervention group that included several interventions designed to improve communication techniques related to goals-of-care conversations

Sixty-nine percent of the physicians were white, while 23% were Asian, 8% were Hispanic, and 5% were black, Dr. Smith said.

Postimaging encounters were audio recorded for 142 patients, more than half of whom were minorities; 32% were black and 26% were Hispanic, according to the investigator, while 38% were white and 4% were Asian.

Overall, time spent with minorities at the scan results visit was 11.5 minutes versus 16.5 minutes for nonminorities (P = .0007), Dr. Smith reported.

When the scan was positive, there was actually no significant difference in time spent on minority versus nonminority visits, (16 versus 18 minutes; P = .59), a finding that Dr. Smith said was “encouraging” in an interview. However, there was a marked difference in length of time spent on minority versus nonminority visits when the scans showed no progression (10 versus 15 minutes; P = .0003).

“There’s something about regular, routine visits, which are still just as important as [positive] scan visits, in which there is a difference in the time spent,” Dr. Smith said in an interview. “We’re really interested in doing a more in-depth analysis of those conversations to see what’s contributing to those differences.”

After adjusting for patient insurance, education, income progression, status, and hospital, investigators found that oncologists spent 13.5 minutes (interquartile range, 12-16) with minority patients versus 16.5 minutes (IQR, 16-19) for nonminority patients (P less than .0001).

In terms of the communications intervention, investigators found no difference in time spent with minorities versus nonminorities among the intervention or control physicians. However, the intervention was aimed at improving the rate of goals of care conversations rather than improving communication based on race or ethnicity, Dr. Smith said.

By contrast, the finding of decreased time spent in communication encounters with minority patients merits further study to see how much of the disparity is mediated by differences in patients versus oncologists, she added.

In literature on communication disparities in other care settings outside of oncology, care conversations with minorities tend to be more closed ended, as opposed to open ended – so instead of asking if a patient is doing well, a physician might start out with a declarative statement that the patient’s findings are positive, she said.

On the other hand, some literature suggests that minority patients may not question the physician as much as nonminorities, or may not spend as much time asking directed questions during the visit. “That may also contribute to decreased time spent during those encounters,” Dr. Smith added.

The research was supported by the Patient Centered Outcomes Research Institute. Dr. Smith reported honoraria and a consulting or advisory role with Teva.

SOURCE: Smith CB et al. PallOnc 2018, Abstract 19.

SAN DIEGO – Oncologists spent on average 3 minutes less with minority patients than with nonminority patients at a critical transition visit to talk about a scan result related to advanced cancer, a study investigator reported.

The gap was most pronounced for visits where a negative scan result was communicated, said investigator Cardinale B. Smith, MD, PhD, director of Quality for Cancer Services, Mount Sinai Health System, New York.

Future work is needed to look at the content of these conversations to determine to what extent physician- or patient-specific factors may have contributed to this difference, according to Dr. Smith.

“This will be critically important to ensure that we provide high-quality care to our minority patients,” Dr. Smith said at the 2018 Palliative and Supportive Care in Oncology Symposium.

The study included 22 oncologists from four hospitals randomized to either a usual-care group or an intervention group that included several interventions designed to improve communication techniques related to goals-of-care conversations

Sixty-nine percent of the physicians were white, while 23% were Asian, 8% were Hispanic, and 5% were black, Dr. Smith said.

Postimaging encounters were audio recorded for 142 patients, more than half of whom were minorities; 32% were black and 26% were Hispanic, according to the investigator, while 38% were white and 4% were Asian.

Overall, time spent with minorities at the scan results visit was 11.5 minutes versus 16.5 minutes for nonminorities (P = .0007), Dr. Smith reported.

When the scan was positive, there was actually no significant difference in time spent on minority versus nonminority visits, (16 versus 18 minutes; P = .59), a finding that Dr. Smith said was “encouraging” in an interview. However, there was a marked difference in length of time spent on minority versus nonminority visits when the scans showed no progression (10 versus 15 minutes; P = .0003).

“There’s something about regular, routine visits, which are still just as important as [positive] scan visits, in which there is a difference in the time spent,” Dr. Smith said in an interview. “We’re really interested in doing a more in-depth analysis of those conversations to see what’s contributing to those differences.”

After adjusting for patient insurance, education, income progression, status, and hospital, investigators found that oncologists spent 13.5 minutes (interquartile range, 12-16) with minority patients versus 16.5 minutes (IQR, 16-19) for nonminority patients (P less than .0001).

In terms of the communications intervention, investigators found no difference in time spent with minorities versus nonminorities among the intervention or control physicians. However, the intervention was aimed at improving the rate of goals of care conversations rather than improving communication based on race or ethnicity, Dr. Smith said.

By contrast, the finding of decreased time spent in communication encounters with minority patients merits further study to see how much of the disparity is mediated by differences in patients versus oncologists, she added.

In literature on communication disparities in other care settings outside of oncology, care conversations with minorities tend to be more closed ended, as opposed to open ended – so instead of asking if a patient is doing well, a physician might start out with a declarative statement that the patient’s findings are positive, she said.

On the other hand, some literature suggests that minority patients may not question the physician as much as nonminorities, or may not spend as much time asking directed questions during the visit. “That may also contribute to decreased time spent during those encounters,” Dr. Smith added.

The research was supported by the Patient Centered Outcomes Research Institute. Dr. Smith reported honoraria and a consulting or advisory role with Teva.

SOURCE: Smith CB et al. PallOnc 2018, Abstract 19.