Ibrahim et al

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.

Breast cancer is one of the most prevalent cancers in women worldwide, with more than 1 million new cases diagnosed annually.¹ Prognosis for the disease has improved significantly, but 25% to 60% of women living with breast cancer experience some level of pain ranging from mild to severe, the nature of which can evolve from acute to chronic.² Pre-, intra-, and post-treatment risk factors have been found to correlate with the development of acute and chronic pain and include young age, type of breast surgery (lumpectomy or total mastectomy), axillary node dissection, radiation therapy, and hormonal therapy.^3-5 Chemotherapy, particularly anthracycline- and taxane-based regimens, has also been shown to induce pain, arthralgia, myalgia, and peripheral neuropathy during treatment.⁶ In particular, postradiation pain may result from subcutaneous fibrosis with fixation to underlying musculature and the development of fibrous flaps in the internal axilla.⁷ These tissue changes are commonly subclinical, occurring 4 to 12 months postradiation,⁸ and can progress undetected until pain and upper-limb disability develop.

The presence of persistent pain has a considerable impact on the quality of life in survivors of breast cancer: psychological distress is prevalent (anxiety, depression, worry, fear), the performance of daily activities is diminished (eg, bathing, dressing, preparing meals, shopping), and economic independence is compromised by the inability to work or reduced employment and income. These factors directly and indirectly contribute to an increase in the use of health care services.^9,10

The management of pain is often characterized by pharmacologic-related treatment, such as the use of opioids and nonsteroidal anti-inflammatory medications, and nonpharmacologic-related treatment, such as exercise. Empirical evidence has shown that rehabilitative exercise programs, which commonly include a combination of resistance training and aerobic exercises, can effectively reduce pain in breast cancer survivors.^10-12 Women living with breast cancer who are directed to rehabilitative exercise programs experience an improvement not only in pain levels but also in their ability to engage in activities of daily living, in their psychological health, and in their overall quality of life.^13-15 However, despite evidence to support exercise programs to reduce pain related to breast cancer treatment, residual pain and upper-limb discomfort are common complaints in breast cancer survivors, and there is little focus on the duration of effectiveness of such programs for reducing pain after treatment for breast cancer. The objective of this study was to determine if an exercise program initiated postradiation would improve long-term pain levels in a carefully selected population of young women who were living with breast cancer and had no history of shoulder pathology or significant treatment complications.
 

Methods

Design

We used a pilot randomized control trial to compare the long-term effectiveness of a 12-week postradiation exercise program versus standard care on residual pain levels in young women (aged 18-45 years) living with breast cancer. The program was initiated 3 to 4 weeks postradiation to allow for acute inflammatory reactions to subside. Pain severity and interference were assessed using the Brief Pain Inventory-Short Form (BPI-SF), a tool for assessing cancer pain.^16,17 Pain levels for isolated shoulder movements were also recorded on examination by a physical therapist. All measures were collected at 6 time points (T1-T6): postsurgery and preradiation (T1, baseline), postradiation and preintervention (T2), and 4 points during an 18-month period postradiation (T3-T6 at 3, 6, 12, and 18 months postradiation).
 

Sample

Young women living with breast cancer who met our eligibility criteria were identified from 2 clinics at the Jewish General Hospital – the Segal Cancer Center and the Department of Radiation Oncology in Montréal, Québec, Canada. Inclusion criteria included women with a diagnosis of stage I to stage III breast cancer, who were 18 to 45 years old, were scheduled for postoperative adjuvant radiation therapy, had an Eastern Cooperative Oncology Group Performance Status of 0 or 1 (normal ambulatory function, minimal symptoms), and who consented to participate in the study. Exclusion criteria included women with a metastatic (stage IV) diagnosis; significant musculoskeletal, cardiac, pulmonary, or metabolic comorbidities that would not allow for participation in physical activity; a previous breast cancer diagnosis with treatment to the ipsilateral or contralateral sides; postsurgical lymphedema; postsurgical capsulitis, tendonitis, or other shoulder inflammatory complications; and any contraindication to exercise. The recruitment goal was outlined as 50 patients per group; however, a protracted accrual time because of the stringent study criteria yielded a sample of 29 and 30 patients for the intervention and control groups, respectively, which was sufficient for significant testing of differences between the 2 study groups.¹⁸
 

Variables and measures

 

Clinical characteristics. We used standardized questions and chart review to document the participants’ clinical characteristics and to capture information on the following: the stage and subtype of breast cancer, hormonal and human epidermal growth factor receptors (HER2) (estrogen receptor, progesterone receptor, and HER2 status), extent of surgery (lumpectomy or total mastectomy), and other modalities of treatment (eg, chemotherapy, radiation therapy).

Pain assessment. The BPI-SF was used to assess participants’ cancer-related pain. Pain severity ranged from 0 (no pain), 1 to 4 (mild pain), 5 to 6 (moderate pain), to 7 to 10 (severe pain).^18,19 The questionnaire also identifies the pain interference in daily activities using a Likert scale ranging from 0 (Does not interfere) to 10 (Completely interferes) in the following 7 domains or subscales: General Activity, Walking, Mood, Sleep, Work, Relations with Others, and Enjoyment of Life.¹⁶ For the purpose of this study, mean scores were tabulated using both pain intensity and interference scales.

Another important component of the BPI-SF instructs participants to localize pain by means of a body diagram. For purpose of analysis, 3 pain regions were established: shoulder girdle/chest wall on the affected side; neck and other upper extremity, including hand(s), forearm(s), wrist(s), and finger(s); and other regions, including abdominal discomfort, leg(s), hip(s), knee(s), ankle(s), lower back, and feet. In addition, pain levels on movement (Yes/No) were recorded for isolated shoulder flexion, abduction, and horizontal abduction (sitting and standing). The measurements were completed by a single physical therapist throughout the course of the study to minimize variance.

Procedure

The study protocol was approved by the Research Ethics Board at the Jewish General Hospital. Recruitment occurred from 2011 through 2015. The research was in accordance with the ethical standards of the responsible committee on human experimentation. Eligible women were recruited by the research coordinator who described the purpose, risks, and benefits of the study; advised on confidentiality, data collection, and intervention allocation procedures; and highlighted voluntary participation. The research coordinator addressed any concerns on the part of the participants before obtaining their written informed consent. Random allocation to the intervention and control groups was established using a web-based randomization plan generator (www.randomization.com). A single individual was responsible for the randomization process, and treatment assignments were revealed after each participant’s name had been entered. A physical therapist performed 6 sequential evaluations (T1-T6) at the time of participants’ medical follow-up appointments.

Intervention

The 12-week exercise intervention started 3 weeks postradiation and was composed of an initial 6-week program of low-level cardiovascular and resistance exercises that progressed to a set of more advanced exercises for the remaining 6 weeks. Participants were instructed to warm up for at least 10 minutes with a cardiovascular exercise of their choice (eg, a recumbent cross trainer, walking, or stairs) before doing a combined strength, endurance, and stretching exercise program for the upper body.²⁰ The final portion of the exercise intervention included a period of light cool-down. Weight training resistance levels were based on a maximum 8 to 10 repetitions for strength and a maximum of 20 repetitions for endurance training exercises, which progressed gradually over the course of the 12-week exercise program to ensure participant safety.^21,22 Participants in the intervention group were supervised at least once a week by an exercise physiologist at a center for oncology patients (Hope & Cope Wellness Centre), and patients were encouraged to perform the program at home 2 to 3 times a week. Those who were not able to exercise consistently at the center were provided with equipment and instructed on how to do the program safely at home.

By comparison, the control group received standard care, which included advice on the benefits of an active lifestyle, including exercise, but without a specific intervention. Participants were not restricted in their physical activity and/or sport participation levels, and their weekly activity levels were calculated using the Metabolic Equivalent of Task and recorded at each of the 6 time points.

Statistical analysis

Descriptive statistics were used to examine participant characteristics. The quantitative data collected through the BPI-SF measures were analyzed with JMP software (version 11.2; SAS Institute, Cary, NC). Continuous variables were tested for statistical significance (P ≤ .05) through the chi-square (categorical), analysis of variance, and nonparametric Wilcoxon tests. The analyses did not include missing data.

Results

A total of 59 young women were randomized into the intervention (n = 29) and control (n = 30) groups. Of those, 2 participants dropped out of the study because of family and time constraints, and 3 participants died, 2 from the control and 1 from the intervention group, after subsequently developing metastatic disease. Baseline data including comparative tumor characteristics, surgical interventions, and treatment interventions have been published in relation to other elements of this study.^23,24 The participants had a mean age of 39.2 years (standard deviation [SD], 5.0). More than half of them had an invasive ductal carcinoma (69.5%) and were estrogen positive (78.0%), progesterone positive (74.6%), or HER2 positive (20.3%), whereas 10.2% were triple negative. Most of the participants had undergone breast-sparing procedures (86.4% lumpectomy), and 18.6% had a total mastectomy. By random chance, the intervention group had higher rates of total mastectomy (24.4% and 13.3%, respectively) and surgical reconstruction (12.2% and 6.7%, respectively) compared with the control group. Most of the women (71.2%) received chemotherapy, and all received radiation therapy. In the intervention group, 37.2% received radiation therapy localized to the axilla, and 88% received a boost of radiation to the surgical bed. Self-reported exercise diaries were returned by 15 of the 29 intervention participants, and training frequencies among them varied significantly (1-6 times a week).

 

The findings showed that there was little variance between the intervention and control groups in BPI-SF severity scores from T1 to T6, so the means and SDs of the BPI-SF scores were grouped at 6 time points (Table 1). There was no statistically significant difference between baseline measures at T1 (1.68; SD, 1.17) and measures at 18 months postintervention (T6: 1.46; SD, 1.37). At baseline, 87.7% of the women reported no pain (31.5%) or mild levels of pain (55.6%), and 13% reported moderate or severe pain. Over the duration of the study from T1 to T6, these primarily low levels of pain (BPI-SF, 0-4) remained consistent with a favorable shift toward having no pain (T1: 31.5%; T6: 24.4%). By 18 months postintervention, 95.7% of women reported no or mild pain, with 4.9% reporting moderate pain.

Similarly, there was little variance over time (T1-T6) and no statistically significant differences between the 2 groups in BPI-SF–measured levels of pain interference in daily activities (Table 2). Moreover, a domain analysis showed that there were no statistically significant differences in pain interference scores when comparing the type and extent of surgery (total mastectomy: 0.59 [1.17]; lumpectomy: 0.94 [1.96]). By chance – and not related directly to the objectives of this study – there was a statistically significant difference between the intervention and control groups in the interference of pain on the Enjoyment of Life domain in favor of the control group.

The sites of pain captured by the BPI-SF shed light on the preceding findings (Figure 1). At baseline (T1, postsurgery and preradiation), 37.0% of participants reported pain in the shoulder girdle–chest wall region, whereas 20.4% reported pain in the general neck–upper extremity region and 50% in other regions. Postradiation, shoulder girdle–chest wall pain was identified as the highest reported site of pain (49.1%; T2, postradiation and preintervention) and remained elevated at 3 months (T3) and 6 months (T4) postradiation (46.9% and 45.5%, respectively). At 12 and 18 months postradiation (T5 and T6), the principal focus of pain shifted once again to “other” regions at 30% and 32.5%, respectively, and the neck–upper extremity region at 10% and 15%, respectively. Shoulder girdle–chest wall pain concomitantly improved at those time points (15% and 25% respectively) but was not eliminated.

Pain levels recorded on physical examination for isolated shoulder range of movements were recently published,²⁴ and they have been abbreviated and reproduced in this paper (Figure 2) to allow for a comparison of findings between the exercise intervention group and the control group to help determine the sensitivity of these tools for use in breast cancer patients. At baseline, pain levels with active movement were noted to be slightly greater in the intervention group for flexion and abduction.

Following the intervention, at 3 and 6 months postradiation (T3 and T4), the intervention group showed a steady decrease in pain levels in flexion and abduction, whereas the control group showed a 5-fold increase in pain with horizontal abduction. Furthermore, participants in the intervention group reported having no pain on movement 12 months postradiation (T5); however, recurrence of pain was apparent with all shoulder movements by 18 months postradiation (T6) in both the intervention and control groups.
 

Discussion

Previous studies have hypothesized that younger age (18-39 years), adjuvant radiotherapy, and axillary node dissection are risk factors for chronic pain in breast cancer survivors.^22,25 Persistent pain is prevalent in 12% to 51% of breast cancer survivors, with up to one-third experiencing some pain more than 5 years after treatment,^26,27 and our study outcomes concur with those findings. In our study, pain, as measured by the BPI-SF, was found to persist for most participants (75.6%) after the 18-month follow-up. The results of our trial showed that a 12-week exercise intervention administered postsurgery and postradiation had no statistically significant effect on long-term (18 months) pain severity and its interference in daily life. It is worth noting that body regions that had not been directly related to either surgical or radiation treatment for breast cancer were commonly identified as areas of pain but were not specifically targeted by our intervention. However, focusing on pain severity (BPI-SF), our findings suggest that the benefits of targeted upper-extremity exercise on pain in the intermediate time course of follow-up (T3, T4, and T5) was notable compared with the control group, which received standard care. The apparent recurrence of pain at 18 months in both groups was not anticipated and needs to be further investigated.

 

More specific objective assessments of pain on active shoulder movement identified distinct patterns of pain that could not be isolated using the BPI-SF alone. The incidence and localization of pain on movement differed between the population of women who received a specific exercise intervention and those who received standard care (Figure 2). Patterns of pain over time fluctuated in the control group, whereas the intervention group reported a linear decrease in pain. Residual pain on shoulder movement remained apparent in both groups at 18-months postradiation, but that finding was not reflected in the BPI-SF results. The literature supports our findings on persistent pain among breast cancer survivors,^3,7,8,28-30 and in our study of young women carefully screened and excluded for pre-existent shoulder conditions or comorbid medical conditions, recurrent articular pain was nonetheless prevalent. It seems that unidentified or multiple factors may be part of the etiology of pain in this young adult cohort.

Although the BPI-SF is a generic measurement tool commonly used to assess and measure cancer patients’ pain levels, the lack of variance in our BPI-SF severity and interference outcomes over time (T1-T6) (Table 1, Table 2), the variety of “other” unrelated regions (Figure 1) identified by the BPI-SF, and the contrast in our findings on specific physical examination emphasize the potential limitations of this clinical tool.

Moreover, the BPI-SF has not been validated specifically for breast cancer. Harrington and colleagues have recommended using the BPI-SF to assess pain in women with breast cancer,³¹ but the use of a more multidimensional measurement tool that evaluates axillary, chest, trunk, and upper-limb pain may prove to be more valuable in this population.

Limitations

Recruitment of young adult women was difficult because of our stringent inclusion criteria, the long-term follow-up, and the relatively small population of breast cancer patients in this age demographic. Therefore, the duration of the recruitment phase, despite our having access to a specialized young adult and adolescent clinic in our institute, greatly surpassed the expectations we had when we designed the study. In addition, there remains an inherent bias in participants who accept participation in a study that includes exercise interventions. Potential participants who exercise regularly or have a positive inclination toward doing exercise are more likely to participate. Despite the prescription of a targeted 12-week upper-limb intervention in this study, the general activity levels of both groups may have had an impact on the significance of this study. In addition, the low adherence to the use of self-reported logs failed to capture the true compliance rates of our participants because their lack of tracking does not indicate failure to comply with the program. The use of weekly or biweekly telephone calls to monitor compliance rates of activity more vigilantly may be used in future studies.

Conclusions

Advances in clinical management of breast cancer have improved survival outcomes, and morbidity over recent years, yet symptoms such as pain remain prevalent in this population. The results of this study showed that a targeted, 12-week upper-limb exercise intervention postradiation transiently improved levels of shoulder pain without a concomitant impact on chronic pain or any positive influence on activities of daily living 18 months posttreatment. Furthermore, future studies should use a variety of measurement tools to evaluate trunk and upper-limb pain in women with breast cancer and investigate the optimal timing of postradiation exercise interventions.

Acknowledgments

The authors thank Hope & Cope, the CURE foundation, and the Jewish General Hospital Foundation/Weekend to End Breast Cancer for providing the financial resources needed to sustain this research study. They also thank the McGill Adolescent and Young Adult program for its continued support. Previous oral presentations of research Muanza TM, et al. Randomized clinical trial of a progressive exercise program for young women with breast cancer undergoing radiation therapy. Int J Radiat Oncol Biol Phys. 2015;93(3):s35-s36.

Breast cancer is one of the most prevalent cancers in women worldwide, with more than 1 million new cases diagnosed annually.¹ Prognosis for the disease has improved significantly, but 25% to 60% of women living with breast cancer experience some level of pain ranging from mild to severe, the nature of which can evolve from acute to chronic.² Pre-, intra-, and post-treatment risk factors have been found to correlate with the development of acute and chronic pain and include young age, type of breast surgery (lumpectomy or total mastectomy), axillary node dissection, radiation therapy, and hormonal therapy.^3-5 Chemotherapy, particularly anthracycline- and taxane-based regimens, has also been shown to induce pain, arthralgia, myalgia, and peripheral neuropathy during treatment.⁶ In particular, postradiation pain may result from subcutaneous fibrosis with fixation to underlying musculature and the development of fibrous flaps in the internal axilla.⁷ These tissue changes are commonly subclinical, occurring 4 to 12 months postradiation,⁸ and can progress undetected until pain and upper-limb disability develop.

The presence of persistent pain has a considerable impact on the quality of life in survivors of breast cancer: psychological distress is prevalent (anxiety, depression, worry, fear), the performance of daily activities is diminished (eg, bathing, dressing, preparing meals, shopping), and economic independence is compromised by the inability to work or reduced employment and income. These factors directly and indirectly contribute to an increase in the use of health care services.^9,10

The management of pain is often characterized by pharmacologic-related treatment, such as the use of opioids and nonsteroidal anti-inflammatory medications, and nonpharmacologic-related treatment, such as exercise. Empirical evidence has shown that rehabilitative exercise programs, which commonly include a combination of resistance training and aerobic exercises, can effectively reduce pain in breast cancer survivors.^10-12 Women living with breast cancer who are directed to rehabilitative exercise programs experience an improvement not only in pain levels but also in their ability to engage in activities of daily living, in their psychological health, and in their overall quality of life.^13-15 However, despite evidence to support exercise programs to reduce pain related to breast cancer treatment, residual pain and upper-limb discomfort are common complaints in breast cancer survivors, and there is little focus on the duration of effectiveness of such programs for reducing pain after treatment for breast cancer. The objective of this study was to determine if an exercise program initiated postradiation would improve long-term pain levels in a carefully selected population of young women who were living with breast cancer and had no history of shoulder pathology or significant treatment complications.
 

Methods

Design

We used a pilot randomized control trial to compare the long-term effectiveness of a 12-week postradiation exercise program versus standard care on residual pain levels in young women (aged 18-45 years) living with breast cancer. The program was initiated 3 to 4 weeks postradiation to allow for acute inflammatory reactions to subside. Pain severity and interference were assessed using the Brief Pain Inventory-Short Form (BPI-SF), a tool for assessing cancer pain.^16,17 Pain levels for isolated shoulder movements were also recorded on examination by a physical therapist. All measures were collected at 6 time points (T1-T6): postsurgery and preradiation (T1, baseline), postradiation and preintervention (T2), and 4 points during an 18-month period postradiation (T3-T6 at 3, 6, 12, and 18 months postradiation).
 

Sample

Young women living with breast cancer who met our eligibility criteria were identified from 2 clinics at the Jewish General Hospital – the Segal Cancer Center and the Department of Radiation Oncology in Montréal, Québec, Canada. Inclusion criteria included women with a diagnosis of stage I to stage III breast cancer, who were 18 to 45 years old, were scheduled for postoperative adjuvant radiation therapy, had an Eastern Cooperative Oncology Group Performance Status of 0 or 1 (normal ambulatory function, minimal symptoms), and who consented to participate in the study. Exclusion criteria included women with a metastatic (stage IV) diagnosis; significant musculoskeletal, cardiac, pulmonary, or metabolic comorbidities that would not allow for participation in physical activity; a previous breast cancer diagnosis with treatment to the ipsilateral or contralateral sides; postsurgical lymphedema; postsurgical capsulitis, tendonitis, or other shoulder inflammatory complications; and any contraindication to exercise. The recruitment goal was outlined as 50 patients per group; however, a protracted accrual time because of the stringent study criteria yielded a sample of 29 and 30 patients for the intervention and control groups, respectively, which was sufficient for significant testing of differences between the 2 study groups.¹⁸
 

Variables and measures

 

Clinical characteristics. We used standardized questions and chart review to document the participants’ clinical characteristics and to capture information on the following: the stage and subtype of breast cancer, hormonal and human epidermal growth factor receptors (HER2) (estrogen receptor, progesterone receptor, and HER2 status), extent of surgery (lumpectomy or total mastectomy), and other modalities of treatment (eg, chemotherapy, radiation therapy).

Pain assessment. The BPI-SF was used to assess participants’ cancer-related pain. Pain severity ranged from 0 (no pain), 1 to 4 (mild pain), 5 to 6 (moderate pain), to 7 to 10 (severe pain).^18,19 The questionnaire also identifies the pain interference in daily activities using a Likert scale ranging from 0 (Does not interfere) to 10 (Completely interferes) in the following 7 domains or subscales: General Activity, Walking, Mood, Sleep, Work, Relations with Others, and Enjoyment of Life.¹⁶ For the purpose of this study, mean scores were tabulated using both pain intensity and interference scales.

Another important component of the BPI-SF instructs participants to localize pain by means of a body diagram. For purpose of analysis, 3 pain regions were established: shoulder girdle/chest wall on the affected side; neck and other upper extremity, including hand(s), forearm(s), wrist(s), and finger(s); and other regions, including abdominal discomfort, leg(s), hip(s), knee(s), ankle(s), lower back, and feet. In addition, pain levels on movement (Yes/No) were recorded for isolated shoulder flexion, abduction, and horizontal abduction (sitting and standing). The measurements were completed by a single physical therapist throughout the course of the study to minimize variance.

Procedure

The study protocol was approved by the Research Ethics Board at the Jewish General Hospital. Recruitment occurred from 2011 through 2015. The research was in accordance with the ethical standards of the responsible committee on human experimentation. Eligible women were recruited by the research coordinator who described the purpose, risks, and benefits of the study; advised on confidentiality, data collection, and intervention allocation procedures; and highlighted voluntary participation. The research coordinator addressed any concerns on the part of the participants before obtaining their written informed consent. Random allocation to the intervention and control groups was established using a web-based randomization plan generator (www.randomization.com). A single individual was responsible for the randomization process, and treatment assignments were revealed after each participant’s name had been entered. A physical therapist performed 6 sequential evaluations (T1-T6) at the time of participants’ medical follow-up appointments.

Intervention

The 12-week exercise intervention started 3 weeks postradiation and was composed of an initial 6-week program of low-level cardiovascular and resistance exercises that progressed to a set of more advanced exercises for the remaining 6 weeks. Participants were instructed to warm up for at least 10 minutes with a cardiovascular exercise of their choice (eg, a recumbent cross trainer, walking, or stairs) before doing a combined strength, endurance, and stretching exercise program for the upper body.²⁰ The final portion of the exercise intervention included a period of light cool-down. Weight training resistance levels were based on a maximum 8 to 10 repetitions for strength and a maximum of 20 repetitions for endurance training exercises, which progressed gradually over the course of the 12-week exercise program to ensure participant safety.^21,22 Participants in the intervention group were supervised at least once a week by an exercise physiologist at a center for oncology patients (Hope & Cope Wellness Centre), and patients were encouraged to perform the program at home 2 to 3 times a week. Those who were not able to exercise consistently at the center were provided with equipment and instructed on how to do the program safely at home.

By comparison, the control group received standard care, which included advice on the benefits of an active lifestyle, including exercise, but without a specific intervention. Participants were not restricted in their physical activity and/or sport participation levels, and their weekly activity levels were calculated using the Metabolic Equivalent of Task and recorded at each of the 6 time points.

Statistical analysis

Descriptive statistics were used to examine participant characteristics. The quantitative data collected through the BPI-SF measures were analyzed with JMP software (version 11.2; SAS Institute, Cary, NC). Continuous variables were tested for statistical significance (P ≤ .05) through the chi-square (categorical), analysis of variance, and nonparametric Wilcoxon tests. The analyses did not include missing data.

Results

A total of 59 young women were randomized into the intervention (n = 29) and control (n = 30) groups. Of those, 2 participants dropped out of the study because of family and time constraints, and 3 participants died, 2 from the control and 1 from the intervention group, after subsequently developing metastatic disease. Baseline data including comparative tumor characteristics, surgical interventions, and treatment interventions have been published in relation to other elements of this study.^23,24 The participants had a mean age of 39.2 years (standard deviation [SD], 5.0). More than half of them had an invasive ductal carcinoma (69.5%) and were estrogen positive (78.0%), progesterone positive (74.6%), or HER2 positive (20.3%), whereas 10.2% were triple negative. Most of the participants had undergone breast-sparing procedures (86.4% lumpectomy), and 18.6% had a total mastectomy. By random chance, the intervention group had higher rates of total mastectomy (24.4% and 13.3%, respectively) and surgical reconstruction (12.2% and 6.7%, respectively) compared with the control group. Most of the women (71.2%) received chemotherapy, and all received radiation therapy. In the intervention group, 37.2% received radiation therapy localized to the axilla, and 88% received a boost of radiation to the surgical bed. Self-reported exercise diaries were returned by 15 of the 29 intervention participants, and training frequencies among them varied significantly (1-6 times a week).

 

The findings showed that there was little variance between the intervention and control groups in BPI-SF severity scores from T1 to T6, so the means and SDs of the BPI-SF scores were grouped at 6 time points (Table 1). There was no statistically significant difference between baseline measures at T1 (1.68; SD, 1.17) and measures at 18 months postintervention (T6: 1.46; SD, 1.37). At baseline, 87.7% of the women reported no pain (31.5%) or mild levels of pain (55.6%), and 13% reported moderate or severe pain. Over the duration of the study from T1 to T6, these primarily low levels of pain (BPI-SF, 0-4) remained consistent with a favorable shift toward having no pain (T1: 31.5%; T6: 24.4%). By 18 months postintervention, 95.7% of women reported no or mild pain, with 4.9% reporting moderate pain.

Similarly, there was little variance over time (T1-T6) and no statistically significant differences between the 2 groups in BPI-SF–measured levels of pain interference in daily activities (Table 2). Moreover, a domain analysis showed that there were no statistically significant differences in pain interference scores when comparing the type and extent of surgery (total mastectomy: 0.59 [1.17]; lumpectomy: 0.94 [1.96]). By chance – and not related directly to the objectives of this study – there was a statistically significant difference between the intervention and control groups in the interference of pain on the Enjoyment of Life domain in favor of the control group.

The sites of pain captured by the BPI-SF shed light on the preceding findings (Figure 1). At baseline (T1, postsurgery and preradiation), 37.0% of participants reported pain in the shoulder girdle–chest wall region, whereas 20.4% reported pain in the general neck–upper extremity region and 50% in other regions. Postradiation, shoulder girdle–chest wall pain was identified as the highest reported site of pain (49.1%; T2, postradiation and preintervention) and remained elevated at 3 months (T3) and 6 months (T4) postradiation (46.9% and 45.5%, respectively). At 12 and 18 months postradiation (T5 and T6), the principal focus of pain shifted once again to “other” regions at 30% and 32.5%, respectively, and the neck–upper extremity region at 10% and 15%, respectively. Shoulder girdle–chest wall pain concomitantly improved at those time points (15% and 25% respectively) but was not eliminated.

Pain levels recorded on physical examination for isolated shoulder range of movements were recently published,²⁴ and they have been abbreviated and reproduced in this paper (Figure 2) to allow for a comparison of findings between the exercise intervention group and the control group to help determine the sensitivity of these tools for use in breast cancer patients. At baseline, pain levels with active movement were noted to be slightly greater in the intervention group for flexion and abduction.

Following the intervention, at 3 and 6 months postradiation (T3 and T4), the intervention group showed a steady decrease in pain levels in flexion and abduction, whereas the control group showed a 5-fold increase in pain with horizontal abduction. Furthermore, participants in the intervention group reported having no pain on movement 12 months postradiation (T5); however, recurrence of pain was apparent with all shoulder movements by 18 months postradiation (T6) in both the intervention and control groups.
 

Discussion

Previous studies have hypothesized that younger age (18-39 years), adjuvant radiotherapy, and axillary node dissection are risk factors for chronic pain in breast cancer survivors.^22,25 Persistent pain is prevalent in 12% to 51% of breast cancer survivors, with up to one-third experiencing some pain more than 5 years after treatment,^26,27 and our study outcomes concur with those findings. In our study, pain, as measured by the BPI-SF, was found to persist for most participants (75.6%) after the 18-month follow-up. The results of our trial showed that a 12-week exercise intervention administered postsurgery and postradiation had no statistically significant effect on long-term (18 months) pain severity and its interference in daily life. It is worth noting that body regions that had not been directly related to either surgical or radiation treatment for breast cancer were commonly identified as areas of pain but were not specifically targeted by our intervention. However, focusing on pain severity (BPI-SF), our findings suggest that the benefits of targeted upper-extremity exercise on pain in the intermediate time course of follow-up (T3, T4, and T5) was notable compared with the control group, which received standard care. The apparent recurrence of pain at 18 months in both groups was not anticipated and needs to be further investigated.

 

More specific objective assessments of pain on active shoulder movement identified distinct patterns of pain that could not be isolated using the BPI-SF alone. The incidence and localization of pain on movement differed between the population of women who received a specific exercise intervention and those who received standard care (Figure 2). Patterns of pain over time fluctuated in the control group, whereas the intervention group reported a linear decrease in pain. Residual pain on shoulder movement remained apparent in both groups at 18-months postradiation, but that finding was not reflected in the BPI-SF results. The literature supports our findings on persistent pain among breast cancer survivors,^3,7,8,28-30 and in our study of young women carefully screened and excluded for pre-existent shoulder conditions or comorbid medical conditions, recurrent articular pain was nonetheless prevalent. It seems that unidentified or multiple factors may be part of the etiology of pain in this young adult cohort.

Although the BPI-SF is a generic measurement tool commonly used to assess and measure cancer patients’ pain levels, the lack of variance in our BPI-SF severity and interference outcomes over time (T1-T6) (Table 1, Table 2), the variety of “other” unrelated regions (Figure 1) identified by the BPI-SF, and the contrast in our findings on specific physical examination emphasize the potential limitations of this clinical tool.

Moreover, the BPI-SF has not been validated specifically for breast cancer. Harrington and colleagues have recommended using the BPI-SF to assess pain in women with breast cancer,³¹ but the use of a more multidimensional measurement tool that evaluates axillary, chest, trunk, and upper-limb pain may prove to be more valuable in this population.

Limitations

Recruitment of young adult women was difficult because of our stringent inclusion criteria, the long-term follow-up, and the relatively small population of breast cancer patients in this age demographic. Therefore, the duration of the recruitment phase, despite our having access to a specialized young adult and adolescent clinic in our institute, greatly surpassed the expectations we had when we designed the study. In addition, there remains an inherent bias in participants who accept participation in a study that includes exercise interventions. Potential participants who exercise regularly or have a positive inclination toward doing exercise are more likely to participate. Despite the prescription of a targeted 12-week upper-limb intervention in this study, the general activity levels of both groups may have had an impact on the significance of this study. In addition, the low adherence to the use of self-reported logs failed to capture the true compliance rates of our participants because their lack of tracking does not indicate failure to comply with the program. The use of weekly or biweekly telephone calls to monitor compliance rates of activity more vigilantly may be used in future studies.

Conclusions

Advances in clinical management of breast cancer have improved survival outcomes, and morbidity over recent years, yet symptoms such as pain remain prevalent in this population. The results of this study showed that a targeted, 12-week upper-limb exercise intervention postradiation transiently improved levels of shoulder pain without a concomitant impact on chronic pain or any positive influence on activities of daily living 18 months posttreatment. Furthermore, future studies should use a variety of measurement tools to evaluate trunk and upper-limb pain in women with breast cancer and investigate the optimal timing of postradiation exercise interventions.

Acknowledgments

The authors thank Hope & Cope, the CURE foundation, and the Jewish General Hospital Foundation/Weekend to End Breast Cancer for providing the financial resources needed to sustain this research study. They also thank the McGill Adolescent and Young Adult program for its continued support. Previous oral presentations of research Muanza TM, et al. Randomized clinical trial of a progressive exercise program for young women with breast cancer undergoing radiation therapy. Int J Radiat Oncol Biol Phys. 2015;93(3):s35-s36.

Breast cancer is one of the most prevalent cancers in women worldwide, with more than 1 million new cases diagnosed annually.¹ Prognosis for the disease has improved significantly, but 25% to 60% of women living with breast cancer experience some level of pain ranging from mild to severe, the nature of which can evolve from acute to chronic.² Pre-, intra-, and post-treatment risk factors have been found to correlate with the development of acute and chronic pain and include young age, type of breast surgery (lumpectomy or total mastectomy), axillary node dissection, radiation therapy, and hormonal therapy.^3-5 Chemotherapy, particularly anthracycline- and taxane-based regimens, has also been shown to induce pain, arthralgia, myalgia, and peripheral neuropathy during treatment.⁶ In particular, postradiation pain may result from subcutaneous fibrosis with fixation to underlying musculature and the development of fibrous flaps in the internal axilla.⁷ These tissue changes are commonly subclinical, occurring 4 to 12 months postradiation,⁸ and can progress undetected until pain and upper-limb disability develop.

The presence of persistent pain has a considerable impact on the quality of life in survivors of breast cancer: psychological distress is prevalent (anxiety, depression, worry, fear), the performance of daily activities is diminished (eg, bathing, dressing, preparing meals, shopping), and economic independence is compromised by the inability to work or reduced employment and income. These factors directly and indirectly contribute to an increase in the use of health care services.^9,10

The management of pain is often characterized by pharmacologic-related treatment, such as the use of opioids and nonsteroidal anti-inflammatory medications, and nonpharmacologic-related treatment, such as exercise. Empirical evidence has shown that rehabilitative exercise programs, which commonly include a combination of resistance training and aerobic exercises, can effectively reduce pain in breast cancer survivors.^10-12 Women living with breast cancer who are directed to rehabilitative exercise programs experience an improvement not only in pain levels but also in their ability to engage in activities of daily living, in their psychological health, and in their overall quality of life.^13-15 However, despite evidence to support exercise programs to reduce pain related to breast cancer treatment, residual pain and upper-limb discomfort are common complaints in breast cancer survivors, and there is little focus on the duration of effectiveness of such programs for reducing pain after treatment for breast cancer. The objective of this study was to determine if an exercise program initiated postradiation would improve long-term pain levels in a carefully selected population of young women who were living with breast cancer and had no history of shoulder pathology or significant treatment complications.
 

Methods

Design

We used a pilot randomized control trial to compare the long-term effectiveness of a 12-week postradiation exercise program versus standard care on residual pain levels in young women (aged 18-45 years) living with breast cancer. The program was initiated 3 to 4 weeks postradiation to allow for acute inflammatory reactions to subside. Pain severity and interference were assessed using the Brief Pain Inventory-Short Form (BPI-SF), a tool for assessing cancer pain.^16,17 Pain levels for isolated shoulder movements were also recorded on examination by a physical therapist. All measures were collected at 6 time points (T1-T6): postsurgery and preradiation (T1, baseline), postradiation and preintervention (T2), and 4 points during an 18-month period postradiation (T3-T6 at 3, 6, 12, and 18 months postradiation).
 

Sample

Young women living with breast cancer who met our eligibility criteria were identified from 2 clinics at the Jewish General Hospital – the Segal Cancer Center and the Department of Radiation Oncology in Montréal, Québec, Canada. Inclusion criteria included women with a diagnosis of stage I to stage III breast cancer, who were 18 to 45 years old, were scheduled for postoperative adjuvant radiation therapy, had an Eastern Cooperative Oncology Group Performance Status of 0 or 1 (normal ambulatory function, minimal symptoms), and who consented to participate in the study. Exclusion criteria included women with a metastatic (stage IV) diagnosis; significant musculoskeletal, cardiac, pulmonary, or metabolic comorbidities that would not allow for participation in physical activity; a previous breast cancer diagnosis with treatment to the ipsilateral or contralateral sides; postsurgical lymphedema; postsurgical capsulitis, tendonitis, or other shoulder inflammatory complications; and any contraindication to exercise. The recruitment goal was outlined as 50 patients per group; however, a protracted accrual time because of the stringent study criteria yielded a sample of 29 and 30 patients for the intervention and control groups, respectively, which was sufficient for significant testing of differences between the 2 study groups.¹⁸
 

Variables and measures

 

Clinical characteristics. We used standardized questions and chart review to document the participants’ clinical characteristics and to capture information on the following: the stage and subtype of breast cancer, hormonal and human epidermal growth factor receptors (HER2) (estrogen receptor, progesterone receptor, and HER2 status), extent of surgery (lumpectomy or total mastectomy), and other modalities of treatment (eg, chemotherapy, radiation therapy).

Pain assessment. The BPI-SF was used to assess participants’ cancer-related pain. Pain severity ranged from 0 (no pain), 1 to 4 (mild pain), 5 to 6 (moderate pain), to 7 to 10 (severe pain).^18,19 The questionnaire also identifies the pain interference in daily activities using a Likert scale ranging from 0 (Does not interfere) to 10 (Completely interferes) in the following 7 domains or subscales: General Activity, Walking, Mood, Sleep, Work, Relations with Others, and Enjoyment of Life.¹⁶ For the purpose of this study, mean scores were tabulated using both pain intensity and interference scales.

Another important component of the BPI-SF instructs participants to localize pain by means of a body diagram. For purpose of analysis, 3 pain regions were established: shoulder girdle/chest wall on the affected side; neck and other upper extremity, including hand(s), forearm(s), wrist(s), and finger(s); and other regions, including abdominal discomfort, leg(s), hip(s), knee(s), ankle(s), lower back, and feet. In addition, pain levels on movement (Yes/No) were recorded for isolated shoulder flexion, abduction, and horizontal abduction (sitting and standing). The measurements were completed by a single physical therapist throughout the course of the study to minimize variance.

Procedure

The study protocol was approved by the Research Ethics Board at the Jewish General Hospital. Recruitment occurred from 2011 through 2015. The research was in accordance with the ethical standards of the responsible committee on human experimentation. Eligible women were recruited by the research coordinator who described the purpose, risks, and benefits of the study; advised on confidentiality, data collection, and intervention allocation procedures; and highlighted voluntary participation. The research coordinator addressed any concerns on the part of the participants before obtaining their written informed consent. Random allocation to the intervention and control groups was established using a web-based randomization plan generator (www.randomization.com). A single individual was responsible for the randomization process, and treatment assignments were revealed after each participant’s name had been entered. A physical therapist performed 6 sequential evaluations (T1-T6) at the time of participants’ medical follow-up appointments.

Intervention

The 12-week exercise intervention started 3 weeks postradiation and was composed of an initial 6-week program of low-level cardiovascular and resistance exercises that progressed to a set of more advanced exercises for the remaining 6 weeks. Participants were instructed to warm up for at least 10 minutes with a cardiovascular exercise of their choice (eg, a recumbent cross trainer, walking, or stairs) before doing a combined strength, endurance, and stretching exercise program for the upper body.²⁰ The final portion of the exercise intervention included a period of light cool-down. Weight training resistance levels were based on a maximum 8 to 10 repetitions for strength and a maximum of 20 repetitions for endurance training exercises, which progressed gradually over the course of the 12-week exercise program to ensure participant safety.^21,22 Participants in the intervention group were supervised at least once a week by an exercise physiologist at a center for oncology patients (Hope & Cope Wellness Centre), and patients were encouraged to perform the program at home 2 to 3 times a week. Those who were not able to exercise consistently at the center were provided with equipment and instructed on how to do the program safely at home.

By comparison, the control group received standard care, which included advice on the benefits of an active lifestyle, including exercise, but without a specific intervention. Participants were not restricted in their physical activity and/or sport participation levels, and their weekly activity levels were calculated using the Metabolic Equivalent of Task and recorded at each of the 6 time points.

Statistical analysis

Descriptive statistics were used to examine participant characteristics. The quantitative data collected through the BPI-SF measures were analyzed with JMP software (version 11.2; SAS Institute, Cary, NC). Continuous variables were tested for statistical significance (P ≤ .05) through the chi-square (categorical), analysis of variance, and nonparametric Wilcoxon tests. The analyses did not include missing data.

Results

A total of 59 young women were randomized into the intervention (n = 29) and control (n = 30) groups. Of those, 2 participants dropped out of the study because of family and time constraints, and 3 participants died, 2 from the control and 1 from the intervention group, after subsequently developing metastatic disease. Baseline data including comparative tumor characteristics, surgical interventions, and treatment interventions have been published in relation to other elements of this study.^23,24 The participants had a mean age of 39.2 years (standard deviation [SD], 5.0). More than half of them had an invasive ductal carcinoma (69.5%) and were estrogen positive (78.0%), progesterone positive (74.6%), or HER2 positive (20.3%), whereas 10.2% were triple negative. Most of the participants had undergone breast-sparing procedures (86.4% lumpectomy), and 18.6% had a total mastectomy. By random chance, the intervention group had higher rates of total mastectomy (24.4% and 13.3%, respectively) and surgical reconstruction (12.2% and 6.7%, respectively) compared with the control group. Most of the women (71.2%) received chemotherapy, and all received radiation therapy. In the intervention group, 37.2% received radiation therapy localized to the axilla, and 88% received a boost of radiation to the surgical bed. Self-reported exercise diaries were returned by 15 of the 29 intervention participants, and training frequencies among them varied significantly (1-6 times a week).

 

The findings showed that there was little variance between the intervention and control groups in BPI-SF severity scores from T1 to T6, so the means and SDs of the BPI-SF scores were grouped at 6 time points (Table 1). There was no statistically significant difference between baseline measures at T1 (1.68; SD, 1.17) and measures at 18 months postintervention (T6: 1.46; SD, 1.37). At baseline, 87.7% of the women reported no pain (31.5%) or mild levels of pain (55.6%), and 13% reported moderate or severe pain. Over the duration of the study from T1 to T6, these primarily low levels of pain (BPI-SF, 0-4) remained consistent with a favorable shift toward having no pain (T1: 31.5%; T6: 24.4%). By 18 months postintervention, 95.7% of women reported no or mild pain, with 4.9% reporting moderate pain.

Similarly, there was little variance over time (T1-T6) and no statistically significant differences between the 2 groups in BPI-SF–measured levels of pain interference in daily activities (Table 2). Moreover, a domain analysis showed that there were no statistically significant differences in pain interference scores when comparing the type and extent of surgery (total mastectomy: 0.59 [1.17]; lumpectomy: 0.94 [1.96]). By chance – and not related directly to the objectives of this study – there was a statistically significant difference between the intervention and control groups in the interference of pain on the Enjoyment of Life domain in favor of the control group.

The sites of pain captured by the BPI-SF shed light on the preceding findings (Figure 1). At baseline (T1, postsurgery and preradiation), 37.0% of participants reported pain in the shoulder girdle–chest wall region, whereas 20.4% reported pain in the general neck–upper extremity region and 50% in other regions. Postradiation, shoulder girdle–chest wall pain was identified as the highest reported site of pain (49.1%; T2, postradiation and preintervention) and remained elevated at 3 months (T3) and 6 months (T4) postradiation (46.9% and 45.5%, respectively). At 12 and 18 months postradiation (T5 and T6), the principal focus of pain shifted once again to “other” regions at 30% and 32.5%, respectively, and the neck–upper extremity region at 10% and 15%, respectively. Shoulder girdle–chest wall pain concomitantly improved at those time points (15% and 25% respectively) but was not eliminated.

Pain levels recorded on physical examination for isolated shoulder range of movements were recently published,²⁴ and they have been abbreviated and reproduced in this paper (Figure 2) to allow for a comparison of findings between the exercise intervention group and the control group to help determine the sensitivity of these tools for use in breast cancer patients. At baseline, pain levels with active movement were noted to be slightly greater in the intervention group for flexion and abduction.

Following the intervention, at 3 and 6 months postradiation (T3 and T4), the intervention group showed a steady decrease in pain levels in flexion and abduction, whereas the control group showed a 5-fold increase in pain with horizontal abduction. Furthermore, participants in the intervention group reported having no pain on movement 12 months postradiation (T5); however, recurrence of pain was apparent with all shoulder movements by 18 months postradiation (T6) in both the intervention and control groups.
 

Discussion

Previous studies have hypothesized that younger age (18-39 years), adjuvant radiotherapy, and axillary node dissection are risk factors for chronic pain in breast cancer survivors.^22,25 Persistent pain is prevalent in 12% to 51% of breast cancer survivors, with up to one-third experiencing some pain more than 5 years after treatment,^26,27 and our study outcomes concur with those findings. In our study, pain, as measured by the BPI-SF, was found to persist for most participants (75.6%) after the 18-month follow-up. The results of our trial showed that a 12-week exercise intervention administered postsurgery and postradiation had no statistically significant effect on long-term (18 months) pain severity and its interference in daily life. It is worth noting that body regions that had not been directly related to either surgical or radiation treatment for breast cancer were commonly identified as areas of pain but were not specifically targeted by our intervention. However, focusing on pain severity (BPI-SF), our findings suggest that the benefits of targeted upper-extremity exercise on pain in the intermediate time course of follow-up (T3, T4, and T5) was notable compared with the control group, which received standard care. The apparent recurrence of pain at 18 months in both groups was not anticipated and needs to be further investigated.

 

More specific objective assessments of pain on active shoulder movement identified distinct patterns of pain that could not be isolated using the BPI-SF alone. The incidence and localization of pain on movement differed between the population of women who received a specific exercise intervention and those who received standard care (Figure 2). Patterns of pain over time fluctuated in the control group, whereas the intervention group reported a linear decrease in pain. Residual pain on shoulder movement remained apparent in both groups at 18-months postradiation, but that finding was not reflected in the BPI-SF results. The literature supports our findings on persistent pain among breast cancer survivors,^3,7,8,28-30 and in our study of young women carefully screened and excluded for pre-existent shoulder conditions or comorbid medical conditions, recurrent articular pain was nonetheless prevalent. It seems that unidentified or multiple factors may be part of the etiology of pain in this young adult cohort.

Although the BPI-SF is a generic measurement tool commonly used to assess and measure cancer patients’ pain levels, the lack of variance in our BPI-SF severity and interference outcomes over time (T1-T6) (Table 1, Table 2), the variety of “other” unrelated regions (Figure 1) identified by the BPI-SF, and the contrast in our findings on specific physical examination emphasize the potential limitations of this clinical tool.

Moreover, the BPI-SF has not been validated specifically for breast cancer. Harrington and colleagues have recommended using the BPI-SF to assess pain in women with breast cancer,³¹ but the use of a more multidimensional measurement tool that evaluates axillary, chest, trunk, and upper-limb pain may prove to be more valuable in this population.

Limitations

Recruitment of young adult women was difficult because of our stringent inclusion criteria, the long-term follow-up, and the relatively small population of breast cancer patients in this age demographic. Therefore, the duration of the recruitment phase, despite our having access to a specialized young adult and adolescent clinic in our institute, greatly surpassed the expectations we had when we designed the study. In addition, there remains an inherent bias in participants who accept participation in a study that includes exercise interventions. Potential participants who exercise regularly or have a positive inclination toward doing exercise are more likely to participate. Despite the prescription of a targeted 12-week upper-limb intervention in this study, the general activity levels of both groups may have had an impact on the significance of this study. In addition, the low adherence to the use of self-reported logs failed to capture the true compliance rates of our participants because their lack of tracking does not indicate failure to comply with the program. The use of weekly or biweekly telephone calls to monitor compliance rates of activity more vigilantly may be used in future studies.

Conclusions

Advances in clinical management of breast cancer have improved survival outcomes, and morbidity over recent years, yet symptoms such as pain remain prevalent in this population. The results of this study showed that a targeted, 12-week upper-limb exercise intervention postradiation transiently improved levels of shoulder pain without a concomitant impact on chronic pain or any positive influence on activities of daily living 18 months posttreatment. Furthermore, future studies should use a variety of measurement tools to evaluate trunk and upper-limb pain in women with breast cancer and investigate the optimal timing of postradiation exercise interventions.

Acknowledgments

The authors thank Hope & Cope, the CURE foundation, and the Jewish General Hospital Foundation/Weekend to End Breast Cancer for providing the financial resources needed to sustain this research study. They also thank the McGill Adolescent and Young Adult program for its continued support. Previous oral presentations of research Muanza TM, et al. Randomized clinical trial of a progressive exercise program for young women with breast cancer undergoing radiation therapy. Int J Radiat Oncol Biol Phys. 2015;93(3):s35-s36.