Effect of Home-Based Exercise and Weight Loss Programs on Breast Cancer–Related Lymphedema Outcomes Among Overweight Breast Cancer Survivors: The WISER Survivor Randomized Clinical Trial | Breast Cancer | JAMA Oncology | JAMA Network
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Figure.  CONSORT Diagram
CONSORT Diagram
Table 1.  Baseline Characteristics of the 351 Study Participants
Baseline Characteristics of the 351 Study Participants
Table 2.  Arm Swelling Outcomes
Arm Swelling Outcomes
Table 3.  Clinical and Self-reported Lymphedema Outcomes
Clinical and Self-reported Lymphedema Outcomes
1.
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Fu  MR, Deng  J, Armer  JM.  Putting evidence into practice: cancer-related lymphedema: evolving evidence for treatment and management from 2009-2014.  Clin J Oncol Nurs. 2014;18(6):68-79. doi:10.1188/14.CJON.S3.68-79PubMedGoogle ScholarCrossref
16.
Schmitz  KH, Ahmed  RL, Troxel  A,  et al.  Weight lifting in women with breast-cancer–related lymphedema.  N Engl J Med. 2009;361(7):664-673. doi:10.1056/NEJMoa0810118PubMedGoogle ScholarCrossref
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Shaw  C, Mortimer  P, Judd  PA.  A randomized controlled trial of weight reduction as a treatment for breast cancer–related lymphedema.  Cancer. 2007;110(8):1868-1874. doi:10.1002/cncr.22994PubMedGoogle ScholarCrossref
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Shaw  C, Mortimer  P, Judd  PA.  Randomized controlled trial comparing a low-fat diet with a weight-reduction diet in breast cancer–related lymphedema.  Cancer. 2007;109(10):1949-1956. doi:10.1002/cncr.22638PubMedGoogle ScholarCrossref
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Sturgeon  KM, Hackley  R, Fornash  A,  et al.  Strategic recruitment of an ethnically diverse cohort of overweight survivors of breast cancer with lymphedema.  Cancer. 2018;124(1):95-104. doi:10.1002/cncr.30935PubMedGoogle ScholarCrossref
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Cheville  AL, McGarvey  CL, Petrek  JA, Russo  SA, Thiadens  SRJ, Taylor  ME.  The grading of lymphedema in oncology clinical trials.  Semin Radiat Oncol. 2003;13(3):214-225. doi:10.1016/S1053-4296(03)00038-9PubMedGoogle ScholarCrossref
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Original Investigation
August 15, 2019

Effect of Home-Based Exercise and Weight Loss Programs on Breast Cancer–Related Lymphedema Outcomes Among Overweight Breast Cancer Survivors: The WISER Survivor Randomized Clinical Trial

Author Affiliations
  • 1Department of Public Health Sciences, Pennsylvania State College of Medicine, Hershey
  • 2Department of Biostatistics, New York University School of Medicine, New York
  • 3Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland
  • 4Department of Hematology/Oncology, Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 5Department of Population and Public Health Sciences, Pennington Biomedical Research Center, Baton Rouge, Louisiana
  • 6Department of Radiology, Harlem Hospital Center, New York, New York
  • 7Department of Physical Therapy, Thomas Jefferson University, Philadelphia, Pennsylvania
  • 8Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 9Division of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
  • 10Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, Minnesota
  • 11Department of Social and Behavioral Sciences, Temple University, Philadelphia, Pennsylvania
JAMA Oncol. 2019;5(11):1605-1613. doi:10.1001/jamaoncol.2019.2109
Key Points

Question  Does weight loss and/or home-based exercise improve breast cancer–related lymphedema more than a supervised, facility-based lymphedema care (control) program previously shown to improve the symptoms and exacerbations of lymphedema?

Findings  In this randomized clinical trial of 351 overweight breast cancer survivors with lymphedema, control group, exercise intervention, weight loss intervention, and combined exercise and weight loss intervention status were not associated with significant between-group differences in the 12-month percentage of change in interlimb difference.

Meaning  Current results compared with previous research suggest that breast cancer survivors may find facility-based exercise more useful than home-based lymphedema care for improving the symptoms of lymphedema.

Abstract

Importance  To our knowledge, no randomized clinical trials have assessed the effects of the combination of weight loss and home-based exercise programs on lymphedema outcomes.

Objective  To assess weight loss, home-based exercise, and the combination of weight loss and home-based exercise with clinical lymphedema outcomes among overweight breast cancer survivors.

Design, Setting, and Participants  This randomized clinical trial (Women in Steady Exercise Research [WISER] Survivor clinical trial ) of 351 overweight breast cancer survivors with breast cancer–related lymphedema (BCRL) was conducted in conference rooms at academic and community hospitals and in the homes of participants from March 12, 2012, to May 28, 2016; follow-up was conducted for 1 year from the start of the intervention. Statistical analysis by intention to treat was performed from September 26, 2018, to October 28, 2018.

Interventions  A 52-week, home-based exercise program of strength/resistance training twice per week and 180 minutes of walking per week, a weight loss program of 20 weeks of meal replacements and 52 weeks of lifestyle modification counseling, and a combination of the home-based exercise and weight loss programs.

Main Outcomes and Measures  The 12-month change in the percentage of interlimb volume difference.

Results  Of 351 participants, 90 were randomized to the control group (facility-based lymphedema care with no home-based exercise or weight loss intervention), 87 to the exercise intervention group, 87 to the weight loss intervention group, and 87 to the combined exercise and weight loss intervention group; 218 (62.1%) were white, 122 (34.8%) were black, and 11 (3.1%) were of other races or ethnicities. Median time since breast cancer diagnosis was 6 years (range, 1-29 years). Mean (SD) total upper extremity score changes from the objective clinical evaluation were −1.40 (11.10) in the control group, −2.54 (13.20) in the exercise group, −3.54 (12.88) in the weight loss group, and −3.84 (10.09) in the combined group. Mean (SD) overall upper extremity score changes from the self-report survey were −0.39 (2.33) in the control group, −0.12 (2.14) in the exercise group, −0.57 (2.47) in the weight loss group, and −0.62 (2.38) in the combined group. Weight loss from baseline was −0.55% (95% CI, −2.22% to 1.11%) in the control group, −8.06% (95% CI, −9.82% to 6.29%) in the combined group, −7.37% (95% CI, −8.90% to −5.84%) in the weight loss group, and −0.44% (95% CI, −1.81% to 0.93%) in the exercise group.

Conclusions and Relevance  Study results indicate that weight loss, home-based exercise, and combined interventions did not improve BCRL outcomes; a supervised facility-based program of exercise may be more beneficial than a home-based program for improving lymphedema outcomes.

Trial Registration  ClinicalTrials.gov identifier: NCT01515124

Introduction

Breast cancer–related lymphedema (BCRL) is a common, feared sequela of curative cancer treatment.1,2 Of 3.6 million breast cancer survivors in the United States,3 approximately 1.44 million are diagnosed with lymphedema.4,5 Women who undergo axillary lymph node dissection are at higher risk of developing BCRL, with a cumulative incidence of 50%.6 A recent shift in surgical practice, away from axillary lymph node dissection and toward sentinel lymph node biopsy, reduces but does not eliminate the risk of BCRL.7 Millions of patients underwent axillary lymph node dissection before evidence was published demonstrating that sentinel lymph node biopsy was noninferior for 10-year overall survival.8 In addition, sentinel lymph node biopsy is sometimes followed by radiotherapy, which also increases the risk of BCRL.9 Furthermore, the shift in surgical procedures toward sentinel lymph node biopsy differs by race/ethnicity, resulting in disparities in lymphedema risk.10 Specifically, black women with pathologically node-negative breast cancer are 33% more likely to undergo axillary lymph node dissection than white women, leading to a 50% increased risk of developing BCRL.10 In short, BCRL has not been eradicated. Women with BCRL deserve evidence-based approaches to improve outcomes for this chronic condition.

Excess body weight is associated with a higher likelihood of onset and a worse clinical course of BCRL.11,12 Leading breast cancer organizations recommend that overweight patients with BCRL achieve and maintain a healthy weight to improve arm swelling and lymphedema symptoms.13-15 The Physical Activity and Lymphedema (PAL) clinical trial previously documented the efficacy of a 12-month, facility-based, slowly progressive resistance exercise intervention that started with 3 months of supervision to decrease lymphedema symptoms by 20% and reduce incident flare-ups (defined as a cellulitic infection requiring antibiotics or as an increase in swelling or symptoms resulting in the need for therapist-delivered treatment) by 50%, with no effect on arm swelling.16 Two pilot studies have examined the effects of a weight loss intervention on arm swelling, with varying results.17,18 The present study sought to test the effects of exercise, weight loss, and combined exercise and weight loss interventions on clinical lymphedema outcomes in comparison with a control group. The study’s hypothesis was that the combined weight loss and exercise program would achieve the greatest reduction in arm swelling and that a lesser degree of arm swelling reduction would be observed with the weight loss–only program. The exercise-only program was designed to provide a comparison group, with no expectation of arm swelling changes.

Methods
Study Design

We conducted a 12-month, 2 × 2 factorial, randomized clinical trial among women with BCRL to assess the individual and combined effects of exercise and weight loss interventions on multiple predefined outcomes, including the percentage of interlimb difference in arm volume (the primary outcome), clinical characteristics of lymphedema, self-reported lymphedema symptoms, and weight loss. Women were assigned to 4 groups of equal size through a computerized process called minimization,19,20 in a manner that was unpredictable and concealed from the study staff members who determined eligibility. This approach balanced important potential confounding variables—lymphedema severity, body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), age, history of radiotherapy, and number of lymph nodes resected—at baseline. The study was approved by the institutional review board of the University of Pennsylvania, Philadelphia. The full trial protocol is available in Supplement 1. Each participant provided signed informed consent and a written physician’s clearance for participation.

Patients

The Women in Steady Exercise Research (WISER) Survivor clinical trial randomized a total of 351 women with BCRL (Figure) from December 5, 2011, to April 21, 2015, in the Philadelphia, Pennsylvania, metropolitan area; follow-up was completed by May 28, 2016. To recruit participants for the study, letters were mailed to potentially eligible women who were identified using local hospital and state tumor registries. Educational sessions were also developed that attracted breast cancer survivors to the trial.21 Eligible patients were women who were diagnosed with BCRL according to the Common Toxicity Criteria for Adverse Events, version 4 (National Cancer Institute),22 or who had a previous diagnosis of lymphedema. In addition, eligible participants were cancer free, 6 months or more posttreatment, had a BMI of 25 to 50 (overweight or obese), were able to walk unaided for more than 6 minutes, and had no medical conditions prohibiting exercise, no plans for additional surgery, no self-report of engaging in resistance exercise or in 3 or more weekly aerobic sessions over the previous 12 months, no current use of any weight loss medication, no weight loss greater than 4.5 kg within the previous 3 months, and no history of bariatric surgery.

Interventions

The interventions are described in detail elsewhere.23 Briefly, all participants were provided with 2 custom-fitted compression garments at the baseline of 6 months and received lymphedema care from study-funded, certified lymphedema therapists throughout the 12 months of the clinical trial. These lymphedema care interventions addressed previously described disparities, such as access to garments and lymphedema care, and they were performed independently from the participant’s intervention group assignment.24 Control group participants received no additional intervention.

Home-Based Exercise Intervention

Participants randomized to the home-based exercise intervention group received exercise instruction from nationally certified fitness professionals with oncology exercise training. Resistance exercises were taught to groups of 2 to 6 women per 90-minute class, and adjustable dumbbells weighing 0.45 to 9.45 kg (PowerBlocks Inc) were shipped to participants’ homes. The 6 initial weekly classes were followed by weekly behavioral support telephone calls and monthly in-person classes from weeks 7 through 52. Women performed twice-weekly home sessions that included warm-ups, stretching, and 10 repetitions each of 9 resistance exercises. Women performed each exercise twice per session during weeks 1 through 6 and 3 times per session thereafter. Resistance progression was symptom-limited by 0.45 to 0.90 kg every 2 weeks, with an upper limit of 9.45 kg. In addition, women were asked to increase aerobic activity to 180 minutes per week. Walking goals per week were: 90 minutes for weeks 1 through 3, 120 minutes for week 4, 150 minutes for weeks 5 and 6, and 180 minutes thereafter. Participants were asked to complete exercise logs, which were reviewed weekly with the exercise intervention staff in person or by telephone.

Weight Loss Intervention

Participants randomized to the weight loss intervention group attended 24 weekly sessions led by a registered dietitian in groups of 2 to 12 women. For the first 20 weeks, participants were asked to follow a meal replacement program (Nutrisystem, Inc) that also included 7 servings of fruits and vegetables daily. The diet used was consistent with guidance from the American Cancer Society.25 Weekly nutritional counseling sessions were adapted from the Improving the Management of Obesity in Primary Care Practice (Power-UP) trial26 and included a weigh-in, a review of the week, and a new behavioral modification lesson (eg, planning ahead or the importance of fruits and vegetables for cancer prevention). During weeks 21 through 24, the focus shifted to learning how to apply the lessons to shopping for and preparing their own food. From weeks 25 through 52, groups met monthly for weigh-ins and additional behavioral modification lessons that focused on weight maintenance. The weight loss goal was 10% of baseline body weight.

Combined Intervention

Participants randomized to the combined intervention group started with 6 weeks of exercise instruction. At week 7, they began receiving the weight loss intervention in addition to the exercise intervention. Thereafter, participants in the combined intervention group received the exercise and weight loss interventions simultaneously.

Study Outcomes

Outcome measurements were taken at baseline and 12 months. Given the complexity of measuring a manifestational outcome such as lymphedema, multiple approaches were used, including objective, clinical, and self-report assessments, as described elsewhere.23 All measurement staff were blinded to the participants’ intervention status; participants were asked to avoid divulging their group assignment to outcome assessors (K.S., Z.Z., and M.E.).

Primary Outcome

Percentage of interlimb volume differences was measured by perometry (Juzo USA).27-29 Intrarater and interrater reliability for the percentage of interlimb differences as measured by perometry were 0.93 and 0.98, respectively.30 The original primary outcome was lymphedema clinical events (eg, incident flare-ups or cellulitis); however, the primary outcome was changed to the percentage of interlimb difference because of the need to reduce the study’s sample owing to a reduction in funding.

Secondary Outcomes

Clinical characteristics of lymphedema were assessed by certified lymphedema therapists using the Clinical Lymphedema Evaluation of the Upper Extremity (CLUE) assessment tool,30 which standardizes clinical assessments of the obscuration of anatomical architecture, deviation from anatomical contour, tissue texture, and the presence of pitting or nonpitting edema. The CLUE assessment30 developed specifically for this clinical trial showed a test-retest reliability of 0.88 and a correlation of 0.79 with the objective measures and 0.53 with the self-reported measures used in the WISER Survivor clinical trial. Self-reported symptoms of lymphedema were assessed using the Norman Lymphedema Survey.31 The survey demonstrated a weighted κ of 0.80 for interobserver agreement, a sensitivity of 0.93 to 0.96, and a specificity of 0.69 to 0.75 for diagnosis of any lymphedema.31 For the purposes of this clinical trial, a lymphedema exacerbation was defined as a change in symptoms that lasted 1 week or more and was verified by a certified lymphedema therapist using the CLUE assessment tool. No specific change in swelling was used as a threshold for exacerbation in acknowledgment of the clinical observation that meaningful symptom exacerbations may occur without significant swelling. Cellulitis was identified as having occurred if antibiotics were prescribed by the participant’s physician in association with a lymphedema exacerbation. Body weight was assessed on a calibrated scale. Objective assessments of physiologic changes expected from the exercise intervention were provided by 1-repetition maximum strength tests and a treadmill test for maximal oxygen uptake using a modified Bruce protocol.32 Demographic and medical history surveys were also administered. Data regarding race/ethnicity were collected by participant self-reporting to document the generalizability of the study sample. Cancer stage, treatment types, number of nodes removed, and years since cancer diagnosis were confirmed by pathology reports.

Statistical Analyses

Statistical analysis by intention to treat was performed from September 26, 2018, to October 28, 2018. Baseline variable descriptive statistics included frequencies for categorical variables and means and SDs for continuous variables. Means and SDs were also calculated for 12-month changes in interlimb difference and lymphedema outcomes. Intervention group comparisons were conducted using χ2 tests for categorical outcomes and F tests or t tests for continuous outcomes (all t tests were unpaired with 2-sided significance thresholds of P = .05).

The primary outcome was the percentage of interlimb volume change from baseline to 12 months. Based on previous studies,16-18 we hypothesized that changes in the percentage of interlimb difference would be 0% for the control group, −2.6% for the exercise intervention group, −5.2% for the weight loss intervention group, and −7.9% for the combined intervention group. The study’s sample size was determined by assuming an SD of 8% and using a sequential Holm-Bonferroni procedure33 to control the overall 2-sided type 1 error rate at P = .05, which indicated that 350 participants would provide 80% power to detect differences and allow for a maximum of 20% loss to follow-up.

Missing data were imputed where necessary using the variables in Table 1 and Table 2 (demographic characteristics, cancer history, perometry, and clinical and self-reported lymphedema) at baseline and/or 12 months. Multiple imputation analyses with 10 replications were conducted to obtain summary results.34 All analyses were performed using SAS, version 9.4 (SAS Institute Inc).

Results

A total of 450 women consented to participate in the clinical trial. Of those, 351 women were randomized to the control group (n = 90), exercise intervention group (n = 87), weight loss intervention group (n = 87), and combined exercise and weight loss intervention group (n = 87). Of those randomized, 280 (79.8%) completed follow-up visits (Figure). Intention-to-treat analyses combined with multiple imputation analyses enabled all 351 randomized participants to be included in the analyses presented herein.

The study sample was diverse with regard to race/ethnicity. Of 351 participants, 218 (62.1%) were white, 122 (34.8%) were black, and 11 (3.1%) were of other races/ethnicities. The sample also included participants who reported wide variations in length of time since breast cancer diagnosis (median, 6 years; range, 1-29 years). There were no between-group differences in any baseline variable (Table 1).

Perometry-Based Lymphedema Outcomes

Table 2 describes the perometry-based lymphedema outcomes (the study’s primary outcome) by group. No between-group differences were noted at baseline or in 12-month changes in percentage or absolute interlimb differences. In comparison with the control group, the percentage of change from baseline was 0.66% (95% CI, −0.88% to 2.20%) in the combined group, 0.53% (95% CI, −1.04% to 2.10%) in the weight loss group, and 0.04% (95% CI, −1.57% to 1.65%) in the exercise group. Individual limb decreases across 12 months were larger for both affected and unaffected limbs in the weight loss and combined intervention groups compared with the control group. This pattern of findings was consistent among women who entered the study with interlimb differences of less than 10% (n = 246), 10% or greater (n = 105), or 15% or greater (n = 74). The pattern was also consistent among subsets of women with a baseline BMI of less than 30 (n = 108), 30 to 34.99 (n = 102), or 35 or greater (n = 141).

Clinical Evaluation and Self-reported Lymphedema Outcomes

Table 3 describes the clinical evaluation and self-reported lymphedema outcomes by intervention group. No between-group differences were noted at baseline or in 12-month changes in clinical lymphedema assessment values or self-reported symptoms. For example, results from the CLUE assessment tool noted that the mean (SD) score changes for the total upper extremity (score range, 0-72) were −1.40 (11.10) in the control group, −2.54 (13.20) in the exercise group, −3.54 (12.88) in the weight loss group, and −3.84 (10.09) in the combined group. Results from the Norman Lymphedema Survey noted that the mean (SD) 12-month score changes for the overall upper extremity (score range, 0-4) were −0.39 (2.33) in the control group, −0.12 (2.14) in the exercise group, −0.57 (2.47) in the weight loss group, and −0.62 (2.38) in the combined group. These findings were consistent among women with a baseline percentage of interlimb differences of less than 10%, 10% or greater, or 15% or greater, and they remained consistent across BMI strata (<30, 30-34.99, and ≥35).

Lymphedema Exacerbations

The percentage of women with lymphedema exacerbations or cellulitis did not differ by group, with 28 of 90 women (31.1%) in the control group, 28 of 87 women (32.2%) in the exercise group, 23 of 87 women (26.4%) in the weight loss group, and 27 of 87 women (31.0%) in the combined group experiencing these outcomes (P > .50 for all pairwise comparisons with the control group).

Weight Loss

Comparisons with the control group were significant for the combined and weight loss groups (P < .001 for both groups vs the control group). Women in the control group lost 0.55% of their baseline weight. In comparison, women in the combined and weight loss groups lost −8.06% (95% CI, −9.82% to −6.29%) and −7.37% (95% CI, −8.90% to −5.84%) of their baseline weight, respectively. Women in the exercise group lost −0.44% (95% CI, −1.81% to 0.93%) of their baseline weight.

Exercise Adherence, Strength, and Aerobic Fitness

Women randomized to the exercise and combined groups completed an average of 72 of the 100 prescribed home-based resistance exercise sessions (72%) and an average of 133 of the 180 prescribed aerobic exercise minutes per week (74%). For the bench press exercise, the maximum weight that could be lifted for 1 repetition increased by 1.4% in the control group, by 16.3% in the exercise group (P = .15 vs the control group), by 4.0% in the weight loss group (P = .80 vs the control group), and by 16.2% in the combined group (P = .22 vs the control group). For the leg press exercise, the maximum weight that could be lifted for 1 repetition increased by 3.0% in the control group, by 23.1% in the exercise group (P = .01 vs the control group), by 10.3% in the weight loss group (P = .33 vs the control group), and by 10.3% in the combined group (P = .34 vs the control group). Aerobic fitness, measured by time completed on a treadmill test using a modified Bruce protocol, improved by 3.4% in the control group, by 9.5% in the exercise group (P = .60 vs the control group), by 10.9% in the weight loss group (P = .50 vs the control group), and by 19.7% in the combined group (P = .19 vs the control group). No significant adverse events were noted.

Discussion

This randomized clinical trial found that participation in 12 months of a home-based exercise or weight loss intervention, alone or in combination, had no effect on the percentage of interlimb difference. These findings contradict previous observational evidence suggesting that lymphedema symptoms may improve with weight loss.11,12 A previous pilot study reported that a 3.8% weight loss in 11 women with a mean of 19% interlimb difference resulted in a 4.2 percentage point reduction in lymphedema symptoms, with negligible change among the 10 women in the control group who did not lose weight.17 In contrast, a second pilot study with 51 participants observed no effect of a 5.8% weight loss on arm swelling.18 The differences between the current WISER Survivor clinical trial and these 2 pilot studies include the magnitude of weight loss (8.1% in this study vs 3.8% and 5.8% in the pilot studies), sample sizes (351 participants in this study vs 21 participants and 51 participants in the pilot studies), and quality of measurements (perometry measurements in this study vs circumferential measurements of arm volume in the pilot studies).17,18 Our findings are contradictory to our own clinical experience, as we have received reports from patients with BCRL who have noted improvements in their lymphedema symptoms after weight loss. Possible explanations for this mismatch of clinical experience and empirical evidence include alterations in aspects of lymphedema, such as tissue composition, that remain challenging to measure with high reliability and validity.

Multiple national organizations currently advise overweight women to achieve and maintain a healthy weight to improve the outcomes of previously diagnosed BCRL.13-15 The empirical evidence base, including data from the present study, does not support the assertion that weight loss as an intervention improves the hallmark measure of BCRL severity, percentage of interlimb difference.

The PAL clinical trial reported that a slowly progressive resistance exercise program reduced the occurrence of lymphedema exacerbations by 50% and improved lymphedema symptoms.16 The lack of effect of the present study’s exercise program on lymphedema outcomes stands in contrast to the findings of the PAL study. Explanations for these contrasting results likely have little to do with the addition of an aerobic exercise component in the present study that was not included in the PAL study’s intervention. We are aware of no physiologic reason or empirical evidence suggesting that aerobic exercise may have a deleterious effect on the benefits of resistance training for patients with BCRL. The PAL clinical trial began with 3 months of twice weekly, supervised, facility-based exercise followed by 9 months of monthly, supervised check-in sessions and otherwise unsupervised facility-based exercise.16 Challenges to implementing the PAL clinical trial intervention included the cost of the intervention, the potential that women may have preferred a home-based rather than a facility-based program, and the difficulty in developing and sustaining the necessary work force at exercise facilities to meet the specific safety needs of women with BCRL.

In response to these challenges, our research team adapted the PAL intervention to a home-based program that could be taught in 6 or fewer sessions by outpatient rehabilitation health care professionals or clinical exercise professionals. Initial comparisons suggested that the home-based program could match the efficacy observed in the PAL clinical trial.35 However, less frequent supervision may have resulted in a decreased focus on crucial elements of resistance exercise training, such as the progression of resistance. Comparison of upper-body strength changes between participants in the PAL and WISER Survivor clinical trials (29.4% vs 16.3%, respectively) supports the hypothesis that training frequency was lower in the WISER Survivor clinical trial. Differences in participant retention (130 of 141 participants [92%] vs 280 of 351 participants [80%]) and adherence to prescribed exercise sessions (88 of 100 sessions [88%] vs 72 of 100 sessions [72%]) in the PAL and WISER Survivor clinical trials, respectively, may also partially explain the differences in study results. Many other examples in the oncology exercise literature document greater physiologic benefit for cancer survivors when more structured exercise programs are used.36,37 These findings suggest that patients with BCRL may want to seek a facility-based, supervised exercise program, at least in the beginning of their resistance training. The PAL clinical trial’s finding that slowly progressive resistance exercise for patients with BCRL was safe (ie, had no adverse effects) was confirmed in the WISER Survivor clinical trial.

Strengths and Limitations

Women who reported that they were of a minority race or ethnicity comprised 133 of the 351 participants (38%) in the WISER Survivor cohort. As such, the results are highly generalizable. Although the clinical trial had sufficient power to withstand 20% attrition, losses were not proportionate across the participant groups. Greater losses to follow-up occurred in the control group than in the exercise, weight loss, and combined intervention groups. Rigorous comparisons of baseline characteristics between those who were lost to follow-up and those who completed the study did not reveal any significant differences. Furthermore, use of multiple imputation analyses addressed this potential limitation. Notably, results for the primary outcome remained consistent when they were analyzed without imputation.

Breast cancer–related lymphedema is a long-term condition, and the 12-month length of the clinical trial may have been too short to observe a sufficient number of clinical events (eg, lymphedema exacerbations) to understand the interventions’ effects. Further, the results of this clinical trial may not be applicable to the limited number of patients with severe lymphedema (ie, patients with interlimb differences >30%). Finally, this study was not designed to detect differences in cellulitis incidence.

Conclusions

Contrary to the clinical recommendations commonly provided by leading national organizations to patients with BCRL, a 12-month weight loss intervention, alone or in combination with a home-based exercise intervention, did not decrease arm swelling or improve the clinical attributes or symptoms of lymphedema. While a home-based exercise program that included walking and slowly progressive resistance exercise was found to be safe, previous research suggests that a supervised, facility-based resistance exercise program may provide greater lymphedema-specific benefits.

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Article Information

Accepted for Publication: April 19, 2019.

Corresponding Author: Kathryn H. Schmitz, PhD, MPH, Department of Public Health Sciences, Pennsylvania State College of Medicine, 500 University Dr., Room T3427, Hershey, PA 17011 (kzs95@psu.edu).

Published Online: August 15, 2019. doi:10.1001/jamaoncol.2019.2109

Author Contributions: Dr Schmitz had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Schmitz, Troxel, DeMichele, Brown, Cheville, Chodosh, Sarwer.

Acquisition, analysis, or interpretation of data: Schmitz, Troxel, Dean, DeMichele, Brown, Sturgeon, Zhang, Evangelisti, Spinelli, Kallan, Denlinger, Cheville, Winkels, Sarwer.

Drafting of the manuscript: Schmitz, Sturgeon, Kallan, Cheville, Sarwer.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Schmitz, Troxel, Dean, Brown, Kallan, Cheville.

Obtained funding: Schmitz, Cheville, Chodosh.

Administrative, technical, or material support: Schmitz, Brown, Sturgeon, Zhang, Evangelisti, Denlinger, Cheville, Winkels, Chodosh, Sarwer.

Supervision: Schmitz, Dean, Sturgeon, Zhang, Denlinger, Sarwer.

Conflict of Interest Disclosures: Dr Schmitz reported receiving grants from the National Cancer Institute and nonfinancial support from BSN Medical during the conduct of the study, personal fees from Klose Training outside the submitted work, and a licensed patent for a Strength After Breast Cancer course. Dr Troxel reported receiving grants from the National Institutes of Health during the conduct of the study. Dr Dean reported receiving grants from the National Cancer Institute, the National Institute of Mental Health, and the National Institute of Allergy and Infectious Diseases during the conduct of the study. Dr DeMichele reported receiving grants from Novartis, Pfizer, Genentech, Calithera, and Menarini outside the submitted work. Dr Brown reported receiving grants from the National Cancer Institute outside the submitted work. Dr Sturgeon reported receiving grants from the National Institutes of Health during the conduct of the study. Dr Denlinger reported receiving grants from the National Cancer Institute during the conduct of the study and grants from BeiGene, AstraZeneca, Sanofi, Amgen, MacroGenics, Agios, Array BioPharma, Lycera, Incyte, Genentech, and Advaxis; grants and personal fees from Bristol-Myers Squibb, Lilly, Bayer, MedImmune, and Merrimack; and personal fees from Merck, EMD Serono, and Carevive outside the submitted work. Dr Cheville reported receiving grants from the National Cancer Institute during the conduct of the study. Dr Chodosh reported receiving personal fees from Imerys Talc America outside the submitted work. Dr Sarwer reported receiving personal fees from BAROnova, Ethicon, Merz, and Novo Nordisk outside the submitted work. No other disclosures were reported.

Funding/Support: This research was supported by grants US54-CA155850 from the National Institutes of Health (Penn Transdisciplinary Research on Energetics and Cancer Survivor Center), UL1TR001878 from the National Center for Advancing Translational Sciences of the National Institutes of Health, and 5P30CA016520-42 (University of Pennsylvania Abramson Cancer Center) and 5P30CA006927-53 (Fox Chase Cancer Center) from the Comprehensive Cancer Center Support Grants of the National Cancer Institute. Compression garments were donated by BSN Medical, and discounted meal replacements were provided by Nutrisystem, Inc. Dr Sarwer was supported by grant R01-DK108628-01 from the National Institutes of Health and the Commonwealth of Pennsylvania. Dr Dean was supported by grants K01CA184288 from the National Cancer Institute, R25MH083620 from the National Institute of Mental Health, P30AI094189 from the Johns Hopkins University Center for AIDS Research, and P30CA006973 from the Sidney Kimmel Cancer Center.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 2.

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