Effects of exercise during chemotherapy on chemotherapy-induced peripheral neuropathy: a multi-center, randomized controlled trial

Ian R. Kleckner; Charles Kamen; Jennifer S. Gewandter; Nimish A. Mohile; Charles E. Heckler; Eva Culakova, Chunkit Fung; Michelle C. Janelsins; Matthew Asare; Po-Ju Lin; Pavan S. Reddy; Jeffrey Giguere; Jeffrey Berenberg; Shelli R. Kesler; Karen M. Mustian. Supportive Care in Cancer (2018) 26:1019–1028

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Effects of exercise during chemotherapy on chemotherapy-induced peripheral neuropathy: a multi-center, randomized controlled trial

Ian R. Kleckner; Charles Kamen; Jennifer S. Gewandter; Nimish A. Mohile; Charles E. Heckler; Eva Culakova, Chunkit Fung; Michelle C. Janelsins; Matthew Asare; Po-Ju Lin; Pavan S. Reddy; Jeffrey Giguere; Jeffrey Berenberg; Shelli R. Kesler; Karen M. Mustian. Supportive Care in Cancer (2018) 26:1019–1028

Purpose Over half of all cancer patients receiving taxane-, platinum-, or vinca alkaloid-based chemotherapy experience chemotherapy-induced peripheral neuropathy (CIPN), which includes numbness, tingling, pain, cold sensitivity, and motor impairment in the hands and feet. CIPN is a dose-limiting toxicity, potentially increasing mortality. There are no FDA approved drugs to treat CIPN, and behavioral interventions such as exercise are promising yet understudied. This secondary analysis of our nation wide phase III randomized controlled trial of exercise for fatigue examines (1) effects of exercise on CIPN symptoms, (2) factors that predict CIPN symptoms, and (3) factors that moderate effects of exercise on CIPN symptoms.

Methods Cancer patients (N=355, 56±11 years, 93% female, 79% breast cancer) receiving taxane-, platinum-, or vinca alkaloid-based chemotherapy were randomized to chemotherapy or chemotherapy plus Exercise for Cancer Patients (EXCAP©®). EXCAP is a standardized, individualized, moderate-intensity, home-based, six-week progressive walking and resistance exercise program. Patients reported CIPN symptoms of numbness and tingling and hot/coldness in hands/feet (0–10 scales) pre-and post-intervention. We explored baseline neuropathy, sex, age, body mass index, cancer stage, and cancer type as possible factors associated with CIPN symptoms and exercise effectiveness.

Results Exercise reduced CIPN symptoms of hot/coldness in hands/feet (−0.46 units, p=0.045) and numbness and tingling (− 0.42 units, p=0.061) compared to the control. Exercise reduced CIPN symptoms more for patients who were older (p=0.086), male (p=0.028), or had breast cancer (p=0.076).

Conclusions Exercise appears to reduce CIPN symptoms in patients receiving taxane-, platinum-, or vinca alkaloid-based chemotherapy. Clinicians should consider prescribing exercise for these patients.

Main findings

  • Large sample size 355
  • CIPN = chemotherapy induced peripheral neuropathy
  • CIPN interferes with daily activities such as buttoning clothes, writing, and typing, and it reduces quality of life. Half of all CIPN patients do not recover 6 months after completing chemotherapy, and many require years to recover, if they recover at all.
  • The etiology of CIPN is not entirely clear but appears to involve inflammation and damage to mitochondria in peripheral sensory neurons. The neuropathic pain component of CIPN appears to involve changes in sensory pathways of the spinal cord, thalamus, and regions of the cortex such as the somatosensory cortex and the insula. These changes in the central nervous system might exacerbate symptoms of peripheral nerve damage.
  • Treatments for CIPN are extremely limited and require further study.
  • In this study participants were randomly assigned to receive 6 weeks of (1) standard care for chemotherapy or (2) standard care for chemotherapy plus exercise. Allocation was concealed from coordinators until after participant registration, and concealed from participants until baseline assessments were complete.
  • Exercise intervention Exercise for Cancer Patients (EXCAP©®) was designed by American College of Sports Medicine (ACSM)-certified exercise scientists at the University of Rochester Medical Center. The intervention consisted of an EXCAP kit, which includes a manual, pedometer, and three resistance bands. The intervention was delivered via one 60-min session by an NCORP clinical research associate in the oncology clinic on the first day of chemotherapy.
    • The first component of EXCAP was a walking prescription intended to provide low to moderately intense aerobic exercise (60–85% of heart rate reserve) daily for the 6-week intervention. Before randomization, patients wore pedometers and recorded steps for four consecutive days. Patients received an individually tailored, progressive walking prescription for the next 6 weeks based on their baseline average daily steps and were encouraged to increase the total number of steps walked daily by 5–20% each week.
    • The second part of the exercise program was a therapeutic band prescription designed to provide low- to moderate intensity resistance exercise (3–5 rated perceived exertion (RPE) scale [28]) daily for the 6-week intervention. Patients were given three color-coded bands with varying levels of resistance (red=medium, green=heavy, blue=extra heavy) and a list of ten band exercises (squat, side bend, leg extension, leg curl, chest press, row, calf raise, overhead press, biceps curl, triceps extension) and four optional band exercises (front raise, lateral raise, internal rotation, external rotation). Patients received an individually tailored, progressive therapeutic band prescription for 6 weeks.
  • Standard care control condition – Control participants completed all study assessments and were followed by study staff in the exact same manner as the exercise participants. Control participants were offered the exercise intervention after all assessments were complete.
  • Measures – Clinical and demographic information were collected from medical records and study-specific forms. Exercise adherence was reported daily using (1) steps from a pedometer, (2) minutes of resistance exercise, and (3) RPE where 1= no exertion and 10=maximal exertion [28]. Patients reported their CIPN symptoms: (1) numbness and tingling and (2) hot/ coldness in hands/feet, both rated on a 0–10 scale, where 0= not present and 10=as bad as you can imagine, during the last 7 days.
  • After the intervention, exercisers increased their average daily steps by 649 (approximately 0.32 miles) and walked significantly more steps than control participants (4820 vs. 4285, respectively; p=0.019, who decreased their average daily steps by 129 (approximately 0.06miles).
  • At post-intervention, participants in the exercise condition reported less severe CIPN symptoms than participants in the control condition by nearly 0.5 units on the 0–10 scales, as assessed by numbness and tingling.
  • All patients reported worse CIPN after 6 weeks of neurotoxic chemotherapy, as expected, but patients randomized to the exercise group showed significantly smaller increases in CIPN prevalence and severity.
  • Our results suggesting that exercise treats CIPN better for older patients are consistent with results that older patients require less exercise to treat CIPN.
  • The reason why exercise might assist CIPN could be the fact that:
    • Exercise reduces chronic inflammation, and inflammation appears to play a role in the etiology and treatment of CIPN. Second, exercise change show sensations from the hands, feet, and rest of the body are processed by the brain.
    • Exercise protects interoceptive brain circuitry from normal age-related declines, thus potentially protecting older brains from the effects of chemotherapy, thereby mitigating symptoms of CIPN.
    • This study lacked information on chemotherapy dose, which might have confounded the observations, for example that exercise is more effective for CIPN symptoms in older patients if older patients received a different (e.g.,lower) chemotherapy dose than younger patients and chemotherapy dose was related to exercise effectiveness.