No one ever said that clinical research is easy, but researchers can be informed by the aphorism about exercise, “no pain, no gain!” Roshni Rao, MD, a breast surgical oncologist at the University of Texas Southwestern Medical Center, recently posed the question, “what is the benefit of exercise in patients with breast cancer?” Certainly, many health benefits of aerobic exercise and physical activity are suggested (1), but the relationship of increased physical activity and lower breast cancer risk has primarily been limited to observational prevention studies (2). The use of new adaptive clinical trial designs in breast cancer treatment protocols using neoadjuvant chemotherapy (NAC) prior to surgery led Dr. Rao to question whether she could study the implications of exercise on the effectiveness of breast cancer treatment during administration of NAC. Thinking about novel timing strategies for trial design, she developed a randomized pilot trial of patients with body mass index (BMI)>25 and Stage II-III estrogen-receptor positive breast cancer who were planned to receive NAC (3). Patients were randomized to a three-times per week exercise “Bootcamp” program in addition to NAC versus standard NAC. Outcomes included tumor size change, insulin-like growth factor levels, Ki-67 staining, C-peptide levels, and BMI change at the time of surgery. All patients were to receive weight-based chemotherapy, so including measurements based on height and weight was straightforward. However, deciding what exercise to do was tougher than expected.
Dr. Rao had initially questioned how she could even reliably encourage her breast cancer patients to exercise. Should all patients be put on treadmills with gas masks that could quantify metabolic equivalent (MET) levels? Do you buy them a gym membership and hope that they attend? Do you make them come to a pre-specified class and location as a group? Adherence, time, and commitment for patients would be a challenge. Serendipity ultimately led to development of the study. Dr. Rao happened to attend a “backyard bootcamp”, where she met a physical trainer who ran her exercise program out of a van and was trying to pitch a mobile program for physical fitness, with several class times and locations throughout Dallas. Dr. Rao suggested bringing this flexible and transportable program directly to her patients. Development of the study protocol ultimately went as expected. Patient accrual seemed feasible because breast cancer is a relatively common problem in women. Power analysis was based on expected numbers of pathologic response rates during therapy. Ultimately financing the study became the major hurdle for accrual, but other small hurdles were present from the start.
Dr. Rao recognized that funding an exercise trial was essential to make her efforts feasible. Getting through her IRB required $2000 to even begin the trial. She applied for a $25,000 pilot grant through her institution. This was rejected. She later submitted the same proposal for a foundation grant and a group called Commercial Real Estate Women (CREW) provided $30,000 to support her efforts. Next, she proceeded with registering her trial with clinicaltrials.gov. Recruitment was limited by a medical oncologist who was not enthusiastic due to concerns about how patients would do with fatigue. Patients were actually very interested, yet they displayed disappointment when they understood they could be allocated in the control arm. The intervention group had the option for supervised exercise performed 3 times per week in the home or in the workplace. Ultimately, only 10 patients were randomized for the pilot trial, as this was limited by available funding for the trainer and biomarker studies.
Compliance was high in this study at 90% and was explained by Dr. Rao to be, “ultimately because the personal trainer had a great personality, plus it’s hard to say no when someone drives to your home and shows up at your door to help you exercise”. Follow-up was excellent since all patients received the intervention during the course of their chemotherapy, with endpoints determined at the time of surgery. There was no obvious evidence of crossover between groups, and BMI was the same in patients who were in the control arm. In retrospect, Dr. Rao wishes they were able to collect other data points including fitness testing and more precise measurements of percentage body fat. Most of the results were not statistically significant, but borderline significant with strong trends towards improvement in numerous outcome measures, and likely subject to issues of small sample size. Dr. Rao proceeded with publishing these findings, recognizing the importance for generalizable knowledge of publishing the results of all clinical trials, especially if negative or borderline significant. She felt that the process of writing was straightforward since all the background was already put together for grant proposals. While the study was underpowered and underfunded, it was published , and recently included in a meta-analysis on the subject of exercise during neoadjuvant therapy for various cancers . Three new pilot and Phase II studies have been published in the short interval after Dr. Rao’s study, all confirming the feasibility, tolerability, and safety of exercise training, with overall benefits that favor exercise in cancer patients . No one ever said clinical research would be easy, but small forward steps lead to overcoming future hurdles.
- Centers for Disease Control and Prevention. Physical Activity and Health. Accessed at cdc.gov/physicalactivity/basics/pa-health/
- McTiernan A, Kooperberg C, White E, Wilcox S, Coates R, Adams-Campbell LL, Woods N, Ockene J. Recreational Physical Activity and the Risk of Breast Cancer in Postmenopausal Women: The Women’s Health Initiative Cohort Study. JAMA 2003; 290(10): 1331-1336.
- Rao R, Cruz V, Peng Y, Harker-Murray A, Haley BB, Zhao H, Xie XJ, Euhus D. Bootcamp during Neoadjuvant Chemotherapy for Breast Cancer: A Randomized Pilot Trial. Breast Cancer: Basic and Clinical Research 2012; 6: 39-46.
- Loughney L, West MA, Kemp GJ, Grocott MP, Jack S. Exercise intervention in people with cancer undergoing neoadjuvant cancer treatment and surgery: a systematic review. Eur J Surg Oncol 2016; 42(1): 28-38.