Not a day goes by in clinic without a patient asking me something like, “What do you think about this supplement?” or “Will changing my diet help?” I usually interpret these questions as a sign that the patient wants to empower himself or herself and “do something” vis-à-vis a lifestyle change. While I actively encourage such self-empowerment and lifestyle change, I also feel compelled to give the caveats that:
1) I can't support something known to interfere with a proven anti-cancer therapy, and 2) It is my duty to educate the patient on the evidence (or lack thereof) regarding the risks and benefits of the lifestyle strategy in question.
In my view, across all cancer types, exercise and physical activity (not supplements or dietary changes) have the most evidence for benefit. In this article, I will focus on the current evidence and potential for future research regarding exercise and physical activity (PA) in renal cell carcinoma (RCC).
First, a few definitions. While the terms are often used synonymously, physical activity broadly refers to all skeletal muscle activity resulting in energy expenditure; whereas, exercise more narrowly refers to repetitive, structured activity performed with the intent of improving health. Furthermore, PA can be broken into categories such as leisure-time, occupational, and household.
Despite growing evidence over the past decade in more common cancers such as prostate, breast, and colorectal, there is precious little evidence on the benefits of PA or exercise in RCC. But while the specifics of exercise (i.e., exact benefit and dose, modality, timing needed to achieve such benefit) may be slightly different in each cancer type, there is no reason to believe benefits are confined to only a few cancers. This is because exercise is pleiotropic, or “dirty,” to use informal pharmacologic terminology often applied to drugs that modulate multiple targets, resulting in a wide range of effects both beneficial and adverse (in the case of drugs at least). Because exercise modulates many pathways, with minimal to no adverse effects, it could simultaneously improve both patient-centric and tumor-specific outcomes.
Exercise benefits in cancer patients may be broadly classified into the following categories: primary prevention (risk reduction), symptom management (i.e., secondary or tertiary prevention to reduce treatment-related adverse events and/or improve disease symptoms), and adjunctive therapy (i.e., modulating to tumor biology to reduce risk of progression or metastasis, alone or as an adjunct to other therapy).
Multiple studies have reported on the association between PA and cancer. For example, reductions in risk have been shown in breast, colon, and endometrial cancers when those with high levels of PA are compared with those with low levels.
A recent study examined the association of leisure time PA with the risk of 26 cancers by body mass index (BMI) and/or smoking (JAMA Intern Med 2016;176:816-25). Data were pooled from 12 U.S. and European cohorts, resulting in a cohort size of 1.44 million participants, resulting in the largest such study ever conducted.
Compared with a low level of PA, a higher level of PA was associated with a significantly lower risk for 13 cancers. Seven cancers had a strong inverse association (>20% risk reduction), including kidney cancer (HR 0.77, 95% CI 0.70-0.85; p<0.001). This association was modestly attenuated, but not nullified, after adjusting for BMI and smoking (both known risk factors for RCC). Although more research is needed, this study suggests that PA can reduce the risk of developing RCC.
Fatigue is a common symptom of both RCC and RCC treatments. For example in the phase III COMPARZ non-inferiority trial of the VEGF receptor TKIs pazopanib and sunitinib, fatigue was the most common all grade adverse event experienced by patients (55% versus 63%). Fatigue scores on patient-reported outcomes questionnaires (FACIT-F) with both drugs demonstrated a sharp decline (corresponding to increased fatigue) within 28 days of initiating treatment; with time, scores drifted toward baseline but remained decreased after eight cycles of therapy.
A Cochrane Database Systemic Review concluded aerobic exercise is beneficial for patients with solid tumors and cancer related-fatigue both during and post-cancer therapy. Exercise for patients with cancer undergoing active treatment also has been shown in another systematic review to have benefits on health-related quality of life (HRQoL) and some HRQoL domains. As might be expected, the majority of trial participants included in these systemic reviews had breast and prostate cancer. To my knowledge, there are no published clinical trials of exercise in patients with RCC. However, exercise should be studied in RCC to reduce treatment-related side effects, such as fatigue, and improve quality of life. Given the above evidence, this seems to be low-hanging fruit.
Besides cancer prevention and symptom management, there is considerable interest in exercise to modulate tumor biology to improve cancer outcomes. Such outcomes include cancer progression, metastasis, progression free survival and, of course, overall survival. For example, there are ongoing or planned trials in prostate and colorectal cancers with the primary endpoints of overall and disease-free survival, respectively. In vivo preclinical studies have demonstrated that multiple systemic factors are modulated by exercise, such as metabolism, inflammation, immune, and reactive oxygen species mediated pathways (Cancer Res 2016; DOI: 10.1158/0008-5472.CAN-16-0887). Based on the fact that approved therapies in RCC include angiogenesis inhibitors and immunotherapies, demonstration of modulation of these pathways would suggest exercise may have activity in RCC.
While no such evidence in RCC models currently exists, two studies in other tumor types may be relevant. While primary tumors were comparable between exercise and non-intervention groups in a mouse model of prostate cancer, there was a trend toward reduced metastasis in the exercise group as well as increased intratumoral protein levels of HIF-1α and VEGF, improved tumor vascularization, and decreased plasma angiogenic cytokines. These data suggests exercise could result in “normalized” vasculature, similar to angiogenesis inhibitors. A recent study in five different mouse tumor models demonstrated exercise leads to natural killer (NK) cell mobilization and redistribution via an epinephrine- and IL-6-dependent mechanism, resulting in suppression of tumor growth (Cell Metab 2016;23:554-62). Because RCC may commonly be protected from NK cell mediated killing and therapy of RCC may work through NK cell mediated mechanisms, exercise could be a rational combination or adjunct to existing therapies. Again, these hypotheses remain to be studied.
In summary, I believe there is great potential for exercise as a therapy in RCC; however, current evidence exists only to demonstrate an association with increased physical activity and decreased risk of kidney cancer. However, based on the fact that exercise has relatively little risk, I feel comfortable recommending exercise for most patients across the RCC disease trajectory.
Many patients need help starting an exercise program and I have found the Livestrong at the YMCA and Silver Sneakers programs, as well as our own Duke Health and Fitness Center, to be invaluable resources. I also encourage patients to search for an ACSM/ACS Certified Cancer Exercise Trainer in their area. Future studies to evaluate the effects of exercise on RCC tumor biology, and both patient-centric and tumor-specific outcomes in RCC, are clearly warranted. It's time to get moving!
MICHAEL R. HARRISON, MD, is an Assistant Professor of Medicine, Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Durham, N.C.