Resistance Training to Reduce Chemotoxicity in Colon Cancer

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ABSTRACT The proportions of fat mass (FM) and muscle mass (MM) in the body may have important implications for calibration of chemotherapy in patients with colon cancer (CC). Chemotherapy dosing is currently based on body surface area (BSA), which is derived from information on height and weight. Body weight or Body Mass Index (BMI), especially among cancer patients, is not an accurate measure of FM or MM. Given this inability to predict FM or MM, dosing by BSA may lead to underdosing (which may impact cancer-specific and overall survival) or overdosing (leading to dose-limiting toxicity [DLT] defined as toxicity from chemotherapy that requires subsequent reductions in or discontinuation of life-saving treatment). Results have shown that those with low MM, or sarcopenia, have a higher risk of DLT than those with normal MM. DLT impacts dose intensity and may compromise efficacy of chemotherapy. We propose to examine the effects of a randomized clinical trial conducted during chemotherapy of home based resistance training (RT) versus a waitlist control on DLT. Participants will be 180 newly diagnosed Stage II and III CC patients from Kaiser Permanente of Northern California (KPNC), the Penn State Cancer Institute (PSCI), and the Dana Farber Cancer Institute (DFCI). The intervention will begin during the first 6 weeks of chemotherapy and continue through the completion of treatment. Specifically, we will examine between group differences for resistance training versus weight list control for dose intensity and grade 3 and 4 toxicities as well as changes in MM and changes in inflammatory markers. Since approximately 40-45% of newly diagnosed CC patients have sarcopenia at diagnosis, we will examine if the benefits of exercise are greater for those who have low MM compared to normal MM. We will also examine specific inflammatory markers (e.g. CRP, IL-6 and TNF-RII) as potential biomarkers of baseline MM, and determine how they change in response to RT. To determine effects of change of MM on chemotherapy-specific drug clearance, we will examine the impact of RT induced body composition changes on the pharmacokinetics (PK) of 5-FU and oxaliplatin. If RT helps to reduce DLT and MM and inflammatory markers can identify those patients most-likely to benefit from tailored exercise guidelines, then assessment of these parameters can be used to help target high risk patients. Given that DLT is a common problem and there are large numbers of newly diagnosed CC patients with undetected sarcopenia, many of whom may require dose reductions due to low MM, this study has the potential to have a large impact on clinical care and improve prognosis of colon cancer.