Virtual Personalized Exercise Program for Subjects With Lung Cancer: a Feasibility Study

Cancer as a chronic disease: Cancer is now considered a chronic disease and the number of cancer survivors is estimated to be more than 22 million individuals in the United States by 2030.[1]

Cancer and exercise: As opposed to chronic conditions such as heart disease, diabetes, and pulmonary disease where exercise has been recommended for decades, exercise recommendations for oncologists has been slow to evolve. However, exercise and rehabilitation interventions are known to benefit cancer survivors. Interestingly, research has been shown that the risk of developing cancer can be reduced by exercising a minimum of 3 - 5 hours per week, reducing the risk of breast cancer by 15 to 20%, decreasing the risk of colorectal cancer by 19-24%, gastric cancer by 19%, kidney cancer by 23%, and esophageal cancer by 21%.[2, 3] While we know a lot about exercise beneficial effects on the heart and skeletal muscle, studies are emerging on its effects on other organs where cancer cells grow including breast, prostate, colon, pancreas, kidney, liver and lung. Exercise can also play a role in cancer treatment by reducing treatment-related toxic and side effects and enhancing the curative effects of other treatments.[2] For those undergoing active cancer treatment, exercise has proven benefits. For example, breast cancer subjects treated with aromatase inhibitors develop decreased cognitive ability and lower bone mass.[2] Exercise is thought to prevent cognitive impairments caused by estrogen deficiency. Similarly, for prostate cancer, physical exercise can improve androgen-deprivation therapy. The most reported issues for cancer survivors are physical problems (muscle mass reduction, pain, and fatigue) and psychosocial problems (depression, cognitive decline, and fear of recurrence) and increased risk of developing secondary comorbidities such as cardiovascular disease.[4] Physical exercise has been shown to improve fatigue related to cancer treatment, likely by mitigating oxidative stress and reducing hormone stimulation. Additionally, those who exercise post-colon resection have a 50% reduction in disease-free survival when comparing 18 to 27 metabolic equivalent task (MET)-hours per week versus less than three MET-hours per week.[5] Observational cohort studies show that subjects who have high physical activity after diagnosis have lower risk of disease recurrence and cancer mortality.[6] Randomized clinical trials have also validated that physical activity interventions both mitigate cancer-impaired quality of life and improve outcomes for cancer survivors. One in ten cancer deaths have been attributed to lack of physical activity.[7] And, a recent meta-analysis of 38,560 cancer survivors demonstrated a 37% lower relative risk of dying from cancer for the most active compared with the least active subjects (HR: 0.63; 95% CI: 0.54-0.73).[8] There are a number of clinical trials focused on the impact of physical activity and/or dietary modifications on ovarian cancer (LIVES - The Lifestyle Intervention for Ovarian Cancer Enhanced Survival), colon cancer (CHALLENGE - The Colon Health and Life-Long Exercise Change), prostate cancer (INTERVAL-GAP4 - Intense Exercise for Survival among Men with Metastatic Castrate-Resistant Prostate Cancer), and breast cancer (BWEL - The Breast Cancer Weight Loss).[12-15] A meta-analysis estimated that each 15 metabolic equivalent task-hour per week increase in physical activity after colorectal cancer diagnosis was associated with a 38% lower risk of mortality.[9]

The science behind beneficial effect of exercise in cancer subjects: There are multiple mechanisms cited for how exercise produces its beneficial effects, including through hormones, dopamine, transforming growth factor-B1 (TGF-B1), insulin-like growth factors (IGFs), microphthalmia/transcription factor E (MiT/TFE), mammalian target of rapamycin (mTOR), and secreted protein and rich in cysteine (SPARC). It has been shown in in-vitro and mice models that exercise inhibits cancer cell proliferation (for moderate- and high-intensity exercise, not low-intensity exercise) and induces apoptosis. One such mechanism involves dopamine release in the prefrontal cortex, serum, and cancer tissues. Dopamine binds to the dopamine receptor 2 (D2) upregulating the kinase phosphorylation and TGF-B1 to inhibit cancer cell proliferation.[10] Another mechanism involves IGFs which regulate mitosis and anti-apoptosis and affect proliferation and differentiation of cancer cells. Studies have shown that postmenopausal women have decreased IGF-1 and IGF-3 after walking training for 6 months, which inhibits IGF's anti-apoptosis effect in breast cancer, for example. Weight loss also reduces levels of IGF-1. Exercise induces skeletal muscle to produce SPARC, which promotes cleavage of caspase-3 and caspace-8, promoting cell apoptosis and inhibiting colon cancer. AMP activated protein kinase (AMPK) is an important center of homeostasis and regulator of mTOR kinase activity. In a mouse study involving hepatocarcinoma, exercise reduced the activity of mTOR kinase by stimulating AMPK, thereby reducing cancer cell proliferation. Finally, exercise can regulate cancer metabolism by inhibiting Warburg anaerobic glycolysis and weakening the hypoxia microenvironment of cancer. Lactic acid is the most important metabolite of glycolysis and cancer cells produce lots of lactic acid, creating a low-pH environment. Lactic acid suppresses the immune response, inhibiting T cells. Therefore, by inhibiting anaerobic glycolysis, exercise suppresses lactic acid production, improving the immune response to target cancer cells.[11] Additionally, exercise stimulates the activity of NK cell function, decreasing inflammation, enhancing antigen presentation, and mitigating the accumulation of aging cells in the elderly.[12]

Guidelines regarding exercise in cancer subjects and survivors: Both the American Cancer Society (ACS) and National Comprehensive Cancer Network (NCCN) have recommendations for cancer survivors regarding maintaining healthy weight and exercise among cancer survivors. [13,14].

The NCCN recommends: