Guest Editor’s Note: With growing evidence indicating that regular physical activity helps control cancer symptoms, oncology guidelines recommend exercise before, during, and after cancer treatment. Observational data also demonstrate a promising association between physical activity and favorable cancer outcomes; however, rigorous clinical trials are needed to understand the mechanisms and establish a causal relationship. In this article, Dr. Jones summarizes findings from an early-phase clinical trial conducted to determine the feasibility, safety, and tumor biological activity of exercise therapy in men with localized prostate cancer.
Lee Jones, PhD
The concept of initiating or maintaining an exercise therapy prescription to lower the risk of cancer or improve outcomes in adults either at high risk of cancer or following a cancer diagnosis is of considerable interest. Over the past 20 years, a new subdiscipline of oncology research has emerged to evaluate the potential role of exercise in cancer.1 This field is now widely referred to as exercise-oncology.1
Background
The roots of exercise-oncology began with early research evaluating whether controlled exercise therapy interventions were safe, feasible, and led to improvements in symptoms among individuals with early-stage disease after completion of primary adjuvant therapy, with most work being conducted in breast cancer. The scope of this work subsequently expanded to evaluate the feasibility and symptom control benefit across a broader range of cancer diagnoses beyond breast cancer, in patients undergoing primary adjuvant therapy, and in those with advanced disease.2 This work led to the first exercise guidelines for cancer patients by the American College of Sports Medicine (ACSM)3; these guidelines were recently updated by the ACSM2 followed by guidelines during treatment from ASCO.4
A substantial portfolio of ongoing trials in exercise-oncology continues to focus on symptom control outcomes. However, landmark work published in 2005 sprouted a new parallel line of investigation. Using data from the Nurses’ Health Study, Holmes and colleagues reported that postdiagnosis self-reported exercise was linked with reduced risk of recurrence and cancer mortality in early-stage breast cancer. These data, published in JAMA,5 showed that the potential of exercise may extend beyond controlling symptoms associated with a cancer diagnosis, with its subsequent treatment also potentially influencing disease outcomes.
Translational Framework
For further development and testing of exercise therapy as a candidate anticancer strategy, we established a translational framework designed specifically to facilitate investigation of exercise therapy from discovery epidemiologic studies to definitive phase II/III trials in a manner like that adopted in drug development.6 Most evidence linking exercise to cancer outcomes comes from observational studies—prospective studies that examined the association between postdiagnosis self-reported exercise and cancer outcomes. In general, postdiagnosis exercise was associated with better outcomes after cancer.
GUEST EDITOR
Jun J. Mao, MD, MSCE
For example, in a pan-cancer analysis of 11,245 patients with cancer (median 16 years of follow-up; 4,519 total deaths observed), postdiagnosis exercise was associated with a significant reduction in the hazard for overall mortality (hazard ratio = 0.75; 95% confidence interval [CI] = 0.70–0.80) and cancer mortality (HR = 0.82; 95% CI = 0.74–0.90) after adjustments were made for key covariates, including stage, comorbidity, body mass index, and cancer treatment.7 These data are supported by a growing body of preclinical evidence demonstrating that exercise suppresses the growth of numerous solid tumors.
Enter the PRESTO-1 Trial
Building on this work, we sought to directly evaluate whether prospective administration of exercise therapy has tumor biological efficacy and to identify the optimal dose to confer such effects. As such, we conducted the “first-of-its-kind” phase Ia dose-finding trial of exercise therapy in cancer (PRESTO-1). The primary objective was to identify the recommended phase II dose of exercise therapy for testing in larger trials.8
Leveraging the preoperative (neoadjuvant) setting—permitting measurement of effects on tumor tissue before and after exercise therapy—we evaluated six escalated doses (90–450 minutes/week) in 53 nonexercising patients with localized prostate cancer. All study procedures including exercise therapy were conducted using a digitized, decentralized platform, which permitted all procedures to be conducted remotely in the patients’ homes. The recommended phase II dose was determined via evaluation of feasibility (ie, compliance; completed vs planned dose) and biological activity (ie, decreases in plasma prostate-specific antigen and tumor cell proliferation [Ki67 index].
Results indicated that all exercise therapy dose levels were feasible, with no serious adverse events observed. Exercise therapy for 225 to 375 minutes per week showed promising biological activity. Considering the feasibility-biological activity ratio, the recommended phase II dose was determined to be 225 minutes/week.8
Future Recommendations
Based on this work, we are currently conducting a phase II randomized trial (ClinicalTrials.gov identifier NCT05751434) to investigate the efficacy of longer-term exercise therapy at the recommended phase II dose on prostate cancer correlative endpoints and clinical disease progression. Whether higher doses beyond the standard recommendation of 150 minutes/week are required to confer biological activity in other solid tumors is not known. This question will be addressed in PRESTO-2, a planned phase Ib dose-expansion trial to determine the feasibility and activity of neoadjuvant exercise therapy at the recommended phase II dose across multiple solid tumors.
We hope these ongoing efforts, as well as others in the field, will provide evidence regarding the beneficial antitumor benefit of exercise therapy. Parallel correlative studies will provide insight into exercise mechanisms of action to further refine exercise prescription guidelines and potentially guide rational exercise-drug combination approaches.
DISCLOSURE: Dr. Jones reported no conflicts of interest.
Dr. Jones is Head of the Exercise Oncology Program, Integrative Medicine Service, Memorial Sloan Kettering Cancer Center, New York.
REFERENCES
- Jones LW, Alfano CM: Exercise-oncology research: Past, present, and future. Acta Oncol 52:195-215, 2013.
- Campbell KL, Winters-Stone KM, Wiskemann J, et al: Exercise guidelines for cancer survivors: Consensus statement from International Multidisciplinary Roundtable. Med Sci Sports Exerc 51:2375-2390, 2019.
- Schmitz KH, Courneya KS, Matthews C, et al: American College of Sports Medicine roundtable on exercise guidelines for cancer survivors. Med Sci Sports Exerc 42:1409-1426, 2010.
- Ligibel JA, Bohlke K, May AM, et al: Exercise, diet, and weight management during cancer treatment: ASCO Guideline. J Clin Oncol 40:2491-2507, 2022.
- Holmes MD, Chen WY, Feskanich D, et al: Physical activity and survival after breast cancer diagnosis. JAMA 293:2479-2486, 2005.
- Jones LW: Precision oncology framework for investigation of exercise as treatment for cancer. J Clin Oncol 33:4134-4137, 2015.
- Lavery JA, Boutros PC, Scott JM, et al: Pan-cancer analysis of postdiagnosis exercise and mortality. J Clin Oncol 41:4982-4992, 2023.
- Jones LW, Moskowitz CS, Lee CP, et al: Neoadjuvant exercise therapy in prostate cancer: A phase 1, decentralized nonrandomized controlled trial. JAMA Oncol 10:1187-1194, 2024.
