Supervised, Multimodal Exercise: The Chemotherapy Supportive Therapy That Almost Does It All

Short abstract

This commentary describes and places the results into context for the recent OptiTrain trial, a three‐arm randomized trial of two different exercise interventions versus usual care on rates of chemotherapy completion, hospitalization, and hematological toxicity.

Delivery of full chemotherapy dose intensity with minimization of adverse chemotherapy‐related events is a primary quality of care indicator in medical oncology. Clinical oncology professionals are also increasingly recognizing patient quality of life as a vital component of cancer care 1. As such, a therapy that could maximize delivery of chemotherapy relative dose intensity (RDI), reduce treatment toxicities, and improve quality of life, with positive side effects of improved physical fitness, reduced anxiety and depression, and extended overall survival, would likely be prescribed by every medical oncologist in every cancer treatment center. Although such a therapy does not currently exist, Mijwel et al. report on a therapy that comes close in this issue of The Oncologist 2.

In this article, Mijwel et al. report results of the OptiTrain trial, a 3‐arm randomized trial of two different exercise interventions versus usual care, on rates of chemotherapy completion, hospitalization, and hematological toxicity 2. The trial compared 16 weeks of high‐intensity aerobic interval training (three sets of 3 minutes with 1‐minute recovery) combined with either resistance training (RT‐HIIT) or moderate‐intensity aerobic training (AT‐HIIT) to usual cancer care. Although this may sound challenging for patients, the exercise sessions took place only twice per week for 60 minutes and were closely supervised in an in‐hospital exercise clinic. Patients in the exercise programs, many of whom had comorbid conditions, attended approximately two thirds of offered exercise sessions throughout chemotherapy and were typically able to complete the exercise prescription at the sessions they attended.

One of the most compelling clinical outcomes of exercise for oncology care providers is thought to be the potential for exercise interventions to enhance patient tolerance of chemotherapy and thereby delivery of the planned RDI 3. Although the rationale for exercise training–related improvement of RDI is robust (preservation of muscle mass and physical function should enhance tolerance), the current research evidence is not. A recent systematic review reported that none of the eight randomized exercise trials that have evaluated RDI have reported clinically relevant effects, although two had statistically significant effects 4. In line with these results, the high‐quality, multimodal OptiTrain interventions did not have an impact on RDI, despite the RT‐HIIT intervention achieving the proposed biologic mechanism of enhanced muscle mass, strength, and physical fitness. There was no difference between either exercise group and usual care in achieved RDI, prevalence of a single dose reduction, or percentage of participants receiving ≥85% of RDI 2. Receipt of >85% of RDI is a known threshold for achievement of chemotherapy effectiveness 5. Notably, although approximately one quarter of all patients in the OptiTrain trial required at least one single chemotherapy dose reduction, the majority (83%) still received >85% RDI, likely thanks to other supportive therapies such as antiemetics and granulocyte colony‐stimulating factor (G‐CSF) offered as standard of care with modern regimens 2. This leaves relatively little room for improvement in chemotherapy tolerance in this population from any supportive therapy. There may be greater potential for clinically relevant effects of exercise on RDI in other patient populations with lower overall chemotherapy tolerance.

Although the current state of the evidence is that there is not a clinically relevant effect of exercise on RDI, it was a secondary outcome in all completed trials to date 4. There are two registered clinical exercise trials in progress with chemotherapy tolerance metrics as the primary outcome. Caan, Schmitz, and Meyerhardt are randomizing 180 patients with stage II or III colon cancer receiving chemotherapy to a targeted muscle‐building intervention consisting of progressive resistance training and protein powder or usual care 6. Body composition alters pharmacokinetics of colon cancer regimens, and thus the investigators designed the intervention with a laudable goal of a quantitative change in body composition—a 1 kg increase in lean body mass. Irwin and Sanft are randomizing 250 women with stage I–III breast cancer receiving chemotherapy to either 11 physical activity and healthy eating counselling sessions or usual care 7. Although this exercise intervention will be less targeted, the addition of dietary behavior change could also enhance chemotherapy tolerance. Both trials have estimated completion dates in 2022 and will provide more conclusive evidence for the impact of exercise on RDI.

In light of the relatively high chemotherapy tolerance and survival rates among modern chemotherapy regimens, minimization of the costs and health impacts of chemotherapy sequelae have become central objectives in the medical management of early stage breast cancer. Exercise can be considered an effective, multifaceted, supportive therapy to achieve these goals. Febrile neutropenia is a common toxicity with myelosuppressive chemotherapy that is associated with substantial morbidity, mortality, and cost 8. The 13% rate of hospitalization for febrile neutropenia reported in the OptiTrain usual care group was similar to that (13.9%) recently reported in a database analysis of 3,314 patients with breast cancer 8. Importantly, the RT‐HIIT OptiTrain intervention significantly reduced hospitalization rates to 3% of patients and also reduced incidence of thrombocytopenia, a less common toxicity that can also increase health care costs. The mean total cost of a hospitalization for febrile neutropenia in the database analysis was U.S. $20,462 8. Using the OptiTrain incidence data, approximately nine patients would need to be treated with the RT‐HIIT exercise intervention for one additional patient to benefit from reduced hospitalization. Therefore, the cost of delivering the exercise intervention for nine patients would have to be less than $20,462 (or $2,274 per patient) to be a cost‐effective therapy for reducing hospitalization rates. We recently reported an estimate of operating costs for a real‐world exercise and nutrition program during and after chemotherapy and radiation for early stage breast cancer to be $1,273 per patient 9. This high‐level cost‐effectiveness analysis is based only on the benefits for hospitalizations and does not include the numerous other health and health care improvements associated with exercise.

Mijwel et al. have previously published results of numerous other benefits of the OptiTrain interventions beyond those reported in this month's issue of The Oncologist. In line with substantial previous evidence 10, both OptiTrain exercise interventions preserved or improved aspects of health‐related quality of life related to physical function 11. Despite the lack of an objective change in chemotherapy completion rate, patients in both exercise groups reported less treatment symptom burden 11. Both interventions also maintained cardiorespiratory fitness during treatment 12. Preservation of cardiorespiratory fitness will likely translate into long‐term morbidity and mortality benefits, as chemotherapy is typically associated with deterioration equivalent to that expected with a decade of aging 13, 14, 15.

In addition to the noted benefits on hospitalizations and thrombocytopenia, the RT‐HIIT intervention may also provide the optimal exercise stimulus to maximize patient‐reported and objectively measured physical outcomes. The RT‐HIIT intervention achieved preservation of cardiorespiratory fitness with a total of only 9 minutes of high‐intensity aerobic training twice per week and also resulted in improvements in upper and lower body muscle strength through biopsy‐confirmed prevention of mitochondrial content decay, muscle fiber cross‐sectional area, and capillaries per muscle fiber 15, 16. Generally, the RT‐HIIT intervention had larger effect sizes on patient‐reported symptoms, especially multidimensional cancer‐related fatigue and preservation of cognitive functioning compared with the AT‐HIIT group 11. These positive effects on total symptoms, cancer‐related fatigue and strength persisted at 1 and 2 years after chemotherapy relative to the usual care group despite no current differences between groups in objectively measured physical activity 17, 18. Taken together, these results demonstrate that the combination of aerobic interval training and resistance training twice per week for 16 weeks throughout chemotherapy treatment improves the patient experience of chemotherapy, prevents negative physiological sequelae of chemotherapy, and improves long‐term patient well‐being.

The OptiTrain trial did not assess the effects of exercise on cancer recurrence or survival. To my knowledge, only two trials have performed exploratory analysis of the effect of exercise during chemotherapy on cancer outcomes in women with early stage breast cancer. Although both trials demonstrated a clear differentiation in disease‐free survival trends between the exercise and usual care groups with 7–8‐year follow‐up, they did not reach statistical significance with total sample sizes of 242 and 337 women 19, 20. Yet, Hayes et al. reported that completing a combined aerobic and resistance exercise intervention during and after chemotherapy (8 months total) significantly reduced the hazard of death by 55% relative to usual care 20. In contrast, Courneya et al. reported that completing either aerobic or resistance training for the duration of chemotherapy only did not result in a significant reduction of the hazard of death compared with usual care 19. As with the enhanced benefits associated with the RT‐HIIT intervention in the OptiTrain trial, the discrepancy in the results of these two studies point to the clinical importance of combined aerobic and resistance training during chemotherapy.

In conclusion, this article and the overall results of the OptiTrain trial contribute significant new knowledge to the quantification of the clinical benefit of exercise as a supportive therapy during chemotherapy treatment for early stage breast cancer. Although current standard of care supportive care therapies such as antiemetics and G‐CSF have substantially improved chemotherapy completion rates in this population, a well‐designed, supervised, exercise intervention clearly has substantial benefits for the patient that are not offered by these therapies. Oncology care providers can expect measurable benefits of such an intervention on treatment toxicity and symptoms and long‐term physical health and well‐being. If in the future, the ongoing trials by Caan and Irwin are able to demonstrate a clinically relevant benefit of exercise on chemotherapy completion rate, that will be another feather in the cap of an already crucial supportive therapy for women receiving chemotherapy for breast cancer.

Disclosures

The author indicated no financial relationships.