Remote Exercise Program for Patients With Metastatic Renal Cell Carcinoma Undergoing Immunotherapy: An EXIO Case Series Report

Introduction

Metastatic Renal Cell Carcinoma Subgroup

This case study evaluates the impact of a 12-week supervised remote exercise program on the health-related quality of life (HRQOL) of 19 patients diagnosed with metastatic renal cell carcinoma (mRCC) undergoing immune checkpoint inhibitors (ICIs) alone or in combination with tyrosine kinase inhibitors (TKIs). The participants’ median age was 67 years (range, 32-88), with 57.9% identifying as male. Most were White (78.9%), married (63.2%), and had at least a college degree (52.7%). Treatment regimens included ipilimumab plus nivolumab (31.6%), nivolumab plus cabozantinib (26.3%), pembrolizumab plus axitinib (26.3%), and nivolumab monotherapy (15.8%).

Supportive interventions such as exercise programs (as evaluated in the case series) are crucial to mitigating the challenges posed by the significant symptom burden associated with ICI-based therapies and TKIs for mRCC. ICI-based combinations and TKIs are current treatment options for mRCC, but they are often accompanied by significant treatment-related adverse events (AEs), including fatigue, that overlap with disease-related symptoms.^1-6 Exercise has been shown to help reduce these symptoms during and after cancer treatment. Higher physical activity levels at the start of ICI treatment are associated with a lower risk of severe immune-related AEs (irAEs).^7,8 Tailored supportive care interventions, such as exercise programs, have emerged as promising strategies to mitigate adverse effects by enhancing physical fitness, reducing fatigue, and improving emotional well-being.^8-10 This underscores the need for an integrated approach to disease management that combines effective cancer treatments with supportive patient care measures.

Background

Patients were invited to participate in a 12-week supervised remote exercise program. Patients were eligible if they had a diagnosis of mRCC and were receiving treatment with ICIs, with or without TKIs. Patients were excluded if they had serious medical or cognitive conditions that would make a home-based exercise program unsafe or unfeasible. To ensure a personalized exercise regimen, the initial telehealth session focused on evaluating each patient’s home exercise environment, including available space and equipment. During this session, the exercise physiologist provided a detailed overview of the program, including instructions on using the Vedius platform. This platform supported exercise adherence by offering instructional videos demonstrating proper exercise techniques and tracking patient engagement. Notably, adherence was defined as completing at least 8 of the 12 weeks of the program.

Findings

Over the 12-week intervention, patients participated in weekly virtual consultations with the exercise physiologist. These sessions involved assessing patients’ physical capabilities, including relevant medical histories (eg, prior surgeries, injuries) and functional abilities such as walking, stair climbing, and lifting objects. The exercise prescription followed the Frequency, Intensity, Time, Type principle: Resistance training was performed twice weekly targeting major muscle groups (eg, squats, wall push-ups, resistance band rows; 2-3 sets of 8-12 repetitions each), aerobic activity consisted of brisk walking or stationary cycling 3 to 5 days per week (20-40 minutes/session), and mobility exercises included dynamic stretching and joint range-of-motion movements incorporated into each session. Intensity levels were guided by the Borg Rating of Perceived Exertion (RPE) scale, targeting a moderate range (RPE, 12-14) with progressive overload applied every 1 to 2 weeks based on tolerance and performance.

To enhance program flexibility, patients could contact the exercise physiologist via WhatsApp for real-time guidance, adjustments, or increased exercise intensity as needed. Notably, patients were assessed before starting the exercise program and 12 weeks later using the Functional Assessment of Cancer Therapy–Immune Checkpoint Modulator (FACT-ICM), the Brief Fatigue Inventory (BFI), and the Edmonton Symptom Assessment System (ESAS).

To evaluate the effectiveness of the 12-week supervised remote exercise program, we assessed whether patients experienced improvements across key health domains. This leads to the following question:

Notably, exercise has been shown to be an effective way to manage common symptoms, such as fatigue and anxiety, while also improving physical function and emotional health.^8-10 The findings from this case series suggest that a 12-week supervised remote exercise program can positively impact multiple dimensions of health among patients with mRCC undergoing treatment with ICIs or ICI-TKI combinations (Table). Participants experienced notable improvements in overall HRQOL (FACT-General mean increase, 9.8 points; P = .001), including a mean increase of 10.1 points in the toxicity subscale (ICM; P = .017). Cohen d for HRQOL was 0.8 (95% CI, 0.3-1.3), indicating a large effect, and supports the reliability of this finding. Fatigue also improved significantly, with a mean decrease in fatigue symptoms of 21.1 points, as measured by the BFI (P = .018), alongside a mean decrease of 5.0 points in ESAS fatigue (P = .001). Cohen d for fatigue –1.5 (95% CI, −2.5 to −0.4) further emphasizes the substantial reduction in fatigue experienced by participants. Additionally, symptom burden (ESAS mean decrease, 12.3; P = .001) and key patient-reported outcomes showed significant gains, including reduced symptoms of anxiety (ESAS mean decrease, 2.7; P = .02), depression (mean decrease, 1.2; P = .01), appetite loss (mean decrease, 2.2 points; P = .01), and sleep disturbances (mean decrease, 1.9; P = .01). Cohen d for these outcomes ranged from −0.5 to −1.1, suggesting moderate to large effects, and their 95% CIs further confirm the statistical significance of these improvements. These results underscore the potential of structured, home-based exercise interventions to enhance physical and emotional well-being in this patient population, despite the challenging adverse effects associated with their cancer therapies.

Discussion

The treatment of mRCC has advanced with ICIs either as monotherapy, in combination with other ICIs, or with TKIs, leading to better survival outcomes. However, these treatments are associated with distinct toxicity profiles due to the combination of agents with different mechanisms of action. ICIs can induce irAEs that significantly affect the HRQOL of patients. For example, combinations of immune-oncology agents with TKIs are associated with a range of toxicities, including hepatobiliary disorders, hypertension, thyroid dysfunction, and dermatologic reactions, as reported in relevant phase 3 trials.^1,5,11

While these toxicities are typically identified and managed clinically by oncologists, symptoms such as fatigue, sleep disturbances, and mood disorders (eg, anxiety and depression) often go unnoticed yet can have a substantial impact on patients’ HRQOL. These symptoms frequently result from overlapping treatment-related AEs, disease-related factors, and the patient’s physiological and psychological condition. Although not usually life-threatening, these issues can lead to significant discomfort, negatively influencing treatment adherence and HRQOL.

The mechanisms underlying these beneficial effects may include modulation of systemic inflammation, improvements in neuroendocrine function, and enhanced muscle metabolism, which collectively contribute to reduced fatigue and improved mood.^10,12,13 Exercise is known to decrease proinflammatory cytokines and regulate the hypothalamic-pituitary-adrenal axis, which may help alleviate cancer-related symptoms and improve QOL.^10,14-16

The benefits of exercise in oncology are increasingly well documented.^8-10 Numerous studies have shown that exercise can improve physical function, reduce treatment-related fatigue, enhance emotional well-being, and improve overall quality of life in patients with cancer.^8-10,11 For instance, both aerobic and resistance exercises have been found to alleviate cancer-related fatigue, a common and debilitating adverse effect of cancer therapies.^9,10 Additionally, exercise can help manage musculoskeletal pain, preserve muscle mass, and enhance cardiovascular health, which is particularly important in patients undergoing therapies with known cardiovascular risks, such as TKIs.^17,18 The American Cancer Society, the American College of Sports Medicine, and the American Society of Clinical Oncology all support the integration of physical activity into cancer care, recommending individualized exercise programs to optimize patient outcomes during treatment.^9,19-21

However, while the benefits of exercise in cancer care are well supported for several types of cancer, data specifically for RCC, particularly mRCC, remain limited. Despite the growing evidence for exercise in oncology more broadly, few studies have focused on its impact in patients with mRCC. This gap in the literature highlights the need for further research to evaluate how exercise interventions can be integrated into treatment regimens for this patient population. Given the unique challenges posed by the adverse effects of ICIs and TKIs, there is a clear need for more targeted studies to explore the role of exercise in improving the health and well-being of patients with mRCC.

Furthermore, the case series demonstrates the potential benefits of integrating structured remote exercise programs into the care of patients with mRCC undergoing ICIs alone or in combination. The program not only improved overall HRQOL but also significantly alleviated key physical and emotional symptoms. These findings underscore the potential of exercise as a supportive intervention in this challenging population. Future studies should aim to dissect the individual contributions of aerobic, resistance, and mobility exercises, as well as the role of remote supervision, using factorial trial designs or component analyses. Such research could clarify which specific elements are most effective, thereby optimizing program design and improving scalability.

Implications for Practice

The results suggest that integrating exercise programs into the supportive care framework for patients with mRCC can improve symptom management and overall well-being. Given the remote nature of the intervention, it can overcome barriers such as geographic location, transportation challenges, and physical limitations, making it a scalable option for broader implementation. However, the question remains regarding which program components—resistance, aerobic, mobility exercises, supervision—are most critical for achieving these benefits. Future studies addressing this question could help refine program design and optimize outcomes.

This study is not without limitations. The small sample size and lack of a control group limit the generalizability of the findings and increase the possibility that nonspecific effects, such as participants’ expectations of benefit and increased attention, may have contributed to the observed improvements in patient-reported outcomes. Additionally, the short duration of the intervention may not fully capture the long-term benefits or adherence challenges of remote physical activity programs. Although patients were consecutively recruited, which reduces the risk of selection bias, and participants were not receiving other structured supportive care interventions during the exercise program, minimizing confounding from concurrent treatments, the potential influence of unmeasured confounding factors and expectancy effects was not fully explored.

Building on the findings of this case series, future research should focus on several key areas. First, conducting randomized controlled trials with larger cohorts is necessary to validate the results observed in this study. Additionally, it is important to investigate the long-term sustainability of the benefits seen in the exercise program to determine whether these improvements are maintained over time. Another crucial aspect of future research is identifying the most impactful components of the program through factorial study designs, which could help optimize the program’s structure and maximize its effectiveness.

Conclusion

This study underscores the potential of structured remote exercise programs to improve HRQOL and alleviate physical and emotional symptoms in patients with mRCC undergoing ICIs alone or in combination. Addressing the closed question posed in this paper will help identify the most effective elements of such programs, paving the way for optimized interventions that can be seamlessly integrated into clinical practice.

Corresponding Author

Paulo Gustavo Bergerot, MD

Oncoclinicas&Co

Av. Pres. Juscelino Kubitschek, 510, 2º andar, Itaim Bibi,

04.543-906 Sao Paulo, SP, Brazil

Email: paulobergerot@gmail.com

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