Oncology
Conditions
Keywords
Oncology, Exercise, immunotherapy, Renal cell carcinoma, immune-related adverse events, randomized controlled trial, immune function
Brief summary
The primary aim of this study is to evaluate the feasibility of a supervised high intensity interval training (HIIT) program during first-line dual immune checkpoint inhibitor (ICI) therapy (nivolumab plus ipilimumab) in patients with advanced renal cell carcinoma (RCC). The second aim is to generate preliminary data on the effects of exercise on the immune cell phenotype and function, gut microbiota composition, physical fitness, patient-reported outcomes and clinical outcomes. This is a two-arm randomized controlled pilot trial in which 30 patients with advanced RCC scheduled to receive first-line nivolumab plus ipilimumab will be randomized in 1:1 ratio to an exercise intervention group or usual care group. The exercise intervention consists of two 60-minute supervised HIIT sessions per week, delivered by oncology-trained physiotherapists and one additional home-based moderate-intensity aerobic exercise sessions per week. The intervention starts with the first cycle of immunotherapy and continues for four treatment cycles. Participants in both groups will receive usual care and general exercise guidelines. Measurements include blood and stool sampling for microbiome and immune parameters analysis, physical fitness assessments, physical fitness monitoring, body composition measurements, and patient-reported outcomes related to quality of life, fatigue, depression, sleep and diet.
Detailed description
There is strong evidence from randomized controlled trials that exercise during cancer treatment can maintain physical fitness, limit fatigue, and enhance health-related quality of life (HRQoL). Some studies also showed that exercise may help patients to better tolerate their treatment. However, most exercise trials have been conducted in patients receiving chemotherapy or radiotherapy, and little is known about the feasibility or effects of exercise during immunotherapy, particularly in patients with advanced RCC. First-line treatment for patients with advanced RCC often consists of dual ICI treatment with nivolumab plus ipilimumab. While this combination has shown to improve survival, a substantial proportion of patients do not respond, and approximately 44% experience any grade immune-related adverse events. Tumor hypoxia, an immunosuppressive tumor microenvironment, and insufficient infiltration of cytotoxic immune cells are key factors believed to contribute to treatment resistance. Preclinical studies in mice have shown that aerobic exercise can positively influence the tumor microenvironment through reduced tumor hypoxia, enhanced tumor perfusion, and increased activity and infiltration of cytotoxic immune cells such as CD8+ T cells and natural killer (NK) cells, while reducing immunosuppressive cell populations. In addition, preclinical studies in mice suggested that exercise-induced changes in the gut microbiome can further support immune activation and improve responses to immunotherapy. Despite this promising biological rationale, no clinical studies have evaluated whether supervised exercise is feasible or beneficial in patients with advanced RCC. The primary objective of this pilot randomized controlled trial is to evaluate the feasibility of a supervised exercise program during first-line dual ICI therapy in patients with advanced RCC. Secondary objectives are to explore the preliminary effects of exercise on immune phenotype and function, inflammatory markers, circulating tumor (ct)DNA, gut microbiome composition, body composition, aerobic fitness, muscle function, physical activity, and patient reported outcomes including HRQoL, fatigue, anxiety, depression, sleep, and diet. In addition, changes in immune function, gut microbiome composition and clinical outcomes will also be explored. This study is a two-arm randomized controlled trial including 30 adult patients with advanced RCC. Participants will be randomized to the intervention arm that receives a supervised HIIT program in addition to usual care or to a usual care control arm. The intervention consists of two supervised 60-minute HIIT-exercise sessions per week, delivered by oncology trained physiotherapists, combined with one additional home-based moderate intensity exercise session of at least 30 min per week. The intervention starts with the first cycle of immunotherapy and continues for four treatment cycles. Blood and stool samples will be collected at baseline and at 6 weeks and 12 weeks during treatment to assess immune and microbiome changes. In addition, in participants allocated to the exercise intervention group, to evaluate the acute effects of exercise on the immune response, blood samples will be collected immediately before and after a supervised exercise session. Physical fitness tests, questionnaires and Fitbit to monitor physical activity will be used to evaluate functional and patient-reported outcomes. This pilot study will provide important information on the feasibility of exercise during immunotherapy and generate preliminary data on potential immunological effects. These findings will inform the design of future larger trials aimed to optimize supportive care and improve treatment outcomes for patients with advanced RCC.
Interventions
BEHAVIORALHIIT
The intervention group will be offered a supervised exercise program consisting of two 60-minute sessions per week, including continuous aerobic exercise and HIIT. Sessions will be supervised by physiotherapists specialized in oncology, and the training load will be tailored to a patient's individual fitness levels throughout the intervention. Following a short warm-up, participants will perform repeated high-intensity cycling intervals targeting 85-95% of their estimated peak heart rate corresponding to a Borg Rating of Perceived Exertion (RPE) 16-18), interspersed with periods of active recovery at light intensity. The HIIT component will be followed by moderate-intensity aerobic exercise at approximately 70% of the estimated heart rate (Borg RPE 13-14), and a cool-down period. In addition, participants will be asked to be physically active for at least 30 minutes at moderate intensity, in accordance with the American College of Sports Medicine (ACSM) guidelines.
Sponsors
Radboud University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥18 years. * Diagnosed with advanced RCC with indication for standard-of-care dual ICI treatment. * Able and willing to give written informed consent.
Exclusion criteria
* Life expectancy \<6 months. * Unable to perform basic activities of daily living such as walking. * Presence of cognitive impairment or severe emotional instability (e.g. schizophrenia, Alzheimer's disease, alcohol addiction), at the discretion of the investigator. * Presence of other disabling comorbidities that may interfere with the ability to perform physical exercise (e.g., heart failure, chronic obstructive pulmonary disease (COPD, GOLD stage 3 or 4), orthopaedic conditions, or neurological disorders such as hernia, paresis, amputation or active rheumatoid arthritis), at the discretion of the investigator. * Current participation in structured vigorous aerobic and/or resistance exercise ≥ 2 times per week at a level comparable to the intervention
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participation rate | Study enrolment period (approximately 24 months) | Calculated by the proportion of eligible patients that participate. An accrual rate lower than 20% will be defined as not feasible. |
| Exercise intervention adherence | 12 weeks (during intervention period) | Adherence will be assesed by attendance and exercise relative dose intensity (ExRDI). Attendence will be assessed by dividing the number of attended sessions by the number of prescribed sessions. ExRDI will be calculated as the percentage of the exercise intensity achieved during the performed sessions relative to the total prescribed exercise intensity expressed as a percentage. The information will be collected using questionnaires and exercise-logs registered by the physical therapists. These logs will be collected by the researcher |
| Immune-related and exercise-related adverse events | 24 weeks (during intervention period of 12 weeks, and 12 weeks post intervention) | Immune related adverse events will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) v5.0 based on medical records and the patient reported outcomes (PRO)-CTCAE completed by patients before each immunotherapy cycle and at 3-month follow up. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Body composition | 12 weeks (Baseline, post-intervention) | Bioelectrical Impedance Analysis (BIA), Length (cm), Body weight (kg), Muscle mass (kg), Body fat percentage (%). Weight and height will be combined to report BMI in kg/m² |
| Estimated aerobic fitness | 12 weeks (Baseline, post-intervention) | Steep ramp test |
| Lower body muscle function | 12 weeks (Baseline, post-intervention) | Lower body muscle function will be assessed using a sit-to-stand test |
| Physical activity | 12 weeks (Baseline, post-intervention) | Modified Godin Leisure-Time Exercise Questionnaire, Fitbit continuously |
| Health-related quality of life (HRQoL) | 12 weeks (Baseline, post-intervention) | European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) questionnaire |
| Fatigue | 12 weeks (Baseline, post-intervention) | European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Fatigue Module (EORTC QLQ FA12) questionnaire |
| Anxiety and depression | 12 weeks (Baseline, post-intervention) | Hospital Anxiety and Depression Scale (HADS) questionnaire |
| Sleep | 12 weeks (Baseline, post-intervention) | Pittsburgh Sleep Quality Index (PSQI) questionnaire |
| Diet | 12 weeks (Baseline, post-intervention) | World Cancer Research Fund / American Institute for Cancer Research (WCRF/AICR) Cancer Prevention Recommendations Questionnaire |
| ctDNA | 12 weeks (baseline, 6 weeks, and post-intervention) | Venous blood sampling, concetration ctDNA (ng/mL) next-generation sequencing |
| Immune cell phenotype and function, and inflammatory markers | 12 weeks (baseline, 6 weeks, and post-intervention) | Venous blood sampling and flow cytometry to determine frequency (%) of circulating immune cells, functional characteristics of circulating immune cells will be determined using functional assays, inflammatory marker concentrations will measured (pg/mL or ng/mL). |
| Gut microbiome composition | 12 weeks (baseline and post-intervention) | Taxonomic features and alpha and beta diversity via 16S rRNA marker gene sequencing of feces samples |
Countries
Netherlands
Contacts
CONTACTLaurien Buffart, PhD
PRINCIPAL_INVESTIGATORLaurien M Buffart, PhD
Radboud University Medical Center
PRINCIPAL_INVESTIGATORSasja F Mulder, MD, PhD
Radboud University Medical Center
PRINCIPAL_INVESTIGATORTheo van Voorthuizen, MD
Rijnstate
Outcome results
None listed