The impact of exercise on tolerability of systemic treatment in metastatic colorectal cancer: A literature review.

This narrative review examines whether structured physical activity can mitigate treatment-related toxicity in metastatic colorectal cancer (mCRC) and thereby reduce toxicity-driven treatment modifications.

Key points:

• Clinical problem:
  • • >50% of CRC patients develop metastatic disease and receive multiple lines of systemic therapy.
  • • At least 40% have toxicity-driven dose reductions, delays, or discontinuations within 3 months, potentially compromising anti-tumor efficacy.
• Scope of the review:
  1. • Overview of common toxicities from chemotherapy and targeted/immunotherapy in mCRC (neurotoxicity, hematologic, gastrointestinal, fatigue; less evidence for dermatologic and immune-related toxicities).
  2. • Synthesis of 15 observational studies on physical activity, fitness, and function versus toxicity-related treatment modification and survival.
  3. • Synthesis of 8 exercise intervention studies in mCRC.
  4. • Discussion of potential biological mechanisms by which exercise may influence toxicity.
• Observational data:
  • • Higher baseline or ongoing physical activity, better cardiorespiratory fitness, and better physical function are consistently associated with improved survival outcomes.
  • • There is suggestive evidence that fitter, more active patients may experience fewer or less severe treatment modifications, although data are limited and heterogeneous.
• Interventional exercise data:
  • • Supervised and/or structured exercise during systemic therapy is feasible in mCRC.
  • • Exercise programs improve patient-reported outcomes (e.g., quality of life, fatigue) and physical fitness.
  • • Current trials are generally small and not powered to robustly evaluate effects on specific toxicities or hard oncologic endpoints.
• Proposed mechanisms:

  The authors summarize plausible pathways by which exercise might attenuate:

  • • Neurotoxicity: via improved microvascular function, neurotrophic factors, and reduced oxidative stress.
  • • Hematologic toxicity: through effects on bone marrow function, inflammation, and systemic metabolism.
  • • Gastrointestinal toxicity: via modulation of gut motility, microbiome, and inflammatory signaling.
  • • Fatigue: through effects on muscle mass, mitochondrial function, sleep, and mood.

  Evidence for effects on dermatologic and immune-related toxicities, particularly from targeted agents and immunotherapy, is essentially absent and identified as a key research gap.

• Clinical implications:
  • • Exercise appears safe and beneficial for quality of life and fitness in mCRC patients on systemic therapy.
  • • There is a credible rationale that exercise could reduce toxicity-induced treatment modifications and potentially improve survival, but this remains to be confirmed.
  • • The authors advocate for integrating structured exercise into mCRC care pathways, alongside rigorous prospective trials specifically designed to test effects on toxicity profiles, treatment adherence/intensity, and oncologic outcomes.
• Implications for survivors/patients in active treatment:
  • • Incorporating appropriately tailored physical exercise during systemic treatment for metastatic disease may help reduce or prevent treatment changes driven by toxicity and could support better long-term outcomes, warranting discussion and individualized planning within oncology care.