Baseline fatigue reported before cancer treatment is strongly associated with a higher risk of severe and fatal treatment related toxic effects, according to a large, pooled analysis of randomised clinical trial data.
Study Design and Patient Population
This cohort study pooled data from 17 phase two and three cancer treatment trials conducted between 1990–2022 and included 7,086 patients across multiple tumour types and treatment settings. Patients had prostate, lung, colorectal, lymphoma, breast, melanoma, ovarian, or pancreatic cancer and provided baseline assessments of fatigue at trial entry. Fatigue was measured using a five-point Likert scale and analysed both as binary thresholds and across increasing severity levels. Adverse events were classified using mapped versions of the Common Terminology Criteria for Adverse Events, with outcomes grouped as symptomatic, haematologic, or non-haematologic. The analysis accounted for clustering by trial and adjusted for age, sex, race, and obesity.
Baseline Fatigue and Toxicity Risk
At treatment initiation, 39.1% of participants reported some or more baseline fatigue. Across the cohort, 44.1% experienced at least one severe adverse event, 14.1% had life threatening events, and 0.9% experienced fatal toxic effects. Patients reporting baseline fatigue had significantly higher risks across all toxicity thresholds. Compared with those reporting no or minimal fatigue, baseline fatigue was associated with severe or worse toxic effects: (odds ratio: 2.09; 95% CI: 1.58–2.78; p<0.001). Life threatening or fatal toxic effects were also more common: (odds ratio: 1.96; 95% CI: 1.36–2.82; p<0.001). Fatal toxic effects alone were increased: (odds ratio: 2.35; 95% CI: 1.07–5.19; p=0.03).
Dose Response and Clinical Relevance
A clear dose response relationship was observed about baseline fatigue severity. Patients reporting quite a lot or very much fatigue had an almost fivefold higher risk of fatal toxic effects: (odds ratio: 4.99; 95% CI: 1.84–13.51; p=0.002). These associations were consistent across symptomatic, haematologic, and non haematologic adverse events. The findings suggest that baseline fatigue may act as an early clinical marker of vulnerability to treatment toxicity and could support more personalised treatment strategies and closer symptom monitoring at therapy initiation.
Reference
Unger JM et al. Baseline fatigue and severe toxic effects in patients with cancer receiving systemic therapy. JAMA Oncol. 2025; doi: 10.1001/jamaoncol.2025.5549.
