Baseline Fatigue and Severe Toxic Effects in Patients With Cancer Receiving Systemic Therapy

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doi:10.1001/jamaoncol.2025.5549

Importance

Fatigue is a common symptom reported by patients with cancer, yet its role as a predictor of treatment-related toxic effects has not been well characterized. Understanding whether fatigue measured at treatment initiation may be associated with subsequent toxic effects could help guide individualized treatment planning and symptom monitoring.

Objective

To evaluate the association between baseline patient-reported fatigue and the risk of adverse events (AEs) in cancer treatment trials.

Design, Setting, and Participants

This cohort study and pooled analysis assessed baseline fatigue data from 17 SWOG phase 2 and 3 trials conducted from 1990 to 2022. Patients were enrolled across multiple cancer types and treatment settings. Data analysis was performed from March 1, 2023, to October 17, 2025.

Exposures

Baseline fatigue, classified on a 5-point Likert scale, analyzed as binary thresholds (eg, &lt;some vs ≥some fatigue) and across fatigue severity levels.

Main Outcomes and Measures

Adverse events were classified using the Common Terminology Criteria for Adverse Events (CTCAE), with multiple versions mapped to version 4. Symptomatic AEs followed the Patient-Reported Outcomes-CTCAE framework; laboratory-based or measurable toxic effects were considered objective (hematologic vs nonhematologic). Primary outcomes were grade 3 or higher (severe), grade 4 or higher (life-threatening), and grade 5 (fatal) AEs. Odds ratios (ORs) were estimated using generalized estimating equations. To account for confounding, the analysis was clustered by trial and adjusted for age, sex, race, and obesity.

Results

Among 7086 patients (mean [SD] age, 62.1 [15.2] years; 2107 females [29.7%] and 4979 males [70.3%]) with prostate, lung, colorectal, lymphoma, breast, melanoma, ovarian, or pancreatic cancer, 103 738 AEs were reported. At baseline, 2771 participants (39.1%) reported some or more fatigue. Proportions with maximum AEs rated grade 3 or higher, grade 4 or higher, and grade 5 were 3128 participants (44.1%), 1001 (14.1%), and 62 (0.9%), respectively. Compared with those reporting no or minimal fatigue, patients with some fatigue or more had higher risks of severe or worse toxic effects (odds ratio [OR], 2.09; 95% CI, 1.58-2.78; P &lt; .001), life-threatening or fatal toxic effects (OR, 1.96; 95% CI, 1.36-2.82; P &lt; .001), and fatal toxic effects (OR, 2.35; 95% CI, 1.07-5.19; P = .03). A dose-response pattern was evident: patients reporting quite a lot or very much fatigue had an approximately 5-fold higher risk of fatal toxic effects (OR, 4.99; 95% CI, 1.84-13.51; P = .002). Findings were consistent across symptomatic, hematologic, and nonhematologic AE categories.

Conclusions and Relevance

This cohort study found that baseline patient-reported fatigue was associated with an increased risk of cancer treatment−related toxic effects. Fatigue assessments at treatment initiation may serve as an early clinical marker of risk for toxic effects and may help inform personalized treatment strategies and symptom monitoring.