Patient fatigue flags risk of toxicity from cancer treatment

Patient fatigue reported before the initiation of cancer treatment appears to be associated with an increased risk of subsequent treatment-related adverse events (AEs), according to new research.

Analysis of data from 17 randomized clinical trials in the US SWOG Cancer Research Network showed that patients who reported some fatigue or more were twice as likely as those who reported no or minimal fatigue to experience severe or worse toxic effects (odds ratio [OR], 2.09, 95 percent confidence interval [CI], 1.58–2.78; p<0.001), life-threatening or fatal toxic effects (OR, 1.96, 95 percent CI, 1.36–2.82; p<0.001), and fatal toxic effects (OR, 2.35, 95 percent CI, 1.07–5.19; p=0.03). [JAMA Oncol 2025;doi:10.1001/jamaoncol.2025.5549]

Each increase in fatigue level was associated with 44-percent greater odds of severe toxic effects (OR, 1.44, 95 percent CI, 1.25–1.65; p<0.001), 44-percent greater odds of life-threatening toxic effects (OR, 1.44, 95 percent CI, 1.20–1.73; p<0.001), and 65-percent greater odds of fatal toxic effects (OR, 1.65, 95 percent CI, 1.17–2.34; p=0.005).

The association between patient-reported fatigue at baseline and cancer treatment-related toxicity followed a dose-response pattern. The proportion of patients who had severe or worse toxic effects increased from 34.2 percent among patients who reported no fatigue to 39.4 percent, 52.8 percent, and 58.3 percent among patients who reported a little, some, or quite a lot/very much fatigue at baseline, respectively. Notably, the odds of fatal toxic effects were roughly five times higher among patients who reported quite a lot or very much fatigue at baseline vs those who reported none (OR, 4.99, 95 percent CI, 1.84–13.51; p=0.002).

Findings were similar for both symptomatic and objective AEs and consistent across symptomatic, haematologic, and nonhematologic AE categories. The associations were not modified by sociodemographic and body type variables. However, patterns of increasing toxic effects with increasing fatigue were especially pronounced among patients with advanced disease but not among patients with adjuvant or early-stage disease.

“Regardless of its biological underpinnings, the capacity of patient-reported fatigue to predict future symptomatic and objective consequences of cancer treatment suggests fatigue may be a practical and useful marker for extant underlying disease processes,” the authors noted.

“These processes are likely latent, not fully accounted for by standard objective measures of disease status, such as disease-specific prognostic factors and stage, and could manifest as both fatigue and a greater susceptibility to adverse reactions to cancer therapy,” they continued.

The authors highlighted the importance of interventions addressing existing fatigue symptoms in cancer patients to reduce symptoms and, potentially, any direct effects on treatment toxic effects. Exercise and mind-body interventions have been shown to improve cancer-related fatigue, possibly by modulating inflammation, and are included in guidelines from the National Comprehensive Cancer Network and the American Society of Clinical Oncology. [J Clin Oncol 2024;42:2456-2487; https://www.nccn.org/professionals/physician_gls/pdf/fatigue.pdf; NPJ Digit Med 2025;8:29; J Natl Cancer Inst 2025;117:1984-1998]

“However, given that fatigue may serve as a marker for biological vulnerability, [exercise and mind-body interventions] are unlikely to fully ameliorate the increased risk of acute severe AEs during treatment. Instead, recognizing fatigue may help clinicians to identify patients at higher risk of treatment toxic effects and to adjust care plans accordingly, especially for those reporting high levels of pretreatment fatigue,” they said.

The study included 7,086 patients (mean age 62.1 years, 70.3 percent male) with prostate, lung, colorectal, lymphoma, breast, melanoma, ovarian, or pancreatic cancer, with a total of 103,738 AEs documented. At baseline, 39.1 percent of patients reported some or more fatigue, which was classified using a 5-point Likert scale.

AEs were defined using the Common Terminology Criteria for Adverse Events. Primary outcomes were grade 3 or higher (severe), grade 4 or higher (life-threatening), and grade 5 (fatal) AEs.