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Women have a substantially greater risk of experiencing severe adverse events (AEs) after undergoing treatments for cancer, according to an analysis of SWOG phase II and III clinical trials.

Women had a 34% increased risk of severe AEs compared with men (OR 1.34, 95% CI 1.27-1.42, P<0.001), reported Joseph Unger, PhD, of Fred Hutchinson Cancer Research Center in Seattle, and colleagues.

An increased risk was particularly pronounced among those receiving immunotherapy, with women having a 49% increased risk of severe AEs versus men (OR 1.49, 95% CI 1.24-1.78, P<0.001).

"These findings support the idea that sex may independently modulate drug toxicity, including for novel treatments," the authors wrote in the .

Unger and team gave several possible explanations for these differences in AEs between the sexes. "For instance, given average body type differences, women may receive greater relative dose, although importantly we included covariate adjustment for obesity status to account for body type," they observed.

They also noted that medication adherence to oral therapies may differ by sex, and that it is possible that sex-related differences in symptom perception could result in differentially reported AEs. They also suggested that pharmacokinetics and pharmacodynamics could play a role.

"There is a linear dose-toxicity relationship for most drugs, yet not all drugs present a clear dose-response relationship," Berna Özdemir, MD, PhD, of Bern University Hospital in Switzerland and a member of the European Society for Medical Oncology Gender Medicine Task Force, told MedPage Today.

"One of the aims of clinical cancer research over the next years should be to develop individualized dosing strategies that take into account the sex and body composition of the patients," said Özdemir, who was not involved in the study. "Given that the body composition changes with age, this strategy would also result in dose adaptations according to age."

"In the era of precision oncology, we should start considering a patient's sex as a robust biomarker, which could be used to improve the balance between efficacy and toxicity of anticancer treatments," she added.

The authors also found that women had higher risks of symptomatic (33.3% vs 27.9% for men; OR 1.33, 95% CI 1.26-1.41) and hematologic (45.2% vs 39.1%, respectively; OR 1.30, 95% CI 1.23-1.37) AEs, with similar patterns among patients treated with immunotherapy (33.7% vs 25.4%; OR 1.66, 95% CI 1.37-2.01).

Among those receiving immunotherapy, the risk of symptomatic AEs was greater for women receiving immune checkpoint inhibitors (19.6% vs 13.0% for men; OR 1.54, 95% CI 1.05-2.26, P=0.03) and immune system modulators (44.1% vs 33.6%, respectively; OR 1.62, 95% CI 1.27-2.06, P<0.001).

Additionally, women had a 25% higher risk of experiencing the most severe AEs (57.4% vs 52.2% for men; OR 1.25, 95% CI 1.18-1.32), with that association strongest for women receiving immunotherapy (OR 1.42, 95% CI 1.14-1.77) or targeted therapy (OR 1.50, 95% CI 1.27-1.78).

"If confirmed, our findings suggest that underlying mechanisms may result in generalized worse toxicity outcomes for women, with or without corresponding survival improvements or detriments," Unger and colleagues wrote. "Therefore, more awareness of symptom differences or reporting differences in women versus men is needed."

Study Details

The authors obtained data from the SWOG Cancer Research Network, which included 23,296 eligible patients (37.9% women) evaluable for AE assessment from 202 phase II and III clinical trials from July 1989 through June 2019.

The primary endpoint of the study was the occurrence of one or more treatment-related severe or greater (grade ≥3) AEs across multiple cancer treatment paradigms, including cytotoxic, immune, and targeted therapies.

Of the patients in the study, 17,417 received chemotherapy, 2,319 received immunotherapy, and 3,560 received targeted therapy. About two-thirds experienced one or more AEs.

The most common cancers were gastrointestinal (26.1%), lung (20.5%), and leukemia (12.1%). Overall, 34.7% of patients were 65 years or older, 9.0% were Black, and 25.6% were obese.

The median treatment time was 88 days (IQR 34-170) for women and 84 days (IQR 37-167) for men (P=0.16).

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