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Greater Severity of Adverse Events in Women Across Multiple Anticancer Treatment Modalities

Large sex differences were observed among patients who received particularly immunotherapy
11 Feb 2022
Cancer in Special Situations / Population;  Palliative and supportive care

Examination of adverse events by sex using combined data from 23,296 patients enrolled in 202 phase II and III clinical studies conducted by SWOG between 1989 and 2019 revealed greater severity of both symptomatic adverse events and haematologic adverse events in women across multiple treatment modalities, indicating that broad-based sex differences exist. This could be due to differences in adverse events reported, pharmacogenomics of drug metabolism/disposition, total dose received, and/or adherence to therapy. Particularly large sex differences were observed in patients receiving immunotherapy, suggesting that studying adverse events from these agents is a priority, according to Joseph M. Unger, PhD of the SWOG Statistics and Data Management Center, Fred Hutchinson Cancer Research Center in Seattle, WA, US and colleagues, who published findings on 4 February 2022 in the Journal of Clinical Oncology.

The authors wrote in the background that despite growing evidence identifying patient sex as a predictor of disease sequelae, sex is rarely included in the evaluation of risk. Among patients with cancer, female sex has been associated with an increased risk of adverse events from cytotoxic therapy. However, almost no research has examined the experience of women and men receiving immune and targeted therapies.

Differences in the side effects and outcomes from treatment may be due to multiple factors, such as subjective differences in reporting, or differences in pharmacokinetics, pharmacodynamics, and pharmacogenomics, or differences in drug therapy received.

In this study, the SWOG researchers systematically examined the role of patient sex in the experience of both symptomatic and objective adverse events across multiple cancer treatment paradigms including cytotoxic, immune, and targeted therapies. To improve power to detect possible sex differences in adverse events, they combined data from several decades of therapeutic clinical studies. Patients receiving care under study are uniformly followed for acute adverse events while on treatment; thus, analyses from a large-scale, well-characterised clinical studies database provides a unique opportunity to explore this issue.

The study team excluded sex-specific cancers. Adverse events codes and grade were categorised by the Common Terminology Criteria for Adverse Events. Symptomatic adverse events were defined as those aligned with the US National Cancer Institute's Patient-Reported Outcome–Common Terminology Criteria for Adverse Events. Laboratory-based or observable/measurable adverse events were designated as objective (haematologic versus non-haematologic). Multivariable logistic regression was used, adjusting for age, race, and disease prognosis. Thirteen symptomatic and 14 objective adverse events categories were examined.

In total, 23,296 patients of whom 8,838 women (37.9%) and 14,458 men (62.1%) from 202 clinical studies experiencing 274,688 adverse events were analyzed. Among analyzed patients, 17,417 received chemotherapy, 2,319 received immunotherapy, and 3,560 received targeted therapy.

Overall, 15,051 patients (64.6%) experienced one or more severe (grade ≥3) adverse events. Women had a 34% increased risk of severe adverse events compared with men (odds ratio [OR] 1.34; 95% confidence interval [CI] 1.27 to 1.42; p < 0.001), including a 49% increased risk among those receiving immunotherapy (OR 1.49; 95% CI 1.24 to 1.78; p < 0.001). Women experienced an increased risk of severe symptomatic adverse events among all treatments, especially immunotherapy (OR 1.66; 95% CI 1.37 to 2.01; p < 0.001).

Women receiving chemotherapy or immunotherapy experienced increased severe haematologic adverse events. No statistically significant sex differences in risk of non-haematologic adverse events were found.

The authors commented that their study showed that women are at substantially greater risk of severe symptomatic adverse events across multiple treatment modalities, including patients receiving immune checkpoint inhibitors and targeted therapies with kinase inhibitors. In fact, women receiving immunotherapy had a 66% increased risk of symptomatic adverse events compared with men. Moreover, women were more likely to experience severe haematologic adverse events among those receiving chemotherapy and immunotherapy. These results are robust because of the large sample size, and the quality of the prospective, clinical study–based data.

These findings support the idea that sex may independently modulate drug toxicity, including for novel treatments. If confirmed, the findings suggest that underlying mechanisms may result in generalised worse toxicity outcomes for women, with or without corresponding survival improvements or detriments. Therefore, more awareness of symptom differences or reporting differences in women versus men is needed. A better understanding of the nature of the underlying mechanisms could potentially lead to interventions or delivery modifications to reduce toxicity, particularly in women.

The study was supported by the US National Institutes of Health, National Cancer Institute, National Cancer Trials Network grants, Community Oncology Research Program grant and by The Hope Foundation for Cancer Research (SWOG Impact Award grant and Secondary Data Analysis grant).

Reference

Unger JM, Vaidya R, Albain KS, et al. Sex Differences in Risk of Severe Adverse Events in Patients Receiving Immunotherapy, Targeted Therapy, or Chemotherapy in Cancer Clinical Trials. JCO; Published online 4 February 2022. DOI: 10.1200/JCO.21.02377

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