Cancer Treatment–Related AEs Are More Prevalent in Women Vs Men

New research shows that women are at an increased risk of developing an adverse event following cancer therapy compared with their male counterparts. This risk is particularly elevated among patients receiving immunotherapy.

Women receiving multiple different cancer therapies are more likely to experience both symptomatic and hematologic adverse events (AEs) compared with men, according to findings recently published in the Journal of Clinical Oncology.

The results were particularly prevalent among patients receiving immunotherapy, indicating that a better understanding of immunotherapy-related AEs should be a priority, the study authors noted.

Investigators evaluated 23,296 patients (women, n = 8838; men, 14,458) across 202 oncology trials. Among participants, 17,417 had received chemotherapy, 2319 received immunotherapy, and 3560 received targeted therapy. Overall, 64.6% (n = 15,051) experienced 1 or more severe AE, which was defined as greater than or equal to a grade 3 event. In total, 274,688 AEs were analyzed.

Overall, women with cancer were 34% more likely to experience a severe AE compared with men with cancer (odds ratio [OR], 1.34; 95% CI, 1.27-1.42; P < .001).

In addition, in those who received immunotherapy, women were 49% more likely to experience a severe AE compared with men (OR, 1.49; 95% CI, 1.24-1.28; P < .001). Furthermore, women were also at an increased risk of severe symptomatic AEs (OR, 1.66; 95% CI, 1.37-2.07; P < .001). Women receiving both chemotherapy and immunotherapy experienced increased severe hematologic AEs, although no statistically significant differences in nonhematologic AEs were identified between the 2 groups.

“Our study showed that women are at substantially greater risk of severe symptomatic AEs across multiple treatment domains, including patients receiving immune checkpoint inhibitor therapy and targeted therapies with kinase inhibitors,” Joseph M. Unger, PhD, SWOG Statistics and Data Management Center, Fred Hutchinson Cancer Research Center, and coinvestigators noted in the study. “Moreover, women were more likely to experience severe hematologic AEs among those receiving chemotherapy and immunotherapy. These results are robust because of the breadth of the data, the large sample size, and the quality of the prospective, clinical trial–based data.”

Investigators analyzed treatment-related AEs in phase 2 and 3 clinical trials conducted by the Southwest Oncology Group (SWOG) between 1980 and 2019 and compared the findings by sex.

AE grades were determined using the Common Terminology Criteria for Adverse Events and symptomatic AEs were measured in alignment with the National Cancer Institute’s Patient-Reported Outcome–Common Terminology Criteria for Adverse Events. Laboratory-based AEs and measurable AEs were designated as objective (either hematologic or nonhematologic) and multivariable logistic regression was applied to adjust for age, race, and disease prognosis. Overall, the investigators assessed a total of 13 symptomatic and 14 objective AE categories.

Historically, AE data had been collected from study flow sheets. However, in 2002, AEs began to be collected in electronic case reports forms. Therefore, in this study, AEs collected in both formats were reviewed and assessed by the investigators.

Patients were categorized based on their received treatment. Those included in the analysis received cytotoxic therapy with or without radiation, immunotherapy, or targeted therapies (including kinase inhibitors). Within the immunotherapy category, immune checkpoint inhibitors and immune system modulators were examined separately. Vaccine-based treatments were not included.

In addition, patients undergoing multiple systemic therapy types, such as cytotoxic therapy plus targeted therapy, were not included because it would not be clear which treatment domain was responsible for the corresponding AE.

“The goal in cancer therapy is to maximize treatment efficacy while limiting toxicity. Increasingly, treatment will be individualized on the basis of patient and tumor characteristics to optimize this relationship,” the study authors added. “Our findings suggest that underlying mechanisms may result in generalized worse toxicity outcomes for women, with or without corresponding survival improvements or detriments.”

The authors concluded that more awareness of symptom differences or reporting differences in women vs men is needed.

“A better understanding of the nature of the underlying mechanisms could potentially lead to interventions or delivery modifications to reduce toxicity in women (in particular),” the study authors concluded. "In such cases, cancer treatment may then be able to be simultaneously modified or augmented, with the ultimate goal of extending therapeutic benefits.”


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. J Clin Oncol. Published online February 4, 2022. doi:10.1200/JCO.21.02377