Sex Differences in Risk of Severe Adverse Events in Patients Receiving Immunotherapy, Targeted Therapy, or Chemotherapy in Cancer Clinical Trials

Abstract

Purpose: Women have more adverse events (AEs) from chemotherapy than men, but few studies have investigated sex differences in immune or targeted therapies. We examined AEs by sex across different treatment domains.

Methods: We analyzed treatment-related AEs by sex in SWOG phase II and III clinical trials conducted between 1980 and 2019, excluding sex-specific cancers. AE codes and grade were categorized using the Common Terminology Criteria for Adverse Events. Symptomatic AEs were defined as those aligned with the National Cancer Institute's Patient-Reported Outcome-Common Terminology Criteria for Adverse Events; laboratory-based or observable/measurable AEs were designated as objective (hematologic v nonhematologic). Multivariable logistic regression was used, adjusting for age, race, and disease prognosis. Thirteen symptomatic and 14 objective AE categories were examined.

Results: In total, N = 23,296 patients (women, 8,838 [37.9%]; men, 14,458 [62.1%]) from 202 trials experiencing 274,688 AEs were analyzed; 17,417 received chemotherapy, 2,319 received immunotherapy, and 3,560 received targeted therapy. Overall, 64.6% (n = 15,051) experienced one or more severe (grade ≥ 3) AEs. Women had a 34% increased risk of severe AEs compared with men (odds ratio [OR] = 1.34; 95% CI, 1.27 to 1.42; P < .001), including a 49% increased risk among those receiving immunotherapy (OR = 1.49; 95% CI, 1.24 to 1.78; P < .001). Women experienced an increased risk of severe symptomatic AEs among all treatments, especially immunotherapy (OR = 1.66; 95% CI, 1.37 to 2.01; P < .001). Women receiving chemotherapy or immunotherapy experienced increased severe hematologic AE. No statistically significant sex differences in risk of nonhematologic AEs were found.

Conclusion: The greater severity of both symptomatic AEs and hematologic AEs in women across multiple treatment modalities indicates that broad-based sex differences exist. This could be due to differences in AE reported, pharmacogenomics of drug metabolism/disposition, total dose received, and/or adherence to therapy. Particularly large sex differences were observed for patients receiving immunotherapy, suggesting that studying AEs from these agents is a priority.

FIG 1.

Forest plot of the association of patient sex with the risk of severe AEs. The boxes indicate the OR, and the horizontal lines indicate the 95% CIs. Boxes to the right of the vertical line (the line of equal odds) indicate increased risk of severe AEs for females, and to the left, for males. For each treatment domain, women had an increased risk of severe AEs of any kind. AE, adverse event; OR, odds ratio.

FIG 2.

Difference in the odds of severe AEs by category of adverse events. AEs were categorized as symptomatic versus objective and hematologic versus objective and nonhematologic. The vertical bars indicate the percentage increased odds, and the vertical lines show the 95% CIs. The observed percentage of patients experiencing severe (grade ≥ 3) AEs for a given category are also shown. AE, adverse event.

FIG 3.

Forest plot of the association of patient sex with the risk of severe AEs in subgroups of immunotherapy treatment. The boxes indicate the OR, and the horizontal lines indicate the 95% CIs. Boxes to the right of the vertical line (the line of equal odds) indicate increased risk of severe AEs for females, and to the left, for males. AE, adverse event; HR, hazard ratio.

FIG 4.

Risk of AEs by sex for individual AE categories by the treatment domain and grade cut point. For each AE, the proportion of patients with grade ≥ 1 through ≥ 4 AEs was analyzed in a logistic regression model, adjusted for covariates. (A) Symptomatic AEs and (B) objective AEs. Within each cell, the observed percentage of women versus men experiencing at least the indicated grade level of AE, with the corresponding multivariable logistic regression model ORs, 95% CIs, and P-values, are shown. OR > 1.0 indicates greater risk of a given AE at the cut point level within the specific treatment domain for females and < 1.0 for males. Instances where women had greater odds of AEs than men are coded red, with blue indicating the reverse and gray indicating no difference or missing because of lack of events. The color intensity corresponds to greater divergence by sex in a given direction; thus, the darker red or darker blue indicates statistically significant (P < .05) findings and lighter red and blue indicate nonstatistically significant trends in favor of greater risk for females and males, respectively. The depiction thus represents a heat map of toxicity outcomes. The predominance of red over blue coloring indicates a generalized pattern of worse AE outcomes for women than men. AE, adverse event; OR, odds ratio.