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Diefenhardt M, Ludmir EB, Hofheinz R, et al. Association of Sex With Toxic Effects, Treatment Adherence, and Oncologic Outcomes in the CAO/ARO/AIO-94 and CAO/ARO/AIO-04 Phase 3 Randomized Clinical Trials of Rectal Cancer. JAMA Oncol. 2020;6(2):294–296. doi:10.1001/jamaoncol.2019.5102
Interest has been increasing regarding the association of sex with toxic effects of treatment and clinical outcome in patients with cancer.1 The risk of toxic effects from chemotherapy is greater in women than in men, as shown in lung and colon cancer, sarcoma, Hodgkin lymphoma, and glioblastoma, which can be explained by different pharmacokinetics and pharmacodynamics.1 Few studies have demonstrated better clinical outcome in women with melanoma, lymphoma, glioblastoma, sarcoma, lung cancer, gastric cancer, and anal cancer compared with men,1 but large confirmatory analyses are lacking. Intriguingly, despite the large number of phase 3 multimodal randomized clinical trials published to date for rectal cancer, the association of sex with treatment-related factors and clinical outcome remains largely unexplored for this disease site.
We examined a cohort of 1016 patients with cT3, cT4, or node-positive rectal cancer treated homogeneously with fluorouracil-based chemoradiotherapy followed by surgery and 4 cycles of adjuvant fluorouracil, as used in the experimental arm of the CAO/ARO/AIO-94 phase 3 randomized clinical trial2 and the control arm of the subsequent CAO/ARO/AIO-04 phase 3 randomized clinical trial.3 The correlations of sex with clinicopathologic factors, surgical procedures, acute toxic effects (using Common Terminology Criteria for Adverse Events version 3.0), and treatment adherence were assessed using the Pearson χ2 test. The prognostic role of sex for disease-free survival (DFS), overall survival, and cumulative incidence of local and distant recurrence was examined with log-rank tests. All statistical tests were 2-sided, and P values less than .05 were considered significant. The retrospective analyses were conducted between February and August 2019. All participating sites of the original randomized clinical trials obtained medical ethics committee approval and patient informed consent.
The median (interquartile range) age in the cohort was 62 (55-69) years, and 291 patients (28.6%) were female. Pretreatment clinical and postchemoradiotherapy pathologic factors did not differ significantly between men and women, whereas women underwent sphincter-sparing surgery more often than men and experienced fewer postoperative complications (Table 1). We observed higher rates of chemoradiotherapy-induced diarrhea and leukopenia in women; however, treatment adherence during neoadjuvant chemoradiotherapy and adjuvant chemotherapy was similar for the 2 groups (Table 2). After a median (interquartile range) follow-up of 59 (39-111) months, sex was not associated with DFS, overall survival, local recurrence, or distant metastasis (Table 2).
To our knowledge, this report represents the first pooled analysis of data from phase 3 randomized clinical trials to assess the association of sex with toxic effects, treatment adherence, surgical procedures, and long-term oncologic outcomes after standard multimodal treatment for rectal cancer. In colorectal cancer, meta-analyses have found minor survival benefits in women, and differences in tumor site, incidence of microsatellite instability, and hormonal factors have been proposed as explanations.4
Several factors could explain the higher incidence of toxic effects observed in women, such as lower levels of the fluorouracil catabolic enzyme dihydropyridine dehydrogenase or sex-specific heterogenous body fat composition, which could potentially result in fluorouracil overdosing in women.1 Conversely, fewer postoperative complications were noted in women, possibly related to the lower rate of abdominoperineal resections. Importantly, we did not detect any sex-specific differences for treatment adherence and long-term clinical outcome.
The results are in line with data from the US Intergroup 0114 trial5 of adjuvant chemoradiotherapy using 4 different fluorouracil drug regimens. Acute toxic effects were significantly increased in women, but no difference occurred for DFS and local control by sex. In a large retrospective Surveillance, Epidemiology, and End Results database analysis with 105 511 patients with stage I to III rectal cancer treated in the United States from 1988 to 2012,6 better DFS was reported in women. However, these data are limited by their retrospective nature and heterogeneous patient cohorts and treatment schedules.
These findings have implications in the clinical setting. Although to our knowledge no data support using different chemotherapy regimens for men and women with rectal cancer, increased awareness of a higher risk of toxic effects among women may facilitate refinement of fluorouracil-based chemoradiotherapy and adjuvant chemotherapy, such as tailored patient education, closer monitoring of adverse effects, and earlier introduction of supportive measures.
Accepted for Publication: September 23, 2019.
Corresponding Author: Markus Diefenhardt, MD, Department of Radiotherapy and Oncology, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany (email@example.com).
Published Online: December 5, 2019. doi:10.1001/jamaoncol.2019.5102
Author Contributions: Drs Diefenhardt and Fokas had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Diefenhardt, Ludmir, Hofheinz, Rödel, Fokas.
Acquisition, analysis, or interpretation of data: Diefenhardt, Ludmir, Ghadimi, Minsky, Rödel, Fokas.
Drafting of the manuscript: Diefenhardt, Hofheinz, Rödel, Fokas.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Diefenhardt, Ludmir, Rödel, Fokas.
Obtained funding: Diefenhardt, Rödel.
Administrative, technical, or material support: Diefenhardt, Hofheinz, Rödel, Fokas.
Study supervision: Diefenhardt, Ghadimi, Minsky, Rödel, Fokas.
Conflict of Interest Disclosures: Dr Hofheinz reported receiving honoraria from Roche, Amgen, Merck Serono, Sanofi, Merck Sharp & Dohme, Bristol-Myers Squibb, Eli Lilly and Company, and Medac; personal fees from Roche, Sanofi, Eli Lilly and Company, Merck Serono, Amgen, Servier Laboratories, Merck Sharp & Dohme, and Bristol-Myers Squibb; and his institution received research funding from Sanofi, Medac, and German Cancer Aid. Dr Rödel reported receiving research funding from German Cancer Aid. No other disclosures were reported.
Funding/Support: The CAO/ARO/AIO-94 and CAO/ARO/AIO-04 trials were funded by grants (70-578, 106-757) of the German Cancer Aid.
Role of the Funder/Sponsor: German Cancer Aid had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
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