Abstract
This pooled analysis of data from phase 3 randomized clinical trials assesses the association of sex with toxic effects, treatment adherence, surgical procedures, and long-term outcomes after standard multimodal treatment in patients with rectal cancer.
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.
Methods
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.
Results
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).
Table 1. Association of Sex With Surgical Procedures and Complications.
| Characteristic | No. | No. (%) | P Valuea | |
|---|---|---|---|---|
| Men (n = 725) | Women (n = 291) | |||
| Surgical procedure | ||||
| Lower anterior resection | 665 | 454 (62.6) | 211 (72.5) | .009 |
| Abdominoperineal resection | 255 | 200 (27.6) | 55 (18.9) | |
| Intersphincteric resection | 66 | 52 (7.2) | 14 (4.8) | |
| Other | 18 | 10 (1.4) | 8 (2.7) | |
| Not reported | 12 | 9 (1.2) | 3 (1.1) | |
| Postsurgical complications (total) | ||||
| Yes | 406 | 312 (43.0) | 94 (32.3) | .005 |
| No | 590 | 398 (54.9) | 192 (66.0) | |
| Not reported | 20 | 15 (2.1) | 5 (1.7) | |
Assessed using the Pearson χ2 test.
Table 2. Association of Sex With Toxic Effects, Treatment Adherence, and Clinical Outcome.
| Characteristic | No. | No. (%)a | P Value | |
|---|---|---|---|---|
| Men | Women | |||
| Leukopenia | ||||
| Grades 1-2 | 401 | 276 of 347 (79.5) | 125 of 175 (71.4) | .04b |
| Grades 3-4 | 121 | 71 of 347 (20.5) | 50 of 175 (28.6) | |
| Diarrhea | ||||
| Grades 1-2 | 606 | 418 of 455 (91.9) | 188 of 227 (82.8) | <.001b |
| Grades 3-4 | 76 | 37 of 455 (8.1) | 39 of 227 (17.2) | |
| Treatment adherence | ||||
| Complete chemoradiotherapy | 693 | 495 of 714 (69.3) | 198 of 288 (68.8) | .43b |
| >80% Chemotherapy and >45.0 Gy | 238 | 173 of 714 (24.2) | 65 of 288 (22.6) | |
| ≤80% Chemotherapy or ≤45.0 Gy | 71 | 46 of 714 (6.4) | 25 of 288 (8.7) | |
| Adjuvant chemotherapy | ||||
| >80% | 611 | 439 of 584 (75.2) | 172 of 245 (70.2) | .14b |
| ≤80% | 218 | 145 of 584 (24.8) | 73 of 245 (29.8) | |
| Clinical outcome after 5-y follow-up, % (95% CI) | ||||
| Disease-free survival | 1016 | 66.8 (63.3-70.3) | 69.9 (64.2-75.6) | .25c |
| Cumulative incidence | ||||
| Local recurrence | 1016 | 6.2 (4.2-8.2) | 7.2 (3.8-10.5) | .95c |
| Distant metastasis | 1016 | 24.9 (21.4-28.4) | 24.2 (18.7-29.7) | .65c |
| Overall survival | 1016 | 77.5 (74.4-80.6) | 76.0 (70.5-81.5) | .80c |
Differences in toxic effects were analyzed for patients with grade 1-4 toxic effects. Adherence to treatment was analyzed throughout the cohort.
Assessed using the Pearson χ2 test.
Assessed using log-rank tests.
Discussion
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.
References
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