Is treatment adherence to neoadjuvant chemoradiotherapy and/or adjuvant chemotherapy associated with disease-free survival among patients with locally advanced rectal cancer?
This post hoc analysis of a phase 3 clinical trial examined 1232 patients who were treated with neoadjuvant fluorouracil-based chemoradiotherapy and adjuvant chemotherapy, both with and without the addition of oxaliplatin, in the CAO/ARO/AIO-04 phase 3 trial. Adherence to neoadjuvant chemoradiotherapy, but not adjuvant chemotherapy, was significantly associated with disease-free survival.
Close monitoring and supportive measures to increase adherence to neoadjuvant chemoradiotherapy should be implemented as an intergral part of study designs.
Despite numerous published phase 3 trials, the association of treatment adherence with outcomes for patients with rectal cancer remains largely unexplored.
To analyze the association of treatment adherence with disease-free survival (DFS) among patients with rectal cancer in the CAO/ARO/AIO-04 trial.
Design, Setting, and Participants
This post hoc analysis of a phase 3 randomized clinical trial was conducted from July 25, 2006, to February 26, 2010, among 1232 patients from 80 centers with T3 to T4 or node-positive rectal adenocarcinoma. Statistical analysis was performed from May 5, 2019, to February 2, 2020.
A total of 625 patients received neoadjuvant fluorouracil-based chemoradiotherapy (nCRT), and a total of 607 patients received fluorouracil-based nCRT with addition of oxaliplatin. Of the 1126 patients who underwent curative surgery, 439 started fluorouracil-based adjuvant chemotherapy and 419 started fluorouracil-based adjuvant chemotherapy with oxaliplatin.
Main Outcomes and Measures
The association of adherence with nCRT and adjuvant chemotherapy with DFS was assessed in both groups in the as-treated population.
Among the 625 patients (442 men; mean age, 63.0 years) who received fluorouracil nCRT and the 607 patients (430 men; mean age, 63.0 years) who received fluorouracil-based nCRT with addition of oxaliplatin, after a median follow-up of 50 months (interquartile range, 38-61 months), 3-year DFS in the as-treated population was 71.1% in the fluorouracil group and 75.8% in the fluorouracil-oxaliplatin group (hazard ratio [HR], 0.803; 95% CI, 0.651-0.990; P = .04). Overall, 419 patients in the fluorouracil nCRT group (67.0%) and 434 patients in the fluorouracil-oxaliplatin nCRT group (71.5%) received full doses of preoperative nCRT. Likewise, 253 of 439 patients in the fluorouracil group (57.6%) and 134 of 419 patients in the fluorouracil-oxaliplatin group (32.0%) received full doses of adjuvant chemotherapy. Adherence to nCRT was associated with 3-year DFS in both the fluorouracil group (complete vs near complete: HR, 1.325; 95% CI, 0.959-1.832; P = .09; complete vs reduced: HR, 1.877; 95% CI, 1.147-3.072; P = .01) and the fluorouracil-oxaliplatin group (complete vs near complete: HR, 1.501; 95% CI, 0.980-2.299; P = .06; complete vs reduced: HR, 1.724; 95% CI, 1.144-2.596; P = .009) in multivariable analyses. In contrast, adjuvant chemotherapy was not associated with DFS in both the fluorouracil group (complete vs near complete: HR, 0.900; 95% CI, 0.559-1.448; P = .66; complete vs incomplete: HR, 1.057; 95% CI, 0.807-1.386; P = .69) and the fluorouracil-oxaliplatin group (complete vs near complete: HR, 1.155; 95% CI, 0.716-1.866; P = .56; complete vs incomplete: HR, 1.073; 95% CI, 0.790-1,457; P = .65).
Conclusions and Relevance
To our knowledge, this is the first analysis of a phase 3 trial to assess the association of treatment adherence with some clinical outcomes for patients with rectal cancer. The findings emphasize the need for appropriate trial design with optimized nCRT dose and schedule and supportive strategies to facilitate good adherence and precision delivery, especially for intensified nCRT.
ClinicalTrials.gov Identifier: NCT00349076
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Diefenhardt M, Ludmir EB, Hofheinz R, et al. Association of Treatment Adherence With Oncologic Outcomes for Patients With Rectal Cancer: A Post Hoc Analysis of the CAO/ARO/AIO-04 Phase 3 Randomized Clinical Trial. JAMA Oncol. Published online July 09, 2020. doi:10.1001/jamaoncol.2020.2394
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