Medical Oncology Department, Hospital Universitario Central de Asturias, Asturias, Spain.
Medical Oncology Department, Oncobell Program IDIBELL Institut Català d'Oncologia Hospital Duran i Reynals, CIBERONC, Barcelona, Spain.
Ann Oncol. 2022 Aug;33(8):786-793. doi: 10.1016/j.annonc.2022.04.010. Epub 2022 Apr 22.
The results of the RAPIDO trial have been accepted as evidence in favour of short-course radiotherapy (SC-RT) followed by chemotherapy before total mesorectal excision in high-risk locally advanced rectal cancer. A noteworthy concern is that the RAPIDO trial did not ensure that all patients in the control arm received adjuvant chemotherapy. This may bias statistical estimates in favour of the experimental arm if adjuvant chemotherapy is active in rectal cancer. Moreover, the 5-year update revealed an increase in the risk of local relapse in the experimental arm.
We carried out sensitivity analyses to determine how plausible effects of adjuvant chemotherapy, adjusted by the proportion of patients in the standard arm receiving adjuvant treatment, would have influenced the observed treatment effect estimate of the RAPIDO trial. The most plausible values for the benefit of adjuvant chemotherapy were determined by Bayesian re-analysis of a prior meta-analysis.
The meta-analysis suggested that oxaliplatin/fluorouracil-based adjuvant chemotherapy may improve disease-free survival (DFS) in rectal cancer although the signal is weak [hazard ratio (HR) 0.84, 95% credible interval, 0.57-1.15]; probability of benefit (HR <1) was 91.2%. In the sensitivity analysis, the HR for disease-related treatment failure would remain <1, thus favouring total neoadjuvant therapy (TNT), on most occasions, but the null hypothesis would not have been rejected in various credible settings. For the RAPIDO data to be consistent with the null effect, a moderate benefit of adjuvant chemotherapy (HR for DFS between 0.75 and 0.80) and 70%-80% of exposed participants would suffice.
The decision to make adjuvant chemotherapy optional in the standard arm may have biased the results in favour of the experimental arm, in a scenario in which TNT does not offset the increase in local recurrences after SC-RT.
RAPIDO 试验的结果已被接受为证据，支持在高危局部进展期直肠癌行全直肠系膜切除术前进行短程放疗（SC-RT）加化疗。值得注意的是，RAPIDO 试验并未确保对照臂中的所有患者都接受辅助化疗。如果辅助化疗对直肠癌有效，这可能会使实验臂的统计估计值产生偏差。此外，5 年更新结果显示实验臂局部复发风险增加。
我们进行了敏感性分析，以确定通过调整标准臂中接受辅助治疗的患者比例来调整辅助化疗的效果，将如何影响 RAPIDO 试验观察到的治疗效果估计。通过对先前荟萃分析的贝叶斯重新分析，确定了辅助化疗获益的最合理值。
荟萃分析表明，奥沙利铂/氟尿嘧啶为基础的辅助化疗可能改善直肠癌的无病生存率（DFS），尽管信号较弱[风险比（HR）0.84，95%置信区间，0.57-1.15]；获益的可能性（HR<1）为 91.2%。在敏感性分析中，在大多数情况下，疾病相关治疗失败的 HR 将保持<1，从而有利于全新辅助治疗（TNT），但在各种可信区间内，零假设不会被拒绝。为了使 RAPIDO 数据与零效应一致，辅助化疗的适度获益（DFS 的 HR 介于 0.75 和 0.80 之间）和 70%-80%的暴露参与者就足够了。
在标准臂中使辅助化疗成为可选治疗的决定可能会使结果偏向实验臂，在这种情况下，TNT 并不能抵消 SC-RT 后局部复发的增加。
