Abstract
Several real-world oncology studies have produced findings that contradict those from randomized clinical trials. Such disparities may be associated with methodological shortcomings. To examine the association between a shortened duration of adjuvant chemotherapy among individuals with stage III colon cancer using real-world data. This comparative effectiveness study included individuals diagnosed with stage III colon cancer between January 2004 and December 2015 who initiated adjuvant chemotherapy at oncology clinics within the province of Alberta, Canada. Patients were identified through record linkage of various administrative databases and were followed up until September 2017. Eligibility criteria were modeled after those used in the International Duration Evaluation of Adjuvant (IDEA) trial. A target trial emulation and naive observational analysis were conducted. Results from both cohorts were benchmarked against findings from the IDEA trial. Data analysis was conducted from March to December 2020. A shortened duration of adjuvant 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX) or capecitabine plus oxaliplatin (CAPOX) chemotherapy, defined as 3 to 5 months of treatment vs 6 months. Overall survival assessed via vital statistics. The per-protocol hazard ratio (HR) was estimated using a weighted pooled logistic regression model. Subgroup analyses were conducted by treatment regimen (ie, FOLFOX vs CAPOX) and cancer stage (ie, T1-3 and N1 vs T4 or N2). From an initial cohort of 3086 patients, 485 (16%) were eligible for inclusion in the target trial analysis. The median age was 59 years (range, 19-81 years), and 230 (47%) were women. The maximum follow-up was 11.6 years. Median overall survival was not reached. A total of 90 patients (19%) died. The 5-year Kaplan Meier overall survival estimate was 0.79 (95% CI, 0.75-0.84). Estimates from the trial emulation were similar to those from the IDEA trial. For example, a shortened duration of adjuvant chemotherapy was not associated with overall survival among patients prescribed CAPOX in the IDEA trial (HR, 0.96; 95% CI, 0.85-1.08) or in the trial emulation (HR, 0.96; 95% CI, 0.43-2.14). In contrast, the naive observational analysis suggested that a shortened duration of CAPOX was significantly associated with worse survival (HR, 3.33; 95% CI, 1.04-10.65). In this study, the explicit emulation of a target trial better approximated results from an analogous well-conducted randomized clinical trial.
Highlights
A shortened duration of adjuvant chemotherapy was not associated with overall survival among patients prescribed capecitabine plus oxaliplatin (CAPOX) in the International Duration Evaluation of Adjuvant (IDEA) trial (HR, 0.96; 95% CI, 0.85-1.08) or in the trial emulation (HR, 0.96; 95% CI, 0.43-2.14)
In 2018, clinical practice guidelines were changed in response to findings from the International Duration Evaluation of Adjuvant (IDEA) trial, a pooled analysis of 6 randomized clinical trials examining the noninferiority of 3 months of adjuvant chemotherapy vs 6 months.[3,4,5,6,7]
In a previous systematic review,[25] we found that observational studies investigating this issue have had biases that could be avoided through the explicit emulation of a target trial and that several of these studies reported findings that contradict those of the IDEA trial
Summary
Since 2005, the standard of care for stage III colon cancer has been surgery followed by 6 months of adjuvant 5-flourouracil/leucovorin plus oxaliplatin (FOLFOX) or capecitabine plus oxaliplatin (CAPOX).[1,2] In 2018, clinical practice guidelines were changed in response to findings from the International Duration Evaluation of Adjuvant (IDEA) trial, a pooled analysis of 6 randomized clinical trials examining the noninferiority of 3 months of adjuvant chemotherapy vs 6 months.[3,4,5,6,7] In the primary analysis, the upper limit of the 95% CI for the disease-free survival hazard ratio (HR) exceeded the prespecified statistical noninferiority threshold of 1.12 (HR, 1.07; 95% CI, 1.00-1.15).[4]. The findings from the IDEA trial have been controversial within the oncology community.[3,7,8] For example, a recent worldwide survey of 145 medical oncologists found that approximately 1 in 3 clinicians supported 6 months of adjuvant chemotherapy as the standard of care.[9] One methodological issue with the IDEA trial was its reliance on an intention-to-treat analysis, which was problematic because rates of adherence were heterogeneous between treatment groups and trials.[8] While a per-protocol analysis was conducted, the investigators did not adjust for postrandomization variables that could affect adherence.[10] In addition, the extent to which the trial findings are generalizable to real-world cancer populations may be problematic. Batra et al[11] found that 59% of individuals with stage II or III colon cancer in a real-world setting would not be eligible for inclusion in a clinical trial
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