Estimating adjuvant treatment effects in Stage II colon cancer: Comparing the synthesis of randomized clinical trial data to real‐world data

Abstract

There is an ongoing discussion regarding the impact of adjuvant chemotherapy in Stage II colon cancer. We therefore estimated adjuvant treatment effect in Stage II colon cancer using pooled disease‐free survival (DFS) data from randomized clinical trials (RCT approach) and compared this to real‐world data (RWD approach) estimates. First, we estimated the treatment effect in RCTs by (i) searching relevant trials reporting DFS data, (ii) generating patient‐level data from reported DFS data and (iii) estimating treatment effect in the patient‐level data. Second, the treatment effect was estimated in an observational cohort of 1,947 patients provided by the Netherlands Cancer Registry using three propensity score methods; matching, weighting and stratification. In the RCT approach, patient‐level data of 4,489 patients (events: 853) were generated from seven trials which compared two of the following treatment arms: control, 5FU/LV or FOLFOX. A Cox model was used to estimate a hazard ratio (HR) of 0.77 (0.43;1.10) for 5FU/LV vs. control and 0.93 (0.72;1.15) for FOLFOX vs. 5FU/LV. In the RWD approach, HRs for any adjuvant treatment vs. control were 0.95 (0.50;1.80), 0.88 (0.24;3.21) and 1.05 (0.04;2.06) using matching, weighting and stratification, respectively. There was no significant difference with the estimates from the RCT approach (interaction test, p > 0.10). The RCT data suggest a clinically relevant benefit of adjuvant chemotherapy in terms of DFS, but the estimate did not reach statistical significance. Stratified analyses are required to evaluate whether treatment effect differs in specific subgroups.

Estimating the effect of adjuvant chemo-therapy for colon-cancer using registry data: a method comparison and validation

“…For example, the meta-analysis by Erlichman and Charles (1999) [7] showed in a pooled analysis a hazard ratio (HR) of 0.83 (90% CI 0.72, 1.07) for disease-free survival and a HR of 0.86 (90 % CI 0.68, 1.07) for overall survival for fluoropyrimidine monotherapy compared to observation. The same finding was also reported [8]: while both RCT and real world data suggest a clinically relevant benefit of adjuvant chemotherapy for stage II colon cancer, the estimates do not reach statistical significance. A borderline significantly improved overall survival was found in stage II cancer in QUASAR trial (Relative Risk 0.82 95% CI 0.7-0.95) and consequently the authors suggest adjuvant chemotherapy for all stage II patients.…”

“…Registry data, without strict patient selection, may truly reveal the clinical relevance and may provide additional evidence regarding the effect of the adjuvant chemotherapy on a population outside the context of trials. Consequently, researchers have recently tuned their interest to such registry data to estimate treatment effects because it covers a large, heterogeneous and country-wide population [8][9][10][11].…”

“…This hinders the estimation of the long-term effect of CAPOX and FOLFOX using existing registry data. To fully utilize the registry data regardless of the limitations, researchers uses a binary variable to indicate the chemotherapy (FU/LV and FOLFOX) and control, and consequentially compares treatment effect using registry data with the estimation from trials (FU/LV vs. control) [8]; an approach we also adopt in the current study.…”

“…Historically, parametric models have been commonly used. For instance, in the majority of published studies about the treatment effect estimation in the field of colorectal oncology [8,23,24] the direct method, using standard logistic regression, is employed. Although these parametric models are efficient and wellunderstood, they impose strong parametric assumptions about the relationship between potential confounders and outcomes.…”

Model-based evaluation of the cost effectiveness of 3 versus 6 months’ adjuvant chemotherapy in high-risk stage II colon cancer patients

“…However, there is uncertainty around these treatment effects. 13,19 To investigate the impact of this uncertainty on the base-case results, we performed a threshold analysis separately for CAPOX and FOLFOX. In this analysis, the HR for treatment effect for 3 months compared with 6 months chemotherapy for CAPOX was increased from 1.0 to 1.17 in accordance with the upper limit of the 20 Ayvaci et al; 21 Hakkaart-van Roijen et al; 22 Lonardi et al 26 Febrile neutropenia €3309 €3309 0.027/0.014 b Nederlandse zorgautoriteit; 20 Ayvaci et al; 21 Hakkaart-van Roijen et al; 22 Lonardi et al 26 Grade 3/4 diarrhea €50 €50 0.064/0.051 b Nederlandse zorgautoriteit; 20 Ayvaci et al; 21 Hakkaart-van Roijen et al; 22 Lonardi et al 26 Absenteeism costs per cycle c Hakkaart-van Roijen et al 22…”