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Lessons learnt from scoring adjuvant colon cancer trials and meta-analyses using the ESMO-Magnitude of Clinical Benefit Scale V.1.1.

ABSTRACT: Click here to listen to the Podcast BACKGROUND: Form 1 of the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) serves to grade therapies with curative intent. Hitherto only few trials with curative intent have been field tested using form 1. We aimed to evaluate the applicability of the scale and to assess the reasonableness of the generated scores in early colon cancer, in order to identify shortcomings that may be rectified in future amendments. METHODS:Adjuvant studies were identified in PubMed, Food and Drug Administration and European Medicines Agency registration sites, as well as ESMO and National Comprehensive Cancer Network guidelines. Studies meeting inclusion criteria were graded using form 1 of the ESMO-MCBS V.1.1 and field tested by ESMO Colorectal Cancer Faculty. Shortcomings of the scale were identified and evaluated. RESULTS:Eighteen of 57 trials and 7 out of 14 meta-analyses identified met criteria for ESMO-MCBS V.1.1 grading. In stage III colon cancer, randomised clinical trials and meta-analyses of modulated 5-fluorouracil (5-FU) based chemotherapy versus surgery scored ESMO-MCBS grade A and randomised controlled trials (RCTs) and meta-analyses comprising oxaliplatin added to this 5-FU backbone showed a more modest additional overall survival benefit (grade A and B). For stage II colon cancer, the findings are less consistent. The fluoropyrimidine trials in stage II were graded 'no evaluable benefit' but the most recent meta-analysis demonstrated a 5.4% survival advantage after 8 years follow-up (grade A). RCTs and a meta-analysis adding oxaliplatin demonstrated no added benefit. Exploratory toxicity evaluation and annotation was problematic given inconsistent toxicity reporting and limited results of late toxicity. Field testers (n=37) reviewed the scores, 25 confirmed their reasonableness, 12 found them mostly reasonable. Moreover, they identified the inability of crediting improved convenience in non-inferiority trials as a shortcoming. CONCLUSION:Form 1 of the ESMO-MCBS V.1.1 provided very reasonable grading for adjuvant colon cancer studies.

SUBMITTER: Knapen DG

PROVIDER: S-EPMC7476457 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Lessons learnt from scoring adjuvant colon cancer trials and meta-analyses using the ESMO-Magnitude of Clinical Benefit Scale V.1.1.

Knapen Daan Geert DG Cherny Nathan I NI Zygoura Panagiota P Latino Nicola Jane NJ Douillard Jean-Yves JY Dafni Urania U de Vries Elisabeth G E EGE de Groot Derk Jan DJ

ESMO open 20200901 5

Click here to listen to the Podcast BACKGROUND: Form 1 of the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) serves to grade therapies with curative intent. Hitherto only few trials with curative intent have been field tested using form 1. We aimed to evaluate the applicability of the scale and to assess the reasonableness of the generated scores in early colon cancer, in order to identify shortcomings that may be rectified in future amendments.<h4>Methods< ...[more]

PMID: 32893188

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Project description:ImportanceRecently, anticancer agents have generated excitement owing to their capacity to preserve long-term durable survival in some patients who are represented by a tail of the survival curve. However, because traditional measures of clinical benefit may not accurately capture durable survival, amendments to various valuation frameworks have been proposed to capture this benefit.ObjectivesTo determine how frequently immune checkpoint inhibitor (ICI) anticancer agents vs non-ICI anticancer agents displayed trends of long-term durable survival, as defined by the American Society of Clinical Oncology Value Framework version 2 (ASCO-VF v2) and European Society of Medical Oncology Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS v1.1), as well as to further analyze the degree of agreement between ASCO and ESMO frameworks.Design, setting, and participantsIn this cohort study, anticancer agents from phase 2 or 3 randomized clinical trials (RCTs) cited for clinical efficacy evidence in drug approval by the US Food and Drug Administration between January 2011 and March 2018 were identified. Data required for the ASCO-VF v2 tail-of-the-curve bonus and the ESMO-MCBS v1.1 immunotherapy-triggered long-term plateau adjustments were extracted from relevant RCTs. Frequency and difference in proportions were calculated to determine how often survival benefits were awarded to anticancer agents overall and to ICI and non-ICI anticancer agents individually.Main outcomes and measuresAmerican Society of Clinical Oncology Value Framework v2 tail-of-the-curve bonuses and ESMO-MCBS v1.1 immunotherapy-triggered long-term plateau adjustments.ResultsIn total, 247 RCTs were identified, and 100 RCTs involving 57 164 patients were included, with 14 examining ICI agents (1 ipilimumab, 5 pembrolizumab, 5 nivolumab, 2 atezolizumab, and 1 durvalumab) and 86 examining non-ICI agents (74 targeted therapy, 8 chemotherapy, 3 hormone therapy, and 1 radiopharmaceutical). Randomized clinical trials were awarded ASCO-VF v2 tail-of-the-curve bonuses more often than ESMO-MCBS v1.1 immunotherapy-triggered long-term plateau adjustments (ASCO-VF v2, 45.0% [8 of 14 ICI RCTs and 37 of 86 non-ICI RCTs] vs ESMO-MCBS v1.1, 2.6% [1 of 12 ICI RCTs and 1 of 66 non-ICI RCTs). Randomized clinical trials for ICIs were not more likely to receive an ASCO-VF v2 bonus or ESMO-MCBS v1.1 adjustment than non-ICI RCTs (ASCO-VF: risk difference, 0.14; 95% CI, -0.14 to 0.42; P = .32; ESMO-MCBS: risk difference, 0.07; 95% CI, -0.09 to 0.23; P = .40). Poor agreement was found between the framework algorithms in identifying long-term survival benefits from RCTs (κ = 0.01; 95% CI, -0.23 to 0.22; P = .50).Conclusions and relevanceThe ASCO-VF v2 and ESMO-MCBS v1.1 may require additional refinement to accurately capture the benefit of durable long-term survival, or ICI agents may not preserve long-term survival as conventionally thought.

Project description:BackgroundContemporary treatment of node-positive (N+) colon cancer consists of adjuvant chemotherapy; however, randomized data supporting this practice were derived from lesions T2 or greater. Minimal data exist regarding the use and need for adjuvant chemotherapy in T1N+ disease.ObjectiveThe aim of this study was to determine treatment trends and the effects of adjuvant chemotherapy on T1N+ colon cancers by using the National Cancer Database.DesignThis was a retrospective study. Baseline demographics, tumor, and cancer treatment characteristics were compared. Groups were matched on the propensity to receive chemotherapy. Adjusted long-term survival stratified by chemotherapy use was compared by using the Kaplan-Meier method with the log-rank test. Predictors of not receiving chemotherapy were identified by using a multivariable logistic regression model.SettingsData were collected from the National Cancer Database, which collects cancer data from over 1500 cancer centers.PatientsWe identified patients from 1998 to 2006 with T1N+ disease, excluding those with metastatic disease or previous cancer. Patients were stratified based on whether or not they received chemotherapy.Main outcome measuresThe primary outcome measure of this study was long-term survival.ResultsThree thousand one hundred thirty-seven patients had T1N+ disease; 70.6% (n = 2216) received chemotherapy, and utilization significantly increased from 1998 to 2011 (p < 0.001). Unadjusted analysis revealed that patients treated with chemotherapy were statistically younger and healthier, and had shorter postoperative lengths of stay (all p < 0.001). Unadjusted 5-year survival was higher in patients receiving chemotherapy (87.9% vs 63.0% in patients with no chemotherapy; p < 0.001) and this persisted after propensity matching with (83.4% and 63.0% in patients with or without chemotherapy; p < 0.001). Only age (OR, 0.29; p < 0.001) predicted not receiving chemotherapy.LimitationsLimitations include potential selection bias as well as the inability to compare disease-free survival/recurrence.ConclusionsAdjuvant chemotherapy appears to significantly improve long-term survival in patients receiving chemotherapy in T1N+ disease. Thus, the use of chemotherapy in T1N+ disease is justified and provides a highly significant survival benefit.

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Lessons learnt from scoring adjuvant colon cancer trials and meta-analyses using the ESMO-Magnitude of Clinical Benefit Scale V.1.1.

Publications

Lessons learnt from scoring adjuvant colon cancer trials and meta-analyses using the ESMO-Magnitude of Clinical Benefit Scale V.1.1.

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