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

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.

Application of the ESMO-Magnitude of Clinical Benefit Scale (V.1.1) to the field of early breast cancer therapies.

Click here to listen to the Podcast BACKGROUND: The European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) is a validated value scale for solid tumour anticancer treatments. Form 1 of the ESMO-MCBS, used to grade therapies with curative intent including adjuvant therapies, has only been evaluated for a limited number of studies. This is the first large-scale field testing in early breast cancer to assess the applicability of the scale to this data set and the reasonableness of derived scores and to identify any shortcomings to be addressed in future modifications of the scale. METHOD: Representative key studies and meta-analyses of the major modalities of adjuvant systemic therapy of breast cancer were identified for each of the major clinical scenarios (HER2-positive, HER2-negative, endocrine-responsive) and were graded with form 1 of the ESMO-MCBS. These generated scores were reviewed by a panel of experts for reasonableness. Shortcomings and issues related to the application of the scale and interpretation of results were identified and critically evaluated. RESULTS: Sixty-five studies were eligible for evaluation: 59 individual studies and 6 meta-analyses. These studies incorporated 101 therapeutic comparisons, 61 of which were scorable. Review of the generated scores indicated that, with few exceptions, they generally reflected contemporary standards of practice. Six shortcomings were identified related to grading based on disease-free survival (DFS), lack of information regarding acute and long-term toxicity and an inability to grade single-arm de-escalation scales. CONCLUSIONS: Form 1 of the ESMO-MCBS is a robust tool for the evaluation of the magnitude of benefit studies in early breast cancer. The scale can be further improved by addressing issues related to grading based on DFS, annotating grades with information regarding acute and long-term toxicity and developing an approach to grade single-arm de-escalation studies.

EHA evaluation of the ESMO-Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS v1.1) for haematological malignancies.

OBJECTIVE: Value frameworks in oncology have not been validated for the assessment of treatments in haematological malignancies, but to avoid overlaps and duplications it appears reasonable to build up experience on existing value frameworks, such as the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS). METHODS: Here we present the results of the first feasibility testing of the ESMO-MCBS v1.1 for haematological malignancies based on the grading of 80 contemporary studies for acute leukaemia, chronic leukaemia, lymphoma, myeloma and myelodysplastic syndromes. The aims were (1) to evaluate the scorability of data, (2) to evaluate the reasonableness of the generated grades for clinical benefit using the current version and (3) to identify shortcomings in the ESMO-MCBS v1.1 that require amendments to improve the efficacy and validity of the scale in grading new treatments in the management of haematological malignancies. RESULTS: In general, the ESMO-MCBS v1.1 was found to be widely applicable to studies in haematological malignancies, generating scores that were judged as reasonable by European Hematology Association (EHA) experts. A small number of studies could either not be graded or were not appropriately graded. The reasons, related to the differences between haematological and solid tumour malignancies, are identified and described. CONCLUSIONS: Based on the findings of this study, ESMO and EHA are committed to develop a version of the ESMO-MCBS that is validated for haematological malignancies. This development process will incorporate all of the usual stringencies for accountability of reasonableness that have characterised the development of the ESMO-MCBS including field testing, statistical modelling, evaluation for reasonableness and openness to appeal and revision. Applying such a scale will support future public policy decision-making regarding the value of new treatments for haematological malignancies and will provide insights that could be helpful in the design of future clinical trials.

Comparative Assessment of Clinical Benefit Using the ESMO-Magnitude of Clinical Benefit Scale Version 1.1 and the ASCO Value Framework Net Health Benefit Score.

PURPOSE: To better understand the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS v1.1) and the ASCO Value Framework Net Health Benefit score version 2 (ASCO-NHB v2), ESMO and ASCO collaborated to evaluate the concordance between the frameworks when used to assess clinical benefit attributable to new therapies. METHODS: The 102 randomized controlled trials in the noncurative setting already evaluated in the field testing of ESMO-MCBS v1.1 were scored using ASCO-NHB v2 by its developers. Measures of agreement between the frameworks were calculated and receiver operating characteristic curves used to define thresholds for the ASCO-NHB v2 corresponding to ESMO-MCBS v1.1 categories. Studies with discordant scoring were identified and evaluated to understand the reasons for discordance. RESULTS: The correlation of the 102 pairs of scores for studies in the noncurative setting is estimated to be 0.68 (Spearman's rank correlation coefficient; overall survival, 0.71; progression-free survival, 0.67). Receiver operating characteristic curves identified thresholds for ASCO-NHB v2 for facilitating comparisons with ESMO-MCBS v1.1 categories. After applying pragmatic threshold scores of 40 or less (ASCO-NHB v2) and 2 or less (ESMO-MCBS v1.1) for low benefit and 45 or greater (ASCO-NHB v2) and 4 to 5 (ESMO-MCBS v1.1) for substantial benefit, 37 discordant studies were identified. Major factors that contributed to discordance were different approaches to evaluation of relative and absolute gain for overall survival and progression-free survival, crediting tail of the curve gains, and assessing toxicity. CONCLUSION: The agreement between the frameworks was higher than observed in other studies that sought to compare them. The factors that contributed to discordant scores suggest potential approaches to improve convergence between the scales.

Indicators of integration at ESMO Designated Centres of Integrated Oncology and Palliative Care.

BACKGROUND: A recent international consensus panel identified 13 major indicators to assess the level of integration between oncology and palliative care. We examined these indicators among European Society for Medical Oncology (ESMO) Designated Centres (ESMO-DCs) of Integrated Oncology and Palliative Care (PC) and determined the centre characteristics associated with greater integration. METHODS: This is a preplanned secondary analysis of a recent survey to characterise the structure, processes and outcomes of the palliative care programmes at ESMO-DCs. We assessed the level of integration using 13 major indicators. We calculated two Palliative Care and Oncology Integration Indexes consisting of all 13 indicators (PCOI-13, range 0-13) and 9 of the 13 indicators (PCOI-9, range 0-9), with a higher index indicating greater integration. RESULTS: The survey response rate was 152/184 (83%). Among the 13 major indicators, interdisciplinary team was most likely to be achieved (95%), while early referral to palliative care (median time from referral to death >6 months before death) was only present in 24 (20%) of ESMO-DCs. The median PCOI-13 was 7.8 (IQR 6.4-9.6) and the median PCOI-9 was 6 (IQR 5-7). The presence of dually trained palliative oncologists was associated with higher PCOI-13 (median 8.4 vs 7.0; p=0.01) and PCOI-9 (median 6 vs 5; p=0.03). Non-tertiary hospitals generally had higher PCOI-13 (median 8.6 vs 7.2; p=0.01) and ESMO-DCs outside of Europe had higher PCOI-9 (median 7 vs 6; p=0.03). CONCLUSIONS: Assessment of the level of integration at ESMO-DCs with PCOIs highlighted strengths, areas for further development and how double-boarded palliative oncologists may promote integration.

Detailed statistical assessment of the characteristics of the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) threshold rules.

BACKGROUND: The European Society for Medical Oncology (ESMO) has developed the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS), a tool to assess the magnitude of clinical benefit from new cancer therapies. Grading is guided by a dual rule comparing the relative benefit (RB) and the absolute benefit (AB) achieved by the therapy to prespecified threshold values. The ESMO-MCBS v1.0 dual rule evaluates the RB of an experimental treatment based on the lower limit of the 95%CI (LL95%CI) for the hazard ratio (HR) along with an AB threshold. This dual rule addresses two goals: inclusiveness: not unfairly penalising experimental treatments from trials designed with adequate power targeting clinically meaningful relative benefit; and discernment: penalising trials designed to detect a small inconsequential benefit. METHODS: Based on 50 000 simulations of plausible trial scenarios, the sensitivity and specificity of the LL95%CI rule and the ESMO-MCBS dual rule, the robustness of their characteristics for reasonable power and range of targeted and true HRs, are examined. The per cent acceptance of maximal preliminary grade is compared with other dual rules based on point estimate (PE) thresholds for RB. RESULTS: For particularly small or particularly large studies, the observed benefit needs to be relatively big for the ESMO-MCBS dual rule to be satisfied and the maximal grade awarded. Compared with approaches that evaluate RB using the PE thresholds, simulations demonstrate that the MCBS approach better exhibits the desired behaviour achieving the goals of both inclusiveness and discernment. CONCLUSIONS: RB assessment using the LL95%CI for HR rather than a PE threshold has two advantages: it diminishes the probability of excluding big benefit positive studies from achieving due credit and, when combined with the AB assessment, it increases the probability of downgrading a trial with a statistically significant but clinically insignificant observed benefit.