An Updated Systematic Review and Meta-Analysis of the MASCC Risk Index for Predicting Severe Complications and Mortality

Title: An Updated Systematic Review and Meta-Analysis of the MASCC Risk Index for Predicting Severe Complications and Mortality in Adult Patients with Febrile Neutropenia Description: Background and Purpose: Febrile neutropenia (FN) is one of the most common and severe complications following cancer chemotherapy. The Multinational Association for Supportive Care in Cancer (MASCC) Risk Index is the primary clinical tool used to identify low-risk FN patients, utilizing a threshold score of 21 (stratifying patients into low-risk [≥21] and high-risk [<21] groups). While previous systematic reviews have evaluated the predictive accuracy of the MASCC score, the continuous publication of new studies and the accumulation of validation data across diverse clinical settings (emergency department, outpatient, and inpatient) necessitate an updated systematic review and meta-analysis. This project aims to comprehensively reassess the pooled diagnostic accuracy and clinical applicability of the MASCC Risk Index in predicting severe complications and/or mortality. Objective: To evaluate the pooled diagnostic accuracy (sensitivity, specificity, positive predictive value, and negative predictive value) of the MASCC Risk Index (threshold of 21) in predicting severe complications and/or mortality in adult patients with febrile neutropenia. Secondary Objectives: To explore sources of heterogeneity across studies (e.g., clinical settings, tumor types, variations in definitions); to perform an indirect comparison with the CISNE (Clinical Index of Stable Febrile Neutropenia) score if data permit; and to assess the certainty of evidence using the GRADE approach. Methods Overview: This study will be conducted and reported in accordance with PRISMA-P (for protocol) and PRISMA-DTA (for the full review) guidelines. We will systematically search PubMed, EMBASE, and the Cochrane Library from the inception of previous reviews (or database inception) to the date of search execution, supplemented by manual searches of reference lists and recent conference abstracts. Two independent reviewers will screen the literature and extract data based on predefined inclusion criteria: adult patients (≥16 years) with FN, utilization of the MASCC score with a threshold of 21, outcomes defined as severe complications (Klastersky definition or equivalent) and/or mortality, and study designs including RCTs, prospective, or retrospective cohort studies. Pediatric studies, non-21 thresholds, and studies with incomparable outcome definitions will be excluded. Data extraction will include study characteristics and 2 × 2 2×2 contingency table data. The risk of bias and applicability will be assessed using the QUADAS-2 tool. Statistical analysis will employ a bivariate random-effects model to pool sensitivity and specificity and generate summary receiver operating characteristic (SROC) curves. Heterogeneity will be evaluated using 2 I 2 and 2 τ 2 statistics. Pre-specified subgroup analyses will be conducted based on clinical setting, tumor type, and study design, alongside sensitivity analyses excluding high-risk-of-bias studies. Expected Outcomes: We expect to provide updated, robust estimates of the pooled sensitivity, specificity, and predictive values of the MASCC score, accompanied by forest plots and SROC curves. This updated meta-analysis will yield a comprehensive GRADE assessment of the current evidence. The findings will clarify the clinical utility of the MASCC index across different settings, quantify its diagnostic performance compared to newer tools like CISNE (via indirect comparison), and ultimately provide evidence-based guidance for risk stratification and management of adult patients with febrile neutropenia.