Definitions and use of tumor bulk in phase 3 lymphoma trials: a comprehensive literature review

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Abstract
Tumor “bulk” has historically been considered an important prognostic marker and a clinical tool to guide treatment in patients with lymphoma. However, its use and definitions in trial designs vary significantly, and it is unclear how this has influenced the relevance of bulk in contemporary practice. This comprehensive literature review evaluated the definitions, applications, and prognostic impact of bulk in phase 3 randomized trials in 4 major lymphoma subtypes. Overall, 87 studies were identified across follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), peripheral T-cell lymphoma (PTCL), and Hodgkin lymphoma (HL) with a wide range of bulk thresholds used (5 cm, 6 cm, 7 cm, 7.5 cm, 10 cm, and >1/3 mediastinal mass ratio [MMR]). The most common threshold was as follows: FL, 7 cm (58%); DLBCL, 7.5 cm and 10 cm (44% each); PTCL, 7.5 cm (66%); and HL, one-third MMR (91%). Bulk threshold was used by trials to determine eligibility (66%), stratification (24%), as a prognostic risk factor (37%), and as a decision tool for risk-adapted treatment, for example, radiotherapy (29%); however, bulk definitions used for these varied both between, and within, lymphoma subtypes and even within single trials in 25%. Furthermore, 32 studies incorporated bulk in prognostic analyses with only 5 showing significance for differential survival outcomes. Our analysis demonstrates high inconsistency in thresholds defining tumor bulk and use of bulk in phase 3 lymphoma trials across eligibility, stratification, therapeutic risk adaptation, and prognostication. This highlights an urgent need for international consensus on definitions of bulk within trials to improve its prognostic and predictive values and refine its application in clinical practice.

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