Clinical Endpoints in Trials of Metastasis-Directed Therapy in Oligometastatic Cancer: A Systematic Review and Surrogacy Analysis.

Abstract

Background: The oligometastatic state is characterized by limited metastatic burden for which metastasis-directed therapy (MDT) may provide durable control. Endpoint selection in MDT trials is poorly standardized and may not reflect long-term benefit or patient priorities. We systematically reviewed clinical endpoints in prospective MDT trials and registrations and evaluated progression-free survival (PFS) as a surrogate for overall survival (OS).

Methods: We searched Ovid MEDLINE, Embase, CENTRAL, and ClinicalTrials.gov from inception to June 2025 for prospective studies that exclusively enrolled oligometastatic patients and evaluated MDT. Two reviewers screened and extracted data, and endpoints were summarized descriptively and stratified by trial phase. We conducted a trial-level surrogacy meta-analysis of randomized trials reporting both PFS and OS hazard ratios.

Findings: We included 235 trials: 29 randomized (25 [86%] phase II), 35 non-randomized, and 171 registrations. In randomized trials, PFS was the most frequent primary endpoint (n = 20, 67%), followed by OS (n = 4, 13%). Among 18 randomized trials reporting both endpoints, PFS and OS were moderately correlated (r = 0.80, 95% CI 0.64-0.91), with a surrogate threshold effect HR of 0.79 (95% CI 0.71-0.87).

Interpretation: Because most trials were phase II, for which OS is neither expected nor appropriate as a sole endpoint, MDT trials predominantly use progression-based endpoints. We recommend phase-appropriate, patient-centered strategies that pair standardized PFS and local control with quality of life or systemic-therapy-free survival, reserving OS or validated surrogates for later-phase trials.