Joseph Salama

IMPORTANCE: Clinical trials for metastatic malignant neoplasms are increasingly being extended to patients with brain metastases. Despite the preeminence of progression-free survival (PFS) as a primary oncologic end point, the correlation of intracranial progression (ICP) and extracranial progression (ECP) events with overall survival (OS) is poorly understood for patients with brain metastases following stereotactic radiosurgery (SRS). OBJECTIVE: To determine the correlation of ICP and ECP with OS among patients with brain metastases completing an initial SRS course. DESIGN, SETTING, AND PARTICIPANTS: This multi-institutional retrospective cohort study was conducted from January 1, 2015, to December 31, 2020. We included patients who completed an initial course of SRS for brain metastases during the study period, including receipt of single and/or multifraction SRS, prior whole-brain radiotherapy, and brain metastasis resection. Data analysis was performed on November 15, 2022. EXPOSURES: Non-OS end points included intracranial PFS, extracranial PFS, PFS, time to ICP, time to ECP, and any time to progression. Progression events were radiologically defined, incorporating multidisciplinary clinical consensus. MAIN OUTCOMES AND MEASURES: The primary outcome was correlation of surrogate end points to OS. Clinical end points were estimated from time of SRS completion via the Kaplan-Meier method, while end-point correlation to OS was measured using normal scores rank correlation with the iterative multiple imputation approach. RESULTS: This study included 1383 patients, with a mean age of 63.1 years (range, 20.9-92.8 years) and a median follow-up of 8.72 months (IQR, 3.25-19.68 months). The majority of participants were White (1032 [75%]), and more than half (758 [55%]) were women. Common primary tumor sites included the lung (757 [55%]), breast (203 [15%]), and skin (melanoma; 100 [7%]). Intracranial progression was observed in 698 patients (50%), preceding 492 of 1000 observed deaths (49%). Extracranial progression was observed in 800 patients (58%), preceding 627 of 1000 observed deaths (63%). Irrespective of deaths, 482 patients (35%) experienced both ICP and ECP, 534 (39%) experienced ICP (216 [16%]) or ECP (318 [23%]), and 367 (27%) experienced neither. The median OS was 9.93 months (95% CI, 9.08-11.05 months). Intracranial PFS had the highest correlation with OS (ρ = 0.84 [95% CI, 0.82-0.85]; median, 4.39 months [95% CI, 4.02-4.92 months]). Time to ICP had the lowest correlation with OS (ρ = 0.42 [95% CI, 0.34-0.50]) and the longest median time to event (median, 8.76 months [95% CI, 7.70-9.48 months]). Across specific primary tumor types, correlations of intracranial PFS and extracranial PFS with OS were consistently high despite corresponding differences in median outcome durations. CONCLUSIONS AND RELEVANCE: The results of this cohort study of patients with brain metastases completing SRS suggest that intracranial PFS, extracranial PFS, and PFS had the highest correlations with OS and time to ICP had the lowest correlation with OS. These data may inform future patient inclusion and end-point selection for clinical trials.

BACKGROUND: While moderately hypofractionated radiotherapy (MHRT) for prostate cancer (PC) is commonly delivered by intensity modulated radiation therapy, IMRT has not been prospectively compared to three-dimensional conformal radiotherapy (3D-CRT) in this context. We conducted a secondary analysis of the phase III RTOG 0415 trial comparing survival and toxicity outcomes for low-risk PC following MHRT with IMRT versus 3D-CRT. METHODS: RTOG 0415 was a phase III, non-inferiority trial randomizing low-risk PC patients to either MHRT or conventionally fractionated radiation with stratification by RT technique. A secondary analysis for differences in overall survival (OS), biochemical recurrence free survival (BRFS), or toxicity by EPIC scores and Common Terminology Criteria for Adverse Events (CTCAE) was performed. RESULTS: 1079 patients received the allocated intervention with a median follow up of 5.8 years. 79.1% of patients were treated with IMRT and radiation technique was balanced between arms. Across all patients, RT technique was not associated with significant differences in BRFS, OS, or rates of acute and late toxicities. For patients completing MHRT, there was a difference in the late GU toxicity distribution between 3D-CRT and IMRT but no difference in late grade 2 or greater GU or GI toxicity. Stratifying patients by RT technique and fractionation, no significant differences were observed in the minimal clinically important difference (MCID) in EPIC urinary and bowel scores following RT. CONCLUSIONS: RT technique did not impact clinical outcomes following MHRT for low-risk PC. Despite different late GU toxicity distributions in patients treated with MHRT by IMRT or 3D-CRT, there was no difference in late Grade 2 or greater GU or GI toxicity or patient reported toxicity. Increases in late GU and GI toxicity following MHRT compared to CFRT, as demonstrated in the initial publication of RTOG 0415, do not appear related to a 3D-CRT treatment technique.