Phase II Randomized Trial Comparing Proton Craniospinal Irradiation with Photon Involved-Field Radiotherapy for Patients with Solid Tumor Leptomeningeal Metastasis

Abstract

<h3>Purpose/Objective(s)</h3> Solid tumor leptomeningeal metastasis (LM) is associated with limited survival and treatments. Photon involved-field radiotherapy (IFRT) is the standard of care radiotherapy (RT) but lacks durability in disease and symptom control. We hypothesized that proton craniospinal irradiation (pCSI) encompassing the central nervous system (CNS) would result in superior disease control. <h3>Materials/Methods</h3> We conducted a randomized phase 2 study comparing pCSI vs. IFRT in patients with non-small cell lung cancer (NSCLC) or breast cancer LM. Eligibility criteria included radiographic and/or cytologic LM and Karnofsky performance status (KPS)≥ 60. Patients were stratified by histology and systemic disease (active vs. stable) and were randomized in a 2:1 ratio favoring pCSI. For all other solid tumor histologies, patients were enrolled on an exploratory cohort and all received pCSI. RT was 3Gy x 10 fractions for all patients. The primary objective is CNS progression-free survival (CNS PFS), defined as time from randomization to CNS progression (POD); the secondary objectives include overall survival (OS) and treatment-related adverse events (TAEs). A target of 81 patients to compare pCSI and IFRT was designed with a one-sided alpha of 0.025 and power of 0.8 based on stratified log-rank test. Analysis is based on intent-to-treat. <h3>Results</h3> From 4/2020-10/2021, 42 and 21 patients were randomized to pCSI and IFRT, respectively. Baseline factors were not different: median age was 56 vs. 61 years (p=0.5), both cohorts included 57% NSCLC and 52% patients with active systemic disease. At median follow up of 7.1 months, 25 patients had CNS POD and 28 died. At planned interim analysis, significant benefit in CNS PFS was observed with pCSI (median=7.5 months, 95% CI: 6.6-NA) vs. IFRT (median=2.0. 95% CI: 1.0-5.1, p<0.001). As a result, the Data and Safety Monitoring Committee recommended early discontinuation of the trial. In addition, OS benefit with pCSI (median= 8.2 months, 95% CI: 7.4-NA) vs. IFRT (median= 4.9 months, 95% CI: 3.1-NA, p=0.04) was observed. In a multivariable analysis including age, KPS and stratification factors, pCSI remained significantly associated with improved CNS PFS (HR=13, 95% CI: 5-33, p<0.001) and OS (HR=2, 95% CI: 1-5, p=0.04). Grade 3 non-heme TAEs occurred in 3 patients with pCSI and 5 with IFRT. The only Grade 4 TAE was lymphopenia (4 patients in each cohort). For the exploratory pCSI cohort, 35 patients enrolled, the median age was 61, 20 (57%) had active systemic disease and ovarian (7 [20%]) was the most common histology. At median follow up of 9.6 months, 7 (20%) had CNS POD and 20 (57%) died. Median CNS PFS was 5.4 months (95% CI: 4.8-9.1), OS was 6.6 months (95% CI: 5.4-12.1), 4 patients had Grade 3 non-heme TAEs and 4 had Grade 4 lymphopenia. <h3>Conclusion</h3> In this pre-planned interim analysis of the first randomized trial of RT for LM, we demonstrated improved CNS PFS of pCSI compared to IFRT, meeting the primary endpoint. pCSI also had a significant OS benefit. Toxicities were comparable.