Randomized Phase II Trial of Proton Craniospinal Irradiation Versus Photon Involved-Field Radiotherapy for Patients With Solid Tumor Leptomeningeal Metastasis

Abstract

Purpose: Photon involved-field radiotherapy (IFRT) is the standard-of-care radiotherapy for patients with leptomeningeal metastasis (LM) from solid tumors. We tested whether proton craniospinal irradiation (pCSI) encompassing the entire CNS would result in superior CNS progression-free survival (PFS) compared with IFRT.

Patients and methods: We conducted a randomized, phase II trial of pCSI versus IFRT in patients with non-small-cell lung cancer and breast cancers with LM. We enrolled patients with other solid tumors to an exploratory pCSI group. For the randomized groups, patients were assigned (2:1), stratified by histology and systemic disease status, to pCSI or IFRT. The primary end point was CNS PFS. Secondary end points included overall survival (OS) and treatment-related adverse events (TAEs).

Results: Between April 16, 2020, and October 11, 2021, 42 and 21 patients were randomly assigned to pCSI and IFRT, respectively. At planned interim analysis, a significant benefit in CNS PFS was observed with pCSI (median 7.5 months; 95% CI, 6.6 months to not reached) compared with IFRT (2.3 months; 95% CI, 1.2 to 5.8 months; P < .001). We also observed OS benefit with pCSI (9.9 months; 95% CI, 7.5 months to not reached) versus IFRT (6.0 months; 95% CI, 3.9 months to not reached; P = .029). There was no difference in the rate of grade 3 and 4 TAEs (P = .19). In the exploratory pCSI group, 35 patients enrolled, the median CNS PFS was 5.8 months (95% CI, 4.4 to 9.1 months) and OS was 6.6 months (95% CI, 5.4 to 11 months).

Conclusion: Compared with photon IFRT, we found pCSI improved CNS PFS and OS for patients with non-small-cell lung cancer and breast cancer with LM with no increase in serious TAEs.

Trial registration: ClinicalTrials.gov NCT04343573.

FIG 1.

CONSORT diagram. IFRT, involved-field radiotherapy; NSCLC, non–small-cell lung cancer; pCSI, proton craniospinal irradiation.

FIG 2.

Patients who were randomly assigned to pCSI had significantly improved (A) CNS time to progression, (B) CNS PFS, and (C) OS. IFRT, involved-field radiotherapy; OS, overall survival; PFS, progression-free survival; pCSI, proton craniospinal irradiation.

FIG 3.

(A) The log CSF CTC count relative to baseline for each subject is shown over time for IFRT (red) and pCSI (blue). Patients who only had baseline CSF CTC counts are not shown. (B) Estimated effect of treatment on CSF CTC count assessed through joint modeling of longitudinal and survival outcomes with shared random effects and an unspecified baseline risk function. From the linear mixed-model component of the joint model of overall survival, we reported the slope from a nonsignificant interaction between histology and treatment arm. Although pCSI was associated with a decreasing CTC count after treatment, increasing CTC count was observed after IFRT. CTC, circulating tumor cell; IFRT, involved-field radiotherapy; NSCLC, non–small-cell lung cancer; pCSI, proton craniospinal irradiation.