Proton Craniospinal Irradiation for Patients with Solid Tumor Leptomeningeal Metastasis- Final Analysis of a Phase II Study

Abstract

Purpose/Objective(s)

Solid tumor leptomeningeal metastasis (LM) is associated with limited survival. We evaluated whether proton craniospinal irradiation (pCSI) would result in improvement in disease control and survival compared to involved-field radiotherapy (IFRT).

Materials/Methods

We conducted a randomized phase 2 study comparing pCSI vs. IFRT in patients with non-small cell lung cancer (NSCLC) or breast cancer LM (NCT04343573). Eligibility criteria included radiographic and/or cytologic LM and Karnofsky performance status (KPS) ≥ 60. Patients were stratified by histology and systemic disease 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 3 Gy x 10 fractions. The primary objective was CNS progression-free survival (CNS PFS), defined as time from randomization to CNS progression (POD); secondary objectives included overall survival (OS), treatment-related adverse events (TAEs), patient reported outcomes (PROs), neurocognitive function (NF).

Results

From April 2020 to October 2021, there were 42 and 21 patients who were randomized to pCSI and IFRT, respectively. Both cohorts included 57% NSCLC and 52% patients with active systemic disease. In the randomized cohorts, 33 patients had CNS POD and 41 died. Patients followed for CNS PFS without POD had a minimum of 18.5 months follow up (range = 18.5-26.8). At 6 months, 22% (95% CI = 9.5-38) pCSI patients vs. 88% (95% CI = 51-98, P < 0.001) IFRT patients had CNS progression. A significant benefit in CNS PFS was observed with pCSI (median = 8.2 months, 95% CI = 6.6-15.3) vs. IFRT (median = 2.3 months, 95% CI = 1.2-4.0, P < 0.001). OS benefit with pCSI (median = 11.3 months, 95% CI = 7.5-18.3) vs. IFRT (median = 4.9 months, 95% CI = 3.9-15.0, P = 0.04) was also observed. In multivariable analysis, pCSI remained significantly associated with improved CNS PFS (HR = 0.14, 95% CI = 0.06-0.30, P < 0.001) and OS (HR = 0.43, 95% CI = 0.22-0.81, P = 0.009). Grade 3 non-heme and/or Grade 4 heme TAEs occurred in 8 patients with pCSI and 7 with IFRT (P = 0.19). For the exploratory pCSI cohort, 35 patients enrolled, 20 (57%) had active systemic disease, and ovarian (7 [20%]) was the most common histology. In this cohort, 13 had CNS POD and 27 died. Median CNS PFS was 5.8 months (95% CI = 4.4-9.1), OS was 7.0 months (95% CI = 5.4-10.6), and 8 patients had Grade 3 non-heme and/or Grade 4 heme TAEs. There was no Grade 5 toxicity in all cohorts. There was no significant difference in PROs scores between patients who received pCSI or IFRT while on study. In patients who received pCSI and had NF evaluated at baseline (n = 12), decline in verbal memory and executive function but no significant change in working memory and attention was observed at 6 months.

Conclusion

In this final analysis of the first randomized trial assessing the optimal radiation treatment for LM, we demonstrated improved CNS PFS and OS with pCSI compared to IFRT, confirming our interim analysis results.