Clinical trial of proton craniospinal irradiation for leptomeningeal metastases

Abstract

Background: Leptomeningeal metastases (LM) are associated with limited survival and treatment options. While involved-field radiotherapy is effective for local palliation, it lacks durability. We evaluated the toxicities of proton craniospinal irradiation (CSI), a treatment encompassing the entire central nervous system (CNS) compartment, for patients with LM from solid tumors.

Methods: We enrolled patients with LM to receive hypofractionated proton CSI in this phase I prospective trial. The primary endpoint was to describe treatment-related toxicity, with dose-limiting toxicity (DLT) defined as any radiation-related grade 3 non-hematologic toxicity or grade 4 hematologic toxicity according to the Common Terminology Criteria for Adverse Events that occurred during or within 4 weeks of completion of proton CSI. Secondary endpoints included CNS progression-free survival (PFS) and overall survival (OS).

Results: We enrolled 24 patients between June 2018 and April 2019. Their median follow-up was 11 months. Twenty patients were evaluable for protocol treatment-related toxicities and 21 for CNS PFS and OS. Two patients in the dose expansion cohort experienced DLTs consisted of grade 4 lymphopenia, grade 4 thrombocytopenia, and/or grade 3 fatigue. All DLTs resolved without medical intervention. The median CNS PFS was 7 months (95% CI: 5-13) and the median OS was 8 months (95% CI: 6 to not reached). Four patients (19%) were progression-free in the CNS for more than 12 months.

Conclusion: Hypofractionated proton CSI using proton therapy is a safe treatment for patients with LM from solid tumors. We saw durable disease control in some patients.

Keywords: craniospinal irradiation; leptomeningeal metastases; proton radiation.

Fig. 1

Kaplan–Meier plot of (A) overall survival of the study cohort (B) central nervous system progression-free survival of the study cohort.

Fig. 2

Event history plot of the 21 evaluable patients for treatment outcomes. Progression in the figure represents CNS progression.

Figure 3.

MDASI score distribution overtime. These plots are a schematic for the distribution of values. The ends of the box represent the 25th and 75th percentiles (or 1st and 3rd quartiles), while the center line and diamond represent the median and mean, respectively. The 75th minus the 25th percentile equals the interquartile range (IQR), and the ends of the whiskers are placed at 1.5 times the IQR. Any values lying outside these boundaries are considered outliers. Higher values indicate worsening symptoms.