Potential New Standard of Care for Leptomeningeal Metastases

WASHINGTON — Proton craniospinal irradiation (CSI) may mark a new standard of care for treating leptomeningeal metastases, a rare but devastating complication of cancer, according to research presented at the American Society for Radiation Oncology (ASTRO) 2024 Annual Meeting.

The trial pitted proton CSI against involved-field radiotherapy — a common treatment for leptomeningeal metastases, used largely for symptom control — and found median overall survival was more than twice as long — 11.3 months vs 4.9 months — among patients receiving proton CSI.

For a complication that’s often considered an end-stage event in cancer, achieving a median overall survival of almost a year with proton CSI is nothing short of “amazing,” said study discussant Jona Hattangadi-Gluth, MD, a radiation oncologist at the University of California, San Diego.

The study has set “a new standard of care” for leptomeningeal metastases, particularly in high-performing patients, like those in the trial, who don’t need immediate radiation for symptom relief, she said.

This study also marks the first time two radiation techniques have been compared head-to-head for leptomeningeal metastases, noted lead investigator Jonathan Yang, MD, a radiation oncologist at NYU Langone Health, New York City.

In leptomeningeal metastases, malignant cells invade and seed the entire leptomeningeal space surrounding the brain and spinal cord. Involved-field radiotherapy uses photon radiation to treat either the whole brain, individual spinal masses, or both depending on patient symptoms. In contrast, proton CSI targets the entire leptomeningeal space at once, treating both the cranium and spinal cord. It also penetrates healthy tissue less than involved-field radiotherapy.

What the trial is really telling us is that treating the entire cerebrospinal axis in a way that minimizes toxicity translates to central nervous system control and an overall survival benefit, Hattangadi-Gluth said.

In the trial, 42 patients were randomized to proton CSI and 21 to involved-field radiotherapy. Enrollment in the trial was stopped early when the benefit of proton CSI became clear.

Randomized patients had either breast or non–small cell lung cancer. Over half had active systemic disease and the majority were women. The total treatment dose in both arms was 30 Gy in 10 fractions.

Central nervous system progression-free survival (PFS) was 8.2 months among those receiving proton CSI and 2.3 months among those receiving involved-field radiotherapy, which translated to an 86% improvement in central nervous system PFS.

Median overall survival was 11.3 months in the proton CSI group and 4.9 months in the involved-field radiotherapy group, which translated to a 57% lower risk for death among those receiving proton CSI (hazard ratio, 0.43; P = .009).

The researchers noted a trend toward fewer grade 3/4 adverse events and less symptom interference in daily activities in the proton CSI group, but overall no statistically significant differences in patient-reported outcomes between the two radiation arms.

Among the 12 patients in the proton CSI group who had baseline neurocognitive testing, patients did experience a decline in executive function and verbal memory at 6 months but no significant change in attention and working memory. There weren’t enough data available from the involved-field radiotherapy arm to compare neurocognitive outcomes.

Although the study focused on patients with breast and non–small cell lung cancer, the trial also included an exploratory arm with 35 patients who had other solid tumor types, largely ovarian and esophageal cancers, and these patients received proton CSI.

In this group, the median central nervous system PFS was 5.8 months, and median overall survival was 7 months.

The exploratory group didn’t do as well as those with breast and lung cancer, likely because they had a higher rate of systemic disease progression. Even so, Yang said he uses proton CSI for these patients in his clinical practice.

Yang also noted that proton CSI must be given as soon as possible in the disease course to maximize benefit and it’s not necessary to pause systemic therapies during treatment.

A wrinkle in the study is that it didn’t compare proton CSI with volumetric modulated arc therapy craniospinal radiation (VMAT CSI), a photon technique that offers similar radiation coverage and safety benefits while being less expensive, more widely available, and quicker to plan.

The reason, Yang explained, is because VMAT CSI wasn’t available at his previous institution when the trial was designed several years ago.

Still, the main point of the study is that CSI improves survival over involved-field radiotherapy, likely regardless of how it’s delivered, Yang said.

The trial was funded by the National Cancer Institute and others. Yang reported several industry ties, including being an independent contractor for and/or receiving research funding from Kazia Therapeutics and AstraZeneca, among others. Hattangadi-Gluth didn’t have any disclosures.

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape Medical News. Alex is also an MIT Knight Science Journalism fellow. Email: [email protected].