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CHICAGO -- An alternative approach to standard radiotherapy for solid tumor patients with leptomeningeal metastasis kept central nervous system (CNS) progression at bay and was associated with improved overall survival, according to an interim analysis of a small randomized trial.

In the phase II study of 63 patients with metastatic lung and breast cancers, the CNS progression rate at 6 months was 92% with standard photon involved-field radiotherapy (IFRT) versus just 22% for those receiving proton craniospinal irradiation (P<0.001), with high-grade toxicity comparable between groups, reported Jonathan Yang, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City.

Median CNS progression-free survival -- the study's primary endpoint -- was significantly improved with proton craniospinal irradiation (7.5 vs 2.3 months with IFRT, P<0.0001), as was overall survival (9.9 vs 6 months, P=0.029).

"This is the first randomized study evaluating the optimal radiotherapy approach for patients with solid tumors who have leptomeningeal metastasis," said Yang at the American Society of Clinical Oncology (ASCO) annual meeting. He added that a data monitoring and safety committee recommended the trial be halted following the interim analysis due to the superior outcomes in the investigational arm.

Yang explained that leptomeningeal disease is a type of lethal metastasis involving seeding of the cerebrospinal fluid (CSF)-filled leptomeningeal space that surrounds the brain and spinal cord. "It can lead to death within 4-6 weeks without treatment or 4-6 months with standard therapies," he said.

While photon IFRT -- such as whole-brain radiotherapy (WBRT) or focal spine radiotherapy -- is effective for relieving symptoms and supported by National Comprehensive Cancer Network guidelines, it does not halt progression along the leptomeningeal space, he said, and does not appear to prolong survival.

"Craniospinal irradiation, on the other hand, may be potentially beneficial in disease control as the entire neuroaxis is targeted," said Yang.

"I call this the 'Where's Waldo?' phenomenon," said ASCO-designated discussant Minesh Mehta, MD, of Baptist Health South Florida, commenting on the study results.

"Radiotherapy that misses disease usually does not work," he noted. "Therefore the positivity of this trial is not really surprising. If you target the entire craniospinal axis and treat the entirety of the disease, you're more likely to achieve a positive clinical benefit."

But Mehta added that proton craniospinal irradiation for leptomeningeal disease is still very much a palliative treatment, and said the benefits beyond survival outcomes need to be studied rigorously. He noted that NRG Oncology is considering a phase III randomized trial to confirm the study findings.

In the interim, however, he said that advanced radiotherapy techniques should not be excluded in the palliative setting and argued that payers should cover this particular approach for leptomeningeal disease based on the improvement in progression-free survival.

From April 2020 to October 2021, the study randomized 63 patients with metastatic non-small cell lung cancer (n=36) or breast cancer (n=27) with leptomeningeal metastasis (established radiographically and/or through CSF cytology) 2:1 to either proton craniospinal irradiation or standard-of-care photon IFRT (each given at 3 Gy over 10 daily fractions). In the IFRT group, 43% received WBRT, 5% received focal spine radiotherapy only, and 38% received both.

After completion of treatment, patients underwent serial MRI and lumbar puncture every 3 months. Median follow-up for the data presented was 9.3 months.

The primary endpoint was CNS progression-free survival, defined as one of the following: clinical development of new neurologic deficit after treatment; radiographic progressive disease on MRI using the leptomeningeal assessment in the Neuro-Oncology Scale; or new positive cytology in patients who previously had negative cytology.

Patients were stratified by tumor type and disease status (active vs stable). Among the inclusion criteria were a Karnofsky Performance Scale (KPS) score of at least 60, and patients were excluded if they had multiple serious major neurologic deficits (such as encephalopathy) or extensive systemic disease and no systemic treatment options.

Baseline characteristics between the groups were balanced, said Yang. Median age was 56-61 years, and most of the patients were women (81-86%). Just over half had active disease, median KPS score was 80, and over two-thirds had brain metastases. Patients had a median of two prior lines of therapy.

High-grade adverse events (AEs) were comparable between groups in the study. In those receiving proton craniospinal irradiation, grade 3 AEs included fatigue, pain, and vomiting (each occurring in 2% of patients); grade 4 lymphopenia occurred in 10%.

Yang also reported outcomes of an exploratory cohort of 35 patients with other tumor types and leptomeningeal metastasis who were all treated with proton craniospinal irradiation. In this group, the median age was 61 years, 57% were women, and 57% had active disease. Tumor types included ovarian cancer in 20%, esophageal cancer in 17%, and melanoma in 17%, among others. Median CNS progression-free survival in this group was 5.8 months and median overall survival was 6.6 months.

Grade 3 AEs in the exploratory cohort included headache, muscle weakness, nausea, and vomiting (each occurring in 3% of patients) and grade 4 lymphopenia in 17% of patients.

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