The role of intra-cerebrospinal fluid (CSF) therapy for the treatment of leptomeningeal metastasis (LM) remains controversial.
We conducted a multicenter randomized open-label study to explore the effect of the addition of liposomal cytarabine to systemic therapy for the treatment of LM from breast cancer. Inclusion was based on the detection of tumor cells in the CSF or typical clinical and magnetic resonance imaging (MRI) signs of LM. Patients were randomly assigned to receive systemic therapy alone (arm A) or systemic therapy plus intra-CSF liposomal cytarabine (5 injections of 50 mg x 2 weeks, followed by monthly injections of 50 mg until progression, unacceptable toxicity or for 1 year) (arm B). Neurological and quality of life evaluation was performed monthly, cerebrospinal MRI every 2 months. The primary endpoint was progression-free survival in the leptomeningeal compartment (LM-PFS); 66 were required to ensure 80% power for a hazard ratio of 0.5, and a two-sided alpha=5%. Overall survival (OS) was a secondary efficacy endpoint.
Thirty-seven patients were assigned to arm A, 36 patients to arm B. Baseline characteristics were similar in both arms. The median number of liposomal cytarabine injections in arm B was 5 (range 1-20). Focal radiotherapy was performed in 6 (16%) and 5 (14%) patients in arms A and B, respectively. Serious adverse events were reported in 6 and 14 patients in arms A and B. In the intent-to-treat population, median LM-PFS as assessed by the local investigator was 2.0 months (95% confidence interval (CI) 1.3 – 2.7) in arm A versus 4.3 months (95% CI 2.3 – 5.7) in arm B (HR = 0.57, 95% CI 0.35 – 0.92, p = 0.02). Sixty-eight patients have died. Actuarial median OS was 4.0 months (95% CI 2.2-6.5) in arm A versus 7.3 months (95%CI 3.9-12.6) in arm B (HR = 0.80, 95% CI 0.50-1.29, p = 0.35). Centrally reviewed LM-PFS, patient-reported outcomes (quality of life, functional, emotional status) over time will also be reported.
The addition of liposomal cytarabine to systemic therapy may improve LM-related PFS but does not significantly improve survival. Quality of life data will be essential to determine a possible clinical benefit afforded by intrathecal chemotherapy.
Clinical trial identification
Legal entity responsible for the study
Oscar Lambret Center, Lille, France.
E. Le Rhun: Research funding: Mundipharma; Honoraria for lecture: Mundipharma. M. Weller: Honoraria for lecture: Mundipharma. All other authors have declared no conflicts of interest.