Intra-CSF liposomal cytarabine plus systemic therapy as initial treatment of breast cancer leptomeningeal metastasis: A randomised, open-label trial

Abstract

Background: The role of intra‐cerebrospinal fluid (CSF) therapy for the treatment of leptomeningeal metastasis (LM) remains controversial. Methods: Weconducted a multicenter randomized open‐label study to explore the effect of the addition of liposomal cytarabine to systemic therapy for the treatment ofLMfrom breast cancer. Inclusion was based on the detection of tumor cells in the CSF or typical clinical andmagnetic resonance imaging (MRI) signs of LM. Patients were randomly assigned to receive systemic therapy alone (armA) or systemic therapy plus intra‐CSF liposomal cytarabine (5 injections of 50mg x 2 weeks, followed by monthly injections of 50 mg until progression, unacceptable toxicity or for 1 year) (armB).Neurological and quality of life evaluation was performed monthly, cerebrospinalMRI every 2months. 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 twosided alpha=5%. Overall survival (OS)was a secondary efficacy endpoint. Results: Thirty‐seven patientswere assigned to armA, 36 patients to armB. Baseline characteristics were similar in both arms. The median number of liposomal cytarabine injections in armB was 5 (range 1‐20). Focal radiotherapy was performed in 6 (16%) and 5 (14%) patients in arms A and B, respectively. Serious adverse eventswere 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 armA versus 4.3months (95%CI 2.3 ‐ 5.7) in armB (HR=0.57, 95% CI 0.35 ‐ 0.92, p=0.02). Sixty‐eight patients have died. ActuarialmedianOSwas 4.0 months (95%CI 2.2‐6.5) in armA versus 7.3months (95%CI 3.9‐12.6) in armB (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. Conclusions: 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.