Intrathecal liposomal cytarabine plus systemic therapy versus systemic chemotherapy alone for newly diagnosed leptomeningeal metastasis from breast cancer

Abstract

Background: DEPOSEIN (NCT01645839) was a randomized open-label phase III study to explore the role of intrathecal chemotherapy in patients with newly diagnosed leptomeningeal metastasis (LM), a common manifestation of breast cancer.

Methods: Patients with newly diagnosed LM defined by tumor cells in the cerebrospinal fluid or combination of clinical and neuroimaging signs of LM were randomized to receive systemic therapy alone (control group) or systemic therapy plus intrathecal liposomal cytarabine (experimental group). Progression-free survival related to LM (LM-PFS) was the primary endpoint.

Results: Thirty-seven and 36 patients were assigned to the control and the experimental groups. Median number of liposomal cytarabine injections in the experimental group was 5 (range 1-20). Focal radiotherapy was performed in 6 (16%) and 3 (8%) patients in the control and experimental groups. In the intent-to-treat population, median LM-PFS was 2.2 months (95% CI: 1.3-3.1) in the control versus 3.8 months (95% CI: 2.3-6.8) in the experimental group (hazard ratio 0.61, 95% CI: 0.38-0.98) (P = 0.04). Seventy-one patients have died. Median overall survival was 4.0 months (95% CI: 2.2-6.3) in the control versus 7.3 months (95% CI: 3.9-9.6) in the experimental group (hazard ratio 0.85, 95% CI: 0.53-1.36) (P = 0.51). Serious adverse events were reported in 22 and 30 patients, respectively. Quality of life until progression did not differ between groups.

Conclusion: The addition of intrathecal liposomal cytarabine to systemic treatment improves LM-related PFS. Confirmatory trials with optimized patient selection criteria and more active drugs may be required to demonstrate a survival benefit from intrathecal pharmacotherapy.

Keywords: brain; cerebrospinal; depocyte; meningitis; neoplastic.

© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Fig. 1

CONSORT chart for the DEPOSEIN trial. For the per protocol analysis, we excluded 6 patients: 2 patients in the control group who did not receive treatment as planned in the protocol; 4 patients in the experimental group, 1 because she was included although not matching the eligibility criteria and 3 because they did not receive treatment as planned per protocol.

Fig. 2

Progression-free survival related to leptomeningeal disease (LM-PFS) (A), overall PFS (B) and OS (C) in the ITT population

Fig. 2

Progression-free survival related to leptomeningeal disease (LM-PFS) (A), overall PFS (B) and OS (C) in the ITT population

Fig. 2

Progression-free survival related to leptomeningeal disease (LM-PFS) (A), overall PFS (B) and OS (C) in the ITT population

Fig. 3

Butterfly plot of adverse events (related or not) in the 2 groups by system organ class. The panel on the left is a butterfly plot showing the proportion of patients experiencing an adverse event coded as related or not to the study treatment, whatever the grade (light blue for control group and yellow for experimental group), and a severe adverse event, grade ≥3 (dark blue for control group and orange for experimental group) according to group of randomization. The panel on the right displays the relative risk of a severe adverse event in patients in the experimental group relative to patients in the control group, with 95% CI. The toxicity items were pooled by system organ class. Details of adverse events are given in Supplementary Table 13.