Role of intrathecal rituximab and trastuzumab in the management of leptomeningeal carcinomatosis

Abstract

Objective: To review evidence for the use of intrathecal rituximab and trastuzumab in the management of leptomeningeal carcinomatosis.

Data sources: A search of MEDLINE (1966-July 2010) and International Pharmaceutical Abstracts (1970-July 2010) was performed using search terms intrathecal, trastuzumab, rituximab, and monoclonal antibody. Additionally, American Society of Clinical Oncology, San Antonio Breast Conference, American Association for Cancer Research, and American Society of Hematology meeting abstracts were searched.

Study selection and data extraction: Publications were reviewed for inclusion. Those reporting use of rituximab and trastuzumab intrathecally are reviewed and include 1 Phase 1 trial, 2 small prospective studies, 1 case series, and 15 case reports.

Data synthesis: The treatment of leptomeningeal carcinomatosis is challenging due to the presence of the blood-brain barrier. Numerous systemically administered therapies do not readily penetrate into the site of leptomeningeal disease and have been ineffective. Intrathecal administration of 2 monoclonal antibodies (trastuzumab and rituximab) has been investigated in case reports and case series. Additionally, intrathecal rituximab has been investigated in a Phase 1 study. Survival after intrathecal trastuzumab ranged from 39 days to greater than 72 months and the drug was well tolerated, with no adverse events attributed to it. Doses used in these reports ranged from 5 to 100 mg. Survival after intrathecal rituximab ranged from 1.1 weeks to greater than 3.5 years. In the Phase 1 trial, the maximum tolerated rituximab dose was 25 mg and 60% of patients responded. Four of the 6 responding patients experienced a complete response. Intrathecal rituximab exhibited minor toxicities that resolved quickly without long-term effects.

Conclusions: Reports suggest that both trastuzumab and rituximab may be utilized intrathecally. Patients with refractory leptomeningeal carcinomatosis may benefit from a trial of intrathecal trastuzumab or rituximab; however, their use remains investigational, as more data and experience are necessary before intrathecal administration can be considered standard.