Intra‐CSF topotecan in treatment of breast cancer patients with leptomeningeal metastases

Abstract

Background There are few treatment options for patients with leptomeningeal metastases (LM). Methods We report a case series of patients with breast cancer and LM treated with intra‐CSF topotecan (TOPO). Outcome was assessed by clinical exam and MRI at baseline, at end of induction (4‐5 weeks), then every 3 months; CSF cytology was determined at baseline and with each treatment. Results Thirty‐one women [median age, 58 (37‐81); median KPS 60 (40‐100)] received treatment. At baseline, 68% had positive CSF cytology, and 90%, leptomeningeal enhancement on MRI. 84% of patients also received focal RT (not during TOPO) and 77% received concomitant systemic hormonal or chemotherapy. Median number of TOPO treatments was 14.5 (range, 3‐71); median duration of treatment, 11 weeks (1‐176); and median OS, 6.9 months (range, 0.9‐48.8). Patients remaining progression‐free during 4‐6 weeks of induction (81%) had a median OS of 11.5 months (range, 1.8‐48.8). Overall neurologic PFS at 6, 12, and 24 months was 39%, 26%, and 6%, respectively. Clearing of CSF malignant cells for >3 consecutive samples occurred in 10/21 (48%) patients with positive CSF cytology at baseline, remaining clear for a median duration of 15.9 months (range, 1.4‐34.5). Grade 3 adverse events included headache or vomiting (3pts), T2 hyperintensity surrounding the ventricular catheter (2 pts), and meningitis (2 pts). Conclusions Intra‐CSF TOPO, with focal RT as needed for symptomatic areas of enhancement produced durable clearing of CSF malignant cells in 48% of patients positive at baseline, with promising median PFS and OS.

The Underlying Biology and Therapeutic Vulnerabilities of Leptomeningeal Metastases in Adult Solid Cancers

“…To date, a small number of clinical trials have been reported specifically studying systemic treatments for breast cancer, lung cancer, and melanoma LM [ 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 ], a small subset of which were randomized studies [ 71 , 72 , 73 , 75 , 89 , 90 ]. Several of these studies employ an intrathecal administration of chemotherapy, meaning that the agents are injected directly into the CSF.…”

Leptomeningeal Carcinomatosis from Solid Tumor Malignancies: Treatment Strategies and Biomarkers

“…Commonly used agents include methotrexate, thiotepa (an alkylating agent) and cytarabine (a pyrimidine analog), 4,25,27,37,41 trastuzumab (an anti-HER2 therapy), and topotecan (a topoisomerase I inhibitor). 37,42 There is also an ongoing trial examining the use of a novel IT iron-chelation treatment for patients with LMD (NCT05184816). Given the promise of ICIs for systemic disease control, there is obvious interest in IT therapy for LMD.…”

Novel approaches to treatment of leptomeningeal metastases

“…Intraventricular delivery has been shown to result in better clinical outcomes [69], especially in chemoagents with shorter half-life [70] along with potential improved patient comfort and compliance. The most commonly given intrathecal agents include MTX (often dosed 10-15 mg) or cytarabine (50-75 mg), thiopeta (10 mg) or topotecan often given twice weekly for 3-5 weeks [71][72][73]. Combination therapies including with MTX and thiopeta as well as MTX and cytarabine have not shown improved outcomes [71,74]…”

“…The most commonly given intrathecal agents include MTX (often dosed 10–15 mg) or cytarabine (50–75 mg), thiopeta (10 mg) or topotecan often given twice weekly for 3–5 weeks [71–73]. Combination therapies including with MTX and thiopeta as well as MTX and cytarabine have not shown improved outcomes [71,74]…”