Application of intrathecal trastuzumab (Herceptin™) for treatment of meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer

Abstract

Leptomeningeal carcinomatosis represents a rare manifestation of metastatic breast cancer (MBC). A 39-yearold female presenting with HER2-overexpressing MBC and suffering from meningeal carcinomatosis was treated with the humanized antibody trastuzumab directed to HER2 by intrathecal administration. The patient was diagnosed with HER2-overexpressing stage III breast cancer in December 2003. In August 2004, the patient developed a singular intracerebral metastasis which was resected by neurosurgery followed by whole-brain radiotherapy. Since MRI and cerebrospinal fluid (CSF) analyses indicated meningeal carcinomatosis, the patient was commenced on trastuzumab (6 mg/kg q3w) and capecitabine (2.500 mg/m 2 d1-14, q3w). Prompted by clinical deterioration, 5 repeated doses of intrathecal methotrexate (15 mg/dose) were administered, yet without clinical improvement. There is initial evidence that trastuzumab does not reach an adequate concentration in CSF after intravenous application. Nevertheless, infiltration of trastuzumab into CSF is facilitated under conditions of an impaired blood-brain barrier, as it is known for meningeal carcinomatosis. For patients with leptomeningeal disease, intrathecal application of trastuzumab may provide an interesting therapeutical approach for patients with HER2 overexpressing metastatic breast cancer. Therefore, an Ommaya reservoir for intrathecal treatment with trastuzumab was placed surgically and intrathecal therapy was begun with escalating doses of trastuzumab (5-20 mg), which proved to be effective and well tolerated by the patient. Within 2 weeks after treatment, the patients' condition improved significantly and cell counts in CSF obtained from the Ommaya reservoir remained low for 11 months after first diagnosis of meningeal carcinomatosis when clinical symptoms and MRI indicated progression of meningeal and cerebral disease.

Complete response in HER2+ leptomeningeal carcinomatosis from breast cancer with intrathecal trastuzumab

“…No clear clinical benefit could be documented, but there were no side effects other than mild local ventricle inflammation at autopsy [10]. This led others to administer IT trastuzumab [11][12][13][14][15][16][17]. Most patients experienced symptoms improvement and no adverse neurological effects.…”

“…No consensus exists on the adequate dosing and frequency of IT trastuzumab, ranging from 5mg [10,17] to 100mg [14] dosing in a weekly [10,[13][14][15][16][17] to every three weeks [11,13] schedule, with 25mg…”

Clinical features of patients with carcinomatous meningitis in the chinese population: report of 4 cases and review of literature

“…Recent evidence suggests that CM originating from lung cancer could be treated with gefitinib (25,10,7,18) and high-dose erlotinib (19) One study also suggested that trastuzumab may benefit some CM patients who had breast cancer (11). Recently, several authors reported successful treatment of meningeal carcinomatosis by intrathecal trastuzumab (17,22,26). Some studies indicate that radiotherapy (whole brain and involved-field irradiation of bulky spinal lesions) and chemotherapy (systemically or intrathecally applied methotrexate, thiotepa, and cytarabine) are both effective and may prolong survival from several weeks to 4-6 months in patients with CM (8, 4).…”

Role of Intrathecal Rituximab and Trastuzumab in the Management of Leptomeningeal Carcinomatosis

“…14,17 The duration of disease control from the initiation of intrathecal trastuzumab ranged from 39 days to greater than 72 months, with 6 patients surviving greater than 5 months. [12][13][14][15][16][17] Interestingly, the patient who died at day 39 of intrathecal trastuzumab treatment died due to progression of visceral metastases and was considered to be in remission with regard to the leptomeningeal carcinomatosis. 10 Tumor cell counts were also found to be eliminated or substantially decreased in 4 of 5 patients.…”

“…Doses of trastuzumab ranged from 5 to 100 mg and were repeated after as little as 3 days in 1 report to as long as 3 weeks in others. 10,[12][13][14] The most common schedule was 20-30 mg weekly. All doses, including doses up to 100 mg, and schedules were well tolerated.…”