High-dose intrathecal trastuzumab for leptomeningeal metastases secondary to HER-2 overexpressing breast cancer.

We are facing an increasing incidence of brain and leptomeningeal metastases (LM) during the history of patients with HER-2-overexpressing breast cancer. This clinical issue is due to the neurotropism of HER-2-overexpressing breast cancer cells, combined with the high antitumoral activity of systemic administrations of trastuzumab but without preventive effect in the brain and leptomeninges. Indeed, trastuzumab is a monoclonal IgG1 antibody to HER-2, which poorly reaches the cerebrospinal fluid (CSF) when given i.v. [1]. Intrathecal (IT) administration of trastuzumab has been scarcely tested [2–5] in patients with LM occurring after a systemic complete remission induced by i.v. trastuzumab (Table 1). Therefore, we eagerly need to accumulate experience on the use of IT trastuzumab in this setting. We report here the case of a patient with HER-2-overexpressing breast cancer who developed LM. We obtained a long-lasting control of the disease progression using high doses of IT trastuzumab. In April 2001, a 55-year-old patient was diagnosed with a breast cancer (T1N0M0, ER+). She was initially treated by surgery, radiotherapy and tamoxifen. Eighteen months later, she developed multiple liver metastases. The breast cancer was tested for HER-2 and was found positive (3+ by immunohistochemistry). She received docetaxel plus epirubicin, then paclitaxel plus trastuzumab and achieved a complete remission. One year later, headaches and ataxia revealed massive involvement of the brain by multiple metastases. A whole-brain irradiation allowed achieving a complete remission of the brain metastases. However, while under i.v. trastuzumab, 15 months after the liver remission and 9 months after the brain remission, she developed midback pain, cerebellar ataxia and headaches, leading to a clinical diagnosis of LM. Cerebral and spinal MRI scans revealed pericerebellar and cervical leptomeningeal foci, consistent with carcinomatous involvement. Initial CSF examination was normal, except for proteins of 0.68 g/l. Computed tomography scans confirmed that she had no recurrence of liver and brain metastases. The patient underwent daily oral corticosteroids and was informed of the poor prognosis for this condition. She refused a conventional treatment by IT high-dose methotrexate as described by Fizazi et al. [6]. Hence, after she gave her informed consent, she was administered weekly IT trastuzumab 20 mg (20 mg being the highest IT dose experienced in humans [2–5]) by lumbar puncture. The first administration was well tolerated and thereafter we carried out a dose escalation every week: 40 mg, then 100 mg weekly, for a total of six cycles of IT trastuzumab over 6 weeks (20 mg · 1, 40 mg · 1, 100 mg · 4). The patient experienced striking clinical neurological improvement, with complete disappearance of headaches and ataxia after 2 weeks of treatment. The changes in CSF are summarized in Table 2. It is noteworthy that the CSF proteins increased with repeated administrations. The cerebral magnetic resonance imaging (MRI) at 6 weeks showed a stable disease. However, 2 months later, the patient’s status worsened due to progression of brain metastases in previously irradiated areas, without evidence of meningeal disease progression. Despite high doses of i.v. corticosteroids, she finally developed intracranial hypertension and died of brain metastases 5 months later, 7 months from the diagnosis of LM. The use of IT IgG1 mAbs is supported by the knowledge that they poorly cross the blood–brain barrier when given i.v. [1, 7], making the CNS a sanctuary for cancer cells. To our knowledge, this case is the first report of a safe administration of IT trastuzumab at high doses (100 mg weekly). The major clinical improvement observed in our patient was not reflected by changes in CSF proteins, whereas MRI scans showed a stable disease. We assume that the discrepancy between clinical improvement and CSF proteins could be due to the accumulation of high doses of trastuzumab in the CSF. However, monitoring of trastuzumab CSF levels as described letters to the editor Annals of Oncology