Annals of Oncology Advance Access published online on October 9, 2008
Annals of Oncology, doi:10.1093/annonc/mdn654
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letter to the editor |
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.
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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 x 1, 40 mg x 1, 100 mg x 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.
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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 by Stemmler et al. [5] were not available at this time, and we were not able to confirm this hypothesis. Another explanation could be a direct role of oral corticoids, although we consider this hypothesis less likely given the prolonged clinical improvement observed in this case.
Finally, the patient experienced progression of the brain metastases and died 7 months from the diagnosis of LM. However, the duration of disease control from the diagnosis of LM compares favorably with the median survival reported in the literature, ranging from 7 to 17 weeks [6]. Hence, given the potential efficacy of IT trastuzumab on the leptomeningeal disease, we would suggest to undergo a concomitant systemic treatment targeting brain metastases, such as high-dose methotrexate, since the brain parenchyma is poorly targeted by IT drugs. Noteworthy, our patient was administered IT trastuzumab by lumbar puncture instead of using an Ommaya reservoir, as previously reported [2–5]. Even though the administration of IT drugs via an Ommaya reservoir was demonstrated to be a valuable option in patients with LM [8], data comparing lumbar puncture versus Ommaya reservoir in breast cancer-related LM are not available to date.
Recent data [7] documented the safety and a potential benefit from IT administration of rituximab (an IgG1 mAb to CD20) in patients with CNS lymphoproliferative disorders. To date, data on the activity of IT trastuzumab are limited and contradictory (Table 1), and a phase I study seems warranted in this setting. Lapatinib, a tyrosine-kinase inhibitor that targets HER-2, displays clinical activity against brain metastases from HER-2-overexpressing breast cancer [9] and could therefore be considered as a valuable concomitant therapeutic option in an attempt to prevent the development of neurological disease in this subset of patients.
Université Paris Descartes, Faculté de Médecine, Assistance Publique–Hôpitaux de Paris, Department of Medical Oncology, Teaching Hospital Cochin, Paris, France
* (E-mail: olivier.mir{at}cch.aphp.fr)
Acknowledgements
The authors declare no conflicts of interest.
References
1. Stemmler HJ, Schmitt M, Willems A, et al. Ratio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2-positive breast cancer patients with brain metastases and impairment of blood-brain barrier. Anticancer Drugs (2007) 18:23–28.[CrossRef][Medline]
2. Platini C, Long J, Walter S. Meningeal carcinomatosis from breast cancer treated with intrathecal trastuzumab. Lancet Oncol (2006) 7:778–780.[CrossRef][Web of Science][Medline]
3. Stemmler HJ, Schmitt M, Harbeck N, et al. Application of intrathecal trastuzumab (Herceptin) for treatment of meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer. Oncol Rep (2006) 15:1373–1377.[Web of Science][Medline]
4. Laufman LR, Forsthoefel KF. Use of intrathecal trastuzumab in a patient with carcinomatous meningitis. Clin Breast Cancer (2001) 2:235.[Medline]
5. Stemmler HJ, Mengele K, Schmitt M, et al. Intrathecal trastuzumab (Herceptin) and methotrexate for meningeal carcinomatosis in HER-2 overexpressing metastatic breast cancer: a case report. Anticancer Drugs (2008) 19:832–36.[CrossRef][Medline]
6. Fizazi K, Asselain B, Vincent-Salomon A, et al. Meningeal carcinomatosis in patients with breast carcinoma. Clinical features, prognostic factors, and results of a high-dose intrathecal methotrexate regimen. Cancer (1996) 77:1315–1323.[CrossRef][Web of Science][Medline]
7. Rubenstein JL, Fridlyand J, Abrey L, et al. Phase I study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma. J Clin Oncol (2007) 25:1350–1356.
8. Ommaya AK. Implantable devices for chronic access and drug delivery to the central nervous system. Cancer Drug Deliv (1984) 1:169–179.[Web of Science][Medline]
9. Chang JE, Robins HI, Mehta MP. Therapeutic advances in the treatment of brain metastases. Clin Adv Hematol Oncol (2007) 5:54–64.[Medline]
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