Neoplastic meningitis (spinnal mets)

[Rich66]

Extensive 9/27/2010 overview of brain/CNS mets treatments from Breast Cancer Watch:
http://bcwatchdigest-brain.evidencewatch.com/




Cancer Chemother Pharmacol. 2010 Jan 28. [Epub ahead of print]
Plasma and cerebrospinal fluid pharmacokinetics of topotecan in a phase I trial of topotecan, tamoxifen, and carboplatin, in the treatment of recurrent or refractory brain or spinal cord tumors.

Morgan RJ, Synold T, Mamelak A, Lim D, Al-Kadhimi Z, Twardowski P, Leong L, Chow W, Margolin K, Shibata S, Somlo G, Yen Y, Frankel P, Doroshow JH.
Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, 1500 E. Duarte Rd., Duarte, CA, 91010, USA, rmorgan@coh.org.
PURPOSE: This study was designed to ascertain the dose-limiting toxicities (DLT) and maximally tolerated doses of the combination of fixed-dose tamoxifen and carboplatin, with escalating doses of topotecan, and to determine the pharmacokinetics of topotecan in the plasma and cerebrospinal fluid. METHODS: Tamoxifen 100 mg po bid, topotecan 0.25, 0.5, 0.75, or 1.0 mg/m(2)/d IV, administered as a 72 h continuous infusion on days 1-3, followed by carboplatin AUC = 3, IV on day 3. Cycles were repeated every 4 weeks. RESULTS: Seventeen patients received 39 cycles of treatment: median 2, (range 1-5). The tumors included glioblastoma (6), anaplastic astrocytoma (2), metastatic non-small cell (3), small cell lung (2), and one each with medulloblastoma, ependymoma, and metastatic breast or colon carcinoma. The median Karnofsky performance status was 70% (range 60-90%) and age: 52 (range 24-75). Eleven patients were female and six male. Toxicities included thrombocytopenia (2), neutropenia without fever lasting 6 days (1), DVT (2), and emesis (1). Topotecan levels, total and lactone, were measured prior to the end of infusion in plasma and cerebrospinal fluid (CSF). At 1.0 mg/m(2)/d, the median CSF/plasma ratio was 19.4% (range 15.1-59.1%). The total plasma topotecan in two pts with DLTs was 4.63 and 5.87 ng/ml, in three without DLTs at the same dose level the mean total plasma topotecan was 3.4 ng/ml (range 3.02-3.83). Plasma lactone levels were 33% of the total; CSF penetration was 20% of the total plasma levels. 4/8 pts with high-grade gliomas had stable disease (median: 3 cycles (range 2-5)). Two had minor responses. One patient with metastatic non-small cell and one with small cell lung cancer had objective PRs. CONCLUSIONS: The recommended phase II doses are: tamoxifen 100 mg po bid, topotecan 0.75 mg/m(2)/d IV continuous infusion for 72 h, followed by carboplatin AUC = 3 IV on day 3. Measurable topotecan levels, both total and lactone, are observed in the CSF.

PMID: 20107803 [PubMed - as supplied by publisher]




Breast Cancer. 2009;16(1):88-92. Epub 2008 May 14.
Successful treatment of leptomeningeal metastases from breast cancer using the combination of trastuzumab and capecitabine: a case report.

Shigekawa T, Takeuchi H, Misumi M, Matsuura K, Sano H, Fujiuchi N, Okubo K, Osaki A, Aogi K, Saeki T.
Department of Breast Oncology, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan. takshige@saitama-med.ac.jp
We report a case of metastatic breast cancer with leptomeninges and multiple bone metastases that showed an excellent response to the combination of trastuzumab and capecitabine; therapeutic effect was evaluated by MRI at follow-up. A 44-year-old woman underwent modified radical mastectomy in February 1997. In April 2003, a tumor at the right basis cerebri and multiple bone metastases were noted, and in October 2003, she underwent enucleation of the tumor. Histopathologically, the tumor was consistent with a basal skull metastasis from breast cancer. In March 2004, the patient began to experience pain, weakness, and paresthesia of both legs. She was diagnosed, with leptomeningeal metastasis (LM) from breast cancer using MRI. In December 2005, the combination of trastuzumab and capecitabine administered as sixth-line treatment was very effective for LM. Although it is generally very difficult to diagnose LM and assess the therapeutic effect with MRI, in this case, it was possible. To our knowledge, there has been no report in the literature describing the combination of trastuzumab and capecitabine for LM from breast cancer. Although the mechanism underlying the efficacy of this combination is still unknown, the treatment would be worth trying because of its few side effects in extensively treated patients with LM from breast cancer. To confirm the antitumor efficacy of trastuzumab and capecitabine, however, further investigations are required.

PMID: 18478315 [PubMed - indexed for MEDLINE]




Int J Radiat Biol. 2008 Dec;84(12):1123-9.
First human treatment of resistant neoplastic meningitis by intrathecal administration of MTX plus (125)IUdR.

Rebischung C, Hoffmann D, Stefani L, Desruet MD, Wang K, Adelstein SJ, Artignan X, Vincent F, Gauchez AS, Zhang H, Fagret D, Vuillez J, Kassis AI, Balosso J.
Department of Oncology, CHU de Grenoble, Grenoble cedex 9, France.
PURPOSE: Neoplastic meningitis is often the final outcome of disseminated cancer and is rapidly lethal. Its limited treatment relies on systemic or intrathecal chemotherapy with methotrexate (MTX) or thiotepa. When 5-iodo-2'-deoxyuridine labeled with (125)I ((125)IUdR) is incorporated into the DNA of mitotic tumor cells, the Auger electrons emitted during iodine decay are highly cytotoxic. The radiotherapeutic efficacy of (125)IUdR administered intrathecally has also been established in animals bearing spinal cord tumors, and MTX is known to potentiate the response. This approach has not been tested in the clinic. METHODS: A 44-year-old woman, with locally advanced pancreatic cancer, was treated for three years with complete systemic remission, but then relapsed with cytologically proven neoplastic meningitis. The patient was given four successive intrathecal injections of MTX (10 mg) every 12 h and, with the fourth dose, 1850 MBq (125)IUdR, followed by four additional MTX doses. The response was monitored by cytology and CA19.9 (carbohydrate antigen 19.9) levels in the cerebrospinal fluid (CSF) as well as by clinical status of the patient. RESULTS: The follow-up of cytology and CA19.9 levels in the CSF showed dramatic improvement within 26 days followed by a biological relapse on Day +36. There was no evidence of local central nervous system toxicity. Three months later, neoplastic meningitis recurred and meningeal tumor infiltration was observed on magnetic resonance imaging. Six months after MTX-(125)IUdR treatment, the patient died. CONCLUSION: (125)IUdR treatment proved to be feasible without acute neurological toxicity and seemed to have produced a biological response. This attempt provides the basis for designing prospective clinical trials.

PMID: 19061137 [PubMed - indexed for MEDLINE]




Anticancer Res. 2009 Dec;29(12):5191-5195.
Neoplastic Meningitis from Breast Cancer: Feasibility and Activity of Long-term Intrathecal Liposomal Ara-C Combined with Dose-dense Temozolomide.
Hoffmann AL, Buhk JH, Strik H.

Department of Neurology, University of Marburg, Rudolf Bultmann Str. 8, D-35039 Marburg, Germany. strik@med.uni-marburg.de.
BACKGROUND: Patients with neoplastic meningitis (NM) from breast cancer have a median survival of 4-8 months with specific treatment. Here, good tolerance and long-term stabilization with combined intrathecal liposomal cytarabine (Ara-C), which is probably the most promising drug for intrathecal chemotherapy to date, near-continuous temozolomide and radiotherapy is reported in two patients with leptomeningeal and solid central nervous system (CNS) metastases from breast cancer. Case Reports: A 42- and a 43-year-old female presented with NM and disseminated CNS metastases from human epidermal growth factor receptor type 2 (Her2)-positive breast cancer. After irradiation of the symptomatic sites, intrathecal liposomal Ara-C every 2-4 weeks was combined with temozolomide 100 mg/m(2) day 1-5/7. Cerebrospinal fluid (CSF) cytology and neurological symptoms improved in both patients and stabilized for several months. The patients survived 10 and 17 months after diagnosis of NM, without signs of neurological toxicity. CONCLUSION: Intensive treatment is complicated by extensive pre-treatment and the lack of active CNS-penetrating systemic drugs. The long-term results with up to 17 intrathecal injections of liposomal Ara-C show that this treatment regimen is feasible and well-tolerated. The stabilization of both patients indicates activity of this combined intrathecal and systemic regimen that is based on long-term exposure of the tumour cells to both Ara-C and temozolomide. The results need to be confirmed prospectively.

PMID: 20044635



J Neurooncol. 2010 Jun 20. [Epub ahead of print]
Prolonged survival of neoplastic meningitis from breast cancer with letrozole and intrathecal methotrexate: a case report.

Peroukides S, Onyenadum A, Starakis I, Koutras A, Makatsoris T, Bouboukas G, Kalofonos H.
Department of Medical Oncology, School of Medicine, University of Patras, 26504 Rio, Patras, Greece, panio@upatras.gr.



Abstract

Neoplastic meningitis from breast cancer has a dismal prognosis and short survival. Treatment is based on the intrathecal administration of chemotherapeutic agents, cranial or craniospinal radiotherapy, and systemic chemotherapy. In this report we describe the case of a woman with neoplastic meningitis from breast carcinoma who developed an excellent response to letrozole combined with intrathecal methotrexate, resulting in long-term survival of more than 36 months. Based on the findings of this case report, we suggest that addition of letrozole to the standard therapeutic approach may be beneficial for some patients.

PMID: 20563832 [PubMed - as supplied by publisher]




Artemisinin is thought to penetrate the CNS and may work: LINK to thread


Strahlenther Onkol. 2010 Feb;186(2):63-69. Epub 2010 Jan 26.
DEGRO Practical Guidelines for Palliative Radiotherapy of Breast Cancer Patients: Brain Metastases and Leptomeningeal Carcinomatosis.

Feyer P, Sautter-Bihl ML, Budach W, Dunst J, Haase W, Harms W, Sedlmayer F, Souchon R, Wenz F, Sauer R.
Klinikum Neukölln, Berlin, Germany, petra.feyer@vivantes.de.
PURPOSE: : To provide recommendations for palliative treatment of brain metastases (BM) and leptomeningeal carcinomatosis (LC) in breast cancer patients with specific emphasis on radiooncologic aspects. METHODS: : The breast cancer expert panel of the German Society of Radiation Oncology (DEGRO) performed a comprehensive survey of the literature comprising national and international guidelines, lately published randomized trials, and relevant retrospective analyses. The search included publications between 1995-2008 (PubMed and Guidelines International Network [G-I-N]). Recommendations were devised according to the panel's interpretation of the evidence referring to the criteria of EBM. RESULTS: : Aim of any treatment of BM and LC is to alleviate symptoms and improve neurologic deficits. Close interdisciplinary cooperation facilitates rapid diagnosis and onset of therapy, tailored to the individual and clinical situation. Treatment decisions for BM should be based on the allocation to three prognostic groups defined by recursive partitioning analysis (RPA). Karnofsky Performance Score (KPS) is the strongest prognostic parameter. Together with the extent of the disease, KPS determines whether excision or radiosurgery/stereotactic radiotherapy is feasible and if exclusive or additional whole-brain radiotherapy (WBRT) is indicated. With adequate therapy, survival may be up to 3 years. For LC, treatment is mostly indicated for patients with positive cytology or in case of strongly indicative signs and symptoms. Radiotherapy (WBRT 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. CONCLUSION: : Radiotherapy is an effective tool for palliative treatment of BM and LC.

PMID: 20127222 [PubMed - as supplied by publisher]


J Cereb Blood Flow Metab. 2010 Mar 10. [Epub ahead of print]
17-beta-Estradiol: a powerful modulator of blood-brain barrier BCRP activity.

Hartz AM, Mahringer A, Miller DS, Bauer B.
Department of Biochemistry and Molecular Biology, Medical School, University of Minnesota, Duluth, Minnesota, USA.
The ATP-driven efflux transporter, breast cancer resistance protein (BCRP), handles many therapeutic drugs, including chemotherapeutics, limiting their ability to cross the blood-brain barrier. This study provides new insight into rapid, nongenomic regulation of BCRP transport activity at the blood-brain barrier. Using isolated brain capillaries from rats and mice as an ex vivo blood-brain barrier model, we show that BCRP protein is highly expressed in brain capillary membranes and functionally active in intact capillaries. We show that nanomolar concentrations of 17-beta-estradiol (E2) rapidly reduced BCRP transport activity in the brain capillaries. This E2-mediated effect occurred within minutes and did not involve transcription, translation, or proteasomal degradation, indicating a nongenomic mechanism. Removing E2 after 1 h fully reversed the loss of BCRP activity. Experiments using agonists and antagonists for estrogen receptor (ER)alpha and ERbeta and brain capillaries from ERalpha and ERbeta knockout mice demonstrated that E2 could signal through either receptor to reduce BCRP transport function. We speculate that this nongenomic E2-signaling pathway could potentially be used for targeting BCRP at the blood-brain barrier, in brain tumors, and in brain tumor stem cells to improve chemotherapy of the central nervous system.

Journal of Cerebral Blood Flow & Metabolism advance online publication, 10 March 2010; doi:10.1038/jcbfm.2010.36.

PMID: 20216549 [PubMed - as supplied by publisher]