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Lani · 08-23-2009, 01:11 PM

pArt two of pubmed search:

Anticancer Drugs. 2008 Sep;19(8):832-6.

Intrathecal trastuzumab (Herceptin) and methotrexate for meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer: a case report.

Stemmler HJ, Mengele K, Schmitt M, Harbeck N, Laessig D, Herrmann KA, Schaffer P, Heinemann V.
Medical Department III, Ludwig-Maximilians-University of Munich, Klinikum Grosshadern, Munich, Germany. Joachim.Stemmler@med.uni-muenchen.de
Leptomeningeal carcinomatosis represents a rare manifestation of metastatic breast cancer (MBC). We herewith report on a patient suffering from HER2 overexpressing MBC who received intrathecal methotrexate and trastuzumab for meningeal carcinomatosis. A 48-year-old woman was diagnosed with breast cancer in December 2002. Following surgery, six cycles of adjuvant FE100C plus irradiation and, subsequently for 1 year, trastuzumab were given. As a result of disseminated metastatic spread in October 2005, the patient received whole-brain radiotherapy for symptomatic central nervous system involvement, and was put on several trastuzumab-based combination regimens (capecitabine, vinorelbine, paclitaxel). In June 2006, the patient developed clinical signs of terminal cone involvement with overflow incontinence and paraparesis of the legs. Immediate radiation led to partial relief from clinical symptoms. Subsequently, the patient was put on the tyrosine kinase inhibitor lapatinib and capecitabine (August to October 2007), but on November 6th the patient suffered again from overflow incontinence and weakness of the legs. Failing to respond to lapatinib, the patient received gemcitabine/cisplatin and, additionally, was recommenced on intravenous trastuzumab. Owing to progressive leptomeningeal disease, the patient received repeated doses of intrathecal methotrexate and trastuzumab. Within 2 weeks and four intrathecal treatments, cerebrospinal fluid cytology showed the absence of tumor cells. Moreover, a striking clinical improvement with resolution of the paraparesis of the legs and overflow incontinence was observed. This case report gives details regarding the clinical course of a breast cancer patient who received intrathecal trastuzumab and methotrexate via lumbar puncture for meningeal carcinomatosis of HER2-overexpressing MBC.
PMID: 18690096 [PubMed - indexed for MEDLINE]
Liposomal cytarabine given concomitantly with radiotherapy in a patient with leptomeningeal metastasis from breast cancer
Journal Journal of Neurology
Publisher Steinkopff
ISSN 0340-5354 (Print) 1432-1459 (Online)
Issue Volume 255, Number 11 / November, 2008
Category Letter to the Editors
DOI 10.1007/s00415-008-0014-8
Pages 1838-1839
Subject Collection Medicine
SpringerLink Date Saturday, July 26, 2008

M. Glas1 , M. Stuplich1, H. Tschampa2, H. Urbach2, K. Rasch1 and U. Herrlinger1

(1) Clinical Neurooncology Unit, Dept. of Neurology, University of Bonn, Medical Center, Bonn, Germany
(2) Dept. of Radiology, University of Bonn, Medical Center, Bonn, Germany
Published online: 25 July 2008

M. Glas
Email: martin.glas@ukb.uni-bonn.de
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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]

J Neurooncol. 2007 Nov;85(2):223-7. Epub 2007 Jul 5. Links

Capecitabine therapy of central nervous system metastases from breast cancer.

Ekenel M, Hormigo AM, Peak S, Deangelis LM, Abrey LE.
Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA. ekenelm@mskcc.org
Central nervous system (CNS) metastases from breast cancer carry a poor prognosis. Systemic chemotherapy is often ineffective due to the impermeability of the blood-brain barrier (BBB) and inherent chemoresistance of CNS metastases. There are limited data supporting the use of capecitabine in this setting. Medical records of seven patients with brain metastases from breast cancer who received capecitabine treatment at Memorial Sloan-Kettering Cancer Center from 1994-2006 were reviewed. Treatment outcomes were analyzed retrospectively in those patients. Median time from breast cancer diagnosis to the development of CNS metastasis was 48 (18-165) months. Four patients had brain metastases alone, two patients had both leptomeningeal and brain metastases and one patient had leptomeningeal metastasis alone. Five out of seven patients had failed other treatment modalities before capecitabine. Three patients showed complete response (CR) and three patients had stable disease (SD) after capecitabine. The patient with leptomeningeal disease improved clinically, but refused repeat cerebrospinal fluid (CSF) studies. Median overall and progression-free survival from initiation of capecitabine was 13 and 8 months, respectively, for all patients. Capecitabine may achieve a CR and provide long-term control in patients with both leptomeningeal and parenchymal CNS metastases from breast cancer.
PMID: 17611719 [PubMed - indexed for M

: Curr Treat Options Neurol. 2007 Jul;9(4):283-293. Links

Leptomeningeal Neoplasms.

Drappatz J, Batchelor TT.
Jan Drappatz, MD Harvard Medical School, Department of Neurology, Brigham and Women’s Hospital and Dana-Farber/Brigham and Women’s Cancer Center, Center for Neuro-Oncology, 44 Binney Street SW 430, Boston, MA 02115, USA. jdrappatz@partners.org.
Leptomeningeal metastasis is becoming an increasingly important late complication of cancer as survival from systemic disease increases, and due to the fact that many novel cancer drugs fail to achieve therapeutic concentrations in the central nervous system. It occurs when neoplastic cells enter cerebrospinal fluid (CSF) pathways, causing diffuse infiltration of the subarachnoid space of the brain and spinal cord. Definitive diagnosis is established by the demonstration of malignant cells in the CSF. However, in certain circumstances the presence of leptomeningeal enhancement on brain or spinal MRI may be sufficient to make the diagnosis. Early diagnosis and aggressive treatment may delay neurologic progression and can lead to prolonged survival and improvement of neurologic function in certain patients. The prognosis depends on the underlying malignancy but is often poor, with a median survival of 4 months, and most treatment interventions are palliative. Nevertheless, some patients respond to treatment, and some survive beyond 1 or 2 years after diagnosis. Areas of radiographic bulky disease or symptomatic tumor should receive radiotherapy. Intrathecal chemotherapy is most effective in patients with lymphoma, leukemia, or breast cancer and without evidence of bulky disease on neuroimaging. Intrathecal chemotherapy requires normal CSF flow, and the most commonly used agents are methotrexate, cytarabine, and thiotepa. In lieu of intrathecal therapy, systemic chemotherapy may occasionally be indicated in select patients in part based on its ability to penetrate into bulky disease. When hydrocephalus occurs, ventriculoperitoneal shunting frequently leads to rapid clinical improvement. There is hope that progress in diagnostic modalities and the development of more effective intrathecal antineoplastic drugs may decrease neurologic morbidity and improve quality of life and survival.
PMID: 17580008 [PubMed - as supplied by publisher]

J Neurooncol. 2007 Aug;84(1):57-62. Epub 2007 Feb 20

Breast cancer leptomeningeal metastasis--the role of multimodality treatment.

Rudnicka H, Niwińska A, Murawska M.
Department of Breast Cancer, Maria Sklodowska Curie Memorial Cancer Center and Institute of Oncology, Roentgen 5 str., 02-781, Warsaw, Poland.
AIM: The aim of the study was to assess the efficacy of multimodality treatment of patients with Leptomeningeal metastasis (LM) and to establish which method of treatment has the greatest positive impact on survival. MATERIAL AND METHODS: Clinical material included 67 consecutive breast cancer patients with LM treated at the Cancer Center in Warsaw between the years 2000 and 2005. Intrathecal chemotherapy was given to 57 pts (85%), intravenous chemotherapy to 41 pts (61%), whole brain radiotherapy to 33 pts (49%) and radiotherapy to the spinal leptomeninges to 10 (15%). For 27 pts (40%) three methods of treatment were used. Univariate and multivariate analyses were used to evaluate the impact of the particular method of treatment on survival and to assess the efficacy of combined modalities. RESULTS: Clinical response was achieved in 49 pts (76%). Median survival calculated from the diagnosis of LM was 16 weeks (range 1-402 weeks). Univariate analysis showed positive impact of systemic intravenous chemotherapy (P = 0.0009), intrathecal chemotherapy (P = 0.008) and whole brain radiotherapy (P = 0.004) on survival. The results of Cox multivariate analysis have shown systemic chemotherapy (P < 0.001) and intrathecal chemotherapy (P = 0.001) to be significant. CONCLUSIONS: Intravenous chemotherapy and, independently, intrathecal chemotherapy improve survival in breast cancer patients with LM. Radiotherapy has a positive impact on the quality of life due to the alleviation of neurological symptoms. The role of radiotherapy in prolonging survival is questionable.
PMID: 17310266 [PubMed - indexed for MEDLINE]

Annals of Oncology 2007 18(1):199-200; doi:10.1093/annonc/mdl290

letters to the editor

Concurrent radiotherapy and capecitabine, followed by high-dose methotrexate consolidation, provided effective palliation in a patient with leptomeningeal metastases from breast cancer

A Carmona-Bayonas*
Medical Oncology and Haematology Department, Hospital Morales Meseguer, Murcia, Spain

* (E-mail: trebla_albert@hotmail.com)

We report the case of a 38-year-old patient, diagnosed with AJCC stage III-A breast cancer (T3N2MO; Estrogen and progesterone receptor negative, her2/neu-negative). She underwent right mastectomy and axillary node dissection. After surgery, she received adjuvant chemotherapy with TAC doxorubicin/docetaxel/cyclophosphamide for six courses.

She was admitted to our hospital while local radiotherapy was being carried out, because of excruciating headache and vomits. Continuous i.v. morphine at a dose of 1000 mg/day was required to achieve pain control. There was not any cranial nerve involvement, and she had an Eastern Cooperative Oncology Group performance status of 1.

Magnetic resonance and cerebrospinal fluid (CSF) cytology revealed leptomeningeal metastases. Twice daily capecitabine (850 m/m2) and whole-brain radiotherapy (30 Gy) were initiated. She also received five doses of twice weekly intrathecal methotrexate and cytarabine, with cytological improvement. During the first 2 weeks, meningeal irritation intensified as a result of intrathecal chemotherapy. From that moment, quality of life (QoL) graduallyimproved and she could be discharged taking sustained-release morphine 30 mg every 12 h, with adequately controlled symptoms. One month later, she received four courses of high-dose (HD) methotrexate (8 g/m2) with further recovery and scarce toxicity (NCI-CTC grade 2 nausea).

Progression-free survival was 6 months from the beginning of radiotherapy (3 months from the end of HD methotrexate), but progression affected mainly axial bones, and only scantily the thecal sac. Subsequently, she was treated with weekly paclitaxel (Taxol; Bristol-Myers Squibb Company, NJ) and capecitabine, for 6 months, with partial response and clinical improvement. At that time, the tumour behaved very aggressively and the patient finally died of rapid leptomeningeal progression. Overall, survival since whole-brain radiotherapy was 12 months, toxic effects were amenable and reported QoL was excellent.

Leptomeningeal carcinomatosis may be present in 2% of cases of breast cancer. A proposed prognostic model stratified patients into four groups on the basis of pretreatment characteristics [1]. According to this system, the survival for this patient should have been 5.5 months, but she finally lived more than twice the expected. This discrepancy is not probably the result of favourable tumour biology, as its short progression-free survival and clinical aggressiveness strongly suggest.

The role of systemic chemotherapy is not unequivocally defined in this condition. A nonrandomized study yielded CSF cytological response in 81% of patients with nonleukemic leptomeningeal cancer, with an overall survival of 13.8 months [2].

Capecitabine has demonstrated activity in metastatic breast cancer, with acceptable toxicity profile. Despite blood-brain-barrier, capecitabine has reported activity in central nervous system metastases [3, 4]. Capecitabine is converted to 5-fluorouracil by the enzyme thymidine phosphorylase (TP). Radiotherapy increases TP activity within tumour cells and is synergistic with capecitabine in human tumour xenografts [5]. A phase I study of capecitabineand concurrent whole-brain radiotherapy informed that combined therapy was safe and well tolerated without unexpected toxic effects.

We believe that opioid reduction and prolonged progression-free survival indicate that induction therapy with capecitabine and concurrent radiotherapy, followed by HD methotrexate, was beneficial for our patient. The main conclusion is that further phase I/II studies evaluating this protocol may contribute to optimize the treatment of this condition.

Clin Breast Cancer. 2006 Jun;7(2):164-6.Links

Long-term clinical response in leptomeningeal metastases from breast cancer treated with capecitabine monotherapy: a case report.

Tham YL, Hinckley L, Teh BS, Elledge R.
Breast Care Center, Baylor College of Medicine, Houston, TX 77030, USA. yltham@breastcenter.tmc.edu
Brain and leptomeningeal metastases from breast cancer carry a poor prognosis and are often less responsive to systemic therapy. It is often thought that systemic therapy has a minimal role in the management of central nervous system (CNS) metastases because of the impermeability of the blood-brain barrier. However, treatments directed to the CNS such as radiation or intrathecal chemotherapy are not effective in managing concurrent non-CNS metastases. We report the long-term control of a woman receiving capecitabine with brain and leptomeningeal metastases. After 3.7 years of capecitabine therapy after whole-brain radiation, the patient remains without neurologic symptoms or deficits, has no evidence of disease on neuroimaging studies, but has a persistent positive cytology. This case report demonstrates that, in principle, systemic therapy can provide long-term complete responses for some patients with CNS metastases. The significance of persistent circulating tumor cells in the CNS in patients without evidence of disease is unclear but should be investigated further.
PMID: 16800978 [PubMed - indexed for MEDLINE]
Oncol Rep. 2006 May;15(5):1373-7. Links

Application of intrathecal trastuzumab (Herceptintrade mark) for treatment of meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer.

Stemmler HJ, Schmitt M, Harbeck N, Willems A, Bernhard H, Lässig D, Schoenberg S, Heinemann V.
Department of Internal Medicine III, Ludwig-Maximilians-University of Munich, Klinikum Grosshadern, D-81377 Munich, Germany. joachim.stemmler@med.uni-muenchen.de
Leptomeningeal carcinomatosis represents a rare manifestation of metastatic breast cancer (MBC). A 39-year-old 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/m2 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.
PMID: 16596213 [PubMed - indexed for MEDLINE]
J Neurooncol. 2006 Jul;78(3):255-60. Links

Erratum in:
J Neurooncol. 2006 Jul;78(3):261. Shah, Gaurav G [corrected to Shah, Gaurav D].
Systemic high-dose intravenous methotrexate for central nervous system metastases.

Lassman AB, Abrey LE, Shah GD, Panageas KS, Begemann M, Malkin MG, Raizer JJ.
Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Lassmana@mskcc.org
BACKGROUND: Treatment options for patients with recurrent central nervous system (CNS) metastases are limited. Rapid infusion of high-dose intravenous methotrexate (HD IV MTX) penetrates the blood-brain barrier (BBB) and has reported activity in leptomeningeal metastases. METHODS: Medical records were reviewed for all patients treated with HD IV MTX (3.5 g/m2) for CNS parenchymal or leptomeningeal metastases. Radiographic response rate, survival, and toxicity were determined. RESULTS: Thirty-one women and one man with a median age of 52 years (range 33-76) were treated with a total of 141 cycles (median 4, range 1-13). Twenty-nine patients had breast cancer, and one each had cancer of unknown primary (CUP), squamous cell carcinoma of the head and neck, and non-small cell lung cancer (NSCLC). An objective radiographic response and stable disease were each observed in nine patients (28%), and 13 (44%) patients progressed. Prior treatment with low-dose MTX for systemic disease did not affect response (P = 0.8). The median overall survival (n = 32) was 19.9 weeks (range 2.9-135.4+) with one patient alive at 135.4 weeks. Myelosuppression and elevated serum hepatic transaminases were the most common acute toxicities (21% and 9% of HD IV MTX cycles, respectively). CONCLUSIONS: HD IV MTX is effective in the treatment of CNS metastases with disease control (response or stable) as a best response in 56% of assessable patients. Further study is warranted.
PMID: 16344918 [PubMed - indexed for MEDLINE]

08-23-2009, 01:11 PM	#12
Lani Senior Member Join Date: Mar 2006 Posts: 4,778	Re: Update: Spinal Fluid me pArt two of pubmed search: Anticancer Drugs. 2008 Sep;19(8):832-6. Intrathecal trastuzumab (Herceptin) and methotrexate for meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer: a case report. Stemmler HJ, Mengele K, Schmitt M, Harbeck N, Laessig D, Herrmann KA, Schaffer P, Heinemann V. Medical Department III, Ludwig-Maximilians-University of Munich, Klinikum Grosshadern, Munich, Germany. Joachim.Stemmler@med.uni-muenchen.de Leptomeningeal carcinomatosis represents a rare manifestation of metastatic breast cancer (MBC). We herewith report on a patient suffering from HER2 overexpressing MBC who received intrathecal methotrexate and trastuzumab for meningeal carcinomatosis. A 48-year-old woman was diagnosed with breast cancer in December 2002. Following surgery, six cycles of adjuvant FE100C plus irradiation and, subsequently for 1 year, trastuzumab were given. As a result of disseminated metastatic spread in October 2005, the patient received whole-brain radiotherapy for symptomatic central nervous system involvement, and was put on several trastuzumab-based combination regimens (capecitabine, vinorelbine, paclitaxel). In June 2006, the patient developed clinical signs of terminal cone involvement with overflow incontinence and paraparesis of the legs. Immediate radiation led to partial relief from clinical symptoms. Subsequently, the patient was put on the tyrosine kinase inhibitor lapatinib and capecitabine (August to October 2007), but on November 6th the patient suffered again from overflow incontinence and weakness of the legs. Failing to respond to lapatinib, the patient received gemcitabine/cisplatin and, additionally, was recommenced on intravenous trastuzumab. Owing to progressive leptomeningeal disease, the patient received repeated doses of intrathecal methotrexate and trastuzumab. Within 2 weeks and four intrathecal treatments, cerebrospinal fluid cytology showed the absence of tumor cells. Moreover, a striking clinical improvement with resolution of the paraparesis of the legs and overflow incontinence was observed. This case report gives details regarding the clinical course of a breast cancer patient who received intrathecal trastuzumab and methotrexate via lumbar puncture for meningeal carcinomatosis of HER2-overexpressing MBC. PMID: 18690096 [PubMed - indexed for MEDLINE] Liposomal cytarabine given concomitantly with radiotherapy in a patient with leptomeningeal metastasis from breast cancer Journal Journal of Neurology Publisher Steinkopff ISSN 0340-5354 (Print) 1432-1459 (Online) Issue Volume 255, Number 11 / November, 2008 Category Letter to the Editors DOI 10.1007/s00415-008-0014-8 Pages 1838-1839 Subject Collection Medicine SpringerLink Date Saturday, July 26, 2008 M. Glas1 , M. Stuplich1, H. Tschampa2, H. Urbach2, K. Rasch1 and U. Herrlinger1 (1) Clinical Neurooncology Unit, Dept. of Neurology, University of Bonn, Medical Center, Bonn, Germany (2) Dept. of Radiology, University of Bonn, Medical Center, Bonn, Germany Published online: 25 July 2008 M. Glas Email: martin.glas@ukb.uni-bonn.de Fulltext Preview (Small, Large) Links 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] J Neurooncol. 2007 Nov;85(2):223-7. Epub 2007 Jul 5. Links Capecitabine therapy of central nervous system metastases from breast cancer. Ekenel M, Hormigo AM, Peak S, Deangelis LM, Abrey LE. Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA. ekenelm@mskcc.org Central nervous system (CNS) metastases from breast cancer carry a poor prognosis. Systemic chemotherapy is often ineffective due to the impermeability of the blood-brain barrier (BBB) and inherent chemoresistance of CNS metastases. There are limited data supporting the use of capecitabine in this setting. Medical records of seven patients with brain metastases from breast cancer who received capecitabine treatment at Memorial Sloan-Kettering Cancer Center from 1994-2006 were reviewed. Treatment outcomes were analyzed retrospectively in those patients. Median time from breast cancer diagnosis to the development of CNS metastasis was 48 (18-165) months. Four patients had brain metastases alone, two patients had both leptomeningeal and brain metastases and one patient had leptomeningeal metastasis alone. Five out of seven patients had failed other treatment modalities before capecitabine. Three patients showed complete response (CR) and three patients had stable disease (SD) after capecitabine. The patient with leptomeningeal disease improved clinically, but refused repeat cerebrospinal fluid (CSF) studies. Median overall and progression-free survival from initiation of capecitabine was 13 and 8 months, respectively, for all patients. Capecitabine may achieve a CR and provide long-term control in patients with both leptomeningeal and parenchymal CNS metastases from breast cancer. PMID: 17611719 [PubMed - indexed for M : Curr Treat Options Neurol. 2007 Jul;9(4):283-293. Links Leptomeningeal Neoplasms. Drappatz J, Batchelor TT. Jan Drappatz, MD Harvard Medical School, Department of Neurology, Brigham and Women’s Hospital and Dana-Farber/Brigham and Women’s Cancer Center, Center for Neuro-Oncology, 44 Binney Street SW 430, Boston, MA 02115, USA. jdrappatz@partners.org. Leptomeningeal metastasis is becoming an increasingly important late complication of cancer as survival from systemic disease increases, and due to the fact that many novel cancer drugs fail to achieve therapeutic concentrations in the central nervous system. It occurs when neoplastic cells enter cerebrospinal fluid (CSF) pathways, causing diffuse infiltration of the subarachnoid space of the brain and spinal cord. Definitive diagnosis is established by the demonstration of malignant cells in the CSF. However, in certain circumstances the presence of leptomeningeal enhancement on brain or spinal MRI may be sufficient to make the diagnosis. Early diagnosis and aggressive treatment may delay neurologic progression and can lead to prolonged survival and improvement of neurologic function in certain patients. The prognosis depends on the underlying malignancy but is often poor, with a median survival of 4 months, and most treatment interventions are palliative. Nevertheless, some patients respond to treatment, and some survive beyond 1 or 2 years after diagnosis. Areas of radiographic bulky disease or symptomatic tumor should receive radiotherapy. Intrathecal chemotherapy is most effective in patients with lymphoma, leukemia, or breast cancer and without evidence of bulky disease on neuroimaging. Intrathecal chemotherapy requires normal CSF flow, and the most commonly used agents are methotrexate, cytarabine, and thiotepa. In lieu of intrathecal therapy, systemic chemotherapy may occasionally be indicated in select patients in part based on its ability to penetrate into bulky disease. When hydrocephalus occurs, ventriculoperitoneal shunting frequently leads to rapid clinical improvement. There is hope that progress in diagnostic modalities and the development of more effective intrathecal antineoplastic drugs may decrease neurologic morbidity and improve quality of life and survival. PMID: 17580008 [PubMed - as supplied by publisher] J Neurooncol. 2007 Aug;84(1):57-62. Epub 2007 Feb 20 Breast cancer leptomeningeal metastasis--the role of multimodality treatment. Rudnicka H, Niwińska A, Murawska M. Department of Breast Cancer, Maria Sklodowska Curie Memorial Cancer Center and Institute of Oncology, Roentgen 5 str., 02-781, Warsaw, Poland. AIM: The aim of the study was to assess the efficacy of multimodality treatment of patients with Leptomeningeal metastasis (LM) and to establish which method of treatment has the greatest positive impact on survival. MATERIAL AND METHODS: Clinical material included 67 consecutive breast cancer patients with LM treated at the Cancer Center in Warsaw between the years 2000 and 2005. Intrathecal chemotherapy was given to 57 pts (85%), intravenous chemotherapy to 41 pts (61%), whole brain radiotherapy to 33 pts (49%) and radiotherapy to the spinal leptomeninges to 10 (15%). For 27 pts (40%) three methods of treatment were used. Univariate and multivariate analyses were used to evaluate the impact of the particular method of treatment on survival and to assess the efficacy of combined modalities. RESULTS: Clinical response was achieved in 49 pts (76%). Median survival calculated from the diagnosis of LM was 16 weeks (range 1-402 weeks). Univariate analysis showed positive impact of systemic intravenous chemotherapy (P = 0.0009), intrathecal chemotherapy (P = 0.008) and whole brain radiotherapy (P = 0.004) on survival. The results of Cox multivariate analysis have shown systemic chemotherapy (P < 0.001) and intrathecal chemotherapy (P = 0.001) to be significant. CONCLUSIONS: Intravenous chemotherapy and, independently, intrathecal chemotherapy improve survival in breast cancer patients with LM. Radiotherapy has a positive impact on the quality of life due to the alleviation of neurological symptoms. The role of radiotherapy in prolonging survival is questionable. PMID: 17310266 [PubMed - indexed for MEDLINE] Annals of Oncology 2007 18(1):199-200; doi:10.1093/annonc/mdl290 letters to the editor Concurrent radiotherapy and capecitabine, followed by high-dose methotrexate consolidation, provided effective palliation in a patient with leptomeningeal metastases from breast cancer A Carmona-Bayonas* Medical Oncology and Haematology Department, Hospital Morales Meseguer, Murcia, Spain * (E-mail: trebla_albert@hotmail.com) We report the case of a 38-year-old patient, diagnosed with AJCC stage III-A breast cancer (T3N2MO; Estrogen and progesterone receptor negative, her2/neu-negative). She underwent right mastectomy and axillary node dissection. After surgery, she received adjuvant chemotherapy with TAC doxorubicin/docetaxel/cyclophosphamide for six courses. She was admitted to our hospital while local radiotherapy was being carried out, because of excruciating headache and vomits. Continuous i.v. morphine at a dose of 1000 mg/day was required to achieve pain control. There was not any cranial nerve involvement, and she had an Eastern Cooperative Oncology Group performance status of 1. Magnetic resonance and cerebrospinal fluid (CSF) cytology revealed leptomeningeal metastases. Twice daily capecitabine (850 m/m2) and whole-brain radiotherapy (30 Gy) were initiated. She also received five doses of twice weekly intrathecal methotrexate and cytarabine, with cytological improvement. During the first 2 weeks, meningeal irritation intensified as a result of intrathecal chemotherapy. From that moment, quality of life (QoL) graduallyimproved and she could be discharged taking sustained-release morphine 30 mg every 12 h, with adequately controlled symptoms. One month later, she received four courses of high-dose (HD) methotrexate (8 g/m2) with further recovery and scarce toxicity (NCI-CTC grade 2 nausea). Progression-free survival was 6 months from the beginning of radiotherapy (3 months from the end of HD methotrexate), but progression affected mainly axial bones, and only scantily the thecal sac. Subsequently, she was treated with weekly paclitaxel (Taxol; Bristol-Myers Squibb Company, NJ) and capecitabine, for 6 months, with partial response and clinical improvement. At that time, the tumour behaved very aggressively and the patient finally died of rapid leptomeningeal progression. Overall, survival since whole-brain radiotherapy was 12 months, toxic effects were amenable and reported QoL was excellent. Leptomeningeal carcinomatosis may be present in 2% of cases of breast cancer. A proposed prognostic model stratified patients into four groups on the basis of pretreatment characteristics [1]. According to this system, the survival for this patient should have been 5.5 months, but she finally lived more than twice the expected. This discrepancy is not probably the result of favourable tumour biology, as its short progression-free survival and clinical aggressiveness strongly suggest. The role of systemic chemotherapy is not unequivocally defined in this condition. A nonrandomized study yielded CSF cytological response in 81% of patients with nonleukemic leptomeningeal cancer, with an overall survival of 13.8 months [2]. Capecitabine has demonstrated activity in metastatic breast cancer, with acceptable toxicity profile. Despite blood-brain-barrier, capecitabine has reported activity in central nervous system metastases [3, 4]. Capecitabine is converted to 5-fluorouracil by the enzyme thymidine phosphorylase (TP). Radiotherapy increases TP activity within tumour cells and is synergistic with capecitabine in human tumour xenografts [5]. A phase I study of capecitabineand concurrent whole-brain radiotherapy informed that combined therapy was safe and well tolerated without unexpected toxic effects. We believe that opioid reduction and prolonged progression-free survival indicate that induction therapy with capecitabine and concurrent radiotherapy, followed by HD methotrexate, was beneficial for our patient. The main conclusion is that further phase I/II studies evaluating this protocol may contribute to optimize the treatment of this condition. Clin Breast Cancer. 2006 Jun;7(2):164-6.Links Long-term clinical response in leptomeningeal metastases from breast cancer treated with capecitabine monotherapy: a case report. Tham YL, Hinckley L, Teh BS, Elledge R. Breast Care Center, Baylor College of Medicine, Houston, TX 77030, USA. yltham@breastcenter.tmc.edu Brain and leptomeningeal metastases from breast cancer carry a poor prognosis and are often less responsive to systemic therapy. It is often thought that systemic therapy has a minimal role in the management of central nervous system (CNS) metastases because of the impermeability of the blood-brain barrier. However, treatments directed to the CNS such as radiation or intrathecal chemotherapy are not effective in managing concurrent non-CNS metastases. We report the long-term control of a woman receiving capecitabine with brain and leptomeningeal metastases. After 3.7 years of capecitabine therapy after whole-brain radiation, the patient remains without neurologic symptoms or deficits, has no evidence of disease on neuroimaging studies, but has a persistent positive cytology. This case report demonstrates that, in principle, systemic therapy can provide long-term complete responses for some patients with CNS metastases. The significance of persistent circulating tumor cells in the CNS in patients without evidence of disease is unclear but should be investigated further. PMID: 16800978 [PubMed - indexed for MEDLINE] Oncol Rep. 2006 May;15(5):1373-7. Links Application of intrathecal trastuzumab (Herceptintrade mark) for treatment of meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer. Stemmler HJ, Schmitt M, Harbeck N, Willems A, Bernhard H, Lässig D, Schoenberg S, Heinemann V. Department of Internal Medicine III, Ludwig-Maximilians-University of Munich, Klinikum Grosshadern, D-81377 Munich, Germany. joachim.stemmler@med.uni-muenchen.de Leptomeningeal carcinomatosis represents a rare manifestation of metastatic breast cancer (MBC). A 39-year-old 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/m2 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. PMID: 16596213 [PubMed - indexed for MEDLINE] J Neurooncol. 2006 Jul;78(3):255-60. Links Erratum in: J Neurooncol. 2006 Jul;78(3):261. Shah, Gaurav G [corrected to Shah, Gaurav D]. Systemic high-dose intravenous methotrexate for central nervous system metastases. Lassman AB, Abrey LE, Shah GD, Panageas KS, Begemann M, Malkin MG, Raizer JJ. Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Lassmana@mskcc.org BACKGROUND: Treatment options for patients with recurrent central nervous system (CNS) metastases are limited. Rapid infusion of high-dose intravenous methotrexate (HD IV MTX) penetrates the blood-brain barrier (BBB) and has reported activity in leptomeningeal metastases. METHODS: Medical records were reviewed for all patients treated with HD IV MTX (3.5 g/m2) for CNS parenchymal or leptomeningeal metastases. Radiographic response rate, survival, and toxicity were determined. RESULTS: Thirty-one women and one man with a median age of 52 years (range 33-76) were treated with a total of 141 cycles (median 4, range 1-13). Twenty-nine patients had breast cancer, and one each had cancer of unknown primary (CUP), squamous cell carcinoma of the head and neck, and non-small cell lung cancer (NSCLC). An objective radiographic response and stable disease were each observed in nine patients (28%), and 13 (44%) patients progressed. Prior treatment with low-dose MTX for systemic disease did not affect response (P = 0.8). The median overall survival (n = 32) was 19.9 weeks (range 2.9-135.4+) with one patient alive at 135.4 weeks. Myelosuppression and elevated serum hepatic transaminases were the most common acute toxicities (21% and 9% of HD IV MTX cycles, respectively). CONCLUSIONS: HD IV MTX is effective in the treatment of CNS metastases with disease control (response or stable) as a best response in 56% of assessable patients. Further study is warranted. PMID: 16344918 [PubMed - indexed for MEDLINE]