Jacot et al. BMC Cancer 2010, 10:257 http://www.biomedcentral.com/1471-2407/10/257 RESEARCH ARTICLE Open Access CarmustineResearch article and methotrexate in combination after whole brain radiation therapy in breast cancer patients presenting with brain metastases: a retrospective study William Jacot*1, Marie-Cécile Gerlotto-Borne1, Simon Thezenas2, Stéphane Pouderoux1, Sylvain Poujol3, Mahdi About2 and Gilles Romieu1 Abstract Background: Since 1999, patients presenting with brain metastases (BM) from breast cancer (BC) are treated in our institution with a carmustine (BCNU) - methotrexate (MTX) combination. We report here our clinical experience regarding this combination. Patients and Methods: Patients were treated by a combination of BCNU 100 mg/m² on day 1 and MTX 600 mg/m² on day 1 and 15 of a 28 day cycle. Treatment was continued until progression or unacceptable toxicity. Results: 50 patients were treated between 1999 and 2007. 94% of the patients presented with concomitant extra- cerebral disease. Median number of previous metastatic setting chemotherapy regimens was 2 (0-5). Median number of cycles was 3 (1-20). There were 11 objective responses (23% [95%CI 12-37]) among 48 evaluable patients. Median progression-free survival and overall survival (OS) were 4.2 (95%CI: 2.8-5.3) and 6.9 (4.2-10.7) months respectively, with a one-year OS rate of 32% (20-46). Median Relative Dose Intensity for BCNU and MTX were 0.98 (0.31-1.1) and 0.96 (0.57- 1.66) respectively. There were 2 presumed treatment-related deaths. One patient developed febrile neutropenia. Performance status, BS-BM score and presence of liver metastases were associated with OS in univariate analysis. Conclusions: This combination appears to be effective and well tolerated in good performance status BC patients presenting with BM. Background Prognosis of patients with multiple BM is poor, with a Fifteen to 30% of patients with advanced breast cancer median survival of <1 year. There is currently no (BC) will develop brain metastases (BM) [1-6]. The vast approved chemotherapy regimen for BM, and the current majority of BC patients with BM have a concomitant standard of care involves whole-brain radiation therapy extra-cerebral metastatic disease, pledging for systemic (WBRT) and control of symptoms with steroids and anti- treatments. Central nervous system (CNS) metastases convulsants [3]. However, WBRT can be associated with occur mainly within 2 years following a diagnosis of met- a risk of neurotoxicity [9], and some patients refuse such astatic disease, with a 13 months median survival period treatment. Furthermore, even if some selected patients from the diagnosis of BM in the HER-2 positive tumors with recurrent metastases previously treated with WBRT setting [7]. Synchronous diagnosis of BC and BM is a rare can be candidates for salvage stereotactic radiosurgery, a event, with a 28-34 months median interval between pri- majority of this population does not receive additional mary diagnosis and the development of CNS involvement brain irradiation. In addition, the existence of an extra- [5,8]. cerebral disease precludes WBRT efficacy in term of overall cancer control, except in the uncommon cases of * Correspondence: [email protected] few (1-3) BM as the only metastatic lesions. 1 Department of Medical Oncology, CRLC Val d'Aurelle, Montpellier, France Full list of author information is available at the end of the article © 2010 Jacot et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Jacot et al. BMC Cancer 2010, 10:257 Page 2 of 10 http://www.biomedcentral.com/1471-2407/10/257 Various chemotherapy regimens have been investigated chemotherapy regimen consisted of a combination of in BC patients with BM. However, standard agents used BCNU 100 mg/m² and MTX 600 mg/m² on day 1 and to treat BC, such as taxanes and anthracyclines, have MTX 600 mg/m² on day 15. A cycle restarted at day 28 demonstrated conflicting results regarding their efficacy pending hematological recovery (absolute neutrophils in the treatment of BM [10,11]. The investigation of che- count ≥1.5.109/L and platelets > 100.109/L) and return to motherapy efficacy for the treatment of BM has been lim- grade 0 or 1 for non hematological toxicity. If one or more ited because of a presumed lack of effectiveness due to of these conditions was not met, then a 1- to 2-week delay the blood-brain barrier (BBB). However, the importance was allowed for recovery. A 50% dose reduction was of the BBB is probably overrated in the case of the neoan- applied to BCNU in case of severe toxicity (grade 4 neu- giogenesis surrounding macroscopic metastases or tropenia ≥ 7 days during the previous cycle; grade 3 or 4 relapsed disease as the BBB has already been disrupted at febrile neutropenia; grade 3 or 4 infection with neutrope- this stage, resulting from the newly developed blood ves- nia; grade 4 anemia or thrombocytopenia or bleeding sels not provided with the physiological properties of the requiring transfusion, or any grade ≥ 3 non-hematologi- common BBB. In such a setting, chemotherapeutic agents cal toxicity). The drug was discontinued in case of a sec- initially known not to cross the BBB, have been demon- ond occurrence of severe toxicity. Methotrexate was strated to penetrate metastatic tissue [12] and so could be administered on day 15 depending on hematological able to induce significant antitumor activity [11]. recovery and return to grade 0 or 1 for non-hematologi- Methotrexate (MTX) is an active drug against breast cal toxicity. Urinary alkalization using sodium bicarbon- and other primary cancers and can be effective when ate (in order to obtain a urinary pH > 7.5) was based on a used at a high dose to reach the CNS and to achieve clini- 4 h 500 ml infusion of 4.2% sodium bicarbonate before cal activity [13]. Carmustine (BCNU) has demonstrated MTX infusion, followed by a 12 h 1.5 l infusion of 1.4% clinical activity in brain metastases from solid tumors sodium bicarbonate solution. Folinic acid supplementa- [14]. Considering the lack of standard treatment validated tion (25 mg every 6 hours day 2 to 5 and day 16 to 19) was in this population and the clinical activity of monother- systematically used to minimize methotrexate hemato- apy methotrexate and BCNU in BM patients, these logical toxicity. Patients presenting with HER-2 over patients are treated in our Institution since 1999 with a expressing tumors received in addition (when commer- combination of BCNU and MTX. We report here our cially available) trastuzumab injections at the dose of 4 clinical experience regarding the efficacy and safety pro- mg/kg on days 1 and 15 of the same cycle. Granulocyte file of this combination. colony-stimulating factors were used as secondary neu- tropenia prophylaxis in case of delays in chemotherapy Patients and methods due to long lasting neutropenia. Concerning patients Patient Eligibility receiving endocrine treatment, the treatment was discon- Patients treated in our institution and affected by BC BM, tinued at the initiation of the chemotherapy combination. diagnosed using either CT-scan or MRI of the brain, who received the combination of BCNU and MTX were con- Study Assessments sidered in this retrospective study. Patients were identi- Pretreatment evaluation included a complete medical fied from the Breast Cancer database of the Val d'Aurelle history and clinical examination with tumor measure- Medical Cancer Center, and records were reviewed for all ments (imaging studies and physical examination when patients treated with at least one cycle of BCNU-MTX appropriate), appropriate radiological tests, concomitant for BC BM between 1999 and 2007. Identified patients treatments, PS, and hematological and biochemical pro- were then followed until death or until February 2008. To files. Tumor measurements were performed every other be considered suitable for this treatment, patients had to cycle during the treatment course and every 3 months have an Eastern Cooperative Oncology Group (ECOG) subsequently until progression. During the treatment performance status (PS) [15] between 0 and 3. Patients duration, complete blood counts including a platelet and were also required to have adequate bone marrow reserve leukocyte differential count were performed weekly. (neutrophils ≥ 1.5.109/L, platelets > 100.109/L). This Response and Toxicity Criteria study was reviewed and approved by our Institutional CT-scans of the brain, chest, abdomen and pelvis were Review Board. performed before the initiation of chemotherapy, then Treatment Plan every 8 weeks (2 cycles) until disease progression or che- Patients were treated by the combination of BCNU and motherapy stop. For this retrospective analysis, patients MTX according to the proposal of our in-site Breast Can- were evaluated for response and progression according to cer Multidisciplinary Committee. Treatment was contin- the RECIST criteria [16]. A minimal duration of 4 weeks ued until progression, unacceptable toxicity, inter-current was required to document a response, and the best disease or patient's refusal to continue. The 4-week-based response was recorded for each patient. A patient with Jacot et al. BMC Cancer 2010, 10:257 Page 3 of 10 http://www.biomedcentral.com/1471-2407/10/257 cerebral and extra-cerebral disease was considered as a vant or metastatic setting. The BM-associated clinico- responder if there was a significant (as per RECIST crite- radiological characteristics are summarized in Table 2. rion) decrease of both cerebral and extra-cerebral lesions. Six patients were clinically asymptomatic at the time of Progressive disease was defined as cerebral and/or extra- BM diagnosis.