BACKGROUNDTo improve the therapeutic index of whole-brain radiation therapy (WBRT) in the treatment of brain metastases (BM) from breast cancer, we investigated the efficacy and safety of WBRT combined with temozolomide (TMZ) in this population.PATIENTS AND METHODSThis phase II multicenter prospective randomized study included patients with newly diagnosed intraparenchymal BMs from breast cancer, unsuitable for surgery or radiosurgery. All patients received conformal WBRT (3 Gy × 10-30 Gy), with or without concomitant TMZ administered at a dosage of 75 mg/m(2)/day during the irradiation period. The primary end point was objective response rate (ORR) 6 weeks after the end of treatment, defined as a partial or complete response on systematic brain MRI (modified WHO criteria). Secondary end points were progression-free survival (PFS) and overall survival (OS), neurologic symptoms, and tolerability.RESULTSBetween February 2008 and November 2010, 100 patients were enrolled in the study (50 in the WBRT + TMZ arm, 50 in the WBRT arm). Median age was 55 years (29-79). Median follow-up was 9.4 months [1.0-68.1]. ORRs at 6 weeks were 36% in the WBRT arm and 30% in the WBRT + TMZ arm (NS). In the WBRT arm, median PFS was 7.4 months and median OS was 11.1 months. In the WBRT + TMZ arm, median PFS was 6.9 months and median OS was 9.4 months. Treatment was well tolerated in this arm: the most common ≥grade 2 acute toxicity was reversible lymphopenia.CONCLUSIONWBRT combined with TMZ did not significantly improve local control and survival in patients with BMs from breast cancer. CLINICALTRIALS.GOV: NCT00875355.

Breast cancer brain metastases (BM) incidence increases with diagnosis and systemic therapeutics progresses. New strategies are needed to improve these patients' prognosis. Temozolomide (TMZ) is an oral alkylating agent with well-known radiosensitizing properties. The association of TMZ with whole-brain radiation therapy (WBRT) showed interesting brain control rates in previous phase 2 studies. However, patients with brain metastases from breast cancer were underrepresented. The purpose of this trial was to assess the efficacy and safety of WBRT combined with TMZ specifically in the treatment of brain metastases from breast cancer. Eligibility criteria for this prospective randomized multicenter phase II study were newly diagnosed intraparenchymal brain metastases from breast cancer, not suitable for surgery or radiosurgery. Patients were randomly assigned to receive WBRT (3 Gy x 10 to 30 Gy) with or without concomitant TMZ administered 75 mg/m2/day during radiation period. The primary end point was radiologic objective response at six weeks after the end of treatment, defined as a partial or complete response on systematic brain MRI (WHO modified criteria). Secondary endpoints were local progression free survival (PFS) and overall survival (OS), neurologic symptoms, and tolerability. A longer clinical-brain MRI follow-up was planned each three months during a two-year period. All patients gave an informed written consent. The study was approved by the ethical research committee. Between February 2008 and December 2010, 100 patients were enrolled (50 in the WBRT + TMZ arm, 50 in the WBRT arm). Median age was 55 (range, 29-79). Fifteen patients in the WBRT alone arm and 18 patients in the association arm had a triple negative breast cancer subtype. Twelve and 7 patients had HER2 positive tumors, respectively. Median time to brain metastases diagnosis was 45 months (range, 0-274). Sixteen patients had metastatic breast cancer at initial diagnosis. Median follow-up was 53.1 months (range, 1-68). The objective response rate at six weeks was 36% in the WBRT arm, and 30% in the WBRT + TMZ arm (NS). There was no complete response. In the WBRT arm, median PFS was 7.4 months and median OS 11.1 months. In the WBRT + TMZ arm, median PFS was 6.9 months and median OS 9.4 months. No improvement in neurologic symptoms was noticed compared to standard arm. Tolerance was good in the association arm. The most frequent upper grade 2 acute toxicity was reversible lymphopenia in this group. Time to brain metastases diagnosis between 6 to 24 months was negatively associated with PFS in multivariate analysis. Whole-brain radiation therapy combined with oral temozolomide did not improve brain control or survival among patients with brain metastases from breast cancer.

Abstract Background: Despite of therapeutics progress in advanced breast cancer, brain metastases occurrence remain a frequent and delicate situation. The efficacy of whole-brain radiation therapy (WBRT), still considered as the standard local treatment in case of multiple brain metastases, is limited. Recently, several phase II studies have shown some efficacy of the association of WBRT and temozolomide (TMZ), an oral alkylating agent already known as a radiosensitizer, with improved brain control rate (44 to 96%). Patients with breast cancer were underrepresented and none of these trials have studied this combined treatment issue in this specific population. The aim of this study was to assess the efficacy and safety of WBRT combined with temozolomide in the treatment of brain metastases from breast cancer. Materials and Methods: A prospective randomized multicenter phase II study was developed, using a modified two-stage Fleming design. Patients with newly diagnosed intraparenchymal brain metastases from breast cancer, not suitable for surgery nor radiosurgery, were included. All patients received conformational WBRT (3 Gy x 10 to 30 Gy). They were randomized to WBRT plus concomitant TMZ administered 75 mg/m2/day during radiation period versus WBRT alone. The primary endpoint was radiologic objective response at six weeks after the end of treatment, defined as a partial or complete response on systematic brain MRI (WHO modified criteria). We also evaluated neurologic symptoms, tolerance, safety, progression free survival (PFS) and overall survival (OS) as secondary endpoints. A longer clinical-brain MRI follow-up was planned, each three months during a two-year period. All of the patients gave their written informed consent to be part of the study, which was approved by the local committee. Results: One hundred patients were enrolled between February 2008 and December 2010 (50 in the WBRT + TMZ arm, 50 in the WBRT arm). The median age was 55 [29 -79]. Eighty (80) patients had brain metastases as single secondary localization. About one third of patients had a triple negative breast cancer subtype (38,3% in the association arm and 35,71% in the WBRT alone arm). There were 26,7% and 14,6% of HER2 positive subtype respectively. The median follow-up was 30 months [range 6-60]. At six months from brain metastases diagnosis (three months after the end of the treatment), objective response rate seems better in the WBRT + TMZ arm: 52% versus 40% in the arm WBRT alone but was not statistically significant (p = 0,54). No complete response was observed. In the WBRT + TMZ group, median PFS and OS at six-months were respectively 55,6% [range 46-7 – 66,0] and 67,7% [range 59,1 – 77,6]. No improvement in neurologic symptoms was noticed. In multivariate analysis, initial TNM status was significantly correlated with PFS and OS. The concurrent use of TMZ with WBRT was well-tolerated. The most frequent upper grade II acute toxicity was reversible leucopenia in the association arm. Conclusion: The addition of temozolomide to WBRT in patients with brain metastases from breast cancer did not improve local control or survival at six months follow-up. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-11-01.

BACKGROUND: A previously published study of temozolomide (TMZ) concurrent with whole-brain radiation therapy (WBRT) reported significant improvement in response rates and a nonsignificant trend toward improved overall survival compared with WBRT alone in patients with brain metastases in different type of tumors. A prospective randomized phase II trial of concurrent WBRT and TMZ versus WBRT alone was conducted to assess whether the concurrent use of WBRT-TMZ resulted in measurable radiological response differences at 6 weeks after the treatment in homogeneous population of breast cancer (BC) patients. PATIENTS AND METHODS: In this intent-to-treat study, patients with metastatic breast cancer to the brain and not suitable for surgery or radio-surgery were enrolled in a randomized prospective multicenter phase II study between February 2008 and December 2010. Patients received temozolomide 75 mg/m(2)/day (days 1–15) concurrently with WBRT 30 Gy/10 fractions. Patients were stratified by type and metastatic sites. The (MRI) response at 6 weeks was the main criteria; response was defined as complete (CR) or partial response (PR). Initial and follow-up MRI were realized on a 1.5T unit (Siemens) by axial SE-T1 WIs and FLAIR WIs with GdDTA injection, EG-3DT1 WIs after GdDTPA. Five target lesions (over 10 mm greatest diameter) were measured in their 3 dimensions. Non measurable lesions were noticed."The treatment tolerance and clinical responses were also evaluated. The study was designed according to a modified Fleming two-stage plan based on response hypotheses of 30% (H0) versus 50% (H1). Twenty or more responses among 50 subjects were needed to declare the treatment effective, with risk errors alpha 9% and beta 7%. RESULTS: One hundred metastatic breast cancer patients were enrolled in the study, as following: 49 in WBRT-TMZ and 51 in WBRT groups. The median age was 55 years [range, 29–79]. The median follow-up was 12 weeks [range, 1–94]. There were 15/49 (31%) partial responses (PR) in WBRT-TMZ and 18/5 1(35%) PR in WBRT group. No complete responses were observed. The symptoms relief was obtained in 27/49 and 31/51 pts, respectively. The treatment tolerance was acceptable in both groups. CONCLUSION: The benefit of adding TMZ to WBRT was not confirmed at 6 weeks. The tolerance was good in both groups. Longer follow-up is needed to evaluate the combination of TMZ with WBRT in terms of progression free survival. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-17-02.