STEREOTACTIC RADIOSURGERY FOR LIMITED BRAIN METASTASES IN IRANIAN BREAST CANCER PATIENTS Yousefi Kashi A. SH, Mofid B. 1 Department of Radiation Oncology,Shohada Tajrish Hospital,Shahid Beheshti University of Medical Sciences, Tehran, Iran 2 Iran Gamma knife center,tehran,iran Corresponding author: Yousefi Kashi A.SH 1.2 ABSTRACT The purpose of this retrospective cohort study was to identify overall survival and related prognostic factors and treatment outcomes of limited(1-3) brain metastases from breast cancer after Stereotactic Radiosurgery (SRS). A total of 106 patients who had received SRS as part of initial management of their breast cancer with 1 to 3 brain metastases from January 2007 through June 2012 and clinical features and outcomes were analyzed with The Kaplan-Meier method and Cox s proportional hazards model were used to assess prognostic factors. The overall median survival duration was 18 months after SRS(95% confidence interval,11.5-25). Most patients died of systemically progressing malignancy. Recursive partitioning analysis Class I and II(RPA) (RR 0.426; p=0.052), Disease free interval>2yeras (RR 0.444; p=0.022), Single brain metastases (RR 0.416; p=0.051),no extracranial metastases (RR 0.344; p=0.042) and systemic chemotherapy after SRS (RR 0.252; p=0.001) were found to be a favorable prognostic factor of overall survival. Age ( 60),Further whole brain radiation therapy and the greatest dimension of the tumor were not found to be significantly associated with overall survival. Overall survival of patients with limited brain metastases from breast cancer who treated with SRS can be affected primarily by RPA, Disease free interval>2years, Single brain metastases, No extracranial metastases and systemic chemotherapy. Treatment outcome and prognosis scoring system could be individualized based on these prognostic factors in addition to traditionally known factors related to stereotactic radiosurgery. KEYWORDS: Breast cancer, Limited brain metastasis, Overall survival, Stereotactic Radiosurgery INTRODUCTION Breast cancer is the most common visceral cancer among Iranian women, and the first most common cause of brain metastases in Iran and can happen clinically in 10 16% with breast carcinoma and indicate a terminal stage of the disease (Lin et al., 2004; Weil et al., 2005). Young age, ER and PR negative status, and HER2 positive have all been associated with increased risk for the development of breast cancer brain metastases (Azadeh et al., 2008). Improvements in the systemic treatment of cancer such as new chemotherapy and targeted therapy and survival mean that the control of brain involvement has become increasingly important to achieve overall disease control. Historically, breast cancer has been known to be a relatively radiosensitive tumor, Therefore, whole-brain radiotherapy (WBRT) is the main treatment for patients with multiple brain metastases. In an attempt to capitalize on these results, some patients with good performance status, limited extracranial disease, and few brain lesions have been treated more aggressively with stereotactic radiosurgery (SRS) (Aoyama, 2011; Wen and Shafman, 2000; Padovani et al., 2012; Lagerwaard et al., 1999; Kased et al., 2009). The current retrospective, single-institution analysis was conducted to present detailed outcome data (adjusted for the effects of prognostic factors) for a large, well defined patient population (106 patients with a combined total of 235 tumors) with brain metastases from breast carcinoma undergoing SRS over a study period of 5.5 years. In this study, we retrospectively reviewed of patient with limited Brain metastasis from breast cancer treated by SRS and assessed the impacts of prognostic factors, treatment methods, and clinical variables on overall survival. MATERIALS AND METHODS Between January 2007 through June 2012, 106 patients with 235 cerebral metastases from breast carcinoma underwent 137 gamma knife procedures (Leksell Gamma Knife;). One hundred twenty-one patients with brain metastases from breast carcinoma were selected for radiosurgery according to the following eligibility criteria: 1) histological diagnosis of breast carcinoma; 2) histologic verification of brain metastases by stereotactic biopsy for patients with uncertain diagnoses; 3) maximum tumor diameter 4 cm;4) Karnofsky performance score (KPS) 60;5) extracranial tumor that was stable or in remission with or without systemic therapy and 6) less than 4 brain metastases. Volume- 4 Issue- 3 (2015) ISSN: 2319 4731 (p); 2319 5037 (e) 2015 DAMA International. All rights reserved. 82 1,2 1
Table 1. Patient characteristics Characteristics Value Age, mean±sem 48.5 ±1.1 RPA class I 15 II 66 III 25 Extracranial metastases Yes 69 No 37 Prescribed dose, mean±sem (Gy) 18.1 ±0.8 Treatment modality SRS 68 SRS+WBRT 38 Disease free interval<2 years 66 Disease free interval>2yeras 40 systemic chemotherapy after SRS Yes 66 No 40 Brain metastases Total no. 235 Single 33 2-3 73 No. of metastases, mean±sem 2.05±0.35 Histologic verification of metastases to the brain By stereotactic biopsy 11 By brain tumor resection 21 median greatest dimension of tumor greatest dimension of tumor mean±sem 2.2 cm (range, 0.5 4cm). 2.2 cm±0.11 RPA:Recursive partitioning analysis Class SRS : Stereotactic Radiosurgery, WBRT : whole brain radiation therapy, Disease free interval :Time from primary diagnosis to brain metastases Gamma knife surgery (GKS) was performed by a specialized neurosurgeon and a radiation oncologist as an outpatient procedure with stereotactic MRI scans for all patients. Patient data were collected prospectively in a computerized data base. Sixty-nine percent of all patients had 2 or 3cerebral metastases. Fifteen patients underwent surgery before SRS to Volume- 4 Issue- 3 (2015) ISSN: 2319 4731 (p); 2319 5037 (e) 2015 DAMA International. All rights reserved. 83
resect large metastases not eligible for radiosurgery. Patients who received WBRT before SRS were not excluded from the study. The histology of the primary tumor was an invasive ductal or lobular carcinoma in most patients. Gadolinium-enhanced MRI scans were used for treatment planning as well as for the follow-up examinations of all patients. Multiple isocenters were chosen to match the tumor volume as accurately as possible. Tables 1 provides detailed summaries of patient and treatment characteristics, respectively. Follow-Up Evaluation Clinical examination and tumor response as verified by stereotactic MRI scans were used to evaluate patients during follow-up. Follow-up examinations were performed at 3 and 6 months after radiosurgery and then every 12 months until death or the date of closure of the study (June 1, 2014). Medical records and imaging findings were reviewed, and the following were included; patient age, SRS with or without WBRT, Recursive partitioning analysis Class (RPA), status of extra cranial metastases, number and the greatest dimension of tumor, administration of systemic chemotherapy, duration of follow-up and Death or last follow-up were defined as study end points. Patients who had received any type of systemic chemotherapy for more than three cycles were defined as having received systemic chemotherapy. Statistical Methods The reference point of our study was the first day of SRS. The endpoint was death. The length of survival was estimated using the Kaplan Meier method.the chi-square test was used to compare group categorical data. For analysis, overall survival time was calculated from SRS to death from any cause. The patients were stratified by clinical characteristics, and survivals were estimated across strata using the Kaplan and Meier method and Comparison of Kaplan Meier curves was performed with the log-rank statistic. Cox s proportional hazards model was used to estimate the relative risks for treatment modalities after adjustment for variables potentially associated with overall survival. Data were analyzed using SPSS version 19.0 and statistical significance was accepted for p values of <0.05. RESULTS In our study total patients (n=106), the mean age at the first time of SRS was 48.5 ±1.1 years, Median overall survival was18 months after SRS(95% confidence interval,11.5-25) and 81 (76.4 %) had RPA no less thaniii. Mean greatest dimension of tumor Was 2.2 cm±0.11. Prescribed mean marginal dose was 18.1 Gy. Seventy-six of the 106 patients had died at the time of review. Overall survival was not different between SRS alone group from SRS with WBRT group. Table2. Uni- and multivariate analysis results for overall survival Variables Univariate Multivariate Hazard ratio 95% CI Age ( 60) 0.332 0.754 1.556 0.36 3 2.45 4 Disease free interval>2years 0.0001 0.022 0.444 0.166 1.022 Single brain metastases 0.0001 0.051 0.416 0.171 1.003 Greatest dimension 0.147 0.951 0.975 0.428 2.219 of Tumor (<2.2cm) RPA(<III) 0.0001 0.052 0.426 0.174 1.2 01 No extracranial 0.0001 0.042 0.3 44 0.173 1.004 metastases Systemic 0.0001 0.001 0.252 0.124 0.645 chemotherapy SRS +WBRT 0.788 0.222 0.649 0.244 1.663 RPA:Recursive partitioning analysis Class, SRS : Stereotactic Radiosurgery WBRT : whole brain radiation therapy, CI : confidence interval Volume- 4 Issue- 3 (2015) ISSN: 2319 4731 (p); 2319 5037 (e) 2015 DAMA International. All rights reserved. 84
Prognostic Factors with Overall Survival In 106 patients who treated SRS as initial treatment, the overall median survival duration was 18 months after SRS (95% confidence interval,11.5-25). Univariate analyses using log-rank test showed RPA less than III(p<0.001),single brain metastas (p<0.001), Disease free interval>2years (p< 0.001)receipt systemic chemotherapy (p< 0.001)and status of extracranial metastases(p<0.001) were associated with favorable outcomes, but Age ( 60) (p=0.332), Greatest dimension of Tumor (<2.2cm) (p=0.147), and omission of WBRT (p= 0.788) were not found to be significantly associated with overall survival. Uni- and multivariate analyses of overall survival showed that a single number of metastases, RPA I and II, the receipt of systemic chemotherapy,no extracranial metastases and Disease free interval>2years predicted longer survival (Table2). However, prognostic factors age,greatest dimension of Tumor (<2.2cm) and additional WBRT were not significantly related to overall survival. DISCUSSION This retrospective cohort study was conducted on breast cancer patients with limited brain metastases (1-3)treated at Gamma knife center from 2007 to 2012. Overall survival in the present study was longer than those reported previously (Aoyama, 2011; Golden, et al., 2008; Goyal, et al., 2005; Monje and Palmer, 2003), because of a high proportion of patients have RPA class I and II and less than 4 brain metastases. Furthermore, previously identified prognostic factors, such as age, SRS +WBRT and greatest dimension of tumor were not found to affect treatment outcomes significantly. On the other hand we also figure out this result to a better understanding early diagnosis of brain metastases, and the adoption of multimodal treatments, which included targeted drug therapies, surgery, radiosurgery, and radiotherapy. Prior retrospective studies have investigated outcomes and prognostic factors for overall survival in patients treated with SRS for breast cancer brain metastasis (Nieder et al., 2009). Kondziolka et al. (2011) reviewed outcomes for a cohort of 350 consecutive patients. In this group, 64.9% had undergone previous WBRT and 67% had multiple lesions, with 22% having 5 metastatic lesions treated. Median survival was 11.2 months and less than to our results, this study also showed a better overall survival in breast cancer brain metastasis patients compared to historical series looking at brain metastasis without respect to tumor histology. In this study, controlled extracranial disease, KPS 70, lower total radiosurgery volume, and HER2/neu overexpression were all predictors of better overall survival on multivariate analysis. Goyal et al. (2005) reviewed 43 patients and found a median survival of 13 months. Predictors for increased overall survival in this cohort were found to be higher KPS score, patients with a SIR index (Score Index for Radiosurgery) 8, and a single lesion. Aoyama (2011) investigated treatment results of breast cancer patients with brain metastases, and concluded that WBRT is still important in this context of modern radiotherapy in spite of delayed adverse effects on cognition and functional independence (Weil et al., 2005; Gu et al., 2009; Le et al., 2007; Lee et al., 2011). In our study, we found that additional WBRT did not influence survival. These findings suggest the effect of WBRT on recurrence does not give significant influence in long term survivors. They caution that treatment scheme should be modified to meet the expectations of physicians and patients (Liu et al., 2006; Matsumoto et al., 2009). Several limitations of our study need consideration. First, this study included patients who were treated with SRS for brain metastases with 1-3 brain metastases. The selection bias may have inflated median survival and deviated the results of analyses. But the main objective of our study was to analyze the effect of SRS on treatment outcomes, therefore we had to select the patients who could provide whole parameters of interest. Also, all 106 patients who underwent SRS as initial treatment showed similar baseline characteristics and similar results on univariate analyses results. Therefore, we thought this data might possess representativeness. Second, we don t include the intrinsic of primary tumor biology such as ER,PR and HER2 in our study. Third, extracranial tumor that was stable or in remission with or without systemic therapy. CONCLUSION In conclusion, the strongest individual clinical prognosticators in our study were RPA, Disease free interval>2years, Single brain metastases, No extracranial metastases and systemic chemotherapy. REFERENCES Aoyama H. (2011). Radiation therapy for brain metastases in breast cancer patients. 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