Background

Brain metastases (BM) are the most common form of intracranial cancer. They exceed the number of primary brain tumors by at least ten times and occur in about 25% of all patients with cancer. Most brain metastases originate from lung (40–50%), breast (15–25%), melanoma (5–20%), and kidney (5–10%). Brain metastases are located in the cerebral hemispheres in about 80%, in the cerebellum in 15%, or in the brainstem in 5% of patients [1]. The median survival of untreated patients may be as short as 1–2 months [2-4]. After radiation therapy an increase in survival is reported in the range from 3 to 6 months [4-6]. The incidence of brain metastases seems to have increased over the past decade, and may be the paradoxical result of the effectiveness of drugs that do not cross the blood – brain barrier (BBB). As a result of the increased survival in patients receiving chemotherapy, brain metastases may become symptomatic [7,8]. Recursive partitioning analysis (RPA) of data from three Radiation Therapy Oncology Group (RTOG) trials (1200 patients) has allowed three prognostic groups to be identified [9]. RPA class was initially developed to categorize patients treated with fractionated external beam brain RT and tested in the radiosurgical treatment of BMs [10-12]. More recently, Lorenzoni et al. [13] proposed a simplified stratification system that uses the evaluation of three main prognostics factors for radiosurgery in brain metastases; this system was called of basic score for brain metastases (BS-BM), and may be calculated by adding the scores (0 or 1) of three main prognostic factors: KPS, control of the primary tumor, and existence of extracranial metastases, ranging from 0 (worst condition) to 3 (best condition) [13]. In this way, the intention of present study was to analyze the prognostic factors in our series of patients with brain metastases from breast cancer treated with Whole brain radiotherapy (WBRT), with an emphasis on to test the potential improvement in survival for patients stratified by the one previously described stratification system for radiosurgery (BS-BM) and compares it with the RTOG recursive partitioning analysis.

Methods

The records of 174 patients with brain metastases, who were treated with WBRT at our institution between January 1996 and December 2004, were analyzed retrospectively. The institutional review boards granted ethical approval of the study. In the sample of the current study (n = 174) we use 81 patients with diagnoses of breast cancer who had been part of a previous study on WBRT for Brain metastases from any site [14]. The study was approved by the institutional review boards. In present study, at diagnosis of brain metastasis, the following variables were analyzed for survival: age, location of brain metastasis, extent of disease, initial Karnofsky score, dose and fractionation of radiotherapy, surgical resection, chemotherapy, RPA class and BS-BM, as showed in table- 1.

Chemotherapy was administered to the patients with systemic disease in activity at same time that WBRT. Supportive care (oral corticosteroids) and neurological status were not evaluated. Brain metastases were detected by contrast-enhanced cerebral computed tomography (CT) or magnetic resonance imaging (MRI). Primary tumor control was defined as remission or stable disease, without any clinical, radiologic, or laboratory findings suggestive of tumor progression at 2 months before WBRT. According to this criteria twenty patients had local or locoregional relapse, the others patients (n = 68) had brain metastases as first cancer diagnosis. WBRT was performed in all patients with cobalt 60 gamma rays or with 4 MV photons of a linear accelerator. The whole brain was irradiated by usual opposed lateral fields encompassed the cranium with a 1 cm margin. Individual shielding blocks were fabricated for all patients, when necessary. Forty two patients received WBRT with fields included leptomeninges. The total dose was 30–40 Gy, with a median of 35 Gy, in daily fractions of 2.0–3.0 Gy. During the study period two fractionation schemes were used: conventional fractionation with daily fractions of 2 Gray (Gy), five days per week to a planned total dose of 40 Gy (n = 66) and hypofractionation with daily fractions of 3 Gy, five days per week to a planned total dose of 30 Gy (n = 108). Surgical resection was indicated in single brain metastases with diameter less than or equal to 3 cm, favorable localization and controlled systemic disease. Biopsy alone and subtotal resection were done in 2 and 1 cases, respectively. All the others patients (n = 24) submitted to surgical resection were considered gross total resection. The supportive care (prednisone oral) was introduced at the beginning of treatment or during radiotherapy. The RPA was used to classify the patients with brain metastases Class I contained all patients with a Karnofsky performance status (KPS) ≥ 70, age < 65 years, controlled primary tumor and no extracerebral metastases, Class III contained patients with a KPS <70, and Class II contained all other patients [9]. BS-BM was calculated by adding the scores (0 or 1) of three main prognostic factors: KPS, control of the primary tumor, and existence of extracranial metastases [13]. The BS-BM ranged from 0 (worst condition) to 3 (best condition).

Statistical Analysis

The endpoint of the study was overall survival. The survival time was calculated from the starting date of WBRT to the date of death or last patient contact using the method of Kaplan Meier. Survival curves were compared using the log-rank test. The covariates examined in all cases were: age, sex, location of brain metastasis, extracranial disease, control of primary tumor, initial Karnofsky score, dose and fractionation radiotherapy schedule, surgical resection, RPA class and BS-BM. All factors with a P value ≤ 0.05 at univariate analysis were entered into a multivariate analysis using the proportional hazards model (Cox Regression) with confidential interval of 95%.