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PurposeBrain metastases are a common sequelae of breast cancer. Survival varies widely based on diagnosis-specific prognostic factors (PF). We previously published a prognostic index (Graded Prognostic Assessment [GPA]) for patients with breast cancer with brain metastases (BCBM), based on cohort A (1985-2007, n = 642), then updated it, reporting the effect of tumor subtype in cohort B (1993-2010, n = 400). The purpose of this study is to update the Breast GPA with a larger contemporary cohort (C) and compare treatment and survival across the 3 cohorts.Methods and materialsA multi-institutional (19), multinational (3), retrospective database of 2473 patients with breast cancer with newly diagnosed brain metastases (BCBM) diagnosed from January 1, 2006, to December 31, 2017, was created and compared with prior cohorts. Associations of PF and treatment with survival were analyzed. Kaplan-Meier survival estimates were compared with log-rank tests. PF were weighted and the Breast GPA was updated such that a GPA of 0 and 4.0 correlate with the worst and best prognoses, respectively.ResultsMedian survival (MS) for cohorts A, B, and C improved over time (from 11, to 14 to 16 months, respectively; P < .01), despite the subtype distribution becoming less favorable. PF significant for survival were tumor subtype, Karnofsky Performance Status, age, number of BCBMs, and extracranial metastases (all P < .01). MS for GPA 0 to 1.0, 1.5-2.0, 2.5-3.0, and 3.5-4.0 was 6, 13, 24, and 36 months, respectively. Between cohorts B and C, the proportion of human epidermal receptor 2 + subtype decreased from 31% to 18% (P < .01) and MS in this subtype increased from 18 to 25 months (P < .01).ConclusionsMS has improved modestly but varies widely by diagnosis-specific PF. New PF are identified and incorporated into an updated Breast GPA (free online calculator available at brainmetgpa.com). The Breast GPA facilitates clinical decision-making and will be useful for stratification of future clinical trials. Furthermore, these data suggest human epidermal receptor 2-targeted therapies improve clinical outcomes in some patients with BCBM.

PurposeTo update the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) for a markedly heterogeneous patient population, patients with melanoma and brain metastases, using a larger, more current cohort, including molecular markers.MethodsThe original Melanoma-GPA is based on data from 483 patients whose conditions were diagnosed between 1985 and 2005. This is a multi-institutional retrospective database analysis of 823 melanoma patients with newly diagnosed brain metastases from January 1, 2006, to December 31, 2015. Multivariable analyses identified significant prognostic factors, which were weighted and included in the updated index (Melanoma-molGPA). Multiple Cox regression was used to select and weight prognostic factors in proportion to their hazard ratios to design the updated Melanoma-molGPA in which scores of 4.0 and 0.0 are associated with the best and worst prognoses, as with all of the diagnosis-specific GPA indices. Log-rank tests were used to compare adjacent classes.ResultsThere were 5 significant prognostic factors for survival (age, Karnofsky performance status [KPS], extracranial metastases [ECM], number of brain metastases, and BRAF status), whereas only KPS and the number of brain metastases were significant in the original Melanoma-GPA. Median survival improved from 6.7 to 9.8 months between the 2 treatment eras, and the median survival times for patients with Melanoma-molGPA of 0 to 1.0, 1.5 to 2.0, 2.5 to 3.0, and 3.5 to 4.0 were 4.9, 8.3, 15.8, and 34.1 months (P

PurposeBrain metastases are a common problem in patients with melanoma, but little is known about the effect of gene mutations on survival in these patients.Methods and materialsWe created a retrospective multi-institutional database of 823 patients with melanoma and brain metastases diagnosed between 2006 and 2015. Clinical parameters, gene mutation status (BRAF, C-KIT, NRAS), and treatment were correlated with survival. Treatment patterns and outcomes were compared with a prior era (1985-2005).ResultsBRAF status was known in 584 of 823 patients (71%). BRAF, NRAS, and C-KIT mutations were present in 51%, 22%, and 11% of tested patients, respectively. The median time from primary diagnosis to brain metastasis was 32 months, and overall median survival (MS) from the time of initial treatment of brain metastases was 10 months. MS for BRAF-positive and BRAF-negative patients was 13 months and 9 months, respectively (P=.02). There was no significant difference in MS in patients with or without NRAS or C-KIT mutations. The time from primary diagnosis to brain metastasis did not vary by mutation and was not associated with survival after the diagnosis of brain metastases. MS for the 1985 to 2005 and 2006 to 2015 cohorts was 6.7 months and 10.0 months, respectively (P

Purpose: To determine prognostic factors for local control of primary or metastatic tumors within the lung or liver treated with stereotactic body radiation therapy (SBRT) within a single institution. Methods and Materials: The records of 141 consecutive patients with 246 lesions treated with three-fraction SBRT from Oct 1999 through Aug 2005 were reviewed. Local control was assessed radiographically. Univariate and multivariate analyses were performed to evaluate the influence of the following factors on local control: total dose, expressed as either nominal prescription dose or equivalent uniform dose (EUD); gross tumor volume; primary site; treatment site (lung vs. other); histologic characteristics (adenocarcinoma vs. other); gender; age; and primary vs. metastatic tumor. Results: On univariate analysis, increased dose (either nominal or EUD) and smaller gross tumor volume were significant predictors of higher local control. Lesions treated to a nominal dose of 54 Gy or greater had a 3-year actuarial local control rate of 89.3% compared with 59.0% and 8.1% for those treated to 36–53.9 Gy and less than 36 Gy. On multivariate analysis, only increased nominal dose and EUD retained statistical significance. Treatment was well tolerated; 5.7% of patients experienced Grade 3 or higher toxicity. Conclusions: This large single-institution series suggests a dose–control relationship within the range of SBRT doses applied. Excellent local control rates are achieved with a nominal dose of 54 Gy or greater, corresponding to an EUD greater than 65.3 Gy. These results support the use of aggressive SBRT regimens when durable tumor control is the primary objective. [Copyright &y& Elsevier]

Purpose: The purpose of this study is to introduce a new prognostic index for patients with brain metastases and compare it with three published indices. Treatment for brain metastases varies widely. A sound prognostic index is thus important to guide both clinical decision making and outcomes research. Methods and Materials: A new index was developed because of limitations in the three existing indices and new data (Radiation Therapy Oncology Group 9508) are available since the others were developed. All four indices were compared using the Radiation Therapy Oncology Group database of 1,960 patients with brain metastases from five randomized trials. The ability of the four indices to distinguish its separate classes was determined statistically. Advantages and disadvantages of each index are discussed. Results: Recursive partitioning analysis (RPA) and the new Graded Prognostic Assessment (GPA) had the most statistically significant differences between classes (p < 0.001 for all classes). Conclusions: The new index, the GPA, is as prognostic as the RPA and more prognostic than the other indices. The GPA is the least subjective, most quantitative and easiest to use of the four indices. Future clinical trials should compare the GPA with the RPA to prospectively validate these findings. [Copyright &y& Elsevier]

Purpose: To describe the radiographic and histopathologic changes after stereotactic radiosurgery (SRS) and epidermal growth factor receptor inhibition in patients with recurrent malignant gliomas. Methods and Materials: A total of 15 patients with recurrent high-grade gliomas were treated on a prospective Phase I trial combining SRS and gefitinib. The SRS dose was escalated from 18 to 36 Gy in three fractions. The planning target volume was the T1-weighted contrast-enhancing (T1C) lesion plus 2 mm. Gefitinib was given at 250 mg daily. Serial brain magnetic resonance imaging scans were analyzed to characterize the volumetric changes in the T1C and T2 abnormalities after treatment. Two patients underwent resection for suspected recurrence. Results: The median pretreatment magnetic resonance imaging T1C and T2 volume was 40.9 and 184.1 cm3, respectively. The median post-SRS percentage of increases in the T1C volume at 1, 2–4, and 5–7 months was 8.9%, 41.3%, and 99.6%, respectively. The median percentage increase in the T2 volume likewise showed a trend upward after SRS, from 18.0% at 1 month to 37.8% at 5–7 months. For the 2 patients who underwent resection after SRS for an increasing T1C volume, the histopathologic analysis revealed therapy-induced vascular injury and necrosis. One patient with an asymptomatic increase in the T1C volume after SRS was treated conservatively. After a peak T1C volume increase at 9 months, the T1C volume had declined to 50% of the maximal volume at 15 months. The patients with the most dramatic increase in T1C volume experienced the longest overall survival. Conclusion: Patients experienced a notable increase in magnetic resonance imaging T1C and T2 volumes after the combination of SRS and epidermal growth factor receptor inhibition. The tissue changes were consistent with a potent treatment effect. [Copyright &y& Elsevier]

Purpose: To determine the maximum tolerated dose (MTD) of fractionated stereotactic radiosurgery (SRS) with gefitinib in patients with recurrent malignant gliomas. Methods and Materials: A Phase I clinical trial was performed. Eligible patients had pathologically proved recurrent anaplastic astrocytoma or glioblastoma. Patients started gefitinib (250 mg/day) 7 days before SRS and continued for 1 year or until disease progression. SRS was delivered in three fractions over 3 days. The planning target volume (PTV) was the T1-weighted MRI postcontrast enhancing lesion + 2 mm. The first cohort received an SRS dose of 18 Gy, and subsequent cohorts received higher doses up to the maximum dose of 36 Gy. Dose-limiting toxicity (DLT) was any Grade 3 toxicity. The MTD was exceeded if 2 of 6 patients in a cohort experienced DLT. Results: Characteristics of the 15 patients enrolled were: 9 men, 6 women; median age, 47 years (range, 23–65 years); 11 glioblastoma, 4 AA; median prior RT dose, 60 Gy (range, 54–61.2 Gy); median interval since RT, 12 months (range, 3–57 months); median PTV, 41 cc (range, 12–151 cc). Median follow-up time was 7 months (range, 2–28 months). Median time on gefitinib was 5 months (range, 2–12 months). No patient experienced a DLT, and the SRS dose was escalated from 18 to 36 Gy. Grade 1–2 gefitinib-related dermatitis and diarrhea were common (10 and 7 patients, respectively). Conclusion: Fractionated SRS to a dose of 36 Gy in three fractions is well tolerated with gefitinib at daily dose of 250 mg. Further studies of SRS and novel molecular targeted agents are warranted in this challenging clinical setting. [Copyright &y& Elsevier]

: PurposeTo analyze the relative contributions of uniformly collected pretreatment patient- and tumor-related variables to survival and to identify the terminal nodes via recursive partitioning analysis (RPA) that could be used as a stratification variable for future Phase III trials.: Methods and materialsFrom two Intergroup trials (85-01, n = 130; and 94-05, n = 218) and one Radiation Therapy Oncology Group trial (92-07, n = 68), we identified 416 patients who were treated with definitive concomitant cisplatin and 5-FU–based chemoradiotherapy and analyzed their data for survival by RPA to define prognostic classes. The following pretreatment factors were evaluated: histologic type, age, weight loss, Karnofsky performance status, gender, race, T stage, tumor location, tumor size, N stage, and degree of dysphagia. The entire data set was considered as the initial node. The criterion for split points was the smallest p value less than unadjusted 0.05.: ResultsOf the 416 patients, 336 (81%) were dead at the time of the analysis. The RPA identified only one significant split: pretreatment weight loss in the prior 6 months of <10% vs. ≥10%. After adjusting for multiple comparisons, no other split approached statistical significance.: ConclusionUnlike our experience with malignant glioma, brain metastases, and locally advanced non–small-cell lung cancer, RPA failed to identify novel prognostic information that could be incorporated into the stratification scheme of future chemoradiotherapy trials for esophageal cancer. Furthermore, our analysis validated the percentage of weight loss as a stratification variable for esophageal cancer. [Copyright &y& Elsevier]