Samuel T. Chao

Summary Report on the Graded Prognostic Assessment: An Accurate and Facile Diagnosis-Specific Tool to Estimate Survival for Patients With Brain Metastases

PURPOSE Our group has previously published the Graded Prognostic Assessment (GPA), a prognostic index for patients with brain metastases. Updates have been published with refinements to create diagnosis-specific Graded Prognostic Assessment indices. The purpose of this report is to present the updated diagnosis-specific GPA indices in a single, unified, user-friendly report to allow ease of access and use by treating physicians. METHODS A multi-institutional retrospective (1985 to 2007) database of 3,940 patients with newly diagnosed brain metastases underwent univariate and multivariate analyses of prognostic factors associated with outcomes by primary site and treatment. Significant prognostic factors were used to define the diagnosis-specific GPA prognostic indices. A GPA of 4.0 correlates with the best prognosis, whereas a GPA of 0.0 corresponds with the worst prognosis. RESULTS Significant prognostic factors varied by diagnosis. For lung cancer, prognostic factors were Karnofsky performance score, age, presence of extracranial metastases, and number of brain metastases, confirming the original Lung-GPA. For melanoma and renal cell cancer, prognostic factors were Karnofsky performance score and the number of brain metastases. For breast cancer, prognostic factors were tumor subtype, Karnofsky performance score, and age. For GI cancer, the only prognostic factor was the Karnofsky performance score. The median survival times by GPA score and diagnosis were determined. CONCLUSION Prognostic factors for patients with brain metastases vary by diagnosis, and for each diagnosis, a robust separation into different GPA scores was discerned, implying considerable heterogeneity in outcome, even within a single tumor type. In summary, these indices and related worksheet provide an accurate and facile diagnosis-specific tool to estimate survival, potentially select appropriate treatment, and stratify clinical trials for patients with brain metastases.

Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients.

PURPOSE Controversy endures regarding the optimal treatment of patients with brain metastases (BMs). Debate persists, despite many randomized trials, perhaps because BM patients are a heterogeneous population. The purpose of the present study was to identify significant diagnosis-specific prognostic factors and indexes (Diagnosis-Specific Graded Prognostic Assessment [DS-GPA]). METHODS AND MATERIALS A retrospective database of 5,067 patients treated for BMs between 1985 and 2007 was generated from 11 institutions. After exclusion of the patients with recurrent BMs or incomplete data, 4,259 patients with newly diagnosed BMs remained eligible for analysis. Univariate and multivariate analyses of the prognostic factors and outcomes by primary site and treatment were performed. The significant prognostic factors were determined and used to define the DS-GPA prognostic indexes. The DS-GPA scores were calculated and correlated with the outcomes, stratified by diagnosis and treatment. RESULTS The significant prognostic factors varied by diagnosis. For non-small-cell lung cancer and small-cell lung cancer, the significant prognostic factors were Karnofsky performance status, age, presence of extracranial metastases, and number of BMs, confirming the original GPA for these diagnoses. For melanoma and renal cell cancer, the significant prognostic factors were Karnofsky performance status and the number of BMs. For breast and gastrointestinal cancer, the only significant prognostic factor was the Karnofsky performance status. Two new DS-GPA indexes were thus designed for breast/gastrointestinal cancer and melanoma/renal cell carcinoma. The median survival by GPA score, diagnosis, and treatment were determined. CONCLUSION The prognostic factors for BM patients varied by diagnosis. The original GPA was confirmed for non-small-cell lung cancer and small-cell lung cancer. New DS-GPA indexes were determined for other histologic types and correlated with the outcome, and statistical separation between the groups was confirmed. These data should be considered in the design of future randomized trials and in clinical decision-making.

The sensitivity and specificity of FDG PET in distinguishing recurrent brain tumor from radionecrosis in patients treated with stereotactic radiosurgery

Radiation necrosis and recurrent brain tumor have similar symptoms and are indistinguishable on both magnetic resonance imaging (MRI) and computed tomograph scans. 18F‐fluorodeoxyglucose (FDG) positron emission tomography (PET) has been proposed as a diagnostic alternative, particularly when co‐registered with MRI. We studied 47 patients with brain tumors treated with stereotactic radiosurgery and followed with FDG PET. For all tumor types, the sensitivity of FDG PET for diagnosing tumor was 75% and the specificity was 81%. For brain metastasis without MRI co‐registration, FDG PET had a sensitivity of 65% and a specificity of 80%. For brain metastasis with MRI co‐registration, FDG PET had a sensitivity of 86% and specificity of 80%. MRI co‐registration appears to improve the sensitivity of FDG PET, making it a useful modality to distinguish between radiation necrosis and recurrent brain metastasis.

Effect of Tumor Subtype on Survival and the Graded Prognostic Assessment for Patients With Breast Cancer and Brain Metastases

PURPOSE The diagnosis-specific Graded Prognostic Assessment (GPA) was published to clarify prognosis for patients with brain metastases. This study refines the existing Breast-GPA by analyzing a larger cohort and tumor subtype. METHODS AND MATERIALS A multi-institutional retrospective database of 400 breast cancer patients treated for newly diagnosed brain metastases was generated. Prognostic factors significant for survival were analyzed by multivariate Cox regression and recursive partitioning analysis (RPA). Factors were weighted by the magnitude of their regression coefficients to define the GPA index. RESULTS Significant prognostic factors by multivariate Cox regression and RPA were Karnofsky performance status (KPS), HER2, ER/PR status, and the interaction between ER/PR and HER2. RPA showed age was significant for patients with KPS 60 to 80. The median survival time (MST) overall was 13.8 months, and for GPA scores of 0 to 1.0, 1.5 to 2.0, 2.5 to 3.0, and 3.5 to 4.0 were 3.4 (n = 23), 7.7 (n = 104), 15.1 (n = 140), and 25.3 (n = 133) months, respectively (p < 0.0001). Among HER2-negative patients, being ER/PR positive improved MST from 6.4 to 9.7 months, whereas in HER2-positive patients, being ER/PR positive improved MST from 17.9 to 20.7 months. The log-rank statistic (predictive power) was 110 for the Breast-GPA vs. 55 for tumor subtype. CONCLUSIONS The Breast-GPA documents wide variation in prognosis and shows clear separation between subgroups of patients with breast cancer and brain metastases. This tool will aid clinical decision making and stratification in clinical trials. These data confirm the effect of tumor subtype on survival and show the Breast-GPA offers significantly more predictive power than the tumor subtype alone.

Challenges With the Diagnosis and Treatment of Cerebral Radiation Necrosis

The incidence of radiation necrosis has increased secondary to greater use of combined modality therapy for brain tumors and stereotactic radiosurgery. Given that its characteristics on standard imaging are no different that tumor recurrence, it is difficult to diagnose without use of more sophisticated imaging and nuclear medicine scans, although the accuracy of such scans is controversial. Historically, treatment had been limited to steroids, hyperbaric oxygen, anticoagulants, and surgical resection. A recent prospective randomized study has confirmed the efficacy of bevacizumab in treating radiation necrosis. Novel therapies include using focused interstitial laser thermal therapy. This article will review the diagnosis and treatment of radiation necrosis.

Aggressive treatment is appropriate for glioblastoma multiforme patients 70 years old or older: a retrospective review of 206 cases *

Elderly patients have largely been excluded from randomized trials for glioblastoma multiforme (GBM). We reviewed the results of treatment approaches, which included surgery, chemotherapy, and radiation in this group of patients. Patients were treated during the period 1979-2007 and were 70 years of age and older with histologically confirmed GBM. Overall survival (OS) was the primary endpoint of this retrospective study. Two hundred six patients 70 years of age and older were identified. Median age was 75 years (range 70-90). Median OS time was 4.5 months. Univariate analysis showed that OS was significantly impacted by KPS score (1.8 months for KPS ≤ 50 to 17.2 months for KPS ≥ 90, P < .001), age at diagnosis (5.1 months for age 70-79 versus 3.1 months for age ≥ 80, P < .001), and extent of disease (worse for bilateral disease [P = .003], multifocal disease [P = .005], and multicentric disease [P = .02]). On multivariate analysis, higher KPS score (P = .006), surgical resection (any surgery beyond biopsy) (P < .001), radiation therapy (P < .001), and chemotherapy (P < .001) were all found to be independently associated with improved OS. In this study of newly diagnosed glioblastoma patients over the age of 70 years, aggressive treatment with radiation, chemotherapy, and surgery is associated with OS.

Salvage stereotactic radiosurgery effectively treats recurrences from whole-brain radiation therapy.

The purpose of the current study was to examine overall survival (OS) and time to local failure (LF) in patients who received salvage stereotactic radiosurgery (SRS) for recurrent brain metastases (BM) after initial management that included whole‐brain radiation therapy (WBRT).

Long-Term Experience With World Health Organization Grade III (Malignant) Meningiomas at a Single Institution

PURPOSE To evaluate the outcomes for patients with Grade III meningiomas as defined by the 2007 World Health Organization standards. METHODS AND MATERIALS The slides from patients who had been treated at the Cleveland Clinic for malignant meningiomas were reviewed by a single neuropathologist. The data from 13 patients treated between 1984 and 2006 satisfied the World Health Organization 2007 definition of Grade III meningioma. A total of 24 surgeries were performed, including 13 primary, 7 salvage, and 4 second salvage. Also, 14 courses of radiotherapy (RT) were administered, including fractionated RT in 3 patients after primary surgery, fractionated RT in 4 patients after salvage surgery, salvage stereotactic radiosurgery to six separate areas in 3 patients, and salvage intensity-modulated RT in 1 patient. RESULTS From the primary surgery, the median survival was 3.4 years, the 5-year survival rate was 47.2%, and the 8-year survival rate was 12.2%. The median time to recurrence was 9.6 months. A trend was seen toward longer survival for patients who had received adjuvant RT after initial surgery compared with those treated with surgery alone. Two patients developed radiation necrosis, and three had surgical complications. CONCLUSION This is one of the few studies reporting the outcomes for malignant meningioma patients according to recent definitions. Our results are consistent with existing reports of the overall poor outcomes for atypical and malignant meningioma patients. From the available data, surgical resection followed by RT and salvage therapy can lead to extended survival.

Recursive Partitioning Analysis Index Is Predictive for Overall Survival in Patients Undergoing Spine Stereotactic Body Radiation Therapy for Spinal Metastases

PURPOSE To generate a prognostic index using recursive partitioning analysis (RPA) for patients undergoing spine stereotactic body radiation therapy (sSBRT) for spinal metastases (sMet). METHODS & MATERIALS From an institutional review board-approved database, 174 patients were treated for sMet with sSBRT between February 2006 and August 2009. Median dose was 14 Gy (range, 8-24 Gy), typically in a single fraction (range, 1-5). Kaplan-Meier analysis was performed to detect any correlation between survival and histology. Histologies were divided into favorable (breast and prostate), radioresistant (renal cell, melanoma and sarcoma), and other (all other histologies). RPA was performed to identify any association of the following variables with overall survival (OS) following sSBRT: histology, gender, age, Karnofsky performance status (KPS), control of primary, extraosseous metastases, time from primary diagnosis (TPD), dose of sSBRT (≤14 Gy vs. >14 Gy), extent of spine disease (epidural only, bone and epidural, bone only), upfront or salvage treatment, presence of paraspinal extension, and previous surgery. RESULTS Median follow-up was 8.9 months. Median OS time from sSBRT was 10.7 months. Median OS intervals for favorable histologies were 14 months, 11.2 months for radioresistant histologies, and 7.3 months for other histologies (p = 0.02). RPA analysis resulted in three classes (p < 0.0001). Class 1 was defined as TPD of >30 months and KPS of >70; Class 2 was TPD of >30 months and KPS of ≤70 or a TPD of ≤30 months and age <70 years old; Class 3 was TPD of ≤30 months and age ≥70 years old. Median OS was 21.1 months for Class 1 (n = 59), 8.7 months for Class 2 (n = 104), and 2.4 months for Class 3 (n = 11). CONCLUSION sSBRT patients treated for sMet have a wide variability in OS. We developed an RPA classification system that is predictive of OS. While many patients are treated for palliation of pain or to avoid symptomatic progression, this index may be used to predict which patients may benefit most from sSBRT.

Single-fraction stereotactic body radiotherapy for spinal metastases from renal cell carcinoma

OBJECT Stereotactic body radiotherapy (SBRT) has emerged as an important treatment option for spinal metastases from renal cell carcinoma (RCC) as a means to overcome RCCs inherent radioresistance. The authors reviewed the outcomes of SBRT for the treatment of RCC metastases to the spine at their institution, and they identified factors associated with treatment failure. METHODS Fifty-seven patients (88 treatment sites) with RCC metastases to the spine received single-fraction SBRT. Pain relief was based on the Brief Pain Inventory and was adjusted for narcotic use according to the Radiation Therapy Oncology Group protocol 0631. Toxicity was scored according to Common Toxicity Criteria for Adverse Events version 4.0. Radiographic failure was defined as infield or adjacent (within 1 vertebral body [VB]) failure on follow-up MRI. Multivariate analyses were performed to correlate outcomes with the following variables: epidural, paraspinal, single-level, or multilevel disease (2-5 sites); neural foramen involvement; and VB fracture prior to SBRT. Kaplan-Meier analysis and Cox proportional hazards modeling were used for statistical analysis. RESULTS The median follow-up and survival periods were 5.4 months (range 0.3-38 months) and 8.3 months (range 1.5-38 months), respectively. The median time to radiographic failure and unadjusted pain progression were 26.5 and 26.0 months, respectively. The median time to pain relief (from date of simulation) and duration of pain relief (from date of treatment) were 0.9 months (range 0.1-4.4 months) and 5.4 months (range 0.1-37.4 months), respectively. Multivariate analyses demonstrated that multilevel disease (hazard ratio [HR] 3.5, p = 0.02) and neural foramen involvement (HR 3.4, p = 0.02) were correlated with radiographic failure; multilevel disease (HR 2.3, p = 0.056) and VB fracture (HR 2.4, p = 0.046) were correlated with unadjusted pain progression. One patient experienced Grade 3 nausea and vomiting; no other Grade 3 or 4 toxicities were observed. Twelve treatment sites (14%) were complicated by subsequent vertebral fractures. CONCLUSIONS Stereotactic body radiotherapy for RCC metastases to the spine offers fast and durable pain relief with minimal toxicity. Stereotactic body radiotherapy seems optimal for patients who have solitary or few spinal metastases. Patients with neural foramen involvement are at an increased risk for failure.