Implant volume as a prognostic variable in brachytherapy decision-making for malignant gliomas stratified by the RTOG recursive partitioning analysis.

PURPOSE: When an initial retrospective review of malignant glioma patients (MG) undergoing brachytherapy was carried out using the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) criteria, it revealed that glioblastoma multiforme (GBM) cases benefit the most from implant. In the present study, we focused exclusively on these GBM patients stratified by RPA survival class and looked at the relationship between survival and implanted target volume, to distinguish the prognostic value of volume in general and for a given GBM class. METHODS AND MATERIALS: Between 1991 and 1998, 75 MG patients were treated with surgery, external beam radiation, and stereotactic iodine-125 (I-125) implant. Of these, 53 patients (70.7%) had GBMs, with 52 (98%) having target volume (TV) data for analysis. Stratification by RPA criteria showed 12, 26, 13, and 1 patients in classes III to VI, respectively. For analysis purposes, classes V and VI were merged. There were 27 (51.9%) male and 25 (48.1%) female patients. Mean age was 57.5 years (range 14-79). Median Karnofsky performance status (KPS) was 90 (range 50-100). Median follow-up time was 11 months (range 2-79). RESULTS: At analysis, 18 GBM patients (34.6%) were alive and 34 (65.4%) were dead. Two-year and 5-year survivals were 42% and 17.5%, respectively, with a median survival time (MST) of 16 months. Two-year survivals and MSTs for the implanted GBM patients compared to the RTOG database were as follows: 74% vs. 35% and 28 months vs. 17.9 months for class III; 32% vs. 15% and 16 months vs. 11.1 months for class IV; 29% vs. 6% and 11 months vs. 8.9 months for class V/VI. Mean implanted TV was 15.5 cc (range 0.8-78), which corresponds to a spherical implant diameter of 3.1 cm. Plotting survival as a function of 5-cc TV increments suggested a trend toward poorer survival as the implanted volume increases. The impact of incremental changes in TV on survival within a given RPA class of GBMs was compared to the RTOG database. Looking at absolute differences in MSTs: for classes III and IV, there was little effect of different TVs on survival; for class V/VI, a survival benefit to implantation was still seen at the target volume cutoff (TV > 25 cc). Within a given RPA class, no significant differences were found within class III; for class IV, the most significant difference was at 10 cc (p = 0.05); and for class V/VI, at 20 cc (p = 0.06). CONCLUSION: For all GBM patients, an inverse relationship between implanted TV size and median survival is suggested by this study. However, when GBM patients are stratified using the RTOG's RPA criteria, the prognostic effect of implant volume disappears within each RPA survival class. At the critical volume of 25 cc, which approximates an implant of 5-cm diameter (upper implantation limit of many CNS brachytherapy protocols), the "poorest" prognosis GBM patients stratified by RPA still demonstrate a survival benefit with implant. We suggest that any GBM patient meeting brachytherapy recognized size criteria be considered for I-125 implant.     

Radiotherapy is effective in patients with glioblastoma multiforme with a limited prognosis and in patients above 70 years of age: a retrospective single institution analysis.

BACKGROUND AND PURPOSE: To evaluate the efficacy of radiotherapy in patients with glioblastoma multiforme (GBM) with a limited prognosis and in patients older than 70 years. PATIENTS AND METHODS: Retrospective analysis of 202 patients with GBM treated between 1990 and 2000 in a single institution. Patients (including patients >or=70 years) were assigned to RPA groups and their survival was compared with RTOG data. RESULTS: Median survival was 8.0 months for the total group and 13.9, 10.6, 3.8, 2.1 months for RPA group III (n=17), IV (n=87), V (n=60) and VI (n=38), respectively. Median survival for patients >or=70 years was 3.6 vs. 8.1 months for 50--70 years and 11.0 months for <50. In each separate RPA group, patients >or=70 years had a similar survival compared to patients of 50--70 years. Irradiated patients (66%) survived significantly longer than non-irradiated patients: 10.6 vs. 1.9 months (P<0.0001). In RPA group V the median survival for irradiated patients was 9.4 vs. 2.1 months for non-irradiated patients. In a multivariate analysis, RT remained the only prognostic factor for survival (HR 8.9, P<0.001). CONCLUSIONS: Prognosis for patients above 70 years of age is not different from younger patients, when analyzed for separate RPA groups. For patients with a poor prognosis (i.e. RPA group V), radiotherapy improves survival significantly.     

Survival following CyberKnife radiosurgery and hypofractionated radiotherapy for newly diagnosed glioblastoma multiforme

Current therapeutic goals for treatment of Glioblastoma Multiforme (GBM) involve gross total resection followed by multifractionated focal external beam radiation therapy (EBRT). Patients treated with optimal therapy have a median survival of approximately 12-15 months. In the present study, we sought to determine whether a hypofractionated dosing schedule using CyberKnife is at least as effective as multifractionated focal EBRT. A retrospective analysis was conducted on 20 histopathologically confirmed GBM patients treated with CyberKnife at Okayama Kyokuto Hospital in Japan after gross total resection (n=11), subtotal resection (n=8), or biopsy (n=1). Eight patients also received adjuvant ACNU and Vincrisitine chemotherapy according to local protocol; however, no patient received any other form of radiation besides post surgical/biopsy CyberKnife treatment. The treated tumor volumes ranged from 9.62 cm(3)-185.81 cm(3) (mean: 86.08 cm(3)). The marginal dose (D90) ranged from 19.99 Gy-41.47 Gy (mean: 34.58 Gy) with a maximum mean dose of 43.99 Gy (range: 23.33 Gy-56.89 Gy). The prescribed isodose line ranged from 50.38%-85.68% with a mean of 79.25%. Treatment was delivered in 1-8 fractions (mean: 5.65). Patients were followed from 2-36 months (mean: 16.45 months). Overall median survival was 16 months with 55% of patients alive at 12 months and 34% of patients alive at 24 months. Median survival of patients in Recursive Partitioning Analysis (RPA) classes III or IV was 32 months versus 12 months for those in RPA class V. Median survival for patients who received gross total resection was 36 months versus 8 months for those who underwent subtotal resection or biopsy. The results of this study using CyberKnife stereotactic radiosurgery (SRS) and hypofractionated radiotherapy compared favorably to historic data using focal EBRT in newly diagnosed post surgical GBM patients. A larger prospective analysis that compares CyberKnife SRS and hypofractionated radiotherapy to focal EBRT is warranted.     

Epidermal growth factor receptor amplification does not have prognostic significance in patients with glioblastoma multiforme

PURPOSE: There have been conflicting reports in the literature regarding the prognostic significance of epidermal growth factor receptor (EGFR) amplification in patients with glioblastoma multiforme (GBM). The purpose of this study is to determine the prognostic significance of EGFR amplification in patients with GBM treated at the Cleveland Clinic Foundation. METHODS AND MATERIALS: A retrospective review of GBM patients treated with surgery at the Cleveland Clinic Foundation was performed. Amplification of EGFR was evaluated with fluorescence in situ hybridization in a total of 107 patients diagnosed between December 1995 and May 2003. In addition to EGFR status, various prognostic factors were evaluated to determine the factors that influenced survival and radiographic response rate. The median follow-up was 9 months. RESULTS: The overall median survival was 9.8 months, with a 1-year survival of 40%. Of the 107 patients in whom EGFR status was evaluated, 36 (33.6%) were found to have EGFR amplification. On multivariate analysis, median survival was found to be significantly improved for patients with age < 60 (12.6 months vs. 8 months, p = 0.0061), patients with Karnofsky Performance Status > or = 70 (12.1 months vs. 4.4 months, p < 0.0001), patients who had undergone subtotal resection or gross total resection (11.1 months vs. 4.1 months, p = 0.002), and patients who received a radiation dose > or = 60 Gy compared with no radiation (12.7 months vs. 3 months, p < 0.0001). There was no association of EGFR amplification with survival. When stratified by age (< 60 vs. > or = 60), EGFR status still did not reach statistical significance in predicting for survival. For the 81 patients who had radiographic follow-up, the 1-year overall local control was 14%. On univariate analysis, only treatment with radiation (< 60 Gy vs. > or = 60 Gy vs. no radiation, p = 0.03) was found to predict for improved local control. Treatment with radiation did not remain statistically significant on multivariate analysis. CONCLUSION: Epidermal growth factor receptor amplification was not found to be a significant prognostic indicator of overall survival or radiographic local control in patients with GBM treated with surgery at the Cleveland Clinic Foundation. Further studies are needed to fully delineate the significance of this molecular marker in patients with GBM.     

Radiotherapy and temozolomide for newly diagnosed glioblastoma and anaplastic astrocytoma: validation of Radiation Therapy Oncology Group-Recursive Partitioning Analysis in the IMRT and temozolomide era

Since the development of the Radiation Therapy Oncology Group-Recursive Partitioning Analysis (RTOG-RPA) risk classes for high-grade glioma, radiation therapy in combination with temozolomide (TMZ) has become standard care. While this combination has improved survival, the prognosis remains poor in the majority of patients. Therefore, strong interest in high-grade gliomas from basic research to clinical trials persists. We sought to evaluate whether the current RTOG-RPA retains prognostic significance in the TMZ era or alternatively, if modifications better prognosticate the optimal selection of patients with similar baseline prognosis for future clinical protocols. The records of 159 patients with newly-diagnosed glioblastoma (GBM, WHO grade IV) or anaplastic astrocytoma (AA, WHO grade III) were reviewed. Patients were treated with intensity-modulated radiation therapy (IMRT) and concurrent followed by adjuvant TMZ (n = 154) or adjuvant TMZ only (n = 5). The primary endpoint was overall survival. Three separate analyses were performed: (1) application of RTOG-RPA to the study cohort and calculation of subsequent survival curves, (2) fit a new tree model with the same predictors in RTOG-RPA, and (3) fit a new tree model with an expanded predictor set. All analyses used a regression tree analysis with a survival outcome fit to formulate new risk classes. Overall median survival was 14.9 months. Using the RTOG-RPA, the six classes retained their relative prognostic significance and overall ordering, with the corresponding survival distributions significantly different from each other (P < 0.01, χ² statistic = 70). New recursive partitioning limited to the predictors in RTOG-RPA defined four risk groups based on Karnofsky Performance Status (KPS), histology, age, length of neurologic symptoms, and mental status. Analysis across the expanded predictors defined six risk classes, including the same five variables plus tumor location, tobacco use, and hospitalization during radiation therapy. Patients with excellent functional status, AA, and frontal lobe tumors had the best prognosis. For patients with newly-diagnosed high-grade gliomas, RTOG-RPA classes retained prognostic significance in patients treated with TMZ and IMRT. In contrast to RTOG-RPA, in our modified RPA model, KPS rather than age represented the initial split. New recursive partitioning identified potential modifications to RTOG-RPA that should be further explored with a larger data set.     

Validation of the RTOG recursive partitioning analysis (RPA) classification for brain metastases

PURPOSE: The Radiation Therapy Oncology Group (RTOG) previously developed three prognostic classes for brain metastases using recursive partitioning analysis (RPA) of a large database. These classes were based on Karnofsky performance status (KPS), primary tumor status, presence of extracranial system metastases, and age. An analysis of RTOG 91-04, a randomized study comparing two dose-fractionation schemes with a comparison to the established RTOG database, was considered important to validate the RPA classes. METHODS AND MATERIALS: A total of 445 patients were randomized on RTOG 91-04, a Phase III study of accelerated hyperfractionation versus accelerated fractionation. No difference was observed between the two treatment arms with respect to survival. Four hundred thirty-two patients were included in this analysis. The majority of the patients were under age 65, had KPS 70-80, primary tumor controlled, and brain-only metastases. The initial RPA had three classes, but only patients in RPA Classes I and II were eligible for RTOG 91-04. RESULTS: For RPA Class I, the median survival time was 6. 2 months and 7.1 months for 91-04 and the database, respectively. The 1-year survival was 29% for 91-04 versus 32% for the database. There was no significant difference in the two survival distributions (p = 0.72). For RPA Class II, the median survival time was 3.8 months for 91-04 versus 4.2 months for the database. The 1-year survival was 12% and 16% for 91-04 and the database, respectively (p = 0.22). CONCLUSION: This analysis indicates that the RPA classes are valid and reliable for historical comparisons. Both the RTOG and other clinical trial organizers should currently utilize this RPA classification as a stratification factor for clinical trials.     

RPA classification has prognostic significance for surgically resected single brain metastasis

PURPOSE: To retrospectively evaluate prognostic factors that correlate with overall survival among patients with a surgically resected single brain metastasis. METHODS AND MATERIALS: An Institutional Review Board-approved database of the Cleveland Clinic Brain Tumor Institute was queried for patients with a single brain metastasis treated by surgical resection between February 1984 and January 2004. The primary endpoint was overall survival from the date of surgery by the Kaplan-Meier method. RESULTS: A total of 271 patients were included. Statistically significant variables for improved survival on multivariate analysis included age <65 years, lack of extracranial metastases, control of primary tumor, histology (non-small-cell lung carcinoma), and use of stereotactic radiosurgery. The median survival for all patients was 10.2 months. Survival of patients in recursive partitioning analysis (RPA) class 1 was better (21.4 months) than those in RPA class 2 (9.0 months, p < 0.001), RPA class 3 (8.9 months, p = 0.15), or the combined group of RPA classes 2 and 3 (9.0 months, p < 0.001). Patients had a median survival of 10.6 months after documented gross total resection and 8.7 months after subtotal resection, which approached statistical significance (p = 0.07). Those who were treated with stereotactic radiosurgery had a median survival of 17.1 months, which was greater than patients who were not treated with stereotactic radiosurgery (8.9 months, p = 0.006). CONCLUSIONS: This analysis supports the prognostic significance of the RPA classification in patients with a single brain metastasis who undergo surgical resection and adjuvant therapy. RPA class 1 patients have a very favorable prognosis with a median survival of 21.4 months.     

Survival Analysis of Glioblastoma Multiforme

Introduction: To evaluate the survival of Glioblastoma Multiforme (GBM). Material and Methods: Patients witha pathological diagnosis of Glioblastoma Multiforme (GBM) between 1 January 1994 and 30 November 2013, wereretrospectively reviewed. Inclusion criteria: 1) GBM patients with confirmed pathology, 2) GBM patients were treatedby multimodality therapy. Exclusion criteria: 1) GBM patients with unconfirmed pathology, 2) GBM patients with spinalinvolvement, 3) GBM patients with incomplete data records. Seventy-seven patients were treated by multimodalitytherapy such as surgery plus post-operative radiotherapy (PORT), post-operative Temozolomide (TMZ) concurrent withradiotherapy (CCRT), post-operative CCRT with adjuvant TMZ. The overall survival was calculated by the Kaplan-Meiermethod and the log-rank test was used to compare the survival curves. A p-value of ≤ 0.05 was considered to bestatistically significant. Results: Seventy-seven patients with a median age of 53 years (range 4-76 years) showeda median survival time (MST) of 12 months. In subgroup analyses, the PORT patients revealed a MST of 11 monthsand 2 year overall survival (OS) rates were 17.2%, the patients with post-operative CCRT with or without adjuvantTMZ revealed a MST of 23 months and 2 year OS rates were 38.2%. The MST of patients by Recursive PartitioningAnalysis (RPA), classifications III, IV, V, VI were 26.8 months, 14.2 months, 9.9 months, and 4.0 months, (p <0.001).Conclusions: The MST of the patients who had post-operative CCRT with or without adjuvant TMZ was better thanthe PORT group. The RPA classification can be used to predict survival. Multimodality therapy demonstrated the mosteffective treatment outcome. Temozolomide might be beneficial for GBM patients in order to increase survival time.     

Phase 2 trial of radiation plus high-dose tamoxifen for glioblastoma multiforme: RTOG protocol BR-0021

Preclinical studies support the concept that inhibition of protein kinase C (PKC) by tamoxifen (TAM) should provide both antineoplastic effects and radiosensitization. High-dose TAM (80 mg/m2 p.o. daily in divided doses) was given with and after conventional radiotherapy (XRT) to inhibit PKC-mediated signaling, which is known to be enhanced in glioblastoma (GBM). Seventy-seven patients were accrued between December 2000 and December 2001; two were ineligible and not included in the efficacy results. Pretreatment characteristics of the patients included the following: 52% were less than 60 years of age, 39% had a Zubrod score of 0, 70% had minor or no neurological symptoms, and 65% were Radiation Therapy Oncology Group-recursive partition analysis (RPA) class III and IV. Eighty-six percent of patients achieved acceptable dosing of TAM. Notable toxicity included late radiation grade 3 in two patients and thromboembolic events in 16 patients (two grade 2, 10 grade 3, three grade 4, and one grade 5), for an incidence of 20.8% (which is lower than expected, based on the literature for deep vein thrombophlebitis in GBM patients not receiving TAM). Median survival time (MST) was 9.7 months as compared (by three different statistical methodologies) to the historical GBM control database of 1457 RPA class III, IV, and V drug/XRT-treated patients. After controlling for RPA class IV, the MST was 11.3 months, which compares to the historical RPA control of 11.3 months (P = 0.37). The results obtained do not exhibit a substantial advance over those of previous studies with various XRT/drug doublets, including BCNU. However, as TAM does not have significant overlapping toxicities with most other drugs, its testing in a combined modality approach with other medications may be justified in future clinical trials. Historically, the incidence of thromboembolic events in GBM patients is approximately 30%. The lower-than-expected incidence seen here has also been observed in other high-dose TAM GBM studies. We speculate that TAM inhibited the PKC-mediated phosphorylation of coagulation factors.     

Fractionated stereotactic radiotherapy boost and weekly paclitaxel in malignant gliomas clinical and pharmacokinetics results

Management of Malignant Gliomas continues to be a challenge. We prospectively studied the role of adding weekly Paclitaxel to Fractionated Stereotactic Radiation Therapy (FSRT) in the treatment of Malignant Gliomas. Twenty-three Glioblastoma Multiforme and two Anaplastic Astrocytoma were studied. Patients received 46 Gy at 2 Gy/fraction followed by a boost utilizing FSRT at a fraction of 2.5 Gy for 8 fractions. Paclitaxel is delivered concomitantly at 150 mg/m(2) weekly for six cycles. Eighteen patients had pharmacokinetic assays of Paclitaxel levels. All patients were followed until death or for a maximum of 36 months. The overall survival of the whole group was 14 months. The median survival for RPA prognostic classes III, IV, V, and VI were 20, 14, 12, and 11 months. Higher survival (14 months) was noted in the subtherapeutic phenytoin level group compared to 10 months in the therapeutic group (P=0.271). No grade 4 CTCAE (version 3.0) toxicities were observed. Enhanced survival was demonstrated with gross tumor resection (20.8 months), KPS > or =80 (18.7 months) and age < or =60 years (27 months) as compared to subtotal resection or biopsy (12.1 months, P< 0.005), KPS < or =70 (10.8 months, P=0. 005) and older age > 60 (10.46 months, P=0.006), respectively. Our study suggests that: i) the use of weekly Paclitaxel and FSRT in Gliomas is well tolerated with a survival of 14 months; ii) the regimen resulted in improvement of survival of RPA classes IV, V, VI; and iii) the use of FSRT boost may be studied with other chemotherapeutic agents to see if superior results can be attained.     

Phase II radiation therapy oncology group trial of weekly paclitaxel and conventional external beam radiation therapy for supratentorial glioblastoma multiforme

PURPOSE: Fractionated external beam radiotherapy (EBRT) +/- carmustine (BCNU) is the standard of care for patients with glioblastoma multiforme (GBM), but survival results remain poor. Preclinical studies indicate synergy between RT and paclitaxel (TAX) in astrocytoma cell lines. Phase I studies in GBM have demonstrated a maximum tolerated dose for TAX of 225 mg/m(2)/3 h/week x 6, during EBRT, with no exacerbation of typical RT-induced toxicities. The Radiation Therapy Oncology Group (RTOG) therefore mounted a Phase II study to determine the feasibility and efficacy of conventional EBRT and concurrent weekly TAX at its MTD. PATIENTS AND METHODS: Sixty-two patients with histologic diagnosis of GBM were enrolled from 8/16/96 through 3/21/97 in a multi-institutional Phase II trial of EBRT and TAX 225 mg/m(2)/3 h (1-3 h before EBRT), administered the first treatment day of each RT week. Total EBRT dose was 60 Gy (200 cGy/fraction), 5 days per week. A smaller treatment field, to include gross disease plus a margin only, was used after 46 Gy. RESULTS: Sixty-one patients (98%) were evaluable. Median age was 55 years (range, 28-78). Seventy-four percent were > or = 50 years. Recursive partitioning analysis (RPA) Classes III, IV, V, VI included 10 (17%), 21 (34%), 25 (41%), and 5 (8%) patients, respectively. Gross total resection was performed in only 16%. There was no Grade 3 or 4 neutropenia or thrombocytopenia. Hypersensitivity reactions precluding further use of TAX occurred in 4 patients. There were 2 instances of late neurotoxicity (4% Grade 3 or 4). Ninety-one percent of patients received treatment per protocol. Seventy-seven percent completed prescribed treatment (6 weeks). Of 35 patients with measurable disease, CR/PR was observed in 23%, MR in 17%, and SD in 43%. Seventeen percent demonstrated progression at first follow-up. Median potential follow-up time is 20 months. Median survival is 9.7 months, with median survivals for RPA classes III, IV, V, and VI of 16.3, 10.2, 9.5, 2.5 months, respectively. Ten patients remain alive. CONCLUSION: Concurrent full-dose EBRT and weekly high-dose TAX is feasible in the majority of GBM patients. Acute toxicity is acceptable; myelosuppression and peripheral sensory neuropathy are surprisingly modest, despite considerably higher overall dose intensity, compared to that achievable in other disease sites. Median survival by RPA class without prolonged adjuvant therapy is comparable to RTOG controls treated with standard EBRT and BCNU (1 year of BCNU).     

Application of recursive partitioning analysis and evaluation of the use of whole brain radiation among patients treated with stereotactic radiosurgery for newly diagnosed brain metastases

PURPOSE: To evaluate the usefulness of whole brain radiotherapy (WBRT) and of the Radiation Therapy Oncology Group recursive partitioning analysis (RPA) for brain metastases among patients receiving stereotactic radiosurgery (SRS). METHODS AND MATERIALS: A retrospective analysis was performed on 135 patients who underwent linear accelerator (Linac) (n = 73) or Gamma Knife (n = 62) SRS for newly diagnosed brain metastases at the Cleveland Clinic Foundation between 8/89 and 12/98. Univariate and multivariate analyses were performed to evaluate the effects of age, primary site, control of the primary, interval to development of brain metastases (disease-free interval [DFI]), number of brain metastases, presence of extracranial metastases, Karnofsky performance status (KPS), treatment of brain metastases, and RPA class on overall survival. RESULTS: Application of the RPA classification revealed 29 patients fit the criteria for class I, 96 for class II, and 10 for class III. All of the patients underwent SRS. Fifty-seven patients also received WBRT at the time of initial presentation (SRS and immediate WBRT), and 78 patients received WBRT only if CNS relapse occurred (SRS alone). The median survival for all patients was 7.9 months (range: 1.1-90.1), and was 11.2 months for RPA class I compared to 6. 9 months for RPA classes II-III (p = 0.016). Median survival was 10. 5 months following SRS alone compared to 6.4 months following SRS and WBRT (p = 0.07). On univariate analysis, KPS >/= 80% (p = 0.002) and absence of systemic disease (p = 0.013) were also associated with longer survival, whereas control of the primary, DFI, and number of brain metastases did not have an impact. Multivariate analysis revealed only RPA class (p = 0.023) to be an independent predictor for overall survival, whereas treatment group (p = 0.079) was only marginally significant. At 2 years, immediate WBRT improved control at the original site of metastases (80% vs. 52%, p = 0.03) and prevention of new metastatic sites within the brain, 74% vs. 48% (p = 0.06). The 2-year intracranial disease-free survival was 60% following SRS and WBRT compared to only 34% following SRS alone (p = 0.03). CONCLUSIONS: Despite the inherent biases to select more favorable patients for SRS, the RPA class retains its prognostic value. Omission of WBRT from the initial management was not detrimental in terms of overall survival; however, progressive disease occurred in over 50% of patients treated in this manner. Further studies are required to determine which, if any, patients should be considered for SRS with WBRT held in reserve.     

Validation and Predictive Power of Radiation Therapy Oncology Group (RTOG) Recursive Partitioning Analysis Classes for Malignant Glioma Patients: A Report Using RTOG 90-06

Purpose: The recursive partitioning analysis (RPA) classes for malignant glioma patients were previously established using data on over 1500 patients entered on Radiation Therapy Oncology Group (RTOG) clinical trials. The purpose of the current analysis was to validate the RPA classes with a new dataset (RTOG 90-06), determine the predictive power of the RPA classes, and establish the usefulness of the database norms for the RPA classes.Patients and Methods: There are six RPA classes for malignant glioma patients that comprise distinct groups of patients with significantly different survival outcome. RTOG 90-06 is a randomized Phase III study of 712 patients accrued from 1990 to 1994. The minimum potential follow-up is 18 months. The treatment arms were combined for the purpose of this analysis. There were 84, 13, 105, 240, 150, and 23 patients in the RPA Classes I–VI from RTOG 90-06, respectively.Results: The median survival times (MST) and 2-year survival rates for the six RPA classes in RTOG 90-06 are compared to those previously published. The MST and 2-year survival rates for the RTOG RPA classes were within 95% confidence intervals of the 90-06 estimates for Classes I, III, IV, and V. The RPA classes explained 43% of the variation (squared error loss). By comparison, a Cox model explains 30% of the variation. The RPA classes within RTOG 90-06 are statistically distinct with all comparisons exceeding 0.0001, except those involving Class II. A survival analysis from a prior RTOG study indicated that 72.0 Gy had superior outcome to literature controls; analysis of this data by RPA classes indicates the survival results were not superior to the RTOG database norms.Conclusion: The validity of the model is verified by the reliability of the RPA classes to define distinct groups with respect to survival. Further evidence is given by prediction of MST and 2-year survival for all classes except Class II. The RPA classes explained a good portion of the variation in survival outcome in the data. Lack of correlation in RPA Class II between datasets may be an artifact of the small sample size or an indication that this class is not distinct. The validation of the RPA classes attests to their usefulness as historical controls for the comparison of future Phase II results.     

Radiosurgery for patients with brain metastases: a multi-institutional analysis, stratified by the RTOG recursive partitioning analysis method

PURPOSE: To estimate the potential improvement in survival for patients with brain metastases, stratified by the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) class and treated with radiosurgery (RS) plus whole brain radiotherapy (WBRT). METHODS AND MATERIALS: An analysis of the RS databases of 10 institutions identified patients with brain metastates treated with RS and WBRT. Patients were stratified into 1 of 3 RPA classes. Survival was evaluated using Kaplan-Meier estimates and proportional hazard regression analysis. A comparison of survival by class was carried out with the RTOG results in similar patients receiving WBRT alone. RESULTS: Five hundred two patients were eligible (261 men and 241 women, median age 59 years, range 26-83). The overall median survival was 10.7 months. A higher Karnofsky performance status (p = 0.0001), a controlled primary (median survival = 11.6 vs. 8.8 months, p = 0.0023), absence of extracranial metastases (median survival 13.4 vs. 9.1 months, p = 0.0001), and lower RPA class (median survival 16.1 months for class I vs. 10.3 months for class II vs. 8.7 months for class III, p = 0.000007) predicted for improved survival. Gender, age, primary site, radiosurgery technique, and institution were not prognostic. The addition of RS boosted results in median survival (16.1, 10.3, and 8.7 months for classes I, II, and III, respectively) compared with the median survival (7.1, 4.2, and 2.3 months, p <0.05) observed in the RTOG RPA analysis for patients treated with WBRT alone. CONCLUSION: In the absence of randomized data, these results suggest that RS may improve survival in patients with BM. The improvement in survival does not appear to be restricted by class for well-selected patients.     

Survival and outcomes of surgical treatment of the elderly NSCLC in China: a retrospective matched cohort study.

AIM: To compare survival and outcomes of pulmonary resection for elderly NSCLC patients with that of younger controls in China. METHODS: A database which included 4792 NSCLC patients who received complete surgery from 1985 to 2005 was used. The elderly patients (>or=70) were matched 1:1 to controls (<70) by 5 variables: gender; stage; histology; pulmonary resection types; adjuvant chemotherapy. The long-term survival rates, the operative mortality and short-term death after surgery were compared. RESULTS: There were 1304 patients: 652 cases were >or=70. The 5-year OS of elderly was 39%; that of the controls was 45% (p=0.06). Operative mortality rate between elderly and the controls was similar (9/652 vs 4/652 p=0.16) but the short-term death within 2 months after the surgeries were different (23/652 vs 7/652 p=0.003). The elderly with lobectomy had a worse 5-year OS than controls (42% vs 46% p=0.05), but the 5-year OS was similar for patients who received pneumonectomy (24% vs 36% p=0.40) and the limited resections (46% vs 39% p=0.27). The 5-year OS in patients who received adjuvant chemotherapy were similar (49% vs 44% p=0.10). CONCLUSION: Elderly have the similar long-term OS with the controls. They should not be denied the curative surgery and adjuvant chemotherapy based on their chronologic age. However, elderly patients had a higher risk of short-term death after the surgery, which suggests that elderly be given more intensive care after the surgery.     

Stereotactic radiosurgery provides equivalent tumor control to Simpson Grade 1 resection for patients with small- to medium-size meningiomas

PURPOSE: To compare tumor control rates after surgical resection or stereotactic radiosurgery for patients with small- to medium-size intracranial meningiomas. MATERIALS AND METHODS: Between 1990 and 1997, 198 adult meningioma patients treated at our center underwent either surgical resection (n = 136) or radiosurgery (n = 62) as primary management for benign meningiomas <35 mm in average diameter. Tumor recurrence or progression rates were calculated by the Kaplan-Meier method according to an independent radiographic review. The mean follow-up was 64 months. RESULTS: The tumor resections were Simpson Grade 1 in 57 (42%), Grade 2 in 57 (42%), and Grade 3-4 in 22 (16%). The mean margin and maximal radiation dose at radiosurgery was 17.7 Gy and 34.9 Gy, respectively. Tumor recurrence/progression was more frequent in the surgical resection group (12%) than in the radiosurgical group (2%; p = 0.04). No statistically significant difference was detected in the 3- and 7-year actuarial progression-free survival (PFS) rate between patients with Simpson Grade 1 resections (100% and 96%, respectively) and patients who underwent radiosurgery (100% and 95%, respectively; p = 0.94). Radiosurgery provided a higher PFS rate compared with patients with Simpson Grade 2 (3- and 7-year PFS rate, 91% and 82%, respectively; p <0.05) and Grade 3-4 (3- and 7-year PFS rate, 68% and 34%, respectively; p <0.001) resections. Subsequent tumor treatments were more common after surgical resection (15% vs. 3%, p = 0.02). Complications occurred in 10% of patients after radiosurgery compared with 22% of patients after surgical resection (p = 0.06). CONCLUSIONS: The PFS rate after radiosurgery was equivalent to that after resection of a Simpson Grade 1 tumor and was superior to Grade 2 and 3-4 resections in our study. If long-term follow-up confirms the high tumor control rate and low morbidity of radiosurgery, this technique will likely become the preferred treatment for most patients with small- to moderate-size meningiomas without symptomatic mass effect.     

Use of the RTOG recursive partitioning analysis to validate the benefit of iodine-125 implants in the primary treatment of malignant gliomas.

PURPOSE: To date, numerous retrospective studies have suggested that the addition of brachytherapy to the conventional treatment of malignant gliomas (MG) (surgical resection followed by radiotherapy +/- chemotherapy) leads to improvements in survival. Two randomized trials have suggested either a positive or no survival benefit with implants. Critics of retrospective reports have suggested that the improvement in patient survival is due to selection bias. A recursive analysis by the RTOG of MG trials has stratified MG patients into 6 prognostically significant classes. We used the RTOG criteria to analyze the implant data at Wayne State University to determine the impact of selection bias. METHODS AND MATERIALS: Between July 1991 and January 1998, 75 patients were treated with a combination of surgery, radiotherapy, and stereotactic I-125 implant as primary MG management. Forty-one (54.7%) were male; 34 (45.3%) female. Median age was 52 years (range 4-79). Twenty-two (29.3%) had anaplastic astrocytoma (AA); 53 (70.7%), glioblastoma multiforme (GBM). Seventy-two patients had data making them eligible for stratification into the 6 RTOG prognostic classes (I-VI). Median Karnofsky performance status (KPS) was 90 (range 50-100). There were 14, 0, 14, 31, 12, and 1 patients in Classes I to VI, respectively. Median follow-up time for AA, GBM, and any surviving patient was 29, 12.5, and 35 months, respectively. RESULTS: At analysis, 29 (40.3%) patients were alive; 43 (59.7%), dead. For AA and GBM patients, 2-year and median survivals were: 58% and 40%; 38 and 17 months, respectively. For analysis purposes, Classes I and II, V and VI were merged. By class, the 2-year survival for implanted patients compared to the RTOG data base was: III--68% vs. I--76%; III--74% vs. 35%; IV--34% vs. 15%; V/VI--29% vs. V--6%. For implant patients, median survival by class was (in months): I/II--37; III--31; IV--16; V/VI--11. CONCLUSION: When applied to MG patients receiving permanent I-125 implant, the criteria of the RTOG recursive partitioning analysis are a valid tool to define prognostically distinct survival groups. As reflected in the RTOG study, a downward survival trend for the implant patients is seen from "best to worse" class patients. Compared to the RTOG database, median survival achieved by the addition of implant is improved most demonstrably for the poorer prognostic classes. This would suggest that selection bias alone does not account for the survival benefit seen with I-125 implant and would contradict the notion that the patients most eligible for implant are those gaining the most benefit from the treatment. In light of the contradictory results from two randomized studies and given the present results, further randomized studies with effective stratification are required since the evidence for a survival benefit with brachytherapy (as seen in retrospective studies) is substantial.     

Brain metastases from breast carcinoma: validation of the radiation therapy oncology group recursive partitioning analysis classification and proposition of a new prognostic score

PURPOSE: To validate the Radiation Therapy Oncology Group Recursive Partitioning Analysis (RTOG RPA) classification and determine independent prognostic factors, to create a simple and specific prognostic score for patients with brain metastases (BM) from breast carcinoma treated with whole-brain radiotherapy (WBRT). METHODS AND MATERIALS: From January 1998 through December 2003, 132 patients with BM from breast carcinoma were treated with WBRT. We analyzed several potential predictors of survival after WBRT: age, Karnofsky performance status, RTOG-RPA class, number of BM, presence and site of other systemic metastases, interval between primary tumor and BM, tumor hormone receptor (HR) status, lymphocyte count, and HER-2 overexpression. RESULTS: A total of 117 patients received exclusive WBRT and were analyzed. Median survival with BM was 5 months. One-year and 2-year survival rates were 27.6% (95% confidence interval [CI] 19.9-36.8%) and 12% (95% CI 6.5-21.2%), respectively. In multivariate analysis, RTOG RPA Class III, lymphopenia (< or =0.7 x 10(9)/L) and HR negative status were independent prognostic factors for poor survival. We constructed a three-factor prognostic scoring system that predicts 6-month and 1-year rates of overall survival in the range of 76.1-29.5% (p = 0.00033) and 60.9-15.9% (p = 0.0011), respectively, with median survival of 15 months, 5 months, or 3 months for patients with none, one, or more than one adverse prognostic factor(s), respectively. CONCLUSIONS: This study confirms the prognostic value of the RTOG RPA classification, lymphopenia, and tumor HR status, which can be used to form a prognostic score for patients with BM from breast carcinoma.     

Quantification of risk of a positive (R1) resection margin following hepatic resection for metastatic colorectal cancer: an aid to clinical decision-making

BACKGROUND AND AIMS: Margin involvement following liver resection for colorectal cancer is associated with early disease recurrence and shorter long-term survival. This study aimed to develop a predictive index for quantifying the likelihood of a positive resection margin (R1) for patients undergoing hepatic resection for metastatic colorectal cancer. METHODS: Clinical, pathological and complete follow-up data were prospectively collected from 1005 consecutive liver resections performed in 929 patients for colorectal liver metastases with curative intent at a single centre between 1987 and 2005. Ninety-four resections in 81 patients with extra-hepatic disease were excluded, leaving 911 resections (844 primary and 67 repeat) in 848 patients for analysis. Multivariate logistic regression was used to identify independent predictors of margin involvement and from the beta-coefficients generated, develop a predictive model that was validated using measures of discrimination and calibration. RESULTS: There were 80 (8.8%) R1 resections, with a 5-year cancer-specific survival for R0 and R1 hepatic resections of 39.7% and 17.8%, respectively; p<0.001. On multivariate analysis, five risk factors were found to be independent predictors of an R1 resection: non-anatomical resection vs. anatomical resection (odds ratio (OR)=4.3, p=0.001), >3 hepatic metastases involving >50% of the liver vs. <3 metastases (OR=4.0, p<0.001); bilobar vs. unilobar disease (OR=2.9, p<0.001); repeat vs. primary hepatic resection (OR=3.1, p=0.006); abnormal vs. normal pre-operative liver function tests (OR=1.6, p=0.044). These five factors were used to develop a predictive model, which when tested, fitted the data well, with an area under the receiver operating characteristic curve of 78.1% (S.E.=2.7%). CONCLUSIONS: This study describes an accurate model for quantifying the risk of a positive margin following hepatic resection for liver metastases. It may be used pre-operatively by multi-disciplinary teams to identify patients who may benefit from neoadjuvant therapy prior to liver surgery, thus minimizing the risk of a positive resection margin.     

Brain metastases and non-small cell lung cancer. Prognostic factors and correlation with survival after irradiation

A total of 250 patients with brain metastases from non-small cell lung cancer (NSCLC) were treated with irradiation of their brain metastases. The median overall survival was 3.1 (95% CI: 2.7-3.5) months. 32/250 patients presenting with solitary brain metastasis underwent surgical resection. Their 1-year survival rate of 58% was significantly better than 89/250 patients with a solitary lesion but without surgery (14%, P=0.001). Patients with an absent or controlled primary tumor (101/250, 40.5%) had a 1-year survival rate of 26% as opposed to 11% for patients presenting with an active primary tumor (P=0.051). Patients presenting with metastases to the brain only showed a significant survival advantage over patients with extracranial metastases (1-year survival of 21% vs 6%, P=0.001). Karnofsky performance score, neurofunction status and response to steroids were also identified as prognostic factors. The total dose whole brain irradiation (WBI) was prognostic of significance with a 1-year survival of 35% for 30 Gy and boost, 23.5% for 30 Gy and 4% for the patients irradiated to a dose of 20 Gy WBI (P=0.001). When patients were grouped into the RTOG RPA (Recursive partitioning analysis) classes, patients within class I (73/250) had a 1-year survival of 28.5%, patients in class II (145/250) a survival of 14% at 1 year and patients into class III only a 6% 1-year survival rate. In a multivariate analysis, surgical resection, neurofunction class, metastatic extent and WBI dose remained significant prognostic factors. Although survival remains poor, there needs to be a continued interest in these patients, probably by participating in clinical trials.