RTOG Recursive Partitioning Analysis Research Articles

Conditional Survival Estimates for Malignant Glioma Patients by RPA Class: Secondary Analysis of RTOG 9006

The RTOG recursive partitioning analysis (RPA) for malignant glioma patients is a key prognostic factor correlated with survival for patients with a malignant glioma, which was established using data from RTOG 9006. While such data is useful when counseling patients on survival outcomes at the time of diagnosis, the utility of such data diminishes over time. Conditional survival (CS) is a way to provide 'real-time' estimates of how survival changes over time. The primary objective of this secondary analysis is to report conditional survival estimates for patients with malignant gliomas enrolled on RTOG 9006 stratified by RPA class. RTOG 9006 was a phase III trial of patients diagnosed with malignant gliomas randomized to BCNU and hyper-fractionated radiation therapy (RT) vs. BCNU and conventionally fractionated RT that showed no significant differences in toxicities or oncologic outcomes. We performed a post-hoc analysis of RTOG 9006 using data obtained from the NCI NCTN Data Archive to evaluate conditional survival estimates for different RPA subgroups. Eligible patients included those with a known RPA class who were enrolled on RTOG 9006 (n = 632). Conditional survival estimates from the time of diagnosis and following 1-, 3-, and 5-y of survival were calculated using the Kaplan-Meier method. Cox proportional hazards modeling was performed to evaluate the prognostic significance of treatment arm, histology, extent of surgical resection, and RPA class following 1-, 3-, and 5-y of survival. For RPA Group I (n = 68), OS at 1-y from diagnosis was 95.58%. At 1- (n = 65), 3- (49) and 5-y (42) of survivorship, the chances of surviving an additional 1-y were 84.62, 91.84, 98.62% respectively (See Table 1). RPA class continued to be significantly correlated with survival following 1- and 3-y of survival irrespective of treatment arm. Treatment arm was not significantly correlated with conditional survival at any time point following treatment completion, and there was no interaction between treatment arm and RPA subgroups. Histology was significant at all time points. Conditional risk of death for patients treated for malignant gliomas in RPA Group I remains low at levels similar to those at initial diagnosis. Conditional risk continuously improves for RPA Groups IV-V as patients live longer. In most groups, the lowest survival odds were found in patients who have already survived 1 year.

A Prospective Study of Intensity-modulated Radiation Therapy Using a Standard Radiation Dose for High-grade Glioma.

We evaluated the treatment outcomes of intensity-modulated radiation therapy (IMRT) using a standard radiation dose in patients with high-grade glioma (HGG). We conducted a prospective, single-institutional, single-arm trial. Patients aged 20-75 years with histologically proven HGG were enrolled. Surgical procedures and chemotherapy regimens were not regulated. The prescribed dose of postoperative IMRT was 60 Gy in 30 fractions over six weeks. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), completion rate of IMRT, and Grade 3 or higher non-hematological toxicity. Between 2016 and 2019, 20 patients were enrolled. According to the World Health Organization 2016 Classification, glioblastoma, anaplastic astrocytoma, and anaplastic oligodendroglioma were present in nine, six, and five of the recruited patients, respectively. Gross total resection, partial resection, and biopsy were performed in four, nine, and seven patients, respectively. All patients received concurrent and adjuvant chemotherapy using temozolomide with or without bevacizumab. The completion rate of IMRT was 100%. The median follow-up period was 29 months (range=6-68 months). Median OS and PFS were 30 and 14 months, respectively. No patients experienced Grade 3 or higher non-hematological toxicity. The 2-year OS rates were 100%, 57%, and 33% in Radiation Therapy Oncology Group-Recursive Partitioning Analysis (RTOG-RPA) classes I/II, IV, and V, respectively (p=0.002; log-rank test). IMRT using the standard radiation dose in patients with HGG can be carried out safely. RTOG-RPA class appears to be useful to estimate patient prognoses.

Effect of Levetiracetam Use Duration on Overall Survival of Isocitrate Dehydrogenase Wild-Type Glioblastoma in Adults: An Observational Study.

The association between levetiracetam and survival with isocitrate dehydrogenase (IDH) wild-type glioblastomas is controversial. We investigated whether the duration of levetiracetam use during the standard chemoradiation protocol affects overall survival (OS) of patients with IDH wild-type glioblastoma. In this observational single-institution cohort study (2010-2018), inclusion criteria were (1) age ≥18 years; (2) newly diagnosed supratentorial tumor; (3) histomolecular diagnosis of IDH wild-type glioblastoma; and (4) standard chemoradiation protocol. To assess the survival benefit of levetiracetam use during the standard chemoradiation protocol (whole duration, part time, and never subgroups), a Cox proportional hazard model was constructed. We performed a case-matched analysis (1:1) between patients with levetiracetam use during the whole duration of the standard chemoradiation protocol and patients with levetiracetam use part time or never according to the following criteria: sex, age, epileptic seizures at diagnosis, Radiation Therapy Oncology Group recursive partitioning analysis (RTOG-RPA) class, tumor location, preoperative volume, extent of resection, and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Patients with unavailable O6-methylguanine-DNA methyltransferase promoter methylation status (48.5%) were excluded. A total of 460 patients were included. The median OS was longer in the 116 patients with levetiracetam use during the whole duration of the standard chemoradiation protocol (21.0 months; 95% confidence interval [CI] 17.2-24.0) than in the 126 patients with part-time levetiracetam use (16.8 months; 95% CI 12.4-19.0) and in the 218 patients who never received levetiracetam (16.0 months; 95% CI 15.5-19.4; p = 0.027). Levetiracetam use during the whole duration of the standard chemoradiation protocol (adjusted hazard ratio [aHR] 0.69; 95% CI 0.52-0.93; p = 0.014), MGMT promoter methylation (aHR 0.53; 95% CI 0.39-0.71; p < 0.001), and gross total tumor resection (aHR 0.57; 95% CI 0.44-0.74; p < 0.001) were independent predictors of longer OS. After case matching (n = 54 per group), a longer OS was found for levetiracetam use during the whole duration of the standard chemoradiation protocol (hazard ratio 0.63; 95% CI 0.42-0.94; p = 0.023). Levetiracetam use during the whole standard chemoradiation protocol possibly improves OS of patients with IDH wild-type glioblastoma. It should be considered in the antitumor strategy of future multicentric trials. This study provides Class III evidence that in individuals with IDH wild-type glioblastoma, levetiracetam use throughout the duration of standard chemotherapy is associated with longer median OS.

A new model outperforming RPA and DS-GPA scores for individualized survival prediction of patients following whole brain irradiation for brain metastasis

PurposeSurvival after whole brain radiation therapy (WBRT) in patients with multiple brain metastases (BM) is currently predicted by group-based scoring systems with limited usability for decision. We aimed to develop a more relevant individualized predictive model than Radiation Therapy Oncology Group – Recursive Partitioning Analysis (RTOG-RPA) and Diagnosis – Specific Graded Prognostic Assessment (DS-GPA) for patients with limited life-expectancy. MethodsBased on a Discovery cohort of patients undergoing WBRT, multivariable piecewise Cox regression models with time cut-offs at 1 and 3 months were developed to predict overall survival (OS). A final parsimonious model was defined, and an external validation cohort was used to assess its discrimination and calibration at one, six, and 12 months. ResultsIn the 173-patient Discovery cohort, the majority of patients had primary lung cancer (56%), presence of extracranial disease (ECD) (75%), Eastern Cooperative Oncolgy Group - Performance Status (ECOG-PS) score 1 (41%) and no intracranial hypertension (ICH) (74%). Most patients were classified as the RPA class II (48%). The final piecewise Cox model was based on primary site, age, ECD, ECOG-PS and ICH. An external validation of the model was carried out using a cohort of 79 patients. Individualized survival estimates obtained with this model outperformed the RPA and DS-GPA scores for overall survival prediction at 1-month, 6-months and 12- months in both Discovery and Validation cohorts. A R/Shiny web application was developed to obtain individualized predictions for new patients, providing an easy-to-use tool for clinicians and researchers. ConclusionOur model provides individualized estimates of survival for poor prognosis patients undergoing WBRT, outperforming actual scoring systems.

EP1.16-44 Survival and Prognostic Association of Non-Small Cell Lung Cancer with Brain Metastases After WBRT: A Multicentre Study

Forty percent of intracranial tumors are metastatic, arising most commonly from lung. To our knowledge, no data is available on prognosis factors of the survival of non-small cell lung cancer (NSCLC) patients with brain metastases in Bangladesh. This study aims to determine overall survival (OS) and identify prognosis factors in NSCLC patients with brain metastases after whole brain radiation therapy (WBRT). The study retrospectively investigated histologically proven NSCLC patients with brain metastases at two tertiary hospitals in Bangladesh from January, 2013 to April, 2018. A total of 62 patients were eligible who received 30 Gy (3 Gy per fraction) of WBRT. The primary end point was OS and the secondary endpoint was prognostic association with various factors including patient age and gender, tumor histology, Karnofsky performance status, pleural effusion, primary not controlled, extracranial metastases, the number of brain metastases, surgical resection and diagnosed initially with brain metastases or developed brain metastases later. RTOG Recursive Partitioning Analysis (RPA) was used to categorize the patients. Survival was calculated by Kaplan-Meier method and compared by Log-rank test. Prognostic association was evaluated with Cox proportional hazards model analysis. Mean survival of the entire cohort was 5.76 months (95% CI: 4.69 – 6.84 months). Patients with brain metastases at diagnosis or developed brain metastases later during disease progression had a statistically similar mean survival (6.18 months vs. 5.49 months; P = 0.422). Among the 62 patients, 16.1%, 30.6% and 53.2% were RPA Class I, II and III respectively. Mean survival differed significantly among the three classes (Class I: 9.10 months, Class II: 6.68 months, Class III: 3.64 months; P = 0.00). Individual prognostic factors were not found to be associated with survival difference except, single vs. multiple brain metastases (P = 0.042) and primary controlled or not (P = 0.026). The study reported survival time of NSCLC patients with brain metastases undergo WBRT, and indicated that higher RPA classes, primary not controlled and greater numbers of brain metastatic lesions are the three prognostic factors of poor survival for this cohort. Our results may help clinicians in patient counseling, treatment selection and designing future clinical trials.

Risk stratification of pediatric high-grade glioma: a newly proposed prognostic score.

High-grade glioma (HGG) is a clinical challenge. Radiation Therapy Oncology Group Recursive Partitioning Analysis (RTOG-RPA) for HGG remains the standard for assessing the prognosis of adult HGG. This study assesses the validity of the RTOG-RPA to be applied to pediatric HGG. A retrospective study was conducted on 59 pediatric HGG treated in the Children's Cancer Hospital, Egypt (CCHE) between 2007 and 2016. Several factors were studied as predictors for the disease survival, including age, gender, increased intracranial hypertension, tumor characteristics and pathology, CSF seeding, performance status, post-surgical residual, and radiation dose. The statistically significant results were integrated into a Cox-regression model to develop a prognostic risk score. Kaplan-Meier statistics identified 13 factors that impacted the overall survival. However, Cox model showed that the histological grade IV [HR 14.2, 95%CI; (3.5-57), P < 0.0001], thalamic infiltration [HR 8.7; 95%CI; (2.9-25.9), P < 0.0001], PS ≥ 60 [HR 0.317; 95%CI; (0.13-0.776); P = 0.012], and maximum tumor dimension > 3.3cm [HR 10.2; 95%CI; (1.58-65.89); P = 0.015] were the independent variables that predicted the overall survival. A risk score was proposed based on the presence of one or more of these factors. The median OS for the low risk (score 0-1), the intermediate-low risk (score 2), the intermediate-high risk (score 3), and the high risk (score 4) were 40, 18.5, 9.5, and 2.5months, respectively, (P < 0.0001). The proposed model and risk score could stratify pediatric patients as the RTOG-RPA do for the adults.

Clinical and Molecular Recursive Partitioning Analysis of High-grade Glioma Treated With IMRT

Despite multimodal treatment for high-grade gliomas, prognosis remains grim. Prior Radiation Therapy Oncology Group-Recursive Partitioning Analysis (RTOG-RPA) reports indicate based on pretreatment and treatment-related factors, a subset of patients experience a significantly improved survival. Since the development of the RTOG-RPA, high-grade gliomas have seen the widespread introduction of temozolomide and tumor oncogenetics. Here we aimed to determine whether the RTOG-RPA retained prognostic significance in the context of modern treatment, as well as generate an updated RPA incorporating both clinical and genetic variables. Patients with histologically proven glioblastoma, gliosarcoma, anaplastic astrocytoma, and anaplastic oligodendroglioma treated with intensity-modulated radiation therapy (IMRT) between 2004 and 2017 were reviewed. The primary endpoint was overall survival from date of diagnosis. Primary analysis compared actual survival rates to that expected of corresponding RTOG-RPA class. Secondary analysis utilized the rpart function to recursively partition overall survival by numerous clinical and genetic pretreatment and treatment-related variables. A tertiary analysis recursively partitioned a subset of patients in which the status of all genetic markers were known. We identified 878 patients with histologically proven high-grade glioma treated with IMRT and 291 patients in our genetic subset. Median overall survival for the entire cohort was 14.2 months (95% confidence interval, 13.1-15.3). Applying the RTOG-RPA to our cohort validated the relative prognostic ordering of the survival classes except class II. Generating our new RPA created 7 significantly different survival classes (P<0.001, χ=584) with median survival ranging from 96.4 to 2.9 months based on age, histology, O6-methylguanine-DNA methyltransferase methylation status, radiation fractions, tumor location, radiation dose, temozolomide status, and resection status. Our second RPA of our genetic subset generated 5 significantly different survival classes (P<0.001, χ=166) with survival ranging from 65.3 to 5.6 months based on age, isocitrate dehydrogenase 1 mutation status, O6-methylguanine-DNA methyltransferase methylation status, neurological functional classification, hospitalization during IMRT, temozolomide status, and Karnofsky performance status. The RTOG-RPA retains partial prognostic significance, however, should be updated to reflect recent advancements. This series represents a large RPA analyzing both clinical and genetic factors and generated 7 distinct survival classes. Further assessment of patients with fully available genetic markers generated 5 distinct survival classes. These survival classifications need to be validated by a prospective data set and compared against the RTOG-RPA to determine whether they provide improved prognostic power.

Whole brain irradiation with simultaneous integrated boost in treatment of oligometastatic brain disease

Background/Aim. Brain metastases occur in 20%?30% of all patients with systemic cancer. We aimed at investigating whether patients with oligometastatic brain disease treated with whole brain radiotherapy (WBRT) and simultaneous integrated boost of brain metastases (SIBmets) improved overall survival (clinical outcomes) compared with patients from the Radiation Therapy Oncology Group (RTOG) 9508 database, treated with WBRT and sequential stereotactic radiosurgery (SRS) boost. Methods. WBRT with SIBmets, using the RapidArc (RA) (Varian Medical Systems, Palo Alto, CA) volumetric modulated arc technique (VMAT), was delivered to 15 patients with computed tomography/ magnetic resonance imaging (CT/MRI) findings of 1?3 brain metastases with a diameter less than 40 mm for the largest lesion. Radiotherapy (RT) plans consisted of WBRT, with a prescribed dose of 20 Gy in 5 fractions, with SIBmets which was also 20 Gy (gray units) in 5 fractions. Results. A group of 15 patients included 8 males and 7 females with the mean age of 56.3 years. Three patients were in the RTOG Recursive Partitioning Analysis (RPA) Class I and other 12 patients in RPA Class II. Four patients had one metastasis and 11 patients had two metastases. Calculated mean survival time (MST) was 7.49 ? 4.36 months with no statistically significant difference compared to RTOG 9508 results (MST = 6.5 months) (p = 0.197). The local control rate for 7 patients after three months was 85.7%. Conclusion. WBRT with SIBmets and WBRT + SRS are clinically equivalent treatment options for the patients with oligometastatic brain disease. In comparison to the WBRT + SRS, the treatment by WBRT + SIBmets technique reduces the treatment time and improves the patient?s treatment comfort.

Prognostic models for patients with brain metastases after stereotactic radiosurgery with or without whole brain radiotherapy: a validation study.

To compare the performance of five prognostic models [RTOG recursive partitioning analysis (RPA), Score Index for Radiosurgery in Brain Metastases (SIR), Barnholtz-Sloan-Kattan nomogram (BSKN), diagnosis-specific Graded Prognostic Assessment (dsGPA), and Graded Prognostic Assessment for Lung Cancer Using Molecular Markers (Lung-molGPA)] against actual survival in patients with brain metastases treated with SRS +/- WBRT. 100 consecutive patients treated with SRS +/- WBRT between January 2006 and July 2012 were retrospectively analyzed. Patients were binned according to 33 percentiles of the predicted survival distribution for the BSKN and dsGPA models to compare with LungmolGPA, RPA and SIR. Pearson's correlation coefficients between predicted and observed survival were estimated to quantify the proportion of variance in observed survival. Median survival for the entire cohort was 13.5 months, with predicted vs actual MS by BSKN, SIR, dsGPA, RPA, adenocarcinoma Lung-molGPA, and nonadenocarcinoma Lung-molGPA was 3.8 vs 15.6 months, 7 vs 13.5 months, 9.4 vs 13.5 months, 10.3 vs 13.5 months, 13.7 vs 13.7 months, and 9.8 vs 9.7 months, respectively. The BSKN model and adenocarcinoma LungmolGPA created three groups with a statistically significantly different MS (p = 0.002 and p = 0.01, respectively). All models under-predicted MS and only the BSKN and Lung-molGPA model stratified patients into three risk groups with statistically significant actual MS. The prognostic groupings of the adenocarcinoma Lung-molGPA group was the best predictor of MS, and showed that we are making improvements in our prognostic ability by utilizing molecular information that is much more widely available in the current treatment era.

Role of Recursive Partitioning Analysis and Graded Prognostic Assessment on Identifying Non-Small Cell Lung Cancer Patients with Brain Metastases Who May Benefit from Postradiation Systemic Therapy.

Background:The role of postradiation systemic therapy in non-small cell lung cancer (NSCLC) patients with brain metastasis (BM) was controversial. Thus, we explored the role of Radiation Therapy Oncology Group recursive partitioning analysis (RTOG-RPA) and graded prognostic assessment (GPA) in identifying population who may benefit from postradiation systemic therapy.Methods:The clinical data of NSCLC patients with documented BM from August 2007 to April 2015 of two hospitals were studied retrospectively. Cox regression was used for multivariate analysis. Survival of patients with or without postradiation systemic therapy was compared in subgroups stratified according to RTOG-RPA or GPA.Results:Of 216 included patients, 67.1% received stereotactic radiosurgery (SRS), 24.1% received whole-brain radiation therapy (WBRT), and 8.8% received both. After radiotherapy, systemic therapy was administered in 58.3% of patients. Multivariate analysis found that postradiation systemic therapy (yes vs. no) (hazard ratio [HR] = 0.361, 95% confidence interval [CI] = 0.202–0.648, P = 0.001), radiation technique (SRS vs. WBRT) (HR = 0.462, 95% CI = 0.238–0.849, P = 0.022), extracranial metastasis (yes vs. no) (HR = 3.970, 95% CI = 1.757–8.970, P = 0.001), and Karnofsky performance status (<70 vs. ≥70) (HR = 5.338, 95% CI = 2.829–10.072, P < 0.001) were independent factors for survival. Further analysis found that subsequent tyrosine kinase inhibitor (TKI) therapy could significantly reduce the risk of mortality of patients in RTOG-RPA Class II (HR = 0.411, 95% CI = 0.183–0.923, P = 0.031) or with a GPA score of 1.5–2.5 (HR = 0.420, 95% CI = 0.182–0.968, P = 0.042). However, none of the subgroups stratified according to RTOG-RPA or GPA benefited from the additional conventional chemotherapy.Conclusion:RTOG-RPA and GPA may be useful to identify beneficial populations in NSCLC patients with BM if TKIs were chosen as postradiation systemic therapy.

A Comparative Analysis of the Usefulness of Survival Prediction Models for Patients with Glioblastoma in the Temozolomide Era: The Importance of Methylguanine Methyltransferase Promoter Methylation, Extent of Resection, and Subventricular Zone Location

Several survival prediction models for patients with glioblastoma have been proposed, but none is widely used. This study aims to identify the predictors of overall survival (OS) and to conduct an independent comparative analysis of 5 prediction models. Multi-institutional data from 159 patients with newly diagnosed glioblastoma who received adjuvant temozolomide concomitant chemoradiotherapy (CCRT) were collected. OS was assessed by Cox proportional hazards regression and adjusted for known prognostic factors. An independent CCRT patient cohort was used to externally validate the 1) RTOG (Radiation Therapy Oncology Group) recursive partitioning analysis (RPA) model, 2) Yang RPA model, and 3) Wee RPA model, Chaichana model, and the RTOG nomogram model. The predictive accuracy for each model at 12-month survival was determined by concordance indices. Calibration plots were performed to ascertain model prediction precision. The median OS for patients who received CCRT was 19.0 months compared with 12.7 months for those who did not (P < 0.001). Independent predictors were:1)subventricular zone II tumors (hazard ratio [HR], 1.6; 95% confidence interval [CI], 1.0-2.5); 2) methylguanine methyltransferase promoter methylation (HR, 0.36; 95% CI, 0.2-0.6); and 3) extent of resection of >85% (HR, 0.59; 95% CI, 0.4-0.9). For 12-month OS prediction, the RTOG nomogram model was superior to the RPA models with a c-index of 0.70. Calibration plots for 12-month survival showed that none of the models was precise, but the RTOG nomogram performed relatively better. The RTOG nomogram best predicted 12-month OS. Methylguanine methyltransferase promoter methylation status, subventricular zone tumor location, and volumetric extent of resection should be considered when constructing prediction models.

Molecular-Based Recursive Partitioning Analysis Model for Glioblastoma in the Temozolomide Era

There is a need for a more refined, molecularly based classification model for glioblastoma (GBM) in the temozolomide era. To refine the existing clinically based recursive partitioning analysis (RPA) model by incorporating molecular variables. NRG Oncology RTOG 0525 specimens (n = 452) were analyzed for protein biomarkers representing key pathways in GBM by a quantitative molecular microscopy-based approach with semiquantitative immunohistochemical validation. Prognostic significance of each protein was examined by single-marker and multimarker Cox regression analyses. To reclassify the prognostic risk groups, significant protein biomarkers on single-marker analysis were incorporated into an RPA model consisting of the same clinical variables (age, Karnofsky Performance Status, extent of resection, and neurologic function) as the existing RTOG RPA. The new RPA model (NRG-GBM-RPA) was confirmed using traditional immunohistochemistry in an independent data set (n = 176). Overall survival (OS). In 452 specimens, MGMT (hazard ratio [HR], 1.81; 95% CI, 1.37-2.39; P < .001), survivin (HR, 1.36; 95% CI, 1.04-1.76; P = .02), c-Met (HR, 1.53; 95% CI, 1.06-2.23; P = .02), pmTOR (HR, 0.76; 95% CI, 0.60-0.97; P = .03), and Ki-67 (HR, 1.40; 95% CI, 1.10-1.78; P = .007) protein levels were found to be significant on single-marker multivariate analysis of OS. To refine the existing RPA, significant protein biomarkers together with clinical variables (age, Karnofsky Performance Status, extent of resection, and neurological function) were incorporated into a new model. Of 166 patients used for the new NRG-GBM-RPA model, 97 (58.4%) were male (mean [SD] age, 55.7 [12.0] years). Higher MGMT protein level was significantly associated with decreased MGMT promoter methylation and vice versa (1425.1 for methylated vs 1828.0 for unmethylated; P < .001). Furthermore, MGMT protein expression (HR, 1.84; 95% CI, 1.38-2.43; P < .001) had greater prognostic value for OS compared with MGMT promoter methylation (HR, 1.77; 95% CI, 1.28-2.44; P < .001). The refined NRG-GBM-RPA consisting of MGMT protein, c-Met protein, and age revealed greater separation of OS prognostic classes compared with the existing clinically based RPA model and MGMT promoter methylation in NRG Oncology RTOG 0525. The prognostic significance of the NRG-GBM-RPA was subsequently confirmed in an independent data set (n = 176). This new NRG-GBM-RPA model improves outcome stratification over both the current RTOG RPA model and MGMT promoter methylation, respectively, for patients with GBM treated with radiation and temozolomide and was biologically validated in an independent data set. The revised RPA has the potential to contribute to improving the accurate assessment of prognostic groups in patients with GBM treated with radiation and temozolomide and to influence clinical decision making. clinicaltrials.gov Identifier: NCT00304031.

P2.05-013 Stereotactic Brain Radiosurgery in Lung Cancer Patients in the Era of Personalized Therapy: A Review of Outcomes and Prognostic Scores Evaluation: Topic: Clinical Outcome

Stereotactic brain radiosurgery (SRS) was demonstrated to provide good local control in patients with oligo-brain metastases (commonly defined as 4 or less). The discovery of different targeted therapies provided significant improvement in survival in the past decade. We reviewed the effectiveness of SRS in lung cancer patients with oligo-brain metastases and identified prognostic factors which potentially can aid better patient selection. Medical records of patients with brain metastases treated with SRS in Prince of Wales Hospital, Hong Kong in Jan 2010-July 2015 were reviewed. Outcomes including local control rate (LCR), distant brain control rate (BCR) and overall survival (OS) were analyzed. Prognostic factors were identified with univariate and multivariate analyses. Correlation with available prognostic scorings including RTOG Recursive Partitioning Analysis, Basic Score for Brain Metastases, the Score Index for Radiosurgery and Graded Prognostic Assessment was evaluated. Forty-eight patients with 66 lesions were treated with LINAC-based SRS with single dose of 12-24Gy (mean dose 18.1Gy). The distribution of different subtypes is as follows: Non-small cell lung cancer (NSCLC)/adenocarcinoma NOS n=18 (37.5%), EGFR mutation n=17 (35.4%), ALK IHC+ n=3 (6.3%), adenocarcinoma of unknown subtype n=2 (4.2%), squamous cell carcinoma n=5 (10.4%), small cell carcinoma n=2 (4.2%) and unknown subtype n=1 (1.8%). The median follow up time was 11.0 months (0.4-71.4 months). Five patients (9.4%) were symptomatic with acute brain edema. Seven patients (14.6%) had delayed seizure after a mean time of 10.1month (2.0-33.5 months). Six patients (12.5%) became steroid dependent. The median OS was 13.0 months. One year actuarial LCR was 73% and distant BCR was 67%. OS correlated significantly with all four scoring systems. Among NSCLC patients, those with activating EGFR mutation (exon 19 deletion or exon 21 L858R mutation) (n=12) had superior OS compared with non-mutational group (p=0.036, HR 2.811 95% CI 1.072-7.369), but there was no statistically significant difference on local or distant brain control. Concomitant whole brain radiotherapy (WBRT) did not significantly affect OS, local and brain control in the whole group and in EGFR activating mutant subgroup. SRS provided good control in patients with primary lung cancer with oligo-brain metastases. Current available prognostic scores provide good estimation of survival. Patients with EGFR activating mutation had superior survival after SRS compared with non-mutational NSCLC group.

Novel risk scores for survival and intracranial failure in patients treated with radiosurgery alone to melanoma brain metastases.

PurposeStereotactic radiosurgery (SRS) alone is an increasingly common treatment strategy for brain metastases. However, existing prognostic tools for overall survival (OS) were developed using cohorts of patients treated predominantly with approaches other than SRS alone. Therefore, we devised novel risk scores for OS and distant brain failure (DF) for melanoma brain metastases (MBM) treated with SRS alone.Methods and materialsWe retrospectively reviewed 86 patients treated with SRS alone for MBM from 2009-2014. OS and DF were estimated using the Kaplan-Meier method. Cox proportional hazards modeling identified clinical risk factors. Risk scores were created based on weighted regression coefficients. OS scores range from 0-10 (0 representing best OS), and DF risk scores range from 0-5 (0 representing lowest risk of DF). Predictive power was evaluated using c-index statistics. Bootstrapping with 200 resamples tested model stability.ResultsThe median OS was 8.1 months from SRS, and 54 (70.1 %) patients had DF at a median of 3.3 months. Risk scores for OS were predicated on performance status, extracranial disease (ED) status, number of lesions, and gender. Median OS for the low-risk group (0-3 points) was not reached. For the moderate-risk (4-6 points) and high-risk (6.5-10) groups, median OS was 7.6 months and 2.4 months, respectively (p < .0001). Scores for DF were predicated on performance status, ED status, and number of lesions. Median time to DF for the low-risk group (0 points) was not reached. For the moderate-risk (1-2 points) and high-risk (3-5 points) groups, time to DF was 4.8 and 2.0 months, respectively (p < .0001). The novel scores were more predictive (c-index = 0.72) than melanoma-specific graded prognostic assessment or RTOG recursive partitioning analysis tools (c-index = 0.66 and 0.57, respectively).ConclusionsWe devised novel risk scores for MBM treated with SRS alone. These scores have implications for prognosis and treatment strategy selection (SRS versus whole-brain radiotherapy).

The prognostic significance of surgically treated hydrocephalus in leptomeningeal metastases

ObjectiveThe median survival of leptomeningeal metastases is short despite therapy and is sometime associated with hydrocephalus. We investigated the prognostic significance of surgically treated hydrocephalus in leptomeningeal metastases. Materials and methodsBetween December 2005 and November 2012, 1343 patients had brain metastases from systemic solid tumors. Of these, 71 patients (5.3%) experienced leptomeningeal metastases from 45 lung cancers, 14 breast cancers, 4 gastric cancers and 8 other cancers. The mean age was 60 years (range 37–89). The clinical symptoms presented in the cerebral hemisphere and cerebellum in 58 patients, cranial nerve in 7 patients and spinal cord and nerves in 6 patients. Twenty-nine (40.8%) patients were Radiation Therapy Oncology Group recursive partitioning analysis (RTOG-RPA) class II and 42 (59.2%) were class III. Hydrocephalus was associated in 18 (25.4%) patients and 7 patients underwent ventriculoperioneal shunt. The primary cancer, clinical symptoms, RTOG-RPA class, surgically treated hydrocephalus and systemic chemotherapy were analyzed as the prognostic factors for overall survival. ResultsThe overall incidence of leptomeningeal seeding was 5.0% of the brain metastases. The median duration of leptomeningeal metastases from first brain metastasis was 4.0 months and 24 (33.8%) patients showed leptomeningeal metastases as the first form of brain metastasis. The median overall survival (OS) was 2.1 months. Based on the univariate and multivariate analyses, RTOG-RPA class II patients, treatment of leptomeningeal metastases (such as radiotherapy or intrathecal chemotherapy) and systemic chemotherapy improved OS with statistical significance. Surgically untreated hydrocephalus (median OS, 1.7 months) showed poor OS compared with surgically treated hydrocephalus (median OS, 5.7 months) and no hydrocephalus (median OS, 2.3 months) without statistical significance. ConclusionsThe leptomeningeal metastases were often associated with hydrocephalus and the surgical treatment was helpful in limited patients. The prognosis was related with RTOG-RPA class and treatment of local and systemic treatment.

Case Series: Gamma Knife as Salvage Therapy for Recurrent Glioblastoma Multiforme

Objectives: Glioblastoma multiforme is a highly malignant primary tumor of the brain. It has a dismal survival prognosis of 14-16 months following initial diagnosis. Despite aggressive upfront therapy, glioblastoma tends to recur in twelve months. Following this recurrence, some patients may benefit from Gamma Knife Radiosurgery (GKRS) treatment. This study analyzes survival outcomes in a case series by studying known prognostic indicators for glioblastoma patients. Methods: 63 patients with recurrent glioblastoma were treated with GKRS as part of a multimodal treatment plan between 2002 and 2011. Overall survival (from date of diagnosis) was compared to expected survival times as indicated by updated RTOG recursive partitioning analysis (RTOG-RPA) Classes. Survival post-GKRS salvage was also investigated. Univariate and multivariate analyses were conducted to determine whether there were significant predictors of overall survival for patients undergoing GKRS salvage. Results: Overall median survival from time of initial diagnosis was 20.2 ± 2.7 months for the entire group. 46 patients were in RTOG-RPA Class IV with a median overall survival of 20.2 ± 2.6 months (expected prognosis: 11.2 months). Median survival following GKRS salvage therapy was 9.9 ± 3.1 months for all patients. Multivariate analysis indicated that KPS was a significant predictor of survival (Hazard Ratio 0.22 compared to a KPS of 80). Conclusions: GKRS may be a safe and effective salvage therapy for selected recurrent glioblastoma patients, providing prolonged survival and quality of life compared to patients not receiving salvage treatment. Treatment options should be appropriately tailored to each patient’s individual situation.

Abstract A110: EGFRvIII expression is associated with shorter progression-free and overall survival in glioblastoma patients treated with standard-of-care temozolomide and radiation: A report from the RTOG-0525 trial.

Abstract Background: Glioblastomas (GBMs) are aggressive primary brain tumors with high levels of genomic heterogeneity impacting prognosis and treatment response. A recurrent in-frame deletion within the extracellular domain of the epidermal growth factor receptor (EGFR variant III, or vIII) is found in a substantial fraction of GBMs. Methods: The Radiation Therapy Oncology Group (RTOG) 0525 trial of temozolomide dosing in newly-diagnosed GBM enrolled 1174 patients. Of these, 494 eligible GBMs were analyzed for EGFRvIII expression by RT-PCR. The Kaplan-Meier method was used to compare the progression free survival (PFS) and overall survival (OS) of GBMs expressing EGFRvIII with those not expressing EGFRvIII. Results: 142 of 494 tested GBMs (29%) had expressed EGFRvIII. There were no significant differences in PFS or OS between patients whose tumors did (494) or did not (631) undergo EGFRvIII expression analysis. EGFRvIII expression was significantly associated with age (p=0.005), Karnofsky performance status (p=0.02), and RTOG recursive partitioning analysis (RPA) class (p=0.005). EGFRvIII expression analyzed in the entire study population did not reveal an association with PFS or OS. In a univariate subgroup analysis of patients treated on the standard-of-care arm of RTOG-0525, EGFRvIII expression was was significantly associated with worse PFS (HR=1.43, 95% CI: [1.05, 1.96], p=0.025), and worse OS (HR 1.45, 95% CI:[1.03, 2.05], p=0.032). However, in multivariate models, when adjusted for RPA class and MGMT methylation status, EGFRvIII was not an independent predictor of either PFS or OS. Conclusion: For GBMs treated with standard-of-care therapy in RTOG-0525, EGFRvIII expression was associated with worse PFS and OS. However, well-established stratification metrics such as age, KPS, and RPA override this prognostic association, suggesting that trials of therapeutic modalities directed against EGFRvIII should utilize these standard prognostic variables when survival is being analyzed or compared. Project Support: This project was supported by RTOG grant U10 CA21661, and CCOP grant U10 CA37422 from the National Cancer Institute (NCI) and Schering-Plough Corporation. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A110. Citation Format: Daniel P. Cahill, Asha George, Mark R. Gilbert, Arnab Chakravarti, Roger Stupp, Monika Hegi, Paul Brown, Kurt A. Jaeckle, Benjamin Corn, Erik P. Sulman, Luis Souhami, Maria Werner-Wasik, Bethany M. Anderson, Minesh Mehta, Kenneth D. Aldape. EGFRvIII expression is associated with shorter progression-free and overall survival in glioblastoma patients treated with standard-of-care temozolomide and radiation: A report from the RTOG-0525 trial. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A110.

Validation of the Score Index for Radiosurgery (SIR) in Predicting Survival of Patients With Brain Metastases Submitted to Radiosurgery

To validate the effectiveness of the SIR to predict overall survival of brain-metastatic patients treated with stereotactic radiosurgery (SRS). We conducted a retrospective analysis for SIR validation in patients treated between April 2010 and July 2012 at a radiosurgery cohort. A comparison with the other 3 major reported scores was performed: The RTOG Recursive Partitioning Analysis (RPA), the Basic Score for Brain Metastases (BSBM) and the Graded Prognostic Assessment (GPA). Each score was categorized into 3 groups according to similar survival, group difference within indexes were compared by log-rank test and differences between indexes by individual Cox regression likelihood-ratios (LR) and hazard-ratios (HR). Independent prognostic factors were compared by multivariate Cox regression model. Overall survival (OS) was considered from the procedure date and survival curves were estimated by Kaplan-Meier method. There were 110 patients with 238 treated lesions. Median follow-up for patients alive was 19.1 months (range, 5.4 - 44.0 months). The median dose was 18 Gy (12 - 22 Gy) and the most common primary sites were lung (40,4%) and breast (17,6%). Median OS was 9.9 months. Median survival for indexes were: grouped SIR from 1 to 3, 4 to 6, and 7 to 10 was 1.7, 7.3 and 19.9 months, respectively (p < 0.0001 / LR = 35.85 - HR = 3.69, 95% CI, 2.36-5.77). RPA classes I, II, and III was 2.1, 9.7 and 32.1 months, respectively (p = 0.0011 / LR = 13,47- HR = 2.17, 95% CI, 1.43-3.30). BSBM from 0, 1 or 2, and 3 was 17.4, 10.4 and 2.5 months, respectively (p < 0.0001 / LR = 17.82- HR = 2.58, 95% CI, 1.64-4.06) and grouped GPA from 0 to 1.5, 2.0 to 3.0, and 3.5 to 4.0 was 5.0, 12.4 months and not reached, respectively (p < 0.0001 / LR = 20.97 - HR = 2.31, 95% CI, 1.60-3.32). On multivariate analysis of prognostic factors, significance was observed for age (p = 0.004 - HR = 1.54, 95% CI, 1.152-2.067), KPS (p < 0.001 - HR = 2.83, 95% CI, 1.874-4.284), extracranial disease status (p = 0.004 - HR = 1.60, 95% CI, 1.162-2.202), volume of the largest lesion (p = 0.004 - HR = 1.84, 95% CI, 1.217-2.792), time to CNS metastases onset from the primary diagnostic date (p = 0.024 - HR = 1.66, 95% CI, 1.217-2.792) and breast as primary site (p = 0,039 - HR = 0.456, 95% CI, 0.217-0.959). No association with survival was observed for number of treated lesions, previous WBRT and enhancement pattern. As previous reports, SIR proved to be a good predictor of overall survival on patients treated with SRS. In our population, this model showed to be the most accurate between the available scores. Prognostic factors such as age, KPS, extracranial disease status, volume of the largest lesion and time to onset of the brain metastases are reliable and should be considered at the time of the patient evaluation.

The clinical utility of prognostic scoring systems in patients with brain metastases treated with radiosurgery

PurposeThe RTOG recursive partitioning analysis (RPA) classification is the gold standard for assessing the prognosis of patients with brain metastases (BM). Newer prognostic scoring systems for BM patients have been proposed, but their superiority over RPA needs to be established for patients treated with radiosurgery. Methods380 patients with 1–3 BM were treated at the VUmc with radiosurgery (RS) from 2002 to 2011. Using baseline characteristics, patient scores were calculated for RPA, the Rotterdam-system, the score index for radiosurgery (SIR), the basic score for BM (BSBM), the graded prognostic assessment (GPA), the diagnosis-specific GPA, the Rades score, and the Golden grading system (GGS) for comparison with survival time and survival classification (⩽3months or ⩾12months). ResultsMedian survival after RS was 7.7months, with 3-month and 1-year overall survival (OS) of 76% and 39%, respectively. Multivariate analysis confirmed the prognostic value of performance status, age, absence of extracranial metastases, primary tumor site, gender, and steroid response for OS. The percentage of patients included within the intermediate prognostic classes ranged from 48% to 77%, and was 64% for the RPA. All scoring systems highly correlated with OS (p<0.001). The specificity for predicting early death ranged from 85% to 98% (RPA 88%), with the unfavorable classes of Rades, GGS, BSBM and SIR performing best. The sensitivity for predicting long-term survival ranged from 10% to 69% (RPA 29%), and was highest for the favorable classes of Rades and GGS. ConclusionsAll prognostic scoring systems correlated very well with OS. All scores shared the limitation of unbalanced proportions of patients within the prognostic classes. As the clinical superiority of more recently developed prognostic scoring systems was only modest in predicting early death and long term survival, the well-known and easy to use RPA system currently remains the standard.

Can MRI-derived factors predict the survival in glioblastoma patients treated with postoperative chemoradiation therapy?

Advanced diagnostic and therapeutic developments may yield novel prognostic factors in patients with glioblastoma multiforme (GBM). To validate the predictive values of pretreatment quantitative diffusion-weighted (DW) magnetic resonance imaging (MRI) and MRI performed within 72 h after surgery in patients with GBM. Between January 2000 and September 2009, 138 patients with GBM underwent postoperative chemoradiation therapy (chemo-RT) and longitudinal MRI before surgery, in the early postoperative period, and at 1-month intervals thereafter. The role of the patient age, Karnofsky performance scale (KPS) score, minimum apparent diffusion coefficient (ADC) on pretreatment DW-MRI, and gross residual tumor on early postoperative MRI were assessed by factor analysis of overall survival (OS). Survival curves were calculated using the Kaplan-Meier method; the multivariate Cox's proportional hazards model was used to adjust for the influence of prognostic factors. Radiation Therapy Oncology Group-recursive partitioning analysis (RTOG-RPA) criteria were used to validate the predictive value of the MRI-derived factors. Substantial independent prognostic factors were the KPS score (hazard ratio [HR], 1.812), minimum ADC (HR, 2.365), and gross residual tumor (HR, 1.777). Based on MRI-derived factors, we assigned the patients to different prognostic groups in the RTOG-RPA classification and grouped them according to the level of risk, i.e. a high-risk group with low minimum ADCs (<0.93 × 10(-3) mm(2)/s) with gross residual tumor and a low-risk group with high minimum ADCs (≥0.93 × 10(-3) mm(2)/s) without gross residual tumor; the other patients were assigned to the intermediate-risk group. Median OS for the low-, intermediate-, and high-risk groups were 28.2, 14.7, and 10.8 months, respectively (P < 0.001). The minimum ADC on pretreatment DW-MRI and gross residual tumor on early postoperative MRI can predict the survival in GBM patients treated with postoperative chemo-RT.