Importance The need for a more refined, molecularly-based classification model for glioblastoma (GBM) in the temozolomide era. Objective Refine the existing clinically-based recursive partitioning analysis (RPA) model by incorporating molecular variables. Design, Setting, and Participants 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 semi-quantitative immunohistochemical validation. Prognostic significance of each protein was examined by single-marker and multi-marker Cox-regression analyses. In order to reclassify the prognostic risk groups, significant protein biomarkers upon single-marker analysis were incorporated into a RPA model consisting of the same clinical variables (age, KPS, 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 dataset (n=176). Main Outcomes and Measures Overall survival (OS) Results MGMT (HR=1.81, 95% CI(1.37, 2.39), p<0.001), survivin (HR=1.36, 95% CI(1.04, 1.76), p=0.02), c-Met (HR=1.53, 95% CI(1.06,2.23), p=0.02), pmTOR (HR=0.76, 95% CI(0.60,0.97), p=0.03), and Ki-67 (HR=1.40, 95% CI(1.10, 1.78), p=0.007), were found to be significant upon single-marker multivariate analysis of OS. To refine the existing RPA, significant protein biomarkers together with clinical variables (age, performance status, extent of resection, and neurological function) were incorporated into a new model. Higher MGMT protein was significantly associated with decreased MGMT promoter methylation and vice-versa. Further, MGMT protein expression had greater prognostic value for OS compared to MGMT promoter methylation. The refined NRG-GBM-RPA consisting of MGMT protein, c-Met protein, and age revealed greater separation of OS prognostic classes compared to 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 dataset (N=176). Conclusions and Relevance The new NRG-GBM-RPA model significantly enhances outcome stratification over both the current RTOG RPA model and MGMT promoter methylation, respectively, for GBM patients treated with radiation and temozolomide and was biologically validated in an independent dataset. The revised RPA has the potential to significantly contribute to improving the accurate assessment of prognostic groups in GBM patients treated with radiation and temozolomide and also influence clinical decision making.
Purpose To evaluate the rate of gastrointestinal (GI) toxicity of neoadjuvant chemoradiation with capecitabine, oxaliplatin, and intensity modulated radiation therapy (IMRT) in cT3-4 rectal cancer. Materials and Methods Patients with localized, non-metastatic T3 or T4 rectal cancer < 12 cm from the anal verge were enrolled in a prospective, multi-institutional, single arm study of preoperative chemoradiation. Patients received 45 Gy with IMRT in 25 fractions, followed by a 3D-conformal boost of 5.4 Gy in 3 fractions with concurrent capecitabine/oxaliplatin (CAPOX). Surgery was performed in 4-8 weeks following completion of therapy. Patients were recommended to receive FOLFOX chemotherapy after surgery. The primary endpoint of the study was acute grade 2-5 GI toxicity. Seventy-one patients provided 80% probability to detect at least a 12% reduction in the specified GI toxicity with the treatment of CAPOX and IMRT, at a significance level of 0.10 (1-sided). Results 79 patients were accrued, of whom 68 were evaluable. 61 patients (89.7%) had cT3 and 37 (54.4%) cN (+) disease. 42/68 patients received post-operative chemotherapy. 58 patients had target contours drawn per protocol, 5 patients with acceptable variation, and 5 patients with unacceptable variations. 35 patients (51.5%) developed grade ≥ 2 GI toxicity. 12 patients (17.6%) developed grade 3 or 4 diarrhea. pCR was achieved in 10 patients (14.7%). With a median follow-up of 3.98 years, the 4-year locoregional failure (LRF) rate was 7.4% (95% CI: 1.0% - 13.7%). 4-year OS and DFS were 82.9% (95% CI: 70.1% - 90.6%) and 60.6% (95% CI: 47.5% - 71.4%), respectively. Conclusion The use of IMRT in neoadjuvant chemoradiation for rectal cancer did not reduce the rate of gastrointestinal toxicity.
Purpose The impact of age on prostate cancer (PCa) outcome has been controversial; therefore, we analyzed the effect of age on overall survival (OS), distant metastasis, prostate cancer-specific death (PCSD), and nonprostate cancer death (NPCD) on patients with locally advanced PCa. Methods and Materials Patients who participated in four Radiation Therapy Oncology Group (RTOG) phase III trials, 8531, 8610, 9202, and 9413, were studied. Cox proportional hazards regression was used for OS analysis, and cumulative events analysis with Fine and Gray's regression was used for analyses of metastasis, PCSD, and NPCD. Results Median follow-up of 4,128 patients with median age of 70 (range, 43-88 years) was 7.3 years. Most patients had high-risk disease: cT3 to cT4 (54%) and Gleason scores (GS) of 7 (45%) and 8 to 10 (27%). Older age (≤70 vs. >70 years) predicted for decreased OS (10-year rate, 55% vs. 41%, respectively; p < 0.0001) and increased NPCD (10-year rate, 28% vs. 46%, respectively; p < 0.0001) but decreased metastasis (10-year rate, 27% vs. 20%, respectively; p < 0.0001) and PCSD (10-year rate, 18% vs. 14%, respectively; p < 0.0001). To account for competing risks, outcomes were analyzed in 2-year intervals, and age-dependent differences in metastasis and PCSD persisted, even in the earliest time periods. When adjusted for other covariates, an age of >70 years remained associated with decreased OS (hazard ratio [HR], 1.56 [95% confidence interval [CI], 1.43-1.70] p < 0.0001) but with decreased metastasis (HR, 0.72 [95% CI, 0.63-0.83] p < 0.0001) and PCSD (HR, 0.78 [95% CI, 0.66-0.92] p < 0.0001). Finally, the impact of the duration of androgen deprivation therapy as a function of age was evaluated. Conclusions These data support less aggressive PCa in older men, independent of other clinical features. While the biological underpinning of this finding remains unknown, stratification by age in future trials appears to be warranted.
Background Angiogenesis, a hallmark of glioblastoma, can potentially be targeted by inhibiting the VEGF pathway using bevacizumab, a humanized monoclonal antibody against VEGF-A. This study was designed to determine the efficacy and safety of these regimens in the cooperative group setting. Methods Eligibility included age ≥ 18, recurrent or progressive GBM after standard chemoradiation. Treatment was intravenous bevacizumab 10 mg/kg and either irinotecan (CPT) 125 mg/m2 every 2 weeks or temozolomide (TMZ) 75–100 mg/m2 day 1–21 of 28 day cycle. Accrual goal was 57 eligible patients per arm. Primary endpoint was 6 month progression-free survival (6-m PFS); a predetermined rate of ≥ 35% to declare efficacy. Results 60 eligible patients were enrolled on TMZ arm and 57 patients on CPT arm. Median age was 56, median KPS was 80. For TMZ arm, the 6-m-PFS rate was 39%(23/59); for the CPT arm, the 6-m-PFS rate was 38.6% (22/57). Objective responses: TMZ arm had 2(3%) CR, 9(16%) PR; CPT arm had 2(4%) CR, 13(24%) PR. Overall there was moderate toxicity: TMZ arm with 33(55%) grade 3, 11(18%) grade 4, and 1(2%) grade 5(fatal) toxicities; CPT arm had 22(39%) grade 3, 7(12%) grade 4, and 3(5%) grade 5 toxicities. Conclusions The 6-m-PFS surpassed the predetermined efficacy threshold for both arms, corroborating the efficacy of bevacizumab and CPT and confirming activity for bevacizumab and protracted TMZ for recurrent/progressive GBM, even after prior temozolomide exposure. Toxicities were within anticipated frequencies with a moderately high rate of venous thrombosis, moderate hypertension and one intracranial hemorrhage.
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