Independently validated sex-specific nomograms for predicting survival in patients with newly diagnosed glioblastoma: NRG Oncology RTOG 0525 and 0825.
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ABSTRACT: Background/purpose
Glioblastoma (GBM) is the most common primary malignant brain tumor. Sex has been shown to be an important prognostic factor for GBM. The purpose of this study was to develop and independently validate sex-specific nomograms for estimation of individualized GBM survival probabilities using data from 2 independent NRG Oncology clinical trials.Methods
This analysis included information on 752 (NRG/RTOG 0525) and 599 (NRG/RTOG 0825) patients with newly diagnosed GBM. The Cox proportional hazard models by sex were developed using NRG/RTOG 0525 and significant variables were identified using a backward selection procedure. The final selected models by sex were then independently validated using NRG/RTOG 0825.Results
Final nomograms were built by sex. Age at diagnosis, KPS, MGMT promoter methylation and location of tumor were common significant predictors of survival for both sexes. For both sexes, tumors in the frontal lobes had significantly better survival than tumors of multiple sites. Extent of resection, and use of corticosteroids were significant predictors of survival for males.Conclusions
A sex specific nomogram that assesses individualized survival probabilities (6-, 12- and 24-months) for patients with GBM could be more useful than estimation of overall survival as there are factors that differ between males and females. A user friendly online application can be found here- https://npatilshinyappcalculator.shinyapps.io/SexDifferencesInGBM/ .
SUBMITTER: Patil N
PROVIDER: S-EPMC8651582 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundGlioblastoma (GBM) is the most common primary malignant brain tumor. Nomograms are often used for individualized estimation of prognosis. This study aimed to build and independently validate a nomogram to estimate individualized survival probabilities for patients with newly diagnosed GBM, using data from 2 independent NRG Oncology Radiation Therapy Oncology Group (RTOG) clinical trials.MethodsThis analysis included information on 799 (RTOG 0525) and 555 (RTOG 0825) eligible and randomized patients with newly diagnosed GBM and contained the following variables: age at diagnosis, race, gender, Karnofsky performance status (KPS), extent of resection, O6-methylguanine-DNA methyltransferase (MGMT) methylation status, and survival (in months). Survival was assessed using Cox proportional hazards regression, random survival forests, and recursive partitioning analysis, with adjustment for known prognostic factors. The models were developed using the 0525 data and were independently validated using the 0825 data. Models were internally validated using 10-fold cross-validation, and individually predicted 6-, 12-, and 24-month survival probabilities were generated to measure the predictive accuracy and calibration against the actual survival status.ResultsA final nomogram was built using the Cox proportional hazards model. Factors that increased the probability of shorter survival included greater age at diagnosis, male gender, lower KPS, not having total resection, and unmethylated MGMT status.ConclusionsA nomogram that assesses individualized survival probabilities (6-, 12-, and 24-mo) for patients with newly diagnosed GBM could be useful to health care providers for counseling patients regarding treatment decisions and optimizing therapeutic approaches. Free software for implementing this nomogram is provided: http://cancer4.case.edu/rCalculator/rCalculator.html.
| S-EPMC5464437 | biostudies-literature
Project description:ImportanceThere is a need for a more refined, molecularly based classification model for glioblastoma (GBM) in the temozolomide era.ObjectiveTo refine the existing clinically based recursive partitioning analysis (RPA) model by incorporating molecular variables.Design, setting, and participantsNRG 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).Main outcomes and measuresOverall survival (OS).ResultsIn 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).Conclusions and relevanceThis 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.Trial registrationclinicaltrials.gov Identifier: NCT00304031.
| S-EPMC5464982 | biostudies-literature
Project description:BackgroundResults of NRG Oncology RTOG 0825 reported adding bevacizumab to standard chemoradiation did not significantly improve survival endpoints and resulted in greater decline in neurocognitive function (NCF) and patient-reported outcomes (PRO) over time in bevacizumab-treated patients. The present report provides additional results of patient-centered outcomes over time and their prognostic association with survival endpoints.MethodsNCF tests, MD Anderson Symptom Inventory - Brain Tumor Module (MDASI-BT), and European Organization for Research and Treatment of Cancer (EORTC) quality of life (QOL) questionnaire with brain cancer module (QLQ-C30/BN20) were completed in a subset of progression-free patients at baseline and longitudinally. The prognostic value of baseline and early changes in NCF and PROs and differences between treatments from baseline to follow-up assessments were evaluated.ResultsA total of 508 randomized patients participated. Baseline/early changes in NCF and PROs were prognostic for OS and PFS. No between-arm differences in time to deterioration were found. At week 6, patients treated with bevacizumab evidenced greater improvement on NCF tests of executive function and the MDASI-BT Cognitive Function scale, but simultaneously reported greater decline on the EORTC Cognitive Function Scale. At later time points (weeks 22, 34, and 46), patients treated with bevacizumab had greater worsening on NCF tests as well as PRO measures of cognitive, communication, social function, motor symptoms, general symptoms, and interference.ConclusionThe collection of patient-centered clinical outcome assessments in this phase III trial revealed greater deterioration in NCF, symptoms, and QOL in patients treated with bevacizumab. Baseline and early change in NCF and PROs were prognostic for survival endpoints.
| S-EPMC8661434 | biostudies-literature
Project description:BackgroundPhase 2 cooperative group meningioma trial assessing the safety and efficacy of risk-adaptive management strategies. This is the initial analysis of the high-risk cohort.Methods and materialsHigh-risk patients were those with a new or recurrent World Health Organization (WHO) grade III meningioma of any resection extent, recurrent WHO grade II of any resection extent, or new WHO grade II after subtotal resection. Patients received intensity-modulated radiotherapy (IMRT) using a simultaneous integrated boost technique (60 Gy high dose and 54 Gy low dose in 30 fractions). Three-year progression-free survival (PFS) was the primary endpoint. Adverse events (AEs) were scored per NCI Common Terminology Criteria for Adverse Events version 3.ResultsOf 57 enrolled patients, 53 received protocol treatment. Median follow-up was 4.0 years (4.8 years for living patients). Two patients withdrew without progression before year 3; for the remaining 51 patients, 3-year PFS was 58.8%. Among all 53 protocol-treated patients, 3-year PFS was 59.2%. Three-year local control was 68.9%, and overall survival was 78.6%. Of 51 patients, 1 patient (1.9%) experienced a late grade-5 necrosis-related AE. All other acute (23 of 53 patients) and late (21 of 51 patients) AEs were grades 1 to 3.ConclusionsPatients with high-risk meningioma treated with IMRT (60 Gy/30) experienced 3-year PFS of 58.8%. Combined acute and late AEs were limited to grades 1 to 3, except for a single necrosis-related grade 5 event. These results support postoperative IMRT for high-risk meningioma and invite ongoing investigations to improve outcomes further.
| S-EPMC7117785 | biostudies-literature
Project description:OBJECTIVE This is the first clinical outcomes report of NRG Oncology RTOG 0539, detailing the primary endpoint, 3-year progression-free survival (PFS), compared with a predefined historical control for intermediate-risk meningioma, and secondarily evaluating overall survival (OS), local failure, and prospectively scored adverse events (AEs). METHODS NRG Oncology RTOG 0539 was a Phase II clinical trial allocating meningioma patients to 1 of 3 prognostic groups and management strategies according to WHO grade, recurrence status, and resection extent. For the intermediate-risk group (Group 2), eligible patients had either newly diagnosed WHO Grade II meningioma that had been treated with gross-total resection (GTR; Simpson Grades I-III) or recurrent WHO Grade I meningioma with any resection extent. Pathology and imaging were centrally reviewed. Patients were treated with radiation therapy (RT), either intensity modulated (IMRT) or 3D conformal (3DCRT), 54 Gy in 30 fractions. The RT target volume was defined as the tumor bed and any nodular enhancement (e.g., in patients with recurrent WHO Grade I tumors) with a minimum 8-mm and maximum 15-mm margin, depending on tumor location and setup reproducibility of the RT method. The primary endpoint was 3-year PFS. Results were compared with historical controls (3-year PFS: 70% following GTR alone and 90% with GTR + RT). AEs were scored using NCI Common Toxicity Criteria. RESULTS Fifty-six patients enrolled in the intermediate-risk group, of whom 3 were ineligible and 1 did not receive RT. Of the 52 patients who received protocol therapy, 4 withdrew without a recurrence before 3 years leaving 48 patients evaluable for the primary endpoint, 3-year PFS, which was actuarially 93.8% (p = 0.0003). Within 3 years, 3 patients experienced events affecting PFS: 1 patient with a WHO Grade II tumor died of the disease, 1 patient with a WHO Grade II tumor had disease progression but remained alive, and 1 patient with recurrent WHO Grade I meningioma died of undetermined cause without tumor progression. The 3-year actuarial local failure rate was 4.1%, and the 3-year OS rate was 96%. After 3 years, progression occurred in 2 additional patients: 1 patient with recurrent WHO Grade I meningioma and 1 patient with WHO Grade II disease; both remain alive. Among 52 evaluable patients who received protocol treatment, 36 (69.2%) had WHO Grade II tumors and underwent GTR, and 16 (30.8%) had recurrent WHO Grade I tumors. There was no significant difference in PFS between these subgroups (p = 0.52, HR 0.56, 95% CI 0.09-3.35), validating their consolidation. Of the 52 evaluable patients, 44 (84.6%) received IMRT, and 50 (96.2%) were treated per protocol or with acceptable variation. AEs (definitely, probably, or possibly related to protocol treatment) were limited to Grade 1 or 2, with no reported Grade 3 events. CONCLUSIONS This is the first clinical outcomes report from NRG Oncology RTOG 0539. Patients with intermediate-risk meningioma treated with RT had excellent 3-year PFS, with a low rate of local failure and a low risk of AEs. These results support the use of postoperative RT for newly diagnosed gross-totally resected WHO Grade II or recurrent WHO Grade I meningioma irrespective of resection extent. They also document minimal toxicity and high rates of tumor control with IMRT. Clinical trial registration no.: NCT00895622 (clinicaltrials.gov).
| S-EPMC5889346 | biostudies-literature
Project description:PurposeRadiation Therapy Oncology Group trial 0525 tested whether dose-intensifying temozolomide versus standard chemoradiotherapy improves overall survival (OS) or progression-free survival (PFS) in newly diagnosed glioblastoma. Tests of neurocognitive function (NCF) and symptoms (using the MD Anderson Symptom Inventory-Brain Tumor module; MDASI-BT) and of quality of life (European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ] -C30/BN20) examined the net clinical benefit (NCB) of therapy.Patients and methodsNCF tests (Hopkins Verbal Learning Test-Revised, Trail Making Test, and Controlled Oral Word Association), MDASI-BT, and EORTC QLQ-C30/BN20 were completed in a subset of patients. Multivariate Cox proportional hazard regression modeling determined the prognostic value of baseline and early change from baseline to cycle 1 for OS and PFS. Two-sample proportional test statistic was used to evaluate differences between treatments (dose-dense v standard-dose) on NCB measures from baseline to cycle 4 in stable patients.ResultsOverall, 182 patients participated in the study. Baseline NCF tests and the physical functioning quality of life scale were associated with OS and PFS. Baseline to cycle 1 in all NCB components were associated with OS and PFS. There was greater deterioration in the dose-dense arm from baseline to cycle 4 in the Global Health and Motor Function subscales (EORTC QLQ-C30/BN20) as well as in overall symptom burden, overall symptom interference, and activity-related symptom interference subscales (MDASI-BT). There were no between-arm differences in NCF.ConclusionLongitudinal collection of NCB measures is feasible in cooperative group studies and provides an added dimension to standard outcome measures. Greater adverse symptom burden and functional interference, as well as decreased global health and motor function were observed in patients randomly assigned to the dose-dense arm. Baseline and early change in NCB measures were associated with decreased rates of survival.
| S-EPMC3816957 | biostudies-literature
Project description:PurposeNRG/RTOG 0841 assessed the feasibility of a depression screening procedure in patients receiving radiation therapy (RT). As a secondary endpoint, availability and barriers to psychosocial care data were collected in hopes of providing recommendations for improved psychosocial care among patients receiving RT.Methods and materialsPatients starting RT were prospectively recruited and assessed with self-reported distress screening tools. Patients exceeding a validated cutoff and a sample of patients who screened negative received the Structured Clinical Interview for DSM-IV (SCID) mood disorder modules via telephone. During that SCID evaluation, patients completed a validated scale ranking interview on barriers to psychosocial care and interest in various psychosocial intervention modalities.ResultsA total of 463 patients from 35 community-based and 2 academic RT oncology sites were recruited. Of the 455 eligible, 75 (16%) exceeded screening cutoffs for depressive symptoms. From this group, 78 patients completed the SCID; most were female (76%), white (88%), and had breast cancer (55%). Overall, the most common barriers to treatment, regardless of insurance, were costs (58%), daily responsibilities (44%), and physical health symptoms (38%). Patients from RT facilities without mental health services were significantly more likely to report difficulty with physical health problems, specifically serious illness and walking, compared with those treated at RT facilities with services (P = .013 and P = .039, respectively). Overall, there was interest in obtaining psychosocial services with face-to-face counseling at the cancer center and printed educational materials as the most commonly preferred interventions. Patients with difficult barriers to psychosocial interventions were significantly less interested in support away from the cancer center (P = .016), telephone and Internet counseling (P = .0062 &P = .011), and Internet support (P = .0048).ConclusionRadiation oncology patients are interested in obtaining psychosocial services but face barriers to access to mental health services including cost, debilitating symptoms, and time constraints that prevent adequate care.
| S-EPMC8238825 | biostudies-literature
Project description:Purpose NRG Oncology/RTOG 1203 was designed to compare patient-reported acute toxicity and health-related quality of life during treatment with standard pelvic radiation or intensity-modulated radiation therapy (IMRT) in women with cervical and endometrial cancer. Methods Patients were randomly assigned to standard four-field radiation therapy (RT) or IMRT radiation treatment. The primary end point was change in patient-reported acute GI toxicity from baseline to the end of RT, measured with the bowel domain of the Expanded Prostate Cancer Index Composite (EPIC). Secondary end points included change in patient-reported urinary toxicity, change in GI toxicity measured with the Patient-Reported Outcome Common Terminology Criteria for Adverse Events, and quality of life measured with the Trial Outcome Index. Results From 2012 to 2015, 289 patients were enrolled, of whom 278 were eligible. Between baseline and end of RT, the mean EPIC bowel score declined 23.6 points in the standard RT group and 18.6 points in the IMRT group ( P = .048), the mean EPIC urinary score declined 10.4 points in the standard RT group and 5.6 points in the IMRT group ( P = .03), and the mean Trial Outcome Index score declined 12.8 points in the standard RT group and 8.8 points in the IMRT group ( P = .06). At the end of RT, 51.9% of women who received standard RT and 33.7% who received IMRT reported frequent or almost constant diarrhea ( P = .01), and more patients who received standard RT were taking antidiarrheal medications four or more times daily (20.4% v 7.8%; P = .04). Conclusion Pelvic IMRT was associated with significantly less GI and urinary toxicity than standard RT from the patient's perspective.
| S-EPMC6097832 | biostudies-literature
Project description:PURPOSE:To evaluate the toxicity and efficacy of adjuvant temozolomide (TMZ) and irinotecan (CPT-11) for 12 months after concurrent chemoradiation in patients with newly diagnosed glioblastoma (GBM). METHODS AND MATERIALS:Trial RTOG 04-20, a single-arm, multi-institutional phase 2 trial, was designed to determine the efficacy and toxicity of concomitant TMZ and radiation therapy (RT) followed by adjuvant TMZ combined with CPT-11 given for 12 cycles compared with historical controls of adjuvant TMZ alone given for 6 cycles. RESULTS:A total of 170 patients were enrolled, 152 of whom were eligible. Adjuvant CPT-11 combined with TMZ was more toxic than expected. A higher rate of hematologic and gastrointestinal toxicities was more frequently noted with the combination regimen compared with adjuvant TMZ alone. Grade 3/4 hematologic toxicity was 38% compared with 14% reported in the Stupp trial. After an early interim analysis, the adjuvant CPT-11 dose was reduced to 100 mg/m2 on days 1 and 5 for the first cycle. CPT-11 dose escalation proceeded over the first 3 cycles if tolerated. Median overall survival for all eligible patients was 16.9 months compared with 13.7 months of the historical control (P = .03). Post hoc subgroup analysis suggested an improvement in overall survival for patients with Radiation Therapy Oncology Group recursive partitioning analysis class 3, although improvement was limited to 22 patients (14% of eligible patients). CONCLUSIONS:Although irinotecan and TMZ for 12 cycles given after chemoradiation for patients with newly diagnosed glioblastoma significantly improved median survival compared with historical control data at the time the study was conducted, the historical control median survival time of 13.7 months does not represent the current benchmark for this patient population. Treatment intensification does prolong overall survival compared with the current standard.
| S-EPMC7034757 | biostudies-literature
Project description:BackgroundWe sought to identify clinical and genetic predictors of temozolomide-related myelotoxicity among patients receiving therapy for glioblastoma.MethodsPatients (n = 591) receiving therapy on NRG Oncology/RTOG 0825 were included in the analysis. Cases were patients with severe myelotoxicity (grade 3 and higher leukopenia, neutropenia, and/or thrombocytopenia); controls were patients without such toxicity. A risk-prediction model was built and cross-validated by logistic regression using only clinical variables and extended using polymorphisms associated with myelotoxicity.Results23% of patients developed myelotoxicity (n = 134). This toxicity was first reported during the concurrent phase of therapy for 56 patients; 30 stopped treatment due to toxicity. Among those who continued therapy (n = 26), 11 experienced myelotoxicity again. The final multivariable clinical factor model included treatment arm, gender, and anticonvulsant status and had low prediction accuracy (area under the curve [AUC] = 0.672). The final extended risk prediction model including four polymorphisms in MGMT had better prediction (AUC = 0.827). Receiving combination chemotherapy (OR, 1.82; 95% CI, 1.02-3.27) and being female (OR, 4.45; 95% CI, 2.45-8.08) significantly increased myelotoxicity risk. For each additional minor allele in the polymorphisms, the risk increased by 64% (OR, 1.64; 95% CI, 1.43-1.89).ConclusionsMyelotoxicity during concurrent chemoradiation with temozolomide is an uncommon but serious event, often leading to treatment cessation. Successful prediction of toxicity may lead to more cost-effective individualized monitoring of at-risk subjects. The addition of genetic factors greatly enhanced our ability to predict toxicity among a group of similarly treated glioblastoma patients.
| S-EPMC9587696 | biostudies-literature