Dataset Information

Biochemical Failure Is Not a Surrogate End Point for Overall Survival in Recurrent Prostate Cancer: Analysis of NRG Oncology/RTOG 9601.

ABSTRACT:

Purpose

Metastasis-free survival (MFS), but not event-free survival, is a validated surrogate end point for overall survival (OS) in men treated for localized prostate cancer. It remains unknown if this holds true in biochemically recurrent disease after radical prostatectomy. Leveraging NRG/RTOG 9601, we aimed to determine the performance of intermediate clinical end points (ICEs) as surrogate end points for OS in recurrent prostate cancer.

Materials and methods

NRG/RTOG 9601 randomly assigned 760 men with recurrence after prostatectomy to salvage radiation therapy with 2 years of placebo versus bicalutamide 150 mg daily. ICEs assessed were biochemical failure (BF) per NRG/RTOG 9601 (prostate-specific antigen nadir + 0.3-0.5 ng/mL or initiation of salvage hormone therapy; [BF1]) and NRG/RTOG 0534 (prostate-specific antigen nadir+2 ng/mL; [BF2]), distant metastasis (DM), and MFS (DM or death). Surrogacy was assessed by the Prentice criteria and a two-stage meta-analytic approach (condition one assessed at the patient level with Kendall's τ and condition two assessed by randomly dividing the entire trial cohort into 10 pseudo trial centers and calculating the average R² between treatment hazard ratios for ICE and OS).

Results

BF1, BF2, DM, and MFS satisfied the four Prentice criteria. However, with the two-condition meta-analytic approach, there was strong correlation between MFS and OS (τ = 0.86), moderate correlation between DM and OS (τ = 0.66), and weaker correlation between BF1 (τ = 0.25) or BF2 (τ = 0.40) and OS. Similarly, for condition two, the treatment effect of antiandrogen therapy on MFS and OS were correlated (R² = 0.67), but this was not true for BF1 (R² = 0.09), BF2 (R² = 0.12), or DM (R² = 0.18) and OS.

Conclusion

MFS is also a strong surrogate for OS in men receiving salvage radiation therapy for recurrence after prostatectomy. Caution should be used when inferring survival benefit from effects on BF in biochemically recurrent prostate cancer. Lack of comorbidity data did not allow us to assess whether BF in men with no/minimal comorbidity could serve as a surrogate for OS.

SUBMITTER: Jackson WC

PROVIDER: S-EPMC9514834 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Publications

Biochemical Failure Is Not a Surrogate End Point for Overall Survival in Recurrent Prostate Cancer: Analysis of NRG Oncology/RTOG 9601.

Jackson William C WC Tang Ming M Schipper Matthew J MJ Sandler Howard M HM Zumsteg Zachary S ZS Efstathiou Jason A JA Shipley William U WU Seiferheld Wendy W Lukka Himanshu R HR Bahary Jean-Paul JP Zietman Anthony L AL Pisansky Thomas M TM Zeitzer Kenneth L KL Hall William A WA Dess Robert T RT Lovett Richard D RD Balogh Alexander G AG Feng Felix Y FY Spratt Daniel E DE

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20220623 27

<h4>Purpose</h4>Metastasis-free survival (MFS), but not event-free survival, is a validated surrogate end point for overall survival (OS) in men treated for localized prostate cancer. It remains unknown if this holds true in biochemically recurrent disease after radical prostatectomy. Leveraging NRG/RTOG 9601, we aimed to determine the performance of intermediate clinical end points (ICEs) as surrogate end points for OS in recurrent prostate cancer.<h4>Materials and methods</h4>NRG/RTOG 9601 ran ...[more]

PMID: 35737923

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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).

Project description:BackgroundSeveral registry-based analyses suggested a survival advantage for married versus single patients with pancreatic cancer. The mechanisms underlying the association of marital status and survival are likely multiple and complex and, therefore, may be obscured in analyses generated from large population-based databases. The goal of this research was to characterize this potential association of marital status with outcomes in patients with resected pancreatic cancer who underwent combined modality adjuvant therapy on a prospective clinical trial.Materials and methodsThis is an ancillary analysis of 367 patients with known marital status treated on NRG Oncology/RTOG 97-04. Survival analysis was performed using the Kaplan-Meier method and compared using the log-rank test. Multivariate analysis was performed using the Cox proportional hazards regression model.ResultsOf 367 patients, 271 (74%) were married or partnered and 96 (26%) were single. Married or partnered patients were more likely to be male. There was no association between marital status and overall survival (OS) or disease-free survival (DFS) on univariate (hazard ratio [HR], 1.09 and 1.01, respectively) or multivariate analyses (HR, 1.05 and 0.98, respectively). Married or partnered male patients did not have improved survival compared with female or single patients.ConclusionAncillary analysis of data from NRG Oncology/RTOG 97-04 demonstrated no association between marital and/or partner status and OS or DFS in patients with resected pancreatic cancer who received adjuvant postoperative chemotherapy followed by concurrent external beam radiation therapy and chemotherapy. Clinical trial identification number. NCT00003216.Implications for practiceSeveral population-based studies have shown an epidemiological link between marital status and survival in patients with pancreatic cancer. A better understanding of this association could offer an opportunity to improve outcomes through psychosocial interventions designed to mitigate the negative effects of not being married. Based on the results of this analysis, patients who have undergone a resection and are receiving adjuvant therapy on a clinical trial are unlikely to benefit from such interventions. Further efforts to study the association between marital status and survival should be focused on less selected subgroups of patients with pancreatic cancer.

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.

Project description:PurposeOur objective was to use interpretable machine learning for choosing dose-volume constraints on cardiopulmonary substructures (CPSs) associated with overall survival (OS) in radiation therapy for locally advanced non-small cell lung cancer.Methods and materialsA total of 428 patients with non-small cell lung cancer were randomly divided into training/validation/test subsets (n = 230/149/49) in Radiation Therapy Oncology Group 0617. Manual or automated contouring was performed to segment CPSs, including heart, atria, ventricles, aorta, left/right ventricle/atrium (LV+RV+LA+RA), inferior/superior vena cava, pulmonary artery, and pericardium. Peri (pericardium-heart), rest (heart-[LV+RV+LA+RA]), clinical target volume (CTV), and lungs-CTV contours were also obtained. Dose-volume histogram features were extracted, including minimum/mean dose to the hottest x% volume (Dx%[Gy]/MOHx%[Gy]), minimum/mean/maximum dose, percent volume receiving at least xGy (VxGy[%]), and overlapping volume of each CPS with planning target volume (PTV_Voverlap[%]). Clinical parameters were collected from the National Clinical Trials Network/Community oncology research program data archive. Feature selection was performed using a series of multiblock sparse partial least squares regression, stability selection supervised principal component analysis, and Boruta. Explainable boosting machine (EBM) was trained using a conditional survival distribution-based approach for imputing censored data, treating survival analysis as a regression problem. Harrell's C-index was used to evaluate OS discrimination performance of EBM, Cox proportional hazards (CPH), random survival forest, extreme gradient boosting survival embeddings, and CPH deep neural network (DeepSurv) models in the test set. Dose-volume constraints were selected using the binary change point detection algorithm in Shapley additive explanations-based partial dependence functions.ResultsSelected features included LA_V60Gy(%), pericardium_D30%(Gy), lungs-CTV_PTV_Voverlap(%), RA_V55Gy(%), and received_cons_chemo. All models ranked LA_V60Gy(%) as the most important feature. EBM achieved the best performance for predicting OS, followed by extreme gradient boosting survival embeddings, random survival forest, DeepSurv, and CPH (C-index = 0.653, 0.646, 0.642, 0.638, and 0.632). EBM global explanations suggested that LA_V60Gy(%) < 25.6, lungs-CTV_PTV_Voverlap(%) < 1.1, pericardium_D30%(Gy) < 18.9, RA_V55Gy(%) < 19.5, and received_cons_chemo = 'Yes' for improved OS.ConclusionsEBM can be used to discriminate OS while also guiding dose-volume constraint selection for optimal management of cardiac toxicity in lung cancer radiation therapy.

Dataset Information

Biochemical Failure Is Not a Surrogate End Point for Overall Survival in Recurrent Prostate Cancer: Analysis of NRG Oncology/RTOG 9601.

Purpose

Materials and methods

Results

Conclusion

Publications

Biochemical Failure Is Not a Surrogate End Point for Overall Survival in Recurrent Prostate Cancer: Analysis of NRG Oncology/RTOG 9601.

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