Dataset Information

Interplay Between Duration of Androgen Deprivation Therapy and External Beam Radiotherapy With or Without a Brachytherapy Boost for Optimal Treatment of High-risk Prostate Cancer: A Patient-Level Data Analysis of 3 Cohorts.

ABSTRACT:

Importance

Radiotherapy combined with androgen deprivation therapy (ADT) is a standard of care for high-risk prostate cancer. However, the interplay between radiotherapy dose and the required minimum duration of ADT is uncertain.

Objective

To determine the specific ADT duration threshold that provides a distant metastasis-free survival (DMFS) benefit in patients with high-risk prostate cancer receiving external beam radiotherapy (EBRT) or EBRT with a brachytherapy boost (EBRT+BT).

Design, settings, and participants

This was a cohort study of 3 cohorts assembled from a multicenter retrospective study (2000-2013); a post hoc analysis of the Randomized Androgen Deprivation and Radiotherapy 03/04 (RADAR; 2003-2007) randomized clinical trial (RCT); and a cross-trial comparison of the RADAR vs the Deprivación Androgénica y Radio Terapía (Androgen Deprivation and Radiation Therapy; DART) 01/05 RCT (2005-2010). In all, the study analyzed 1827 patients treated with EBRT and 1108 patients treated with EBRT+BT from the retrospective cohort; 181 treated with EBRT and 203 with EBRT+BT from RADAR; and 91 patients treated with EBRT from DART. The study was conducted from October 15, 2020, to July 1, 2021, and the data analyses, from January 5 to June 15, 2021.

Exposures

High-dose EBRT or EBRT+BT for an ADT duration determined by patient-physician choice (retrospective) or by randomization (RCTs).

Main outcomes and measures

The primary outcome was DMFS; secondary outcome was overall survival (OS). Natural cubic spline analysis identified minimum thresholds (months).

Results

This cohort study of 3 studies totaling 3410 men (mean age [SD], 68 [62-74] years; race and ethnicity not collected) with high-risk prostate cancer found a significant interaction between the treatment type (EBRT vs EBRT+BT) and ADT duration (binned to <6, 6 to <18, and ≥18 months). Natural cubic spline analysis identified minimum duration thresholds of 26.3 months (95% CI, 25.4-36.0 months) for EBRT and 12 months (95% CI, 4.9-36.0 months) for EBRT+BT for optimal effect on DMFS. In RADAR, the prolongation of ADT for patients receiving only EBRT was not associated with significant improvements in DMFS (hazard ratio [HR], 1.01; 95% CI, 0.65-1.57); however, for patients receiving EBRT+BT, a longer duration was associated with improved DMFS (DMFS HR, 0.56; 95% CI, 0.36-0.87; P = .01). For patients receiving EBRT alone (DART), 28 months of ADT was associated with improved DMFS compared with 18 months (RADAR HR, 0.37; 95% CI, 0.17-0.80; P = .01).

Conclusions and relevance

These cohort study findings suggest that the optimal minimum ADT duration for treatment with high-dose EBRT alone is more than 18 months; and for EBRT+BT, it is 18 months or possibly less. Additional studies are needed to determine more precise minimum durations.

SUBMITTER: Kishan AU

PROVIDER: S-EPMC8778608 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Publications

Interplay Between Duration of Androgen Deprivation Therapy and External Beam Radiotherapy With or Without a Brachytherapy Boost for Optimal Treatment of High-risk Prostate Cancer: A Patient-Level Data Analysis of 3 Cohorts.

Kishan Amar U AU Steigler Alison A Denham James W JW Zapatero Almudena A Guerrero Araceli A Joseph David D Maldonado Xavier X Wong Jessica K JK Stish Bradley J BJ Dess Robert T RT Pilar Avinash A Reddy Chandana C Wedde Trude B TB Lilleby Wolfgang A WA Fiano Ryan R Merrick Gregory S GS Stock Richard G RG Demanes D Jeffrey DJ Moran Brian J BJ Tran Phuoc T PT Martin Santiago S Martinez-Monge Rafael R Krauss Daniel J DJ Abu-Isa Eyad I EI Pisansky Thomas M TM Choo C Richard CR Song Daniel Y DY Greco Stephen S Deville Curtiland C McNutt Todd T DeWeese Theodore L TL Ross Ashley E AE Ciezki Jay P JP Tilki Derya D Karnes R Jeffrey RJ Tosoian Jeffrey J JJ Nickols Nicholas G NG Bhat Prashant P Shabsovich David D Juarez Jesus E JE Jiang Tommy T Ma T Martin TM Xiang Michael M Philipson Rebecca R Chang Albert A Kupelian Patrick A PA Rettig Matthew B MB Feng Felix Y FY Berlin Alejandro A Tward Jonathan D JD Davis Brian J BJ Reiter Robert E RE Steinberg Michael L ML Elashoff David D Boutros Paul C PC Horwitz Eric M EM Tendulkar Rahul D RD Spratt Daniel E DE Romero Tahmineh T

JAMA oncology 20220317 3

<h4>Importance</h4>Radiotherapy combined with androgen deprivation therapy (ADT) is a standard of care for high-risk prostate cancer. However, the interplay between radiotherapy dose and the required minimum duration of ADT is uncertain.<h4>Objective</h4>To determine the specific ADT duration threshold that provides a distant metastasis-free survival (DMFS) benefit in patients with high-risk prostate cancer receiving external beam radiotherapy (EBRT) or EBRT with a brachytherapy boost (EBRT+BT). ...[more]

PMID: 35050303

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Project description:BackgroundLocalized Gleason Grade Group 5 (GG5) prostate cancer has a poor prognosis and is associated with a higher risk of treatment failure, metastases, and death. Treatment intensification with the addition of a brachytherapy (BT) boost to external beam radiation (EBRT) maximizes local control, which may translate into improved survival outcomes.MethodsA systematic review and meta-analysis was performed to compare survival outcomes for Gleason GG5 patients treated with androgen deprivation therapy (ADT) and either EBRT or EBRT + BT. The MEDLINE (PubMed), EMBASE and Cochrane databases were searched to identify relevant studies. Survival probabilities for distant metastasis-free survival (DMFS), prostate cancer-specific survival (PCSS), and overall survival (OS) were extracted and pooled to create a summary survival curve for each treatment modality, which were then compared at fixed points in time. An additional analysis was performed among studies directly comparing EBRT and EBRT + BT using a random-effects model.ResultsEight retrospective studies were selected for inclusion, representing a total of 1393 EBRT patients and 877 EBRT + BT patients. EBRT + BT was associated with higher DMFS starting at 6 years (86.8 % vs 78.8 %; p = 0.018) and extending out to 10 years (81.8 % vs 66.1 %; p < 0.001), with an overall hazard ratio of 0.53 (p = 0.02). There was no difference in PCSS or OS between treatment modalities. Differences in toxicity were not assessed. There was a wide range of heterogeneity between studies.ConclusionThe addition of BT boost is associated with improved long-term DMFS in Gleason GG5 prostate cancer, but its impact on PCSS and OS remains unclear. These results may be confounded by the heterogeneity across study populations with concern for a risk of bias. Therefore, prospective studies are necessary to further elucidate the survival advantage associated with BT boost, which must ultimately be weighed against the toxicity-related implications of this treatment strategy.

Project description:ImportanceUnderstanding adverse effects of contemporary treatment approaches for men with favorable-risk and unfavorable-risk localized prostate cancer could inform treatment selection.ObjectiveTo compare functional outcomes associated with prostate cancer treatments over 5 years after treatment.Design, setting, and participantsProspective, population-based cohort study of 1386 men with favorable-risk (clinical stage cT1 to cT2bN0M0, prostate-specific antigen [PSA] ≤20 ng/mL, and Grade Group 1-2) prostate cancer and 619 men with unfavorable-risk (clinical stage cT2cN0M0, PSA of 20-50 ng/mL, or Grade Group 3-5) prostate cancer diagnosed in 2011 through 2012, accrued from 5 Surveillance, Epidemiology and End Results Program sites and a US prostate cancer registry, with surveys through September 2017.ExposuresTreatment with active surveillance (n = 363), nerve-sparing prostatectomy (n = 675), external beam radiation therapy (EBRT; n = 261), or low-dose-rate brachytherapy (n = 87) for men with favorable-risk disease and treatment with prostatectomy (n = 402) or EBRT with androgen deprivation therapy (n = 217) for men with unfavorable-risk disease.Main outcomes and measuresPatient-reported function, based on the 26-item Expanded Prostate Index Composite (range, 0-100), 5 years after treatment. Regression models were adjusted for baseline function and patient and tumor characteristics. Minimum clinically important difference was 10 to 12 for sexual function, 6 to 9 for urinary incontinence, 5 to 7 for urinary irritative symptoms, and 4 to 6 for bowel and hormonal function.ResultsA total of 2005 men met inclusion criteria and completed the baseline and at least 1 postbaseline survey (median [interquartile range] age, 64 [59-70] years; 1529 of 1993 participants [77%] were non-Hispanic white). For men with favorable-risk prostate cancer, nerve-sparing prostatectomy was associated with worse urinary incontinence at 5 years (adjusted mean difference, -10.9 [95% CI, -14.2 to -7.6]) and sexual function at 3 years (adjusted mean difference, -15.2 [95% CI, -18.8 to -11.5]) compared with active surveillance. Low-dose-rate brachytherapy was associated with worse urinary irritative (adjusted mean difference, -7.0 [95% CI, -10.1 to -3.9]), sexual (adjusted mean difference, -10.1 [95% CI, -14.6 to -5.7]), and bowel (adjusted mean difference, -5.0 [95% CI, -7.6 to -2.4]) function at 1 year compared with active surveillance. EBRT was associated with urinary, sexual, and bowel function changes not clinically different from active surveillance at any time point through 5 years. For men with unfavorable-risk disease, EBRT with ADT was associated with lower hormonal function at 6 months (adjusted mean difference, -5.3 [95% CI, -8.2 to -2.4]) and bowel function at 1 year (adjusted mean difference, -4.1 [95% CI, -6.3 to -1.9]), but better sexual function at 5 years (adjusted mean difference, 12.5 [95% CI, 6.2-18.7]) and incontinence at each time point through 5 years (adjusted mean difference, 23.2 [95% CI, 17.7-28.7]), than prostatectomy.Conclusions and relevanceIn this cohort of men with localized prostate cancer, most functional differences associated with contemporary management options attenuated by 5 years. However, men undergoing prostatectomy reported clinically meaningful worse incontinence through 5 years compared with all other options, and men undergoing prostatectomy for unfavorable-risk disease reported worse sexual function at 5 years compared with men who underwent EBRT with ADT.

Project description:Importance:The optimal treatment for Gleason score 9-10 prostate cancer is unknown. Objective:To compare clinical outcomes of patients with Gleason score 9-10 prostate cancer after definitive treatment. Design, Setting, and Participants:Retrospective cohort study in 12 tertiary centers (11 in the United States, 1 in Norway), with 1809 patients treated between 2000 and 2013. Exposures:Radical prostatectomy (RP), external beam radiotherapy (EBRT) with androgen deprivation therapy, or EBRT plus brachytherapy boost (EBRT+BT) with androgen deprivation therapy. Main Outcomes and Measures:The primary outcome was prostate cancer-specific mortality; distant metastasis-free survival and overall survival were secondary outcomes. Results:Of 1809 men, 639 underwent RP, 734 EBRT, and 436 EBRT+BT. Median ages were 61, 67.7, and 67.5 years; median follow-up was 4.2, 5.1, and 6.3 years, respectively. By 10 years, 91 RP, 186 EBRT, and 90 EBRT+BT patients had died. Adjusted 5-year prostate cancer-specific mortality rates were RP, 12% (95% CI, 8%-17%); EBRT, 13% (95% CI, 8%-19%); and EBRT+BT, 3% (95% CI, 1%-5%). EBRT+BT was associated with significantly lower prostate cancer-specific mortality than either RP or EBRT (cause-specific HRs of 0.38 [95% CI, 0.21-0.68] and 0.41 [95% CI, 0.24-0.71]). Adjusted 5-year incidence rates of distant metastasis were RP, 24% (95% CI, 19%-30%); EBRT, 24% (95% CI, 20%-28%); and EBRT+BT, 8% (95% CI, 5%-11%). EBRT+BT was associated with a significantly lower rate of distant metastasis (propensity-score-adjusted cause-specific HRs of 0.27 [95% CI, 0.17-0.43] for RP and 0.30 [95% CI, 0.19-0.47] for EBRT). Adjusted 7.5-year all-cause mortality rates were RP, 17% (95% CI, 11%-23%); EBRT, 18% (95% CI, 14%-24%); and EBRT+BT, 10% (95% CI, 7%-13%). Within the first 7.5 years of follow-up, EBRT+BT was associated with significantly lower all-cause mortality (cause-specific HRs of 0.66 [95% CI, 0.46-0.96] for RP and 0.61 [95% CI, 0.45-0.84] for EBRT). After the first 7.5 years, the corresponding HRs were 1.16 (95% CI, 0.70-1.92) and 0.87 (95% CI, 0.57-1.32). No significant differences in prostate cancer-specific mortality, distant metastasis, or all-cause mortality (≤7.5 and >7.5 years) were found between men treated with EBRT or RP (cause-specific HRs of 0.92 [95% CI, 0.67-1.26], 0.90 [95% CI, 0.70-1.14], 1.07 [95% CI, 0.80-1.44], and 1.34 [95% CI, 0.85-2.11]). Conclusions and Relevance:Among patients with Gleason score 9-10 prostate cancer, treatment with EBRT+BT with androgen deprivation therapy was associated with significantly better prostate cancer-specific mortality and longer time to distant metastasis compared with EBRT with androgen deprivation therapy or with RP.

Project description:PurposeTo compare patient-reported disease-specific functional outcomes after external beam radiation therapy (EBRT) and EBRT combined with low-dose-rate brachytherapy prostate boost (EB-LDR) among men with localized prostate cancer.Methods and materialsThe prospective, population-based Comparative Effectiveness Analysis of Surgery and Radiation study enrolled men with localized prostate cancer in 2011 to 2012. The 26-item Expanded Prostate Cancer Index Composite measured patient-reported disease-specific function at baseline and at 6, 12, and 36 months. Higher domain scores indicate better function. Minimal clinically important difference was defined as 6 for urinary incontinence, 5 for urinary irritative function, 4 for bowel function, 12 for sexual function, and 4 for hormonal function. Multivariable linear and logistic regression models were fit to estimate the effect of treatment on patient-reported outcomes.ResultsFive-hundred seventy-eight men received EBRT and 109 received EB-LDR. Median patient age was 69 years, and 70% had intermediate- or high-risk disease. Men in the EB-LDR group were younger (P < .001) and less likely to receive androgen deprivation therapy (P < .001). Baseline urinary, bowel, sexual, and hormonal function was similar between treatment groups (P > .05). On multivariable analyses, men receiving EB-LDR reported worse urinary irritative function at 6 months (adjusted mean difference [AMD] -14.4, P < .001), 12 months (AMD -12.9, P < .001), and 36 months (AMD -4.7, P = .034) than men receiving EBRT. At 12 months, men receiving EB-LDR reported worse bowel function (AMD -5.8, P = .002), but these differences were not seen at 36 months. There were no significant differences in sexual or hormone function between treatment groups.ConclusionsMen treated with EB-LDR report worse bowel function at 1 year and worse urinary irritative function through 3 years compared with men treated with EBRT alone. These side effect profiles should be discussed with patients when considering EB-LDR versus EBRT treatment.

Project description:BackgroundRegistering CTs for patients receiving external beam radiotherapy (EBRT) with a boost dose from high-dose-rate brachytherapy (HDR) can be challenging due to considerable image discrepancies (e.g. rectal fillings, HDR needles, HDR artefacts and HDR rectal packing materials). This study is the first to comparatively evaluate image processing and registration methods used to register the rectums in EBRT and HDR CTs of prostate cancer patients. The focus is on the rectum due to planned future analysis of rectal dose-volume response.MethodsFor 64 patients, the EBRT CT was retrospectively registered to the HDR CT with rigid registration and non-rigid registration methods in VelocityAI. Image processing was undertaken on the HDR CT and the rigidly-registered EBRT CT to reduce the impact of discriminating features on alternative non-rigid registration methods applied in the software suite for Deformable Image Registration and Adaptive Radiotherapy Research (DIRART) using the Horn-Schunck optical flow and Demons algorithms. The propagated EBRT-rectum structures were compared with the HDR structure using the Dice similarity coefficient (DSC), Hausdorff distance (HD) and average surface distance (ASD). The image similarity was compared using mutual information (MI) and root mean squared error (MSE). The displacement vector field was assessed via the Jacobian determinant (JAC). The post-registration alignments of rectums for 21 patients were visually assessed.ResultsThe greatest improvement in the median DSC relative to the rigid registration result was 35 % for the Horn-Schunck algorithm with image processing. This algorithm also provided the best ASD results. The VelocityAI algorithms provided superior HD, MI, MSE and JAC results. The visual assessment indicated that the rigid plus deformable multi-pass method within VelocityAI resulted in the best rectum alignment.ConclusionsThe DSC, ASD and HD improved significantly relative to the rigid registration result if image processing was applied prior to DIRART non-rigid registrations, whereas VelocityAI without image processing provided significant improvements. Reliance on a single rectum structure-correspondence metric would have been misleading as the metrics were inconsistent with one another and visual assessments. It was important to calculate metrics for a restricted region covering the organ of interest. Overall, VelocityAI generated the best registrations for the rectum according to the visual assessment, HD, MI, MSE and JAC results.

Project description:To compare the outcomes of localized prostate cancer treatment with high-dose-rate brachytherapy (HDR-BT) and low-dose-rate brachytherapy (LDR-BT), we examined 924 patients treated with HDR-BT + external beam radiotherapy (EBRT) and 500 patients treated with LDR-BT ± EBRT using multi-institutional retrospective data. The HDR-BT treated advanced disease with more hormonal therapy than LDR-BT. To reduce background selection bias, we performed inverse probability of treatment weighting (IPTW) analysis using propensity scores and excluded patients with T3b-4 disease/ initial prostate-specific antigen (PSA) levels > 50 ng/ml. The actuarial 5-year biochemical control rates (5y-bNED) were 96.3% and 95.7% in the HDR-BT and LDR-BT groups, respectively. The corresponding values were 100% and 96.5% in the low-risk group; 97.4% and 97.1% in the intermediate-risk group (97.2% and 97% in the higher titer group and 97.5% and 94.6% in the lower titer group, respectively); and 95.7% and 94.9% in the selected high-risk group, respectively. IPTW correction indicated no significant difference among the groups. The 5y-bNED in the HDR-BT + EBRT, LDR-BT + EBRT, and LDR-BT alone groups were 96.3%, 95.5%, and 97%, respectively (P = 0.3011). The corresponding values were 97.4%, 94.7%, and 96.6% (P = 0.1004) in the intermediate-risk group (97.5%, 100%, and 94.5% in the lower titer group [P = 0.122] and 97.2%, 96.2%, and 100% [P = 0.664] in the higher titer group, respectively) and 95.7%, 95.5%, and 100% (P = 0.859) in the high-risk group, respectively. The HDR-BT group showed a lower incidence of acute grade ≥ 2 genitourinary toxicities; the incidence of other early and late grade ≥ 2 toxicities were similar between the HDR-BT and LDR-BT groups. Acute genitourinary toxicity predicted the occurrence of late genitourinary toxicity. EBRT increased the risk of grade ≥ 2 gastrointestinal toxicity. HDR-BT + EBRT is a good alternative to LDR-BT ± EBRT for low-, intermediate-, and selected high-risk patients.

Dataset Information

Interplay Between Duration of Androgen Deprivation Therapy and External Beam Radiotherapy With or Without a Brachytherapy Boost for Optimal Treatment of High-risk Prostate Cancer: A Patient-Level Data Analysis of 3 Cohorts.

Importance

Objective

Design, settings, and participants

Exposures

Main outcomes and measures

Results

Conclusions and relevance

Publications

Interplay Between Duration of Androgen Deprivation Therapy and External Beam Radiotherapy With or Without a Brachytherapy Boost for Optimal Treatment of High-risk Prostate Cancer: A Patient-Level Data Analysis of 3 Cohorts.

Similar Datasets

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