Advertisement

A comparative analysis of overall survival between high-dose-rate and low-dose-rate brachytherapy boosts for unfavorable-risk prostate cancer

Published:January 09, 2019DOI:https://doi.org/10.1016/j.brachy.2018.12.007

      Abstract

      Purpose

      External beam radiation therapy (EBRT) with low-dose-rate (LDR) brachytherapy boost has been associated with improved biochemical progression–free survival and overall survival (OS) compared with dose-escalated EBRT (DE-EBRT) alone for unfavorable-risk prostate cancer. However, it is not known whether high-dose-rate (HDR) boost provides a similar benefit. We compare HDR boost against LDR boost and DE-EBRT with respect to OS.

      Methods

      Using the National Cancer Database, we identified 122,896 patients who were diagnosed with National Comprehensive Cancer Network intermediate- or high-risk prostate cancer between 2004 and 2014 and treated with DE-EBRT (75.6–86.4 Gy), LDR boost, or HDR boost. We compared the OS among the three groups using multivariable Cox proportional hazards regression. Inverse probability treatment weighting was used to adjust for covariate imbalance.

      Results

      On multivariable Cox proportional hazards regression, HDR boost was associated with a similar OS to LDR boost (adjusted hazard ratio [AHR] 1.03 [0.96, 1.11]; p = 0.38) but significantly better OS than DE-EBRT (AHR 1.36 [1.29, 1.44]; p < 0.001). Inverse probability treatment weighting analysis yielded similar results. There was no significant difference between LDR and HDR boosts for National Comprehensive Cancer Network intermediate-risk (AHR 1.05 [0.96, 1.15]; p = 0.32) and high-risk (AHR 1.00 [0.89, 1.12]; p = 0.98) subgroups (p-interaction = 0.55).

      Conclusions

      Our results suggest that HDR brachytherapy boost yields similar OS benefits compared with LDR brachytherapy boost for unfavorable-risk prostate cancer. HDR boost may be a suitable alternative to LDR boost.

      Keywords

      Introduction

      Recently, the Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (ASCENDE-RT) randomized controlled trial demonstrated a significant improvement in biochemical progression–free survival (bPFS) with the addition of low-dose-rate (LDR) brachytherapy boost to EBRT compared with dose-escalated EBRT (DE-EBRT) alone (78 Gy) in men with intermediate- and high-risk prostate cancer (
      • Morris W.J.
      • Tyldesley S.
      • Rodda S.
      • et al.
      Androgen suppression combined with elective nodal and dose escalated radiation therapy (the ASCENDE-RT trial): An analysis of survival endpoints for a randomized trial comparing a low-dose-rate brachytherapy boost to a dose-escalated external beam boost for high- and intermediate-risk prostate cancer.
      ). Although this trial was not powered to show a statistically significant difference in overall survival (OS), a recent retrospective analysis using data from the National Cancer Database did report a significant improvement in OS with LDR boost (
      • Johnson S.B.
      • Lester-Coll N.H.
      • Kelly J.R.
      • et al.
      Brachytherapy boost utilization and survival in unfavorable-risk prostate cancer.
      ). Recent American Society of Clinical oncology/Cancer Care Ontario guidelines recommend that brachytherapy boost be offered to patients with intermediate- and high-risk patients receiving EBRT (
      • Chin J.
      • Rumble R.B.
      • Kollmeier M.
      • et al.
      Brachytherapy for patients with prostate cancer: American Society of Clinical Oncology/Cancer Care Ontario Joint guideline update.
      ).
      However, the enthusiasm for LDR boost has been dampened by higher incidences of acute and late genitourinary morbidity from the ASCENDE-RT trial (
      • Rodda S.
      • Tyldesley S.
      • Morris W.J.
      • et al.
      ASCENDE-RT: An analysis of treatment-related morbidity for a randomized trial comparing a low-dose-rate brachytherapy boost with a dose-escalated external beam boost for high- and intermediate-risk prostate cancer.
      ). High-dose-rate (HDR) brachytherapy is an alternative modality that may allow for faster recovery of acute urinary symptoms compared with LDR in the monotherapy setting (
      • Hathout L.
      • Mahmoud O.
      • Barkati M.
      • et al.
      A phase 2 randomized pilot study comparing high-dose rate bracytherapy and low-dose rate brachytherapy as monotherapy in localized prostate cancer.
      ). Although two randomized controlled trials have shown that HDR brachytherapy boost was associated with significantly improved bPFS compared with EBRT, none of these trials compared HDR brachytherapy boost against current dose-escalated EBRT regimens (
      • Sathya J.R.
      • Davis I.R.
      • Julian J.A.
      • et al.
      Randomized trial comparing iridium implant plus external-beam radiation therapy with external-beam radiation therapy alone in node-negative locally advanced cancer of the prostate.
      ,
      • Hoskin P.J.
      • Colombo A.
      • Henry A.
      • et al.
      GEC/ESTRO recommendations on high dose rate afterloading brachytherapy for localised prostate cancer: An update.
      ). Furthermore, it is not known whether HDR boost provides a similar clinical benefit as LDR boost. As a result, we performed a comparative analysis of HDR boost against LDR boost and DE-EBRT with OS as the primary endpoint using a large national database.

      Methods

      From the National Cancer Database (
      • Bilimoria K.Y.
      • Stewart A.K.
      • Winchester D.P.
      • et al.
      The national cancer data base: A powerful initiative to improve cancer care in the United States.
      ), we identified 122,896 patients with National Comprehensive Cancer Network (NCCN) intermediate- (Gleason 7, prostate specific antigen (PSA) 10–20 ng/mL, or cT2b-T2c) or high-risk (Gleason 8–10 or PSA 20–40 ng/mL and ≤c3) prostate cancer who were diagnosed between 2004 and 2014 and treated with DE-EBRT (75.6–86.4 Gy), LDR boost, or HDR boost (Fig. 1). We compared the OS among these three groups using multivariable Cox proportional hazards regression, after adjusting for clinical and demographic factors. Clinical factors included age, PSA value, Gleason grade (6, 7, 8–10), clinical T-stage (T1, T2, T3), Charlson-Deyo score (0, 1, 2+), and androgen deprivation therapy use (yes, no). Demographic factors included race (non-Hispanic white, black, Hispanic, other), facility location (Northeast, Midwest, South, West, NA), facility type (nonacademic, academic), educational attainment, income, and insurance (Medicare, Medicaid, private, uninsured, other). Baseline characteristics were compared using t-tests for continuous variables and chi squared tests for categorical variables.
      Figure thumbnail gr1
      Fig. 1Formulation of study cohort. EBRT = External beam radiation therapy; SBRT = stereotactic body radiation therapy.
      To reduce imbalances in baseline characteristics among the three groups, we also performed weighted Cox regression using inverse probability of treatment weighting (IPTW). IPTW is a propensity scoring method, in which subjects are weighted according to the inverse of the probability of receiving the treatment that the subject actually received. This allows for the generation of a synthetic sample, in which the distribution of baseline covariates is independent of the treatment assignment (
      • Austin P.C.
      The use of propensity score methods with survival or time-to-event outcomes: Reporting measures of effect similar to those used in randomized experiments.
      ). In this analysis, we generated IPTW weights among the three treatment arms using a generalized boosted model with the TWANG package (
      • McCaffrey D.F.
      • Griffin B.A.
      • Almirall D.
      • et al.
      A tutorial on propensity score estimation for multiple treatments using generalized boosted models.
      ,
      • Ridgeway G.
      • McCaffrey D.
      • Morral A.
      • et al.
      Twang: Toolkit for weighting and analysis of nonequivalent groups.
      ). Unadjusted and IPTW-adjusted Kaplan-Meier curves were reported.
      We also performed unweighted Cox regressions for patient subgroups defined by Gleason grade, clinical T-stage, NCCN risk category (intermediate, high), and androgen deprivation therapy use. For the NCCN risk category subgroup, Gleason grade, clinical T-stage, and PSA were not included in the models. For each subgroup, the significance of interaction terms between the subgroup and boost modality was estimated with the Wald test. An additional subgroup analysis was also run for patients with Gleason 9 or 10 disease (
      • Kishan A.U.
      • Shaikh T.
      • Wang P.-C.
      • et al.
      Clinical outcomes for patients with Gleason score 9–10 prostate adenocarcinoma treated with radiotherapy or radical prostatectomy: A multi-institutional comparative analysis.
      ,
      • Kishan A.U.
      • Cook R.R.
      • Ciezki J.P.
      • et al.
      Radical prostatectomy, external beam radiotherapy, or external beam radiotherapy with brachytherapy boost and disease progression and mortality in patients with Gleason score 9-10 prostate cancer.
      ). Multivariate hazard ratios for boost modality are included in Forest plots for each subgroup. All statistical analysis was performed using R version 3.5.0 (The R Foundation for Statistical Computing). This work was performed with approval of our institutional review board.

      Results

      The median followup for the entire cohort was 5.0 years (interquartile range: 3.0, 7.4). Table 1 summarizes baseline clinical and demographic factors among the three groups. Small but statistically significant differences in baseline characteristics were observed for all factors. Fig. 2a shows respective Kaplan-Meier curves before IPTW adjustment. On multivariable Cox proportional hazards regression, HDR boost was associated with a similar OS to LDR boost (adjusted hazard ratio [AHR] 1.03 [0.96, 1.11]; p = 0.38) but significantly better OS than DE-EBRT (AHR 1.36 [1.29, 1.44]; p < 0.001). Detailed results are shown in Table 2. After IPTW adjustment, there were no statistically significant differences among the three treatment groups for any baseline factor. IPTW-weighted Cox proportional hazards model yielded no significant OS difference with LDR boost (AHR 1.01 [0.93, 1.10]; p = 0.77) but significantly better OS than DE-EBRT (AHR 1.31 [1.23, 1.39]; p < 0.001). IPTW-adjusted Kaplan-Meier curves are shown in Fig. 2b.
      Table 1Baseline characteristics based on treatment (HDR boost, LDR boost, and DE-EBRT)
      FactorTotalUnadjustedIPTW-adjusted
      HDR boostLDR boostDE-EBRTp (min)p (min)
      n(n = 8526)(n = 9877)(n = 104486)
      Age—Mean (SD)-67.1 (7.6)66.7 (7.6)69.9 (7.6)<0.0010.12
      Prostate specific antigen—Mean (SD)-9.1 (6.7)9.0 (6.6)10.0 (7.2)<0.0010.19
      Gleason grade
       613902 (11.3%)8.7%9.7%11.7%<0.0010.07
       773337 (59.7%)63.3%65.5%58.8%
       8–1035657 (29.0%)28.0%24.7%29.5%
      Clinical T-stage
       T171149 (57.9%)53.5%58.6%58.2%<0.0010.09
       T245121 (36.7%)39.5%37.8%36.4%
       T36626 (5.4%)7.0%3.6%5.4%
      Race
       Non-Hispanic white93599 (76.2%)76.1%75.5%76.2%<0.0010.34
       Black19894 (16.2%)14.5%18.5%16.1%
       Hispanic4682 (3.8%)3.3%3.0%3.9%
       Other4721 (3.8%)6.1%2.9%3.7%
      Charlson-Deyo score
       0105047 (85.5%)86.3%85.4%85.4%<0.0010.57
       114663 (11.9%)11.8%12.5%11.9%
       2+3186 (2.6%)2.0%2.1%2.7%
      Facility location
       Northeast31896 (25.9%)21.5%22.0%26.6%<0.0010.47
       Midwest30962 (25.2%)21.9%18.8%26.1%
       South39911 (32.5%)29.0%48.3%31.3%
       West20182 (16.4%)27.6%10.8%16.0%
       NA5 (0.0%)0.0%0.0%0.0%
      Facility type
       Nonacademic85273 (69.4%)66.4%77.4%68.9%<0.0010.62
       Academic37623 (30.6%)33.6%22.6%31.1%
      Educational attainment
       Quartile 1–lowest20074 (16.3%)12.9%18.2%16.4%<0.0010.09
       Quartile 231053 (25.3%)22.6%25.5%25.5%
       Quartile 340756 (33.2%)32.0%32.6%33.3%
       Quartile 4–highest30151 (24.5%)32.0%22.4%24.1%
       NA862 (0.7%)0.4%1.3%0.7%
      Income
       Quartile 1–lowest21607 (17.6%)13.5%18.6%17.8%<0.0010.13
       Quartile 228043 (22.8%)20.5%24.1%22.9%
       Quartile 332506 (26.5%)24.1%23.3%26.9%
       Quartile 4–highest39790 (32.4%)41.5%32.6%31.6%
       NA950 (0.8%)0.5%1.4%0.7%
      Insurance
       Medicare77352 (62.9%)55.2%55.5%64.3%<0.0010.20
       Medicaid3322 (2.7%)1.6%2.6%2.8%
       Other5382 (4.4%)2.7%2.7%4.7%
       Private35067 (28.5%)39.7%38.3%26.7%
       Uninsured1773 (1.4%)0.7%0.9%1.5%
      Androgen deprivation therapy
       No64041 (52.1%)59.6%56.9%51.0%<0.0010.43
       Yes58855 (47.9%)40.4%43.1%49.0%
      DE-EBRT = dose-escalated external beam radiation therapy; HDR = high-dose-rate; IPTW = inverse probability of treatment weighting; LDR = low-dose-rate.
      Unadjusted p-values (min) and IPTW-adjusted p-values (min) are reported.
      p (min) represents the minimum p-value among the 3-group comparisons (HDR vs. LDR, HDR vs. DE-EBRT, LDR vs. DE-EBRT).
      Figure thumbnail gr2
      Fig. 2(a) Unadjusted and (b) IPTW-adjusted Kaplan-Meier curves for HDR boost, LDR boost, and DE-EBRT. IPTW = inverse probability treatment weighting; HDR = high-dose-rate; LDR = low-dose-rate; DE-EBRT = dose-escalated EBRT.
      Table 2Cox proportional hazards regression model for overall survival
      FactorHazard ratio (95% CI)p-Value
      Age (continuous)1.05 (1.05, 1.05)<0.001
      Prostate specific antigen (continuous)1.01 (1.01, 1.02)<0.001
      Gleason grade
       61.0 (Ref)-
       71.12 (1.07, 1.16)<0.001
       8–101.51 (1.44, 1.57)<0.001
      Clinical T-stage
       T11.0 (Ref)-
       T21.10 (1.07, 1.13)<0.001
       T31.23 (1.16, 1.29)<0.001
      Race
       Non-Hispanic white1.0 (Ref)-
       Black0.96 (0.92, 1.00)0.03
       Hispanic0.69 (0.63, 0.75)<0.001
       Other0.73 (0.67, 0.79)<0.001
      Charlson-Deyo comorbidity score
       01.0 (Ref)-
       11.42 (1.37, 1.48)<0.001
       2+2.31 (2.16, 2.46)<0.001
      Facility location
       Northeast1.0 (Ref)-
       Midwest1.02 (0.99, 1.06)0.20
       South1.05 (1.01, 1.08)0.01
       West0.85 (0.81, 0.89)<0.001
      Facility type
       Nonacademic1.0 (Ref)-
       Academic0.89 (0.87, 0.92)<0.001
      Educational attainment
       Quartile 1–lowest1.0 (Ref)-
       Quartile 20.92 (0.88, 0.96)<0.001
       Quartile 30.88 (0.84, 0.92)<0.001
       Quartile 4–highest0.82 (0.78, 0.87)<0.001
      Income
       Quartile 1–lowest1.0 (Ref)-
       Quartile 20.98 (0.94, 1.02)0.27
       Quartile 30.91 (0.87, 0.95)<0.001
       Quartile 4–highest0.85 (0.80, 0.89)<0.001
      Insurance
       Medicare1.0 (Ref)-
       Medicaid1.31 (1.20, 1.44)<0.001
       Other1.16 (1.09, 1.24)<0.001
       Private0.88 (0.85, 0.91)<0.001
       Uninsured0.92 (0.80, 1.06)0.24
      Androgen deprivation therapy
       No1.0 (Ref)-
       Yes0.95 (0.92, 0.98)<0.001
      Boost modality
       HDR boost1.0 (Ref)-
       LDR boost1.03 (0.96, 1.11)0.38
       DE-EBRT1.36 (1.29, 1.44)<0.001
      CI = confidence interval; DE-EBRT = dose-escalated external beam radiation therapy; HDR = high-dose-rate; IPTW = inverse probability of treatment weighting; LDR = low-dose-rate.
      As shown in Fig. 3, there was no significant difference between LDR and HDR boosts for patient subgroups divided by Gleason grade, clinical T-stage, NCCN risk category, or androgen deprivation therapy. All interaction terms between analyzed subgroups and boost modality were not significant. For the Gleason 9–10 subgroup, AHRs for LDR boost and DE-EBRT were 1.03 ([0.84, 1.25]; p = 0.81) and 1.25 ([1.09, 1.44]; p = 0.001), respectively.
      Figure thumbnail gr3
      Fig. 3Forest plots of multivariable hazard ratios with 95% confidence intervals for LDR boost (left) and DE-EBRT (right) against HDR boost as baseline for specific subgroups. p (int) represents p-values for the interaction terms. DE-EBRT = dose-escalated external beam radiation therapy; HDR = high-dose-rate; HR = hazard ratio; LDR = low-dose-rate; NCCN = National Comprehensive Cancer Network.

      Discussion

      Previous studies have suggested that LDR and HDR brachytherapies in the monotherapy setting have equivalent bPFS outcomes (
      • Shah C.
      • Lanni T.B.
      • Ghilezan M.I.
      • et al.
      Brachytherapy provides comparable outcomes and improved cost-effectiveness in the treatment of low/intermediate prostate cancer.
      ,
      • Grimm P.
      • Billiet I.
      • Bostwick D.
      • et al.
      Comparative analysis of prostate-specific antigen free survival outcomes for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. Results from the Prostate Cancer Results Study Group.
      ). A large multiinstitutional retrospective propensity-adjusted analysis also showed no difference in distant metastasis or prostate cancer specific mortality between LDR vs. HDR brachytherapy boost (
      • Kishan A.U.
      • Cook R.R.
      • Ciezki J.P.
      • et al.
      Radical prostatectomy, external beam radiotherapy, or external beam radiotherapy with brachytherapy boost and disease progression and mortality in patients with Gleason score 9-10 prostate cancer.
      ). Our analysis using a large National Cancer Database also suggests that both LDR and HDR brachytherapy boost provide equivalent OS outcomes for unfavorable-risk prostate cancer. It is reassuring that similar results were obtained after propensity score adjustment with IPTW, which allowed for partial mitigation of treatment imbalances among the three treatment groups. Furthermore, consistent results were obtained for each of the evaluated patient subgroups. As a result, either LDR or HDR brachytherapy boost could be reasonably offered to patients across the clinical spectrum of NCCN intermediate- and high-risk disease. This is especially relevant because many centers only offer either LDR or HDR brachytherapy.
      It is important that the results of this study are interpreted in light of the limitations of this retrospective analysis. These include selection bias and lack of data on androgen deprivation therapy duration, brachytherapy dosing regimens, and other clinically relevant endpoints (bPFS, metastasis-free survival, prostate cancer–specific mortality). As such, only an adequately powered randomized controlled trial could definitively demonstrate equivalent efficacy between LDR and HDR brachytherapy boosts.
      It is unclear whether HDR boost is associated with less acute and late toxicities than LDR boost. With respect to short-term toxicity, a preliminary analysis of a randomized controlled trial of HDR vs. LDR in the monotherapy setting reported lower acute urinary toxicity, improved quality of life, and shorter time to urinary symptom resolution with HDR (
      • Hathout L.
      • Mahmoud O.
      • Barkati M.
      • et al.
      A phase 2 randomized pilot study comparing high-dose rate bracytherapy and low-dose rate brachytherapy as monotherapy in localized prostate cancer.
      ). These results could be attributed to the prolonged half-life of the iodine-125 seeds. Seeds with shorter half-life, such as palladium-103 (
      • Wallner K.
      • Merrick G.
      • True L.
      • et al.
      1–125 versus Pd-103 for low-risk prostate cancer: Morbidity outcomes from a prospective randomized multicenter trial.
      ) or cesium-131, may also be associated with a shorter time to urinary symptom resolution. With respect to long-term toxicity, a recent analysis using the Surveillance, Epidemiology, and End Results Medicare database was unable to show a statistically significant difference in grade three urinary adverse events between LDR and HDR (
      • Tward J.D.
      • Jarosek S.
      • Chu H.
      • et al.
      Time course and accumulated risk of severe urinary adverse events after high- versus low-dose-rate prostate brachytherapy with or without external beam radiation therapy.
      ). Results from the currently accruing BrachyQOL randomized controlled trial (NCT01936883) may provide a more definitive comparison of short- and long-term toxicity profiles between these two modalities in the boost setting (
      Improving quality of life after prostate brachytherapy: a comparison of HDR and LDR brachytherapy - full text view - ClinicalTrials.gov.
      ). However, given reports of greater toxicity and worse quality of life with brachytherapy boost compared with DE-EBRT (
      • Rodda S.
      • Tyldesley S.
      • Morris W.J.
      • et al.
      ASCENDE-RT: An analysis of treatment-related morbidity for a randomized trial comparing a low-dose-rate brachytherapy boost with a dose-escalated external beam boost for high- and intermediate-risk prostate cancer.
      ,
      • Rodda S.
      • Morris W.J.
      • Hamm J.
      • et al.
      An analysis of health-related quality of life for a randomized trial comparing low-dose-rate brachytherapy boost with dose-escalated external beam boost for high- and intermediate-risk prostate cancer.
      ), further research is urgently needed to mitigate toxicities for both LDR and HDR boost techniques, so that patients who receive these treatments can better preserve their quality of life.

      Acknowledgements

      This work was supported by the Prostate Cancer Foundation, the Wood Family Foundation, the Baker Family, the Freedman Family, Fitz’s Cancer Warriors, David and Cynthia Chapin, the Frashure Family, Hugh Simons in honor of Frank and Anne Simons, the Campbell Family in honor of Joan Campbell, the Scott Forbes and Gina Ventre Fund, and a grant from an anonymous family foundation.

      References

        • Morris W.J.
        • Tyldesley S.
        • Rodda S.
        • et al.
        Androgen suppression combined with elective nodal and dose escalated radiation therapy (the ASCENDE-RT trial): An analysis of survival endpoints for a randomized trial comparing a low-dose-rate brachytherapy boost to a dose-escalated external beam boost for high- and intermediate-risk prostate cancer.
        Int J Radiat Oncol Biol Phys. 2017; 98: 275-285
        • Johnson S.B.
        • Lester-Coll N.H.
        • Kelly J.R.
        • et al.
        Brachytherapy boost utilization and survival in unfavorable-risk prostate cancer.
        Eur Urol. 2017; 72: 738-744
        • Chin J.
        • Rumble R.B.
        • Kollmeier M.
        • et al.
        Brachytherapy for patients with prostate cancer: American Society of Clinical Oncology/Cancer Care Ontario Joint guideline update.
        J Clin Oncol. 2017; 13: 392-394
        • Rodda S.
        • Tyldesley S.
        • Morris W.J.
        • et al.
        ASCENDE-RT: An analysis of treatment-related morbidity for a randomized trial comparing a low-dose-rate brachytherapy boost with a dose-escalated external beam boost for high- and intermediate-risk prostate cancer.
        Int J Radiat Oncol Biol Phys. 2017; 98: 286-295
        • Hathout L.
        • Mahmoud O.
        • Barkati M.
        • et al.
        A phase 2 randomized pilot study comparing high-dose rate bracytherapy and low-dose rate brachytherapy as monotherapy in localized prostate cancer.
        Brachytherapy. 2018; 17: S56
        • Sathya J.R.
        • Davis I.R.
        • Julian J.A.
        • et al.
        Randomized trial comparing iridium implant plus external-beam radiation therapy with external-beam radiation therapy alone in node-negative locally advanced cancer of the prostate.
        J Clin Oncol. 2005; 23: 1192-1199
        • Hoskin P.J.
        • Colombo A.
        • Henry A.
        • et al.
        GEC/ESTRO recommendations on high dose rate afterloading brachytherapy for localised prostate cancer: An update.
        Radiother Oncol. 2013; 107: 325-332
        • Bilimoria K.Y.
        • Stewart A.K.
        • Winchester D.P.
        • et al.
        The national cancer data base: A powerful initiative to improve cancer care in the United States.
        Ann Surg Oncol. 2008; 15: 683-690
        • Austin P.C.
        The use of propensity score methods with survival or time-to-event outcomes: Reporting measures of effect similar to those used in randomized experiments.
        Stat Med. 2014; 33: 1242-1258
        • McCaffrey D.F.
        • Griffin B.A.
        • Almirall D.
        • et al.
        A tutorial on propensity score estimation for multiple treatments using generalized boosted models.
        Stat Med. 2013; 32: 3388-3414
        • Ridgeway G.
        • McCaffrey D.
        • Morral A.
        • et al.
        Twang: Toolkit for weighting and analysis of nonequivalent groups.
        2017 (Available at:)
        https://CRAN.R-project.org/package=twang
        Date accessed: September 1, 2018
        • Kishan A.U.
        • Shaikh T.
        • Wang P.-C.
        • et al.
        Clinical outcomes for patients with Gleason score 9–10 prostate adenocarcinoma treated with radiotherapy or radical prostatectomy: A multi-institutional comparative analysis.
        Eur Urol. 2017; 71: 766-773
        • Kishan A.U.
        • Cook R.R.
        • Ciezki J.P.
        • et al.
        Radical prostatectomy, external beam radiotherapy, or external beam radiotherapy with brachytherapy boost and disease progression and mortality in patients with Gleason score 9-10 prostate cancer.
        JAMA. 2018; 319: 896-905
        • Shah C.
        • Lanni T.B.
        • Ghilezan M.I.
        • et al.
        Brachytherapy provides comparable outcomes and improved cost-effectiveness in the treatment of low/intermediate prostate cancer.
        Brachytherapy. 2012; 11: 441-445
        • Grimm P.
        • Billiet I.
        • Bostwick D.
        • et al.
        Comparative analysis of prostate-specific antigen free survival outcomes for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. Results from the Prostate Cancer Results Study Group.
        BJU Int. 2012; 109: 22-29
        • Wallner K.
        • Merrick G.
        • True L.
        • et al.
        1–125 versus Pd-103 for low-risk prostate cancer: Morbidity outcomes from a prospective randomized multicenter trial.
        Cancer J. 2002; 8: 69
        • Tward J.D.
        • Jarosek S.
        • Chu H.
        • et al.
        Time course and accumulated risk of severe urinary adverse events after high- versus low-dose-rate prostate brachytherapy with or without external beam radiation therapy.
        Int J Radiat Oncol Biol Phys. 2016; 95: 1443-1453
      1. Improving quality of life after prostate brachytherapy: a comparison of HDR and LDR brachytherapy - full text view - ClinicalTrials.gov.
        (Available at:)
        • Rodda S.
        • Morris W.J.
        • Hamm J.
        • et al.
        An analysis of health-related quality of life for a randomized trial comparing low-dose-rate brachytherapy boost with dose-escalated external beam boost for high- and intermediate-risk prostate cancer.
        Int J Radiat Oncol Biol Phys. 2017; 98: 581-589