Advertisement

Real-world utilisation of brachytherapy boost and patient-reported functional outcomes in men who had external beam radiation therapy for prostate cancer in Australia

  • Wee Loon Ong
    Correspondence
    Corresponding author at: Alfred Health Radiation Oncology, 55 Commercial Road, Melbourne 3004, VIC, Australia.
    Affiliations
    Alfred Health Radiation Oncology, Melbourne VIC, Australia

    Central Clinical School, Monash University, Melbourne, VIC, Australia

    Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada
    Search for articles by this author
  • Melanie Evans
    Affiliations
    School of Public Health and Preventive Medicine, Monash University, Melbourne VIC, Australia
    Search for articles by this author
  • Nathan Papa
    Affiliations
    School of Public Health and Preventive Medicine, Monash University, Melbourne VIC, Australia
    Search for articles by this author
  • Jeremy Millar
    Affiliations
    Alfred Health Radiation Oncology, Melbourne VIC, Australia

    Central Clinical School, Monash University, Melbourne, VIC, Australia

    School of Public Health and Preventive Medicine, Monash University, Melbourne VIC, Australia
    Search for articles by this author
Open AccessPublished:August 18, 2022DOI:https://doi.org/10.1016/j.ctro.2022.08.009

      Highlights

      • Only 1-in-20 men who had EBRT for prostate cancer in Australia had BT-boost.
      • BT-boost was not associated with worse PRO 12-months post-treatment at a population-based level.
      • Age, sociodemographic, and treatment institutions were associated with BT-boost use.

      Abstract

      Background and purpose

      We aimed to evaluate utilisation of brachytherapy (BT) boost in men who had external beam radiation therapy (EBRT) for prostate cancer, and to compare patient-reported functional outcomes (PRO) following each approach in a population-based setting in Australia.

      Materials and methods

      This is a population-based cohort of men with localised prostate cancer enrolled in the Victorian Prostate Cancer Outcomes Registry, who had EBRT between 2015 and 2020. Primary outcomes were proportion who had BT-boost, and PRO (assessed using the EPIC-26 questionnaires) 12 months post-treatment. Multivariable logistic regressions were used to evaluate factors associated with BT-boost, and linear regressions were used to estimate differences in EPIC-26 domain scores between EBRT alone and EBRT + BT.

      Results

      Of the 1,626 men in the study, 88 (5.4 %) had BT-boost. Factors independently associated with BT-boost were younger age, higher socioeconomic status, and treatment in public institutions. 1,555 men completed EPIC-26 questionnaires. No statistically or clinically significant differences in EPIC-26 urinary, sexual and bowel functional domain scores were observed between men who had EBRT + BT vs EBRT alone, with adjusted mean differences in urinary incontinence, urinary irritative/ obstruction, sexual, and bowel domain of 1.28 (95 %CI = −3.23 to 5.79), −2.87 (95 %CI = −6.46 to 0.73), 0.49 (95 %CI = −4.78 to 5.76), and 2.89 (95 %CI = −0.83 to 6.61) respectively.

      Conclusion

      1-in-20 men who had EBRT for prostate cancer had BT-boost. This is the first time that PRO following EBRT+/-BT is reported at a population-based level in Australia, with no evidence to suggest worse PRO with addition of BT-boost 12 months post-treatment.

      Keywords

      Introduction

      Brachytherapy (BT) boost is an approach for dose escalation in men with prostate cancer treated with external beam radiation therapy (EBRT). BT-boost has been shown in several randomized trials to be associated with improved biochemical disease-free survival [
      • Sathya J.R.
      • Davis I.R.
      • Julian J.A.
      • Guo Q.
      • Daya D.
      • Dayes I.S.
      • 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.
      ,
      • Dayes I.S.
      • Parpia S.
      • Gilbert J.
      • Julian J.A.
      • Davis I.R.
      • Levine M.N.
      • et al.
      Long-term results of a 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.
      • Rojas A.M.
      • Bownes P.J.
      • Lowe G.J.
      • Ostler P.J.
      • Bryant L.
      Randomised trial of external beam radiotherapy alone or combined with high-dose-rate brachytherapy boost for localised prostate cancer.
      ,
      • Morris W.J.
      • Tyldesley S.
      • Rodda S.
      • Halperin R.
      • Pai H.
      • McKenzie M.
      • 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.
      ]. Recent multi-institutional pooled analyses showed BT-boost to be associated with reduced prostate cancer specific mortality and distant metastases in men with very high-risk disease [
      • Kishan A.U.
      • Cook R.R.
      • Ciezki J.P.
      • Ross A.E.
      • Pomerantz M.M.
      • Nguyen P.L.
      • 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.
      ]. Notwithstanding this, population-based studies have shown that BT utilization remains low for various reasons [
      • Martin J.M.
      • Handorf E.A.
      • Kutikov A.
      • Uzzo R.G.
      • Bekelman J.E.
      • Horwitz E.M.
      • et al.
      The rise and fall of prostate brachytherapy: use of brachytherapy for the treatment of localized prostate cancer in the National Cancer Data Base.
      ,
      • Orio 3rd, P.F.
      • Nguyen P.L.
      • Buzurovic I.
      • Cail D.W.
      • Chen Y.W.
      The decreased use of brachytherapy boost for intermediate and high-risk prostate cancer despite evidence supporting its effectiveness.
      ,
      • Jackson M.W.
      • Amini A.
      • Jones B.L.
      • Kavanagh B.
      • Maroni P.
      • Frank S.J.
      • et al.
      Prostate brachytherapy, either alone or in combination with external beam radiation, is associated with longer overall survival in men with favorable pathologic Group 4 (Gleason score 8) prostate cancer.
      ,
      • Johnson S.B.
      • Lester-Coll N.H.
      • Kelly J.R.
      • Kann B.H.
      • Yu J.B.
      • Nath S.K.
      Brachytherapy boost utilization and survival in unfavorable-risk prostate cancer.
      ,
      • Malouff T.
      • Mathy N.W.
      • Marsh S.
      • Walters R.W.
      • Silberstein P.T.
      Trends in the use of radiation therapy for stage IIA prostate cancer from 2004 to 2013: a retrospective analysis using the National Cancer Database.
      ,
      • Mahmood U.
      • Pugh T.
      • Frank S.
      • Levy L.
      • Walker G.
      • Haque W.
      • et al.
      Declining use of brachytherapy for the treatment of prostate cancer.
      ,
      • Ong W.L.
      • Evans S.M.
      • Millar J.L.
      Under-utilisation of high-dose-rate brachytherapy boost in men with intermediate-high risk prostate cancer treated with external beam radiotherapy.
      ]. Some of these include: reimbursement disincentive for BT which varies between different healthcare system in different countries, the belief that dose-escalation can be achieved with advancement in LINAC-based techniques such as stereotactic radiation therapy boost [
      • Pryor D.
      • Sidhom M.
      • Arumugam S.
      • Bucci J.
      • Gallagher S.
      • Smart J.
      • et al.
      Phase 2 multicenter study of gantry-based stereotactic radiotherapy boost for intermediate and high risk prostate cancer (PROMETHEUS).
      ,
      • Alayed Y.
      • Loblaw A.
      • Chu W.
      • Al-Hanaqta M.
      • Chiang A.
      • Jain S.
      • et al.
      Stereotactic body radiation therapy boost for intermediate-risk prostate cancer: a phase 1 dose-escalation study.
      ], and the decline in BT exposure during radiation oncology training, which translates into shortfall of radiation oncologist proficient in BT in the long-term [
      • Orio 3rd, P.F.
      • Nguyen P.L.
      • Buzurovic I.
      • Cail D.W.
      • Chen Y.W.
      Prostate brachytherapy case volumes by academic and nonacademic practices: implications for future residency training.
      ,
      • Ong W.L.
      • Byrne A.
      • Chelvarajah R.
      • Chong C.
      • Gallo J.
      • Kain M.
      • et al.
      Survey of brachytherapy training experience among radiation oncology trainees and fellows in the Royal Australian and New Zealand College of Radiologists (RANZCR).
      ].
      There is also concern regarding increased risk of urinary toxicities with BT boost [
      • Rodda S.
      • Tyldesley S.
      • Morris W.J.
      • Keyes M.
      • Halperin R.
      • Pai H.
      • 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.
      ,
      • Lawton C.A.
      • Yan Y.
      • Lee W.R.
      • Gillin M.
      • Firat S.
      • Baikadi M.
      • et al.
      Long-term results of an RTOG Phase II trial (00–19) of external-beam radiation therapy combined with permanent source brachytherapy for intermediate-risk clinically localized adenocarcinoma of the prostate.
      ], with late Grade 3 urinary toxicity reported to be as high as 18 % at 5 years in the low-dose-rate (LDR) BT-boost arm in the ASCENDE-RT trials [
      • Rodda S.
      • Tyldesley S.
      • Morris W.J.
      • Keyes M.
      • Halperin R.
      • Pai H.
      • 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.
      ]. However, in the Hoskin trials, no differences in early and late urinary and bowel toxicities were reported between men who had EBRT with or without high-dose-rate (HDR) BT-boost at a median follow-up of more than 10 years, assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and General (FACT-G) tool [
      • Hoskin P.J.
      • Rojas A.M.
      • Ostler P.J.
      • Hughes R.
      • Lowe G.J.
      • Bryant L.
      Quality of life after radical radiotherapy for prostate cancer: longitudinal study from a randomised trial of external beam radiotherapy alone or in combination with high dose rate brachytherapy.
      ]. The understanding of the toxicity outcomes of BT-boost is especially important in guiding patients’ treatment decision-making, given the excellent long-term oncological outcomes in prostate cancer, and the multiple curative treatment options available for men with prostate cancer [
      • Bekelman J.E.
      • Rumble R.B.
      • Chen R.C.
      • Pisansky T.M.
      • Finelli A.
      • Feifer A.
      • et al.
      Clinically Localized Prostate Cancer: ASCO Clinical Practice Guideline Endorsement of an American Urological Association/American Society for Radiation Oncology/Society of Urologic Oncology Guideline.
      ]. While several single institutional retrospective studies [
      • Spratt D.E.
      • Zumsteg Z.S.
      • Ghadjar P.
      • Kollmeier M.A.
      • Pei X.
      • Cohen G.
      • et al.
      Comparison of high-dose (86.4 Gy) IMRT vs combined brachytherapy plus IMRT for intermediate-risk prostate cancer.
      ,
      • Sutani S.
      • Ohashi T.
      • Sakayori M.
      • Kaneda T.
      • Yamashita S.
      • Momma T.
      • et al.
      Comparison of genitourinary and gastrointestinal toxicity among four radiotherapy modalities for prostate cancer: conventional radiotherapy, intensity-modulated radiotherapy, and permanent iodine-125 implantation with or without external beam radiotherapy.
      ] have reported on the toxicity outcomes following EBRT + BT-boost, few included patient-reported outcomes (PRO) data [
      • Choudhury A.
      • Arthur C.
      • Malik J.
      • Mandall P.
      • Taylor C.
      • Alam N.
      • et al.
      Patient-reported outcomes and health-related quality of life in prostate cancer treated with a single fraction of high dose rate brachytherapy combined with hypofractionated external beam radiotherapy.
      ,
      • Morton G.C.
      • Loblaw D.A.
      • Chung H.
      • Tsang G.
      • Sankreacha R.
      • Deabreu A.
      • et al.
      Health-related quality of life after single-fraction high-dose-rate brachytherapy and hypofractionated external beam radiotherapy for prostate cancer.
      ,
      • Pinkawa M.
      • Fischedick K.
      • Treusacher P.
      • Asadpour B.
      • Gagel B.
      • Piroth M.D.
      • et al.
      Dose-volume impact in high-dose-rate Iridium-192 brachytherapy as a boost to external beam radiotherapy for localized prostate cancer–a phase II study.
      ]. There is also extremely limited published toxicity outcomes data at population-based level [
      • Parry M.G.
      • Nossiter J.
      • Cowling T.E.
      • Sujenthiran A.
      • Berry B.
      • Cathcart P.
      • et al.
      Patient-reported functional outcomes following external beam radiation therapy for prostate cancer with and without a high-dose rate brachytherapy boost: a national population-based study.
      ,
      • Parry M.G.
      • Nossiter J.
      • Sujenthiran A.
      • Cowling T.E.
      • Patel R.N.
      • Morris M.
      • et al.
      Impact of high-dose-rate and low-dose-rate brachytherapy boost on toxicity, functional and cancer outcomes in patients receiving external beam radiation therapy for prostate cancer: a national population-based study.
      ].
      In this study, we aim to evaluate 1) the utilisation of BT-boost in men who had EBRT for prostate cancer, and 2) the PRO following EBRT with or without BT-boost in real-life Australian population-based setting.

      Methods

      Study population

      This is a population-based cohort of men with prostate cancer enrolled in the Victorian Prostate Cancer Outcomes Registry (PCOR-Vic), a state-wide clinical quality registry, which currently captures over 80% of incident prostate cancer cases in Victoria, the second most populous state in Australia with a population of approximately 6 million people. Detailed recruitment and data collection methodology have been previously described [
      • Evans S.M.
      • Millar J.L.
      • Wood J.M.
      • Davis I.D.
      • Bolton D.
      • Giles G.G.
      • et al.
      The Prostate Cancer Registry: monitoring patterns and quality of care for men diagnosed with prostate cancer.
      ]. Briefly, all men with newly diagnosed prostate cancer were notified to PCOR-Vic, with an opt-out consent process to maximise recruitment. Trained data collectors reviewed medical records and made follow-up phone interviews with patients to verify treatment details. All men were contacted 12-months post-treatment to complete the Expanded Prostate Cancer Index Composite short form 26 questionnaire (EPIC-26), a validated PRO tool for prostate cancer [
      • Szymanski K.M.
      • Wei J.T.
      • Dunn R.L.
      • Sanda M.G.
      Development and validation of an abbreviated version of the expanded prostate cancer index composite instrument for measuring health-related quality of life among prostate cancer survivors.
      ]. The questionnaire was initially administered by phone or sent out to patients by post, but has been predominantly administered via email since April 2018, with a minority still completing the survey by phone or post. The EPIC-26 included urinary incontinence, urinary obstructive, sexual, bowel, and hormonal function domain scores, ranging from 0 to 100, with higher score representing better outcomes. Due to the nature of recruitment into PCOR-Vic, all men would have been started on treatment by the time they were enrolled in PCOR-Vic, and hence it was not possible to capture baseline EPIC-26 within PCOR-Vic. For this study, we included all men who had definitive EBRT, with or without BT-boost, as primary treatment for localised prostate cancer between 1 January 2015 and 31 December 2020.

      Primary outcomes and covariables

      The primary outcomes were 1) proportion of men who had BT-boost and factors associated with that, and 2) differences in EPIC-26 functional domains outcomes at 12 months post-treatment between men who had EBRT and EBRT + BT. Covariables available within PCOR-Vic include year of treatment, age at treatment, PSA level at diagnosis, ISUP grade group, clinical T categories, NCCN risk categories (low, intermediate, or high risk), use of androgen deprivation therapy (ADT), residential postcode, and treatment centres. Based on the residential postcode, the area of residence was classified as major city, inner regional, or outer regional/remote using the Australian Statistical Geographical Standard (ASGS) remoteness structure. In addition, the socioeconomic status was derived from the residential postcode using the Socio-Economic Indexes for Areas (SEIFA) index for relative socioeconomic disadvantaged based on the Australian Bureau of Statistics. This was further subdivided into quintiles based on the Victorian population. There were four public and two private radiation therapy service providers in Victoria, and each provided radiation therapy services through several treatment centres throughout Victoria. These treatment centres were classified as metropolitan or regional depending on the location of the treatment centres based on the ASGS structure. BT boosts were largely offered only in two public metropolitan centres that were equipped with HDR-BT expertise. Recognizing that men may have the EBRT and BT at separate centres, for the study purpose, the treatment institution classification (public or private, and metropolitan or regional) was based on the institution where they received EBRT.

      Statistical analyses

      Differences in covariables between men who had EBRT and EBRT + BT were compared using Pearson’s chi-squared test for categorical variables and Student’s t-test (or Mann-Whitney U test for expected non-normality in PSA values) for continuous variables. Multivariable logistic regression was used to evaluate association of covariables with EBRT + BT use. Covariables included in multivariable analyses were pre-selected based on clinical knowledge, and these included year of treatment, age at treatment, NCCN risk categories, ADT use, socioeconomic status, area of residence and treatment centres. Differences in the EPIC-26 domain scores between EBRT and EBRT + BT were estimated using multivariable linear regression, adjusting for available covariables. EBRT alone was the reference group, and negative differences indicated poorer outcomes compared to EBRT alone, and positive differences indicated better outcomes compared to EBRT alone. Minimally clinically important differences (MCID) in the adjusted EPIC-26 domain scores were defined based on previous study [
      • Skolarus T.A.
      • Dunn R.L.
      • Sanda M.G.
      • Chang P.
      • Greenfield T.K.
      • Litwin M.S.
      • et al.
      Minimally important difference for the Expanded Prostate Cancer Index Composite Short Form.
      ], i.e., 6, 5, 10, 4 and 4 for urinary incontinence, urinary obstruction, sexual, bowel and hormonal domains respectively. A two-sided P-value < 0.05 was considered to indicate statistical significance. All statistical analyses were performed using Stata/MP16 (StataCorp College Station, TX, USA). The study was approved by the Alfred Health Human Research Ethics Committee (HREC/16/Alfred/98).

      Results

      A total of 1,626 men who had definitive EBRT between 2015 and 2020 were included in the study (Fig. 1). Of these, 88 (5.4 %) had EBRT + BT (Table 1). There was no significant change in utilisation of EBRT + BT use over time – 6.2 % (27/437) in 2015–2016, 4.8 % (31/640) in 2017–2018, and 5.5 % (30/549) in 2019–2020 (P = 0.6). Higher proportion of younger men had EBRT-BT – 17 % (12/72) in men aged under 60 years, compared to 1.7 % (31/78) in men aged 80 years and above (P < 0.001). There were no statistically significant differences in EBRT + BT use by ISUP Grade Group, PSA level, clinical T categories and NCCN risk categories, as well as ADT use. There was a higher proportion of EBRT + BT use in men from the highest socioeconomic quintiles (36/360, 10 %) compared to those from the lowest socioeconomic quintiles (8/341, 2.3 %) (P < 0.001). There was also higher proportion of EBRT + BT use in men who lived in major city (77/963, 8.0 %) compared to regional or remote area (11/660, 1.7 %) (P < 0.001). Men treated in public institutions were also more likely to have EBRT + BT (74/1120, 6.6 %) compared to those treated in private institutions (14/506, 2.8 %) (P = 0.002). Men treated in metropolitan centres were also more likely to have EBRT + BT (84/1013, 8.3 %) compared to those treated in regional centres (4/613, 0.6 %) (P < 0.001).
      Table 1Patient, tumor, and treatment characteristics of the study cohort.
      Overall

      N = 1626
      EBRT alone

      N = 1538 (94.6 %)
      EBRT + BT

      N = 88 (5.4 %)
      P-value
      Year of treatment0.6
      2015–2016437 (26.9 %)410 (93.8 %)27 (6.2 %)
      2017–2018640 (39.4 %)609 (95.2 %)31 (4.8 %)
      2019–2020549 (33.8 %)519 (94.5 %)30 (5.5 %)
      Age at treatment
      Mean (SD)72.8 (6.5)73.0 (6.4)69.4 (6.8)<0.001
      <6072 (4.4 %)60 (83.3 %)12 (16.7 %)<0.001
      60–69417 (25.7 %)387 (92.8 %)30 (7.2 %)
      70–79959 (59.0 %)916 (95.5 %)43 (4.5 %)
      >=80178 (11.0 %)175 (98.3 %)3 (1.7 %)
      PSA at diagnosis
      Median (IQR)9.5 (7.0–14.3)9.5 (7.0–14.3)9.7 (7.0–13.1)0.5
      <10 ng/mL817 (50.3 %)775 (94.9 %)43 (5.1 %)0.5
      10–20 ng/mL486 (29.9 %)456 (93.4 %)34 (6.6 %)
      >20 ng/mL211 (13.0 %)203 (95.7 %)9 (4.3 %)
      Missing112 (6.9 %)110 (95.5 %)5 (4.5 %)
      ISUP Grade Group0.3
      Group 165 (4.0 %)64 (98.5 %)1 (1.5 %)
      Group 2509 (31.3 %)485 (95.3 %)25 (4.7 %)
      Group 3415 (25.5 %)393 (94.7 %)22 (5.3 %)
      Group 4259 (15.9 %)238 (91.9 %)21 (8.1 %)
      Group 5316 (19.4 %)299 (94.6 %)17 (5.4 %)
      Missing62 (3.8 %)59 (95.2 %)3 (4.8 %)
      Clinical T categories0.07
      T1496 (30.5 %)462 (93.2 %)34 (6.9 %)
      T2644 (39.6 %)605 (93.9 %)41 (6.1 %)
      T3134 (8.2 %)128 (95.5 %)6 (4.5 %)
      T415 (0.9 %)15 (100 %)0 (0 %)
      Missing337 (20.7 %)328 (97.3 %)9 (2.7 %)
      NCCN risk categories0.6
      Low30 (1.8 %)29 (96.7 %)1 (3.3 %)
      Intermediate662 (40.7 %)627 (94.7 %)35 (5.3 %)
      High744 (45.8 %)699 (94.0 %)45 (6.1 %)
      Missing190 (11.7 %)183 (96.3 %)7 (3.7 %)
      Androgen deprivation therapy use0.1
      No515 (31.7 %)494 (95.9 %)21 (4.1 %)
      Yes1111 (68.3 %)1044 (94.0 %)67 (6.0 %)
      Socioeconomic status<0.001
      Quintile 1 (lowest)341 (21.0 %)333 (97.7 %)8 (2.3 %)
      Quintile 2313 (19.3 %)307 (98.1 %)6 (1.9 %)
      Quintile 3275 (16.9 %)259 (94.2 %)16 (5.8 %)
      Quintile 4334 (20.5 %)312 (93.4 %)22 (6.6 %)
      Quintile 5 (highest)360 (22.1 %)324 (90 %)36 (10 %)
      Missing3 (0.2 %)3 (100 %)0 (0 %)
      Area of residence<0.001
      Major city963 (59.2 %)886 (92.0 %)77 (8.0 %)
      Regional/ remote660 (40.6 %)649 (98.3 %)11 (1.7 %)
      Missing3 (0.2 %)3 (100 %)0 (0 %)
      Treatment institution type0.002
      Public1120 (68.9 %)1046 (93.4 %)74 (6.6 %)
      Private506 (31.1 %)492 (97.2 %)14 (2.8 %)
      Treatment institution location<0.001
      Metropolitan1013 (62.3 %)929 (91.7 %)84 (8.3 %)
      Regional613 (37.7 %)609 (99.4 %)4 (0.6 %)
      EBRT = external beam radiation therapy; BT = brachytherapy.
      In multivariable analyses, covariables that were independently associated with EBRT + BT use were age at treatment, socioeconomic status, and treatment centres and location (Table 2). For every 5 years increase in age, there is a relative 36 % (OR = 0.64; 95 %CI = 0.54–0.76; P < 0.001) reduced likelihood of having EBRT + BT. Men from the highest socioeconomic quintiles were more likely to have EBRT + BT compared to men from lowest socioeconomic quintiles (OR = 4.27; 95 %CI = 1.74–10.48; P = 0.002). Compared to men had treatment in public institutions, those treated in private institutions were less likely to have EBRT + BT (OR = 0.24; 95 %CI = 0.12–0.48; P < 0.001).
      Table 2Covariables associated with use of brachytherapy boost with external beam radiation therapy.
      OR (95 %CI)P-value
      Year of treatment
      2015–2016Reference
      2017–20180.82 (0.46–1.44)0.5
      2019–20200.94 (0.51–1.70)0.8
      Age at treatment (for every 5 years increase)0.64 (0.54–0.76)<0.001
      NCCN risk categories
      Low/ intermediateReference
      High1.18 (0.70–2.00)0.5
      Androgen deprivation therapy use
      NoReference
      Yes1.40 (0.75–2.59)0.3
      Socioeconomic status
      Quintile 1 (lowest)Reference
      Quintile 21.29 (0.42–4.00)0.7
      Quintile 32.57 (0.99–6.70)0.05
      Quintile 43.07 (1.22–7.72)0.02
      Quintile 5 (highest)4.27 (1.74–10.48)0.002
      Area of residence
      Major cityReference
      Regional/ remote0.25 (0.12–0.52)<0.001
      Treatment institution type
      PublicReference
      Private0.24 (0.12–0.48)<0.001
      There were 1555 (96 %) men who completed the EPIC-26 questionnaire (Fig. 1). The EPIC-26 questionnaires were completed at a median of 13.5 months post treatment (IQR: 13.0–13.9 months) and this did not vary between the two groups (P = 0.8). Overall, there were high EPIC-26 urinary and bowel functions domain score in all men included in the study (Table 3). There were no statistically or clinically significant differences in EPIC-26 score for urinary, bowel and sexual function domain between men who had EBRT vs EBRT + BT – the adjusted mean differences in urinary incontinence, urinary obstructive, sexual, and bowel function domain scores between ERBT and EBRT + BT were: 1.28 (95 %CI = −3.23 to 5.79), −2.87 (95 %CI = −6.46 to 0.73), 0.49 (95 %CI = −4.78 to 5.76), and 2.89 (95 %CI = −0.83 to 6.61) respectively, and none reach the MCID. There was better hormonal function domain score in men who had EBRT + BT compared to men who had EBRT alone, with adjusted mean differences of 4.45 (95 %CI = 0.11–8.79). However, the lower margin of the 95 %CI is less than MCID of 4 points for hormonal function domain, hence there is uncertainty whether the difference is clinically significant.
      Table 3EPIC-26 domain scores between different EBRT alone and EBRT + BT (n = 1555).
      EPIC-26 domainEBRT alone

      (n = 1471)
      EBRT + BT

      (n = 84)
      Adjusted mean differences* (95 % CI)P-value
      Urinary incontinence(n = 1452) #(n = 83) #
      Median (IQR)100 (79.3–100)100 (81.3–100)
      Mean (SD)87.7 (19.0)89.3 (17.7)1.28 (−3.23–5.79)0.6
      Urinary obstructive/ irritative(n = 1454) #(n = 83) #
      Median (IQR)93.8 (81.3–100)87.5 (81.3–100)
      Mean (SD)88.1 (15.3)85.8 (16.5)−2.87 (−6.46–0.73)0.1
      Sexual(n = 1374) #(n = 83) #
      Median (IQR)16.7 (12.5–32)16.7 (8.3–40.3)
      Mean (SD)25.3 (23.3)27.2 (27.1)0.49 (−4.78–5.76)0.8
      Bowel(n = 1460) #(n = 83) #
      Median (IQR)95.8 (83.3–100)95.8 (87.5–100)
      Mean (SD)89.3 (15.7)91.5 (12.4)2.89 (−0.83–6.61)0.1
      Hormonal(n = 1450) #(n = 84) #
      Median (IQR)85 (70–100)87.5 (70–100)
      Mean (SD)80.2 (19.2)82.0 (18.9)4.45 (0.11–8.79)0.05
      *Negative differences represent poorer outcomes in patients who had EBRT + BT; adjusted for year of treatment, age at treatment, NCCN risk category, use of androgen deprivation therapy, socioeconomic status, area of residence, and treatment institution.
      #Differences in sample size is due to not all questions in EPIC-26 being answered by all men.

      Discussion

      In this contemporary Australian population-based study, we reported persistent low utilisation of BT-boost in men who had EBRT for localized prostate cancer, compared to earlier study period [
      • Ong W.L.
      • Evans S.M.
      • Millar J.L.
      Under-utilisation of high-dose-rate brachytherapy boost in men with intermediate-high risk prostate cancer treated with external beam radiotherapy.
      ]. This is the first time that PRO between men who had EBRT vs EBRT + BT is reported at a population-based level in Australia.
      The decline and under-utilisation of BT in prostate cancer is well-recognized and have been reported in multiple population-based studies using the US National Cancer Database (NCDB) [
      • Martin J.M.
      • Handorf E.A.
      • Kutikov A.
      • Uzzo R.G.
      • Bekelman J.E.
      • Horwitz E.M.
      • et al.
      The rise and fall of prostate brachytherapy: use of brachytherapy for the treatment of localized prostate cancer in the National Cancer Data Base.
      ,
      • Orio 3rd, P.F.
      • Nguyen P.L.
      • Buzurovic I.
      • Cail D.W.
      • Chen Y.W.
      The decreased use of brachytherapy boost for intermediate and high-risk prostate cancer despite evidence supporting its effectiveness.
      ,
      • Jackson M.W.
      • Amini A.
      • Jones B.L.
      • Kavanagh B.
      • Maroni P.
      • Frank S.J.
      • et al.
      Prostate brachytherapy, either alone or in combination with external beam radiation, is associated with longer overall survival in men with favorable pathologic Group 4 (Gleason score 8) prostate cancer.
      ,
      • Johnson S.B.
      • Lester-Coll N.H.
      • Kelly J.R.
      • Kann B.H.
      • Yu J.B.
      • Nath S.K.
      Brachytherapy boost utilization and survival in unfavorable-risk prostate cancer.
      ,
      • Malouff T.
      • Mathy N.W.
      • Marsh S.
      • Walters R.W.
      • Silberstein P.T.
      Trends in the use of radiation therapy for stage IIA prostate cancer from 2004 to 2013: a retrospective analysis using the National Cancer Database.
      ] and Surveillance, Epidemiology and End Results (SEER) [
      • Mahmood U.
      • Pugh T.
      • Frank S.
      • Levy L.
      • Walker G.
      • Haque W.
      • et al.
      Declining use of brachytherapy for the treatment of prostate cancer.
      ] database. Previous Australian population-based study between 2010 and 2015 reported only 7 % of men who had EBRT for prostate cancer had BT-boost [
      • Ong W.L.
      • Evans S.M.
      • Millar J.L.
      Under-utilisation of high-dose-rate brachytherapy boost in men with intermediate-high risk prostate cancer treated with external beam radiotherapy.
      ], and in the current study BT-boost utilisation remains low at 5.4 %. This is similar to a UK linkage study between the UK Cancer Registry, National Radiotherapy Dataset (RTDS), and Hospital Episodes Statistics (HES), which showed that of the 54,642 men who had EBRT for prostate cancer between 2010 and 2016, 3,095 (6 %) had BT-boost [
      • Parry M.G.
      • Nossiter J.
      • Sujenthiran A.
      • Cowling T.E.
      • Patel R.N.
      • Morris M.
      • et al.
      Impact of high-dose-rate and low-dose-rate brachytherapy boost on toxicity, functional and cancer outcomes in patients receiving external beam radiation therapy for prostate cancer: a national population-based study.
      ]. This contrasts with the findings in a Canadian study, which reported increasing BT utilisation in Ontario between 2006 and 2017, and this is largely driven by BT-boost in men who had EBRT, instead of BT monotherapy [
      • Corkum M.T.
      • Morton G.
      • Louie A.V.
      • Bauman G.S.
      • Mendez L.C.
      • Chin J.
      • et al.
      Is prostate brachytherapy a dying art? Trends and variation in the definitive management of prostate cancer in Ontario, Canada.
      ]. Among all men who had EBRT for prostate cancer, the proportion who had EBRT + BT-boost increased from 4 % in 2007 to 21 % in 2017 [
      • Corkum M.T.
      • Morton G.
      • Louie A.V.
      • Bauman G.S.
      • Mendez L.C.
      • Chin J.
      • et al.
      Is prostate brachytherapy a dying art? Trends and variation in the definitive management of prostate cancer in Ontario, Canada.
      ]. The observed differences in the trend of BT utilisation in Canada and the other studies are likely multifactorial, including differences in patient population, provider factors, as well as healthcare funding model [
      • Corkum M.T.
      • Morton G.
      • Louie A.V.
      • Bauman G.S.
      • Mendez L.C.
      • Chin J.
      • et al.
      Is prostate brachytherapy a dying art? Trends and variation in the definitive management of prostate cancer in Ontario, Canada.
      ]. Nonetheless, we believe that the low utilisation of BT boost is unlikely to change within the current Australian healthcare setting, unless there is convincing high-level evidence showing improved oncological outcomes of BT-boost beyond biochemical survival benefits compared to other novel techniques in the era of dose-escalated radiation therapy, such as stereotactic body radiation therapy, and that more radiation oncologists are well-trained in BT [
      • Ong W.L.
      • Byrne A.
      • Chelvarajah R.
      • Chong C.
      • Gallo J.
      • Kain M.
      • et al.
      Survey of brachytherapy training experience among radiation oncology trainees and fellows in the Royal Australian and New Zealand College of Radiologists (RANZCR).
      ].
      We observed variations in the utilisation of BT-boost. Unsurprisingly, younger men were more likely to have BT-boost, and this could be due to combination of reasons. Elderly patients are more likely to have multiple medical comorbidities and deemed medically unfit for operative procedures e.g., on long-term anticoagulation that may be unsafe to be discontinued for BT procedure. However, data on comorbidities was not consistently collected in PCOR-Vic to be included in our analyses. Also, local failure following radiation therapy has been shown to be prognostic for long-term risk of distant metastases and overall survival [
      • Ma T.M.
      • Chu F.-I.
      • Sandler H.
      • Feng F.Y.
      • Efstathiou J.A.
      • Jones C.U.
      • et al.
      Local failure events in prostate cancer treated with radiotherapy: a pooled analysis of 18 randomized trials from the meta-analysis of randomized trials in cancer of the prostate consortium (LEVIATHAN).
      ], and younger men may have less competing risk of death in the longer term and will derive greater benefit from the improved local control from BT boost [
      • Dayes I.S.
      • Parpia S.
      • Gilbert J.
      • Julian J.A.
      • Davis I.R.
      • Levine M.N.
      • et al.
      Long-term results of a 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.
      • Rojas A.M.
      • Bownes P.J.
      • Lowe G.J.
      • Ostler P.J.
      • Bryant L.
      Randomised trial of external beam radiotherapy alone or combined with high-dose-rate brachytherapy boost for localised prostate cancer.
      ,
      • Morris W.J.
      • Tyldesley S.
      • Rodda S.
      • Halperin R.
      • Pai H.
      • McKenzie M.
      • 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.
      ]. We did not observe differences in utilisation of BT-boost by ADT use. Some of the earlier studies have suggested that clinicians may omit ADT in the setting of dose escalation with BT-boost [
      • Chen Y.-W.
      • Muralidhar V.
      • Mahal B.A.
      • Nezolosky M.D.
      • Beard C.J.
      • Choueiri T.K.
      • et al.
      Factors associated with the omission of androgen deprivation therapy in radiation-managed high-risk prostate cancer.
      ]. However, individual patient-data meta-analyses from multiple randomised trials have shown that dose escalation alone in the absence of ADT did not improve oncological outcomes [
      • Kishan A.U.
      • Wang X.
      • Sun Y.
      • Romero T.
      • Michalski J.M.
      • Ma T.M.
      • et al.
      High-dose Radiotherapy or Androgen Deprivation Therapy (HEAT) as treatment intensification for localized prostate cancer: an individual patient-data network meta-analysis from the MARCAP consortium.
      ].
      We reported higher utilisation of BT-boost in men from higher socioeconomic status in Australia. This pattern of higher BT utilisation in patients with higher income or socioeconomic group have been previously reported in the US [
      • Orio 3rd, P.F.
      • Nguyen P.L.
      • Buzurovic I.
      • Cail D.W.
      • Chen Y.W.
      The decreased use of brachytherapy boost for intermediate and high-risk prostate cancer despite evidence supporting its effectiveness.
      ,
      • Mahmood U.
      • Pugh T.
      • Frank S.
      • Levy L.
      • Walker G.
      • Haque W.
      • et al.
      Declining use of brachytherapy for the treatment of prostate cancer.
      ]. This may reflect patients’ access to medical information, and these patients (from higher socioeconomic group) may have sought second opinions and treatment in centres that offer BT services. At the same time, we observed lower utilisation of BT-boost in patient treated in private centres, and this is likely reflective of the general decline in the interest in BT services in private centres. It is also important to note that while evidence from the most recent ASCENDE-BT trial used LDR-BT as BT-boost, LDR-BT is only funded as monotherapy for low to intermediate risk prostate cancer in the current Australian Medicare Benefits Schedule (MBS), and hence, all BT-boost delivered in combination with EBRT in Australia were HDR-BT. HDR-BT service provision is generally centralised given the high resource need. Apart from lower reimbursement for prostate BT, the disadvantageous manner in which capital costs for BT technology is supported in both public and private facilities, compared to capital support for new or replacement of LINACs, have largely limited the options of BT-boost for prostate cancer to men treated in two main public metropolitan radiation oncology facilities in Victoria with HDR-BT services.
      A major strength of the current study is the use of validated PRO tools, consistent with recommendation by international consortium group [
      • Martin N.E.
      • Massey L.
      • Stowell C.
      • Bangma C.
      • Briganti A.
      • Bill-Axelson A.
      • et al.
      Defining a standard set of patient-centered outcomes for men with localized prostate cancer.
      ], to capture toxicity outcomes at a population-based level, which allows us to continuously monitor and benchmark radiation therapy practice across different centres. Given that clinicians often under-estimate patients’ symptoms [
      • Laugsand E.A.
      • Sprangers M.A.G.
      • Bjordal K.
      • Skorpen F.
      • Kaasa S.
      • Klepstad P.
      Health care providers underestimate symptom intensities of cancer patients: a multicenter European study.
      ], the use of PRO is increasingly being recognized, and is commonly incorporated in clinical trials these days. We did not observe statistically or clinically significant differences in PRO for urinary, bowel and sexual function between men who had EBRT vs EBRT + BT at a population-based level in Australia (Table 3). However, we have to acknowledge the limitation of the use of convenience sample of real-world data, whereby there is disproportionately small number of patients who had EBRT + BT in our cohort, with resultant large range in confidence interval and uncertainty in the observed (lack of) differences in PRO. Nonetheless, we did observe statistically significant difference in hormonal domain score between the two groups. This is reflective of the impact of ADT rather than that of BT-boost. While there were no differences in ADT use between the two groups (Table 1), the difference in the hormonal domain score is most likely reflective of the duration of ADT use in the two groups (which were not captured in PCOR-Vic) in relation to the timing of completion of the EPIC-26 questionnaire.
      The only other population-based study that had reported on PRO, using the EPIC-26 questionnaire, between men who had EBRT and EBRT + BT was from the UK National Prostate Cancer Audit (NPCA) [
      • Parry M.G.
      • Nossiter J.
      • Cowling T.E.
      • Sujenthiran A.
      • Berry B.
      • Cathcart P.
      • et al.
      Patient-reported functional outcomes following external beam radiation therapy for prostate cancer with and without a high-dose rate brachytherapy boost: a national population-based study.
      ]. In that study, Parry et al reported worse urinary irritative/ obstructive domain score with EBRT + BT compared to EBRT alone (mean adjusted difference: −6.1, 95 %CI: −8.8 to −3.4); however, it is uncertain as to whether it is clinically significant [
      • Parry M.G.
      • Nossiter J.
      • Cowling T.E.
      • Sujenthiran A.
      • Berry B.
      • Cathcart P.
      • et al.
      Patient-reported functional outcomes following external beam radiation therapy for prostate cancer with and without a high-dose rate brachytherapy boost: a national population-based study.
      ]. When comparing our findings with that from the UK NPCA, we observed consistently higher EPIC domain scores for men who had EBRT with or without BT across all functional domains, despite the EPIC questionnaire being completed at a similar period of approximately 12 months post-treatment (Table 4). This is an important finding for future international benchmarking effort, as it appears to suggest that at a population-based level, men treated with EBRT + BT in Australia had better PRO compared to men treated in the UK. However, a common limitation in both NPCA and PCOR-Vic, is the lack of information on pre-treatment PRO. Earlier studies have shown that different level of pre-treatment function produced distinct treatment-related changes from baseline [
      • Chen R.C.
      • Clark J.A.
      • Talcott J.A.
      Individualizing quality-of-life outcomes reporting: how localized prostate cancer treatments affect patients with different levels of baseline urinary, bowel, and sexual function.
      ]. It remains unknown if men in the UK had worse pre-treatment function, or if they had bigger decline in functional outcomes following treatment, compared to men in Australia.
      Table 4Comparison of EPIC-26 domain scores between Prostate Cancer Outcomes Registry Victoria (PCOR-Vic) and UK National Prostate Cancer Audit (NPCA) (26).
      PCOR-VicNPCA
      EPIC-26 domainEBRT alone

      (n = 1471)
      EBRT + BT

      (n = 84)
      EBRT alone

      (n = 12,503)
      EBRT + BT

      (n = 756)
      Urinary incontinence
      Mean (SD)87.7 (19.0)89.3 (17.7)86.2 (19.3)85.6 (19.9)
      Urinary obstructive/irritative
      Mean (SD)88.1 (15.3)85.8 (16.5)86.3 (15.2)80.7 (18.4)
      Sexual
      Mean (SD)25.3 (23.3)27.2 (27.1)17.9 (21.5)18.0 (21.6)
      Bowel
      Mean (SD)89.3 (15.7)91.5 (12.4)85.9 (18.3)87.0 (17.2)
      Hormonal
      Mean (SD)80.2 (19.2)82.0 (18.9)70.5 (23.3)70.4 (22.8)
      Apart from the lack of pre-treatment PRO, there are several other limitations in the current study, which are inherent limitations within the PCOR-Vic dataset. Given that some of the late treatment-related toxicities may be delayed for years, it will be important to capture and compare the late PRO between EBRT and EBRT + BT. However, current funding within PCOR-Vic has limited PRO collection up to 12 months post-treatment, and future funding is required to allow assessment of longer-term follow-up for men enrolled in PCOR-Vic. There are varying dose-fractionation schedules used for EBRT component which may confound the PRO; however, previous Australian population-based study has shown no clinically significant difference in PRO between men treated with conventional fractionated and hypofractionated EBRT [
      • Pryor D.I.
      • Martin J.M.
      • Millar J.L.
      • Day H.
      • Ong W.L.
      • Skala M.
      • et al.
      Evaluation of hypofractionated radiation therapy use and patient-reported outcomes in men with nonmetastatic prostate cancer in Australia and New Zealand.
      ].

      Conclusion

      In summary, the most contemporary Australian population-based data suggests that utilisation of BT-boost with EBRT for prostate cancer remains low compared to earlier studies. Within the limitation of the study, reassuringly, there is no evidence at a population-based level indicating clinically significant differences in PRO in men who had EBRT compared to EBRT + BT at 12 months post-treatment. However, longer-term follow-up is required. The current findings also need to be interpreted in the absence of baseline PRO, and future work is needed to enable collection of baseline PRO in men enrolled in PCOR-Vic.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgement

      The Prostate Cancer Outcomes Registry Victoria (PCOR-Vic) is funded by Movember Foundation.

      Data sharing

      Research data is stored in institutional repository and will be shared upon reasonable request to the corresponding author.

      References

        • Sathya J.R.
        • Davis I.R.
        • Julian J.A.
        • Guo Q.
        • Daya D.
        • Dayes I.S.
        • 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
        • Dayes I.S.
        • Parpia S.
        • Gilbert J.
        • Julian J.A.
        • Davis I.R.
        • Levine M.N.
        • et al.
        Long-term results of a 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.
        Int J Radiat Oncol Biol Phys. 2017; 99: 90-93
        • Hoskin P.J.
        • Rojas A.M.
        • Bownes P.J.
        • Lowe G.J.
        • Ostler P.J.
        • Bryant L.
        Randomised trial of external beam radiotherapy alone or combined with high-dose-rate brachytherapy boost for localised prostate cancer.
        Radiother. Oncol. 2012; 103: 217-222
        • Morris W.J.
        • Tyldesley S.
        • Rodda S.
        • Halperin R.
        • Pai H.
        • McKenzie M.
        • 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
        • Kishan A.U.
        • Cook R.R.
        • Ciezki J.P.
        • Ross A.E.
        • Pomerantz M.M.
        • Nguyen P.L.
        • 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, J Am Med Assoc. 2018; 319: 896
        • Martin J.M.
        • Handorf E.A.
        • Kutikov A.
        • Uzzo R.G.
        • Bekelman J.E.
        • Horwitz E.M.
        • et al.
        The rise and fall of prostate brachytherapy: use of brachytherapy for the treatment of localized prostate cancer in the National Cancer Data Base.
        Cancer. 2014; 120: 2114-2121
        • Orio 3rd, P.F.
        • Nguyen P.L.
        • Buzurovic I.
        • Cail D.W.
        • Chen Y.W.
        The decreased use of brachytherapy boost for intermediate and high-risk prostate cancer despite evidence supporting its effectiveness.
        Brachytherapy. 2016; 15: 701-706
        • Jackson M.W.
        • Amini A.
        • Jones B.L.
        • Kavanagh B.
        • Maroni P.
        • Frank S.J.
        • et al.
        Prostate brachytherapy, either alone or in combination with external beam radiation, is associated with longer overall survival in men with favorable pathologic Group 4 (Gleason score 8) prostate cancer.
        Brachytherapy. 2017; 16: 790-796
        • Johnson S.B.
        • Lester-Coll N.H.
        • Kelly J.R.
        • Kann B.H.
        • Yu J.B.
        • Nath S.K.
        Brachytherapy boost utilization and survival in unfavorable-risk prostate cancer.
        Eur Urol. 2017; 72: 738-744
        • Malouff T.
        • Mathy N.W.
        • Marsh S.
        • Walters R.W.
        • Silberstein P.T.
        Trends in the use of radiation therapy for stage IIA prostate cancer from 2004 to 2013: a retrospective analysis using the National Cancer Database.
        Prostate Cancer Prostatic Dis. 2017; 20: 334-338
        • Mahmood U.
        • Pugh T.
        • Frank S.
        • Levy L.
        • Walker G.
        • Haque W.
        • et al.
        Declining use of brachytherapy for the treatment of prostate cancer.
        Brachytherapy. 2014; 13: 157-162
        • Ong W.L.
        • Evans S.M.
        • Millar J.L.
        Under-utilisation of high-dose-rate brachytherapy boost in men with intermediate-high risk prostate cancer treated with external beam radiotherapy.
        J Med Imaging Radiat Oncol. 2018; 62: 256-261
        • Pryor D.
        • Sidhom M.
        • Arumugam S.
        • Bucci J.
        • Gallagher S.
        • Smart J.
        • et al.
        Phase 2 multicenter study of gantry-based stereotactic radiotherapy boost for intermediate and high risk prostate cancer (PROMETHEUS).
        Front Oncol. 2019; 9
        • Alayed Y.
        • Loblaw A.
        • Chu W.
        • Al-Hanaqta M.
        • Chiang A.
        • Jain S.
        • et al.
        Stereotactic body radiation therapy boost for intermediate-risk prostate cancer: a phase 1 dose-escalation study.
        Int J Radiat Oncol Biol Phys. 2019; 104: 1066-1073
        • Orio 3rd, P.F.
        • Nguyen P.L.
        • Buzurovic I.
        • Cail D.W.
        • Chen Y.W.
        Prostate brachytherapy case volumes by academic and nonacademic practices: implications for future residency training.
        Int J Radiat Oncol Biol Phys. 2016; 96: 624-628
        • Ong W.L.
        • Byrne A.
        • Chelvarajah R.
        • Chong C.
        • Gallo J.
        • Kain M.
        • et al.
        Survey of brachytherapy training experience among radiation oncology trainees and fellows in the Royal Australian and New Zealand College of Radiologists (RANZCR).
        J Med Imaging Radiat Oncol. 2022;
        • Rodda S.
        • Tyldesley S.
        • Morris W.J.
        • Keyes M.
        • Halperin R.
        • Pai H.
        • 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
        • Lawton C.A.
        • Yan Y.
        • Lee W.R.
        • Gillin M.
        • Firat S.
        • Baikadi M.
        • et al.
        Long-term results of an RTOG Phase II trial (00–19) of external-beam radiation therapy combined with permanent source brachytherapy for intermediate-risk clinically localized adenocarcinoma of the prostate.
        Int J Radiat Oncol Biol Phys. 2012; 82: e795-e801
        • Hoskin P.J.
        • Rojas A.M.
        • Ostler P.J.
        • Hughes R.
        • Lowe G.J.
        • Bryant L.
        Quality of life after radical radiotherapy for prostate cancer: longitudinal study from a randomised trial of external beam radiotherapy alone or in combination with high dose rate brachytherapy.
        Clin Oncol (R Coll Radiol). 2013; 25: 321-327
        • Bekelman J.E.
        • Rumble R.B.
        • Chen R.C.
        • Pisansky T.M.
        • Finelli A.
        • Feifer A.
        • et al.
        Clinically Localized Prostate Cancer: ASCO Clinical Practice Guideline Endorsement of an American Urological Association/American Society for Radiation Oncology/Society of Urologic Oncology Guideline.
        J Clin Oncol. 2018; 36: 3251-3258
        • Spratt D.E.
        • Zumsteg Z.S.
        • Ghadjar P.
        • Kollmeier M.A.
        • Pei X.
        • Cohen G.
        • et al.
        Comparison of high-dose (86.4 Gy) IMRT vs combined brachytherapy plus IMRT for intermediate-risk prostate cancer.
        BJU Int. 2014; 114: 360-367
        • Sutani S.
        • Ohashi T.
        • Sakayori M.
        • Kaneda T.
        • Yamashita S.
        • Momma T.
        • et al.
        Comparison of genitourinary and gastrointestinal toxicity among four radiotherapy modalities for prostate cancer: conventional radiotherapy, intensity-modulated radiotherapy, and permanent iodine-125 implantation with or without external beam radiotherapy.
        Radiother Oncol. 2015; 117: 270-276
        • Choudhury A.
        • Arthur C.
        • Malik J.
        • Mandall P.
        • Taylor C.
        • Alam N.
        • et al.
        Patient-reported outcomes and health-related quality of life in prostate cancer treated with a single fraction of high dose rate brachytherapy combined with hypofractionated external beam radiotherapy.
        Clin Oncol (R Coll Radiol). 2014; 26: 661-667
        • Morton G.C.
        • Loblaw D.A.
        • Chung H.
        • Tsang G.
        • Sankreacha R.
        • Deabreu A.
        • et al.
        Health-related quality of life after single-fraction high-dose-rate brachytherapy and hypofractionated external beam radiotherapy for prostate cancer.
        Int J Radiat Oncol Biol Phys. 2011; 80: 1299-1305
        • Pinkawa M.
        • Fischedick K.
        • Treusacher P.
        • Asadpour B.
        • Gagel B.
        • Piroth M.D.
        • et al.
        Dose-volume impact in high-dose-rate Iridium-192 brachytherapy as a boost to external beam radiotherapy for localized prostate cancer–a phase II study.
        Radiother Oncol. 2006; 78: 41-46
        • Parry M.G.
        • Nossiter J.
        • Cowling T.E.
        • Sujenthiran A.
        • Berry B.
        • Cathcart P.
        • et al.
        Patient-reported functional outcomes following external beam radiation therapy for prostate cancer with and without a high-dose rate brachytherapy boost: a national population-based study.
        Radiother Oncol. 2021; 155: 48-55
        • Parry M.G.
        • Nossiter J.
        • Sujenthiran A.
        • Cowling T.E.
        • Patel R.N.
        • Morris M.
        • et al.
        Impact of high-dose-rate and low-dose-rate brachytherapy boost on toxicity, functional and cancer outcomes in patients receiving external beam radiation therapy for prostate cancer: a national population-based study.
        Int J Radiat Oncol Biol Phys. 2021; 109: 1219-1229
        • Evans S.M.
        • Millar J.L.
        • Wood J.M.
        • Davis I.D.
        • Bolton D.
        • Giles G.G.
        • et al.
        The Prostate Cancer Registry: monitoring patterns and quality of care for men diagnosed with prostate cancer.
        BJU Int. 2013; 111: E158-E166
        • Szymanski K.M.
        • Wei J.T.
        • Dunn R.L.
        • Sanda M.G.
        Development and validation of an abbreviated version of the expanded prostate cancer index composite instrument for measuring health-related quality of life among prostate cancer survivors.
        Urology. 2010; 76: 1245-1250
        • Skolarus T.A.
        • Dunn R.L.
        • Sanda M.G.
        • Chang P.
        • Greenfield T.K.
        • Litwin M.S.
        • et al.
        Minimally important difference for the Expanded Prostate Cancer Index Composite Short Form.
        Urology. 2015; 85: 101-106
        • Corkum M.T.
        • Morton G.
        • Louie A.V.
        • Bauman G.S.
        • Mendez L.C.
        • Chin J.
        • et al.
        Is prostate brachytherapy a dying art? Trends and variation in the definitive management of prostate cancer in Ontario, Canada.
        Radiother Oncol. 2020; 152: 42-48
        • Ma T.M.
        • Chu F.-I.
        • Sandler H.
        • Feng F.Y.
        • Efstathiou J.A.
        • Jones C.U.
        • et al.
        Local failure events in prostate cancer treated with radiotherapy: a pooled analysis of 18 randomized trials from the meta-analysis of randomized trials in cancer of the prostate consortium (LEVIATHAN).
        Eur Urol. 2022;
        • Chen Y.-W.
        • Muralidhar V.
        • Mahal B.A.
        • Nezolosky M.D.
        • Beard C.J.
        • Choueiri T.K.
        • et al.
        Factors associated with the omission of androgen deprivation therapy in radiation-managed high-risk prostate cancer.
        Brachytherapy. 2016; 15: 695-700
        • Kishan A.U.
        • Wang X.
        • Sun Y.
        • Romero T.
        • Michalski J.M.
        • Ma T.M.
        • et al.
        High-dose Radiotherapy or Androgen Deprivation Therapy (HEAT) as treatment intensification for localized prostate cancer: an individual patient-data network meta-analysis from the MARCAP consortium.
        Eur Urol. 2022;
        • Martin N.E.
        • Massey L.
        • Stowell C.
        • Bangma C.
        • Briganti A.
        • Bill-Axelson A.
        • et al.
        Defining a standard set of patient-centered outcomes for men with localized prostate cancer.
        Eur Urol. 2015; 67: 460-467
        • Laugsand E.A.
        • Sprangers M.A.G.
        • Bjordal K.
        • Skorpen F.
        • Kaasa S.
        • Klepstad P.
        Health care providers underestimate symptom intensities of cancer patients: a multicenter European study.
        Health Qual Life Outcomes. 2010; 8: 104
        • Chen R.C.
        • Clark J.A.
        • Talcott J.A.
        Individualizing quality-of-life outcomes reporting: how localized prostate cancer treatments affect patients with different levels of baseline urinary, bowel, and sexual function.
        J Clin Oncol. 2009; 27: 3916-3922
        • Pryor D.I.
        • Martin J.M.
        • Millar J.L.
        • Day H.
        • Ong W.L.
        • Skala M.
        • et al.
        Evaluation of hypofractionated radiation therapy use and patient-reported outcomes in men with nonmetastatic prostate cancer in Australia and New Zealand.
        JAMA Netw Open. 2021; 4: e2129647