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Clinical outcomes of high-dose-rate brachytherapy and external beam radiotherapy in the management of clinically localized prostate cancer

Open AccessPublished:July 26, 2012DOI:https://doi.org/10.1016/j.brachy.2012.05.003

      Abstract

      Purpose

      To report prostate-specific antigen (PSA) relapse-free survival and treatment-related toxicity outcomes after combining high-dose-rate (HDR) brachytherapy with external beam radiotherapy (EBRT) for patients with clinically localized prostate cancer.

      Methods and Materials

      Between 1998 and 2009, 229 patients were treated with HDR brachytherapy followed 3 weeks later by supplemental EBRT. The HDR brachytherapy boost consisted of three fractions of 192Ir (5.5–7.5 Gy per fraction), and EBRT consisted of intensity-modulated radiotherapy delivering an additional 45.0–50.4 Gy directed to the prostate gland and seminal vesicles. Median follow-up was 61 months.

      Results

      Seven-year PSA relapse-free survival for low-, intermediate-, and high-risk patients were 95%, 90%, and 57%, respectively (p<0.001). Among high-risk patients treated with biological equivalent doses in excess of 190 Gy, 7-year PSA relapse-free survival was 81%. In multivariate analysis, Gleason scores of ≥8 predicted for increased risk of biochemical failure, whereas the use of short-term neoadjuvant androgen deprivation therapy did not influence tumor-control outcomes even among intermediate- or high-risk patients. Seven-year incidence of distant metastases for low-, intermediate-, and high-risk patients were 5%, 3%, and 17%, respectively. Seven-year incidence of late Grade 2 and 3 genitourinary toxicities were 22.1% and 4.9%, respectively and the 7-year incidence of Grade 2 and 3 gastrointestinal toxicities were 1% and 0.4%, respectively.

      Conclusion

      HDR prostate brachytherapy in conjunction with supplemental EBRT results in excellent biochemical relapse-free survival rates with a low incidence of severe late genitourinary or gastrointestinal toxicities. The use of short-term neoadjuvant androgen deprivation did not influence long-term biochemical tumor control in this cohort.

      Keywords

      Introduction

      In the radiotherapeutic management of clinically localized prostate cancer, dose escalation studies have been consistently associated with improved biochemical control outcomes and a reduction in distant metastases [DMs (
      • Pollack A.
      • Zagars G.K.
      • Starkschall G.
      • et al.
      Prostate cancer radiation dose response: Results of the M. D. Anderson phase III randomized trial.
      ,
      • Zietman A.L.
      • Bae K.
      • Slater J.D.
      • et al.
      Randomized trial comparing conventional-dose with high-dose conformal radiation therapy in early-stage adenocarcinoma of the prostate: Long-term results from Proton Radiation Oncology Group/American College of Radiology 95-09.
      ,
      • Peeters S.T.
      • Heemsbergen W.D.
      • Koper P.C.
      • et al.
      Dose-response in radiotherapy for localized prostate cancer: Results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy.
      ,
      • Dearnaley D.P.
      • Sydes M.R.
      • Graham J.D.
      • et al.
      Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: First results from the MRC RT01 randomised controlled trial.
      ,
      • Kuban D.A.
      • Levy L.B.
      • Cheung M.R.
      • et al.
      Long-term failure patterns and survival in a randomized dose-escalation trial for prostate cancer. Who dies of disease?.
      )]. Furthermore, this favorable treatment response to higher radiation doses is most evident in patients with intermediate- and high-risk disease. Therefore, in an effort to escalate the intraprostatic dose without compromising periprostatic dose coverage, external beam radiation therapy (EBRT) has been used in combination with a high-dose-rate (HDR) brachytherapy boost. Recent evidence from our institution has demonstrated that the use of this combination treatment approach improves tumor control in those patients with intermediate-risk disease and selected patients with high-risk disease (
      • Deutsch I.
      • Zelefsky M.J.
      • Zhang Z.
      • et al.
      Comparison of PSA relapse-free survival in patients treated with ultra-high-dose IMRT versus combination HDR brachytherapy and IMRT.
      ).
      In the present study, we report our long-term efficacy and toxicity outcomes using EBRT in combination with HDR brachytherapy for patients with clinically localized prostate cancer. Consistent with other reports (
      • Deutsch I.
      • Zelefsky M.J.
      • Zhang Z.
      • et al.
      Comparison of PSA relapse-free survival in patients treated with ultra-high-dose IMRT versus combination HDR brachytherapy and IMRT.
      ,
      • Mate T.P.
      • Gottesman J.E.
      • Hatton J.
      • et al.
      High dose-rate afterloading 192-Iridium prostate brachytherapy: Feasibility report.
      ,
      • Eulau S.
      • Van Hollebeke L.
      • Cavanagh W.
      • et al.
      High dose rate 192-Iridium brachytherapy in localized prostate cancer: Results and toxicity with maximum follow-up of 10 years.
      ,
      • Galalae R.M.
      • Kovács G.
      • Schultze J.
      • et al.
      Long-term outcome after elective irradiation of the pelvic lymphatics and local dose escalation using high-dose-rate brachytherapy for locally advanced prostate cancer.
      ,
      • Astrom L.
      • Pedersen D.
      • Mercke C.
      • et al.
      Long-term outcome of high dose rate brachytherapy in radiotherapy of localised prostate cancer.
      ,
      • Deger S.
      • Boehmer D.
      • Roigas J.
      • et al.
      High dose rate (HDR) brachytherapy with conformal radiation therapy for localized prostate cancer.
      ,
      • Hsu I.
      • Chow J.
      • Cabrera A.R.
      • et al.
      Combined modality treatment with high-dose-rate brachytherapy boost for locally advanced prostate cancer.
      ,
      • Demanes D.J.
      • Rodriguez R.R.
      • Schour L.
      • et al.
      High-dose-rate intensity-modulated brachytherapy with external beam radiotherapy for prostate cancer: California endocurietherapy's 10-year results.
      ,
      • Chin Y.
      • Bullard J.
      • Bryant L.
      • et al.
      High dose rate iridium-192 brachytherapy as a component of radical radiotherapy for the treatment of localised prostate cancer.
      ,
      • Yamada Y.
      • Bhatia S.
      • Zaider M.
      • et al.
      Favorable clinical outcomes of three-dimensional computer-optimized high-dose-rate prostate brachytherapy in the management of localized prostate cancer.
      ), our data show that this combination treatment regimen is associated with excellent tumor control rates for favorable- and intermediate-risk patients and acceptably low rates of late genitourinary (GU) and gastrointestinal (GI) treatment-related toxicities.

      Methods and materials

      Between 1998 and 2010, 229 patients with clinically localized, biopsy-proven adenocarcinoma of the prostate were treated with HDR brachytherapy followed 3 weeks later by EBRT at Memorial Sloan-Kettering Cancer Center. The clinical characteristics of patients in this study are summarized in Table 1. The patients were stratified into prognostic risk category groups based on the National Comprehensive Cancer Network classification system (www.nccn.com). This retrospective study was approved by the internal Institutional Review Board.
      Table 1Patient characteristics
      CharacteristicsN (%)
      Age (y)
       <65104 (45.4)
       ≥65125 (54.6)
      Gleason score
       645 (19.7)
       7137 (59.8)
       825 (10.9)
       920 (8.7)
       102 (0.9)
      Pretreatment PSA (ng/mL)
       <10177 (77.3)
       10–2043 (18.8)
       >209 (3.9)
      T-stage
       T1–T2a151 (65.9)
       T2b–T2c60 (26.2)
       T3a–T418 (7.9)
      Neoadjuvant ADT
       No131 (57.2)
       Yes98 (42.8)
      Baseline IPSS
       <8126 (72.8)
       ≥847 (27.2)
      NCCN risk group
       Low27 (11.8)
       Intermediate141 (61.6)
       High61 (26.6)
      PSA=prostate-specific antigen; ADT=androgen deprivation therapy; IPSS=International Prostate Symptom Score; NCCN=National Comprehensive Cancer Network.
      The HDR brachytherapy technique in use at our institution has been described previously (
      • Yamada Y.
      • Bhatia S.
      • Zaider M.
      • et al.
      Favorable clinical outcomes of three-dimensional computer-optimized high-dose-rate prostate brachytherapy in the management of localized prostate cancer.
      ). In brief, the catheter placement is carried out under general anesthesia using a transperineal approach with a template-based technique using real-time transrectal ultrasound guidance. The clinical target volume (CTV) is defined as the prostate gland and the base of seminal vesicles, and the planning target volume is defined as a 3-mm margin around the CTV. Treatment planning for earlier cases in the series was performed using a software package developed at Memorial Sloan-Kettering Cancer Center with the following constraints relative to the prescription dose: 100% target coverage, 100–120% maximum urethra dose, and rectal maximum dose ≤100% of prescribed dose. Treatment planning for the latter part of the series was done using Brachyvision (Varian Medical Systems, Inc., Palo Alto, CA) with similar dose constraints. All patients in this series were treated with 192Ir using GammaMed 12i or aGammaMed Plus remote afterloader (Varian). The first 45 patients were prescribed a peripheral dose of 550 cGy per fraction, the subsequent 40 patients received 600 cGy, the next 32 patients received 650 cGy, the next 108 patients received 700 cGy per fraction (the current dose in use at our institution), and 4 patients received 750 cGy per fraction. Each patient was treated with HDR brachytherapy delivered in three fractions at least 4 h apart. Patients were typically treated on the day of the implant and subsequent fractions were delivered on the following day with a minimum interfraction interval of 4 h to deliver the total dose within a 24-h time period.
      Approximately 3 weeks after the HDR procedure, EBRT was initiated using conformal techniques described previously (
      • Yamada Y.
      • Bhatia S.
      • Zaider M.
      • et al.
      Favorable clinical outcomes of three-dimensional computer-optimized high-dose-rate prostate brachytherapy in the management of localized prostate cancer.
      ). The CTV was defined for this phase of therapy as the prostate gland and seminal vesicles. The planning target volume was defined as a 1-cm margin around the CTV and a 3-mm margin at the prostate rectal interface. The first 11 patients received 4500 cGy in 25 fractions and 1 patient received 4860 cGy; all remaining patients (n=216) were prescribed 5040 cGy in 28 fractions. One patient was only able to undergo two fractions of brachytherapy (1400 cGy) as prescribed and underwent a course of EBRT to a total dose of 59.4 Gy. As of 2002, all patients were treated with intensity-modulated radiotherapy (IMRT) technique where a five- to seven-field treatment plan was used. EBRT was delivered to the prostate gland and seminal vesicles. The lymph nodes were not incorporated into the treatment fields.
      For patients who received neoadjuvant androgen deprivation therapy (ADT; n=98; 42%), treatment was usually initiated 3 months before the three-dimensional conformal radiotherapy/IMRT and discontinued at the completion of radiotherapy. The ADT was given to patients with large prostates to achieve pretreatment volume reduction or to high-risk patients, and adjuvant ADT even for high-risk patients was not routinely given. The median duration of ADT used in these patients was 9 months (range, 1–33 months).
      The median follow-up for the entire cohort of patients was 61.2 months (range, 3–150 months). Follow-up examinations consisted of an assessment of serum prostate-specific antigen (PSA), patient symptom assessment, and digital rectal examination. New or worsening acute and late GU and GI toxicities were scored according to the National Cancer Institute Common Terminology Criteria for Adverse Events toxicity scale, version 3. Acute toxicity was defined as symptoms experienced by patients during the course of therapy and up to 90 days from the completion of EBRT. The International Prostate Symptom Score (IPSS) was used to assess urinary functioning (urinary frequency, hesitancy, urgency, intermittence, weak urinary stream, and nocturia) both before and after the treatment.
      The patient's status was determined at the time of analysis in October 2011. The Phoenix definition of biochemical failure (absolute nadir plus 2 ng/mL with the corresponding date) was used for this analysis (
      • Thames H.
      • Kuban D.
      • Levy L.
      • et al.
      Comparison of alternative biochemical failure definitions based on clinical outcome in 4839 prostate cancer patients treated by external beam radiotherapy between 1986 and 1995.
      ). Actuarial likelihood of complication probabilities and disease-specific survival were calculated according to the product-limit estimate (Kaplan–Meier) method. The threshold of statistical significance for differences was set at 0.05.

      Results

      Tumor control and clinical outcomes

      The 7-year PSA relapse-free survival rates were 95% (95% confidence interval [CI], 86.5–100.0%), 90% (95% CI, 84.4–96.9%), and 57% (95% CI, 38.2–80.8%) for low-, intermediate-, and high-risk patients, respectively (Fig. 1). The median follow-up for each risk group was 69 months (range, 11–137 months), 64 months (range, 3–150 months), and 47 months (range, 5–140 months) for low-, intermediate-, and high-risk patients, respectively. In 206 patients who were free of biochemical relapse, 142 patients (69%) were noted to have PSA levels lower than 0.2 ng/mL at the time of last follow-up, and the PSA was undetectable (<0.05 ng/mL) at last follow-up in 85 (36%) of these patients.
      Figure thumbnail gr1
      Fig. 1PSA relapse-free survival. PSA=prostate-specific antigen.
      The 7-year DMs-free survival for low-, intermediate-, and high-risk patients were 95%, 98%, and 83%, respectively. In the high-risk group among the 12 patients who developed a biochemical failure, 7 patients developed evidence of DMs at a median of 38 months after the treatment. At the time of last follow-up, 212 patients (93%) were alive. The incidence of prostate-specific mortality at 7 years for low-, intermediate-, and high-risk patients were 0%, 1.1% (95% CI, 0–3.1%), and 5.4% (95% CI, 0–16.1%), respectively.
      The dose for the HDR boost ranged from 5.5 Gy×3 to 7.5 Gy×3 and were converted to biological equivalent doses (BEDs) as described in prior reports (
      • Stock R.G.
      • Stone N.N.
      • Cesaretti J.A.
      • et al.
      Biologically effective dose values for prostate brachytherapy on PSA failure and posttreatment biopsy results.
      ,
      • Kollmeier M.A.
      • Pei X.
      • Algur E.
      • et al.
      A comparison of the impact of isotope (I-125 vs Pd-103) on toxicity and biochemical outcome following interstitial brachytherapy and external beam radiation therapy for clinically localized prostate cancer.
      ), and these BED levels ranged from 171 to 226 Gy with a median BED of 191.5 Gy. Although overall we did not appreciate any influence of BED on outcomes across all the patients, among high-risk patients there was apparent improved biochemical control and DMs-free survival outcomes among patients with BED values >190 Gy. Among patients with higher BED values (n=56), the incidence of PSA relapse and DMs at 7 years were 19% and 11% vs. 40% and 40%, respectively, among patients with lower BED values (n=5; p=0.03 for PSA outcomes and p=0.02 for DM outcomes).

      GU toxicity

      The frequency of GU toxicity is summarized in Table 2. Thirty-five patients (15%) reported acute Grade 2 urinary toxicity (moderate urgency, frequency, dysuria, nocturia, or gross hematuria). Of these patients, 72% experienced symptom resolution at a median time of 7.3 months after therapy. Nine patients (4%) reported an acute urinary toxicity of Grade 3, manifesting as urinary retention, which resolved shortly with urinary catheterization. Seventy-five patients (33%) reported no acute urinary problems. The 7-year incidence of Grade 2 and 3 late urinary toxicities were 22% and 4.9%, respectively. None of the patients experienced acute or late grade 4 urinary toxicity.
      Table 2Incidence and resolution of acute and late genitourinary toxicity
      Genitourinary
      GradeAcute, n (%)% ResolvedMedian time to resolution (mo)Late, n (%)% ResolvedMedian time to resolution (mo)
      075 (32.8)109 (47.6)
      1110 (48.0)79 (71.8)7.383 (36.2)40 (48.2)12.2
      235 (15.3)19 (54)6.630 (13.1)10 (33.3)10.7
      39 (3.9)6 (66.7)2.37 (3.1)3 (42.9)19.3
      40 (0)0 (0)
      Pre- and posttreatment IPSS data were analyzed to evaluate GU toxicity levels in these patients in more detail. Pretreatment IPSS data was recorded for 173 patients and posttreatment IPSS data was recorded for 212 patients. The median pretreatment IPSS was 5 (range, 0–27) with 126 patients (73%) reporting mild symptoms (IPSS, 0–7), 42 patients (24%) with moderate symptoms (IPSS, 8–19), and 5 patients (3%) with severe urinary symptoms (IPSS, 20–35). For those patients with IPSS recorded at the last follow-up, the median posttreatment IPSS was 5–6 (range, 0–34) with 131 patients (62%) reporting mild symptoms, 65 patients (31%) with moderate symptoms, and 16 patients (7.5%) with severe urinary symptoms. A multivariate analysis, including age, the use of ADT, acute rectal toxicity, NCCN risk group, and baseline IPSS, did not reveal any variables predicting for increased risk of ≥Grade 2 late GU toxicity (see Table 3). Because urethral dose constraints were maintained in a tight range of 115–120% of the prescription dose, there was not a broad range of doses to analyze the influence of the urethral dose on toxicity in this cohort of patients.
      Table 3Multivariate predictors of the incidence of late Grade 2 genitourinary toxicity
      Predictorsp-ValueHR
      Age (<65 vs. ≥65)0.0852.28
      ADT (no vs. yes)0.092.09
      IPSS (<8 vs. ≥8)0.731.16
      HR=hazard ratio; ADT=androgen deprivation therapy; IPSS=International Prostate Symptoms Score.
      Age in univariate analysis is significant, p=0.049.

      GI toxicity

      As shown in Table 4, 69 patients (30%) experienced acute Grade 1 GI toxicity, mostly in the form of diarrhea and pelvic discomfort. These side effects resolved in 87% of patients at a median of 4 months after treatment. Only 2 patients (0.9%) reported a rectal toxicity of grade 2 (moderate diarrhea in both cases), which resolved in 1 patient and improved significantly in the second patient, shortly after treatment. No patients reported acute GI Grade 3 or 4 GI toxicity.
      Table 4Incidence and resolution of acute and late gastrointestinal toxicity
      Gastrointestinal toxicity
      GradeAcute, n (%)Resolved, n (%)Median time to resolution (mo)Late, n (%)Resolved, n (%)Median time to resolution (mo)
      0158 (69.0)165 (72.1)
      169 (30.1)60 (87.0)4.062 (27.1)36 (58.1)9.1
      22 (0.9)1 (50)10.41 (0.4)0 (0)
      30 (0)1 (0.4)1 (100)5.8
      40 (0)0 (0)
      The 7-year incidence of Grade 2 and 3 late rectal toxicities were 1% and 0.4%, respectively. One patient (0.4%) reported Grade 3 GI toxicity (daily rectal bleeding requiring transfusion, which resolved after cauterization). Approximately 1 year after completing radiation therapy, 1 patient was found to have a midsigmoid stricture with fibrosis and angulation of the sigmoid distally on regular screening colonoscopy. The patient did not complain of abdominal pain and had regular bowel movements. The area of the stricture was laparoscopically resected and final pathology was consistent with diverticulitis and abscess formation. The location of the stricture was inside the treatment field of the EBRT, but outside of the high dose region of the brachytherapy treatment volume.

      Discussion

      In the management of patients with intermediate- and high-risk prostate adenocarcinoma, dose-escalation studies have demonstrated an improvement in tumor control, disease-free survival, and freedom from DMs (
      • Pollack A.
      • Zagars G.K.
      • Starkschall G.
      • et al.
      Prostate cancer radiation dose response: Results of the M. D. Anderson phase III randomized trial.
      ,
      • Zietman A.L.
      • Bae K.
      • Slater J.D.
      • et al.
      Randomized trial comparing conventional-dose with high-dose conformal radiation therapy in early-stage adenocarcinoma of the prostate: Long-term results from Proton Radiation Oncology Group/American College of Radiology 95-09.
      ,
      • Peeters S.T.
      • Heemsbergen W.D.
      • Koper P.C.
      • et al.
      Dose-response in radiotherapy for localized prostate cancer: Results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy.
      ,
      • Dearnaley D.P.
      • Sydes M.R.
      • Graham J.D.
      • et al.
      Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: First results from the MRC RT01 randomised controlled trial.
      ,
      • Kuban D.A.
      • Levy L.B.
      • Cheung M.R.
      • et al.
      Long-term failure patterns and survival in a randomized dose-escalation trial for prostate cancer. Who dies of disease?.
      ,
      • Zelefsky M.J.
      • Pei X.
      • Chou J.F.
      • et al.
      Dose escalation for prostate cancer radiotherapy: Predictors of long-term biochemical tumor control and distant metastases-free survival outcomes.
      ). Yet, the benefits of dose escalation must be weighed against the risks of toxicity to the surrounding normal tissue structures. For patients with disease localized to the prostate, HDR brachytherapy has been shown to be a favorable method of increasing the intraprostatic dose while minimizing the dose to peripheral sensitive structures. Our results indicate that a treatment regimen combining EBRT with a HDR brachytherapy boost is associated with a low likelihood of developing Grade 3 or higher GU or GI toxicities.
      An interesting finding in our report was the observation of improved outcomes in the high-risk patient cohort when higher BED doses were delivered with the HDR. Among patients with BED doses >190 Gy (α/β ratio of 2), the 7-year PSA relapse-free survival outcome for high-risk patients was 81% compared with 60% for patients who received lower dose levels (p=0.02). In addition, dose escalation for this high-risk cohort was also associated with a reduction in improvement in the 7-year DMs-free survival outcomes from 60% to 89% for those who received lower and higher BED dose levels. These improved biochemical control outcomes for high-risk patients using higher doses appear to be consistent with what has been reported in the literature (See Table 5). Martinez et al. (
      • Martinez A.A.
      • Gonzalez J.
      • Ye H.
      • et al.
      Dose escalation improves cancer-related events at 10 years for intermediate- and high-risk prostate cancer patients treated with hypofractionated high-dose-rate boost and external beam radiotherapy.
      ) had reported the outcomes of a cohort of 472 patients with intermediate- and high-risk disease treated with HDR brachytherapy and supplemental EBRT who were followed for a median of 8 years. The authors noted improved biochemical control and DMs-free survival outcomes with higher BED values. In that report, an α/β ratio of 1.2 was assumed and a 10-year PSA relapse rate of 19% and DMs incidence of 6% with BED values >268 was reported. In our cohort of high-risk patients, it is also possible that longer courses of ADT and the use of elective nodal irradiation for this cohort could have further improved the tumor control outcomes. We recognize that in these patients a significant component of failure was DM. Patients developed metastases as confirmed by radionuclide bone scan and/or positron emission tomography imaging at a median of 38 months after treatment.
      Table 5PSA relapse-free survival outcomes for high-risk patients treated with HDR brachytherapy and EBRT
      Series authorYearNStudy median follow-up (y)EBRT regimen (Gy/fx)HDR brachytherapy dose (Gy/fx)5-Y PSA-PFS (ASTRO, %)5-Y PSA-PFS (Phoenix, %)
      Eulau et al.
      • Eulau S.
      • Van Hollebeke L.
      • Cavanagh W.
      • et al.
      High dose rate 192-Iridium brachytherapy in localized prostate cancer: Results and toxicity with maximum follow-up of 10 years.
      2000226.150.40/2812–16/449
      Galalae et al.
      • Galalae R.M.
      • Martinez A.
      • Mate T.
      • et al.
      Long-term outcome by risk factors using conformal high-dose-rate brachytherapy (HDR-BT) boost with or without neoadjuvant androgen suppression for localized prostate cancer.
      20043595.345.6–50/2516–23/2–469
      Deger et al.
      • Deger S.
      • Boehmer D.
      • Roigas J.
      • et al.
      High dose rate (HDR) brachytherapy with conformal radiation therapy for localized prostate cancer.
      2005295540–50.4/20–2818 or 20/259
      Demanes et al.
      • Demanes D.J.
      • Rodriguez R.R.
      • Schour L.
      • et al.
      High-dose-rate intensity-modulated brachytherapy with external beam radiotherapy for prostate cancer: California endocurietherapy's 10-year results.
      2005477.2536/2022–24/47483
      Pellizzon et al.
      • Pellizzon A.C.
      • Salvajoli J.
      • Novaes P.
      • et al.
      Updated results of high-dose rate brachytherapy and external beam radiotherapy for locally and locally advanced prostate cancer using the RTOG-ASTRO phoenix definition.
      2008675.336–54/20–3016–24/468.5
      Viani et al.
      • Viani G.A.
      • Pellizzon A.C.
      • Guimarães F.S.
      • et al.
      High dose rate and external beam radiotherapy in locally advanced prostate cancer.
      200966545–50.4/25–2820–24/471
      Ágoston et al.
      • Ágoston P.
      • Major T.
      • Fröhlich G.
      • et al.
      Moderate dose escalation with single-fraction high-dose rate brachytherapy boost for clinically localized intermediate- and high-risk prostate cancer: 5-Year outcome of the first 100 consecutively treated patients.
      2011615.160/308 or 10/180.686.4
      Prada et al.
      • Prada P.J.
      • Mendez L.
      • Fernández J.
      • et al.
      Long-term biochemical results after high-dose-rate intensity modulated brachytherapy with external beam radiotherapy for high risk prostate cancer.
      20122526.146/2321–23/284
      Present Study57
      Cohort of patients with BED >190Gy.
      5.150.4/2818–21/381
      PSA=prostate-specific antigen; ASTRO=American Society for Therapeutic Radiation and Oncology; HDR=high-dose rate; EBRT=external beam radiation therapy; PFS=progression-free survival; BED=biological equivalent dose.
      a Cohort of patients with BED >190 Gy.
      There are a several studies in addition to randomized controlled trials, which have reported outcomes and toxicity data for patients receiving HDR brachytherapy in addition to EBRT. A randomized phase III trial has demonstrated that HDR brachytherapy dose escalation resulted in a statistically significant reduction in the incidence of acute rectal toxicity and rectal discharge, which were considered surrogate markers for proctitis. Additionally, in patients with at least 2-year follow-up data available, there was no increase in late toxicities in patients receiving the HDR brachytherapy boost compared with the patients who received EBRT alone (
      • Hoskin P.J.
      • Motohashi K.
      • Bownes P.
      • et al.
      High dose rate brachytherapy in combination with external beam radiotherapy in the radical treatment of prostate cancer: Initial results of a randomised phase three trial.
      ). Another randomized trial with a median follow-up of 8.2 years demonstrated that the addition of a HDR brachytherapy boost was superior to EBRT alone for patients with locally advanced-staged prostate cancer. In that report, 29% of the patients in the HDR combined modality arm developed a biochemical failure compared with 61% in the EBRT arm (p=0.024). In addition, the incidence of a positive posttreatment biopsy (2 years after treatment) in the HDR arm was significantly lower compared with the EBRT arm (24% vs. 51%; p=0.015) (
      • 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.
      ). In a retrospective comparison from our institution, we also demonstrated that HDR brachytherapy combined with EBRT, especially for intermediate-risk patients, was associated with superior biochemical control outcomes compared with outcomes in a cohort of patients treated with high-dose IMRT (
      • Deutsch I.
      • Zelefsky M.J.
      • Zhang Z.
      • et al.
      Comparison of PSA relapse-free survival in patients treated with ultra-high-dose IMRT versus combination HDR brachytherapy and IMRT.
      ). An additional advantage of combined brachytherapy and EBRT dose escalation regimens for intermediate- and high-risk patients may be the opportunity, in selected cases, to avoid ADT, which has not been shown to be associated with improved outcomes (
      • Martinez A.A.
      • Demanes D.J.
      • Galalae R.
      • et al.
      Lack of benefit from a short course of androgen deprivation for unfavorable prostate cancer patients treated with an accelerated hypofractionated regime.
      ,
      • Demanes D.J.
      • Brandt D.
      • Schour L.
      • Hill D.R.
      Excellent results from high dose rate brachytherapy and external beam for prostate cancer are not improved by androgen deprivation.
      ).
      We recognize the limitations of this study owing to it being a retrospective analysis, which reported on relatively small number of patients. It is also difficult to make any definitive conclusions regarding the BED dose advantage we observed in this study given the small number of patients comprising lower BED dose levels. Nevertheless, excellent biochemical control rates for patients with favorable- and intermediate-risk patients were achieved with this modality. An additional limitation of this study is that patients with high-risk disease were generally treated with short courses (≤6–8 months) of ADT and it is possible that the use of longer courses of ADT could have further improved outcomes for this cohort.

      Conclusion

      HDR brachytherapy in combination with EBRT provides a high dose of irradiation to the prostate and is associated with excellent tumor-control rates. Higher BED doses were particularly important for improved local tumor control and reduced incidence of DMs for high-risk patients. We did not observe improved outcomes for patients treated with short-course ADT in conjunction with this combined-modality regimen, yet further studies will be required to determine if longer courses of adjuvant ADT would further improve outcomes in particular for high-risk prostate cancer patients.

      References

        • Pollack A.
        • Zagars G.K.
        • Starkschall G.
        • et al.
        Prostate cancer radiation dose response: Results of the M. D. Anderson phase III randomized trial.
        Int J Radiat Oncol Biol Phys. 2002; 53: 1097-1105
        • Zietman A.L.
        • Bae K.
        • Slater J.D.
        • et al.
        Randomized trial comparing conventional-dose with high-dose conformal radiation therapy in early-stage adenocarcinoma of the prostate: Long-term results from Proton Radiation Oncology Group/American College of Radiology 95-09.
        J Clin Oncol. 2010; 28: 1106-1111
        • Peeters S.T.
        • Heemsbergen W.D.
        • Koper P.C.
        • et al.
        Dose-response in radiotherapy for localized prostate cancer: Results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy.
        J Clin Oncol. 2006; 24: 1990-1996
        • Dearnaley D.P.
        • Sydes M.R.
        • Graham J.D.
        • et al.
        Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: First results from the MRC RT01 randomised controlled trial.
        Lancet Oncol. 2007; 8: 475-487
        • Kuban D.A.
        • Levy L.B.
        • Cheung M.R.
        • et al.
        Long-term failure patterns and survival in a randomized dose-escalation trial for prostate cancer. Who dies of disease?.
        Int J Radiat Oncol Biol Phys. 2011; 79: 1310-1317
        • Deutsch I.
        • Zelefsky M.J.
        • Zhang Z.
        • et al.
        Comparison of PSA relapse-free survival in patients treated with ultra-high-dose IMRT versus combination HDR brachytherapy and IMRT.
        Brachytherapy. 2010; 9: 313-318
        • Mate T.P.
        • Gottesman J.E.
        • Hatton J.
        • et al.
        High dose-rate afterloading 192-Iridium prostate brachytherapy: Feasibility report.
        Int J Radiat Oncol Biol Phys. 1998; 41: 525-533
        • Eulau S.
        • Van Hollebeke L.
        • Cavanagh W.
        • et al.
        High dose rate 192-Iridium brachytherapy in localized prostate cancer: Results and toxicity with maximum follow-up of 10 years.
        Int J Radiat Oncol Biol Phys. 2000; 48 (Abstract): 149
        • Galalae R.M.
        • Kovács G.
        • Schultze J.
        • et al.
        Long-term outcome after elective irradiation of the pelvic lymphatics and local dose escalation using high-dose-rate brachytherapy for locally advanced prostate cancer.
        Int J Radiat Oncol Biol Phys. 2002; 52: 81-90
        • Astrom L.
        • Pedersen D.
        • Mercke C.
        • et al.
        Long-term outcome of high dose rate brachytherapy in radiotherapy of localised prostate cancer.
        Radiother Oncol. 2005; 74: 157-161
        • Deger S.
        • Boehmer D.
        • Roigas J.
        • et al.
        High dose rate (HDR) brachytherapy with conformal radiation therapy for localized prostate cancer.
        Eur Urol. 2005; 47: 441-448
        • Hsu I.
        • Chow J.
        • Cabrera A.R.
        • et al.
        Combined modality treatment with high-dose-rate brachytherapy boost for locally advanced prostate cancer.
        Brachytherapy. 2005; 4: 202-206
        • Demanes D.J.
        • Rodriguez R.R.
        • Schour L.
        • et al.
        High-dose-rate intensity-modulated brachytherapy with external beam radiotherapy for prostate cancer: California endocurietherapy's 10-year results.
        Int J Radiat Oncol Biol Phys. 2005; 61: 1306-1316
        • Chin Y.
        • Bullard J.
        • Bryant L.
        • et al.
        High dose rate iridium-192 brachytherapy as a component of radical radiotherapy for the treatment of localised prostate cancer.
        Clin Oncol. 2006; 18: 474-479
        • Yamada Y.
        • Bhatia S.
        • Zaider M.
        • et al.
        Favorable clinical outcomes of three-dimensional computer-optimized high-dose-rate prostate brachytherapy in the management of localized prostate cancer.
        Brachytherapy. 2006; 5: 157-164
        • Thames H.
        • Kuban D.
        • Levy L.
        • et al.
        Comparison of alternative biochemical failure definitions based on clinical outcome in 4839 prostate cancer patients treated by external beam radiotherapy between 1986 and 1995.
        Int J Radiat Oncol Biol Phys. 2003; 57: 929-943
        • Stock R.G.
        • Stone N.N.
        • Cesaretti J.A.
        • et al.
        Biologically effective dose values for prostate brachytherapy on PSA failure and posttreatment biopsy results.
        Int J Radiat Oncol Biol Phys. 2006; 64: 527-533
        • Kollmeier M.A.
        • Pei X.
        • Algur E.
        • et al.
        A comparison of the impact of isotope (I-125 vs Pd-103) on toxicity and biochemical outcome following interstitial brachytherapy and external beam radiation therapy for clinically localized prostate cancer.
        Brachytherapy. 2012; 11: 271-276
        • Zelefsky M.J.
        • Pei X.
        • Chou J.F.
        • et al.
        Dose escalation for prostate cancer radiotherapy: Predictors of long-term biochemical tumor control and distant metastases-free survival outcomes.
        Eur Urol. 2011; 60: 1133-1139
        • Martinez A.A.
        • Gonzalez J.
        • Ye H.
        • et al.
        Dose escalation improves cancer-related events at 10 years for intermediate- and high-risk prostate cancer patients treated with hypofractionated high-dose-rate boost and external beam radiotherapy.
        Int J Radiat Oncol Biol Phys. 2011; 79: 363-370
        • Hoskin P.J.
        • Motohashi K.
        • Bownes P.
        • et al.
        High dose rate brachytherapy in combination with external beam radiotherapy in the radical treatment of prostate cancer: Initial results of a randomised phase three trial.
        Radiother Oncol. 2007; 84: 114-120
        • 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
        • Martinez A.A.
        • Demanes D.J.
        • Galalae R.
        • et al.
        Lack of benefit from a short course of androgen deprivation for unfavorable prostate cancer patients treated with an accelerated hypofractionated regime.
        Int J Radiat Oncol Biol Phys. 2005; 62: 1322-1331
        • Demanes D.J.
        • Brandt D.
        • Schour L.
        • Hill D.R.
        Excellent results from high dose rate brachytherapy and external beam for prostate cancer are not improved by androgen deprivation.
        Am J Clin Oncol. 2009; 32: 342-347
        • Galalae R.M.
        • Martinez A.
        • Mate T.
        • et al.
        Long-term outcome by risk factors using conformal high-dose-rate brachytherapy (HDR-BT) boost with or without neoadjuvant androgen suppression for localized prostate cancer.
        Int J Radiat Oncol Biol Phys. 2004; 58: 1048-1055
        • Pellizzon A.C.
        • Salvajoli J.
        • Novaes P.
        • et al.
        Updated results of high-dose rate brachytherapy and external beam radiotherapy for locally and locally advanced prostate cancer using the RTOG-ASTRO phoenix definition.
        Int Braz J Urol. 2008; 34: 293-301
        • Viani G.A.
        • Pellizzon A.C.
        • Guimarães F.S.
        • et al.
        High dose rate and external beam radiotherapy in locally advanced prostate cancer.
        Am J Clin Oncol. 2009; 32: 187
        • Ágoston P.
        • Major T.
        • Fröhlich G.
        • et al.
        Moderate dose escalation with single-fraction high-dose rate brachytherapy boost for clinically localized intermediate- and high-risk prostate cancer: 5-Year outcome of the first 100 consecutively treated patients.
        Brachytherapy. 2011; 10: 376-384
        • Prada P.J.
        • Mendez L.
        • Fernández J.
        • et al.
        Long-term biochemical results after high-dose-rate intensity modulated brachytherapy with external beam radiotherapy for high risk prostate cancer.
        Risk. 2012; 70: 35