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Prostate high dose-rate brachytherapy as monotherapy for low and intermediate risk prostate cancer: Early toxicity and quality-of life results from a randomized phase II clinical trial of one fraction of 19Gy or two fractions of 13.5Gy

Published:November 04, 2016DOI:https://doi.org/10.1016/j.radonc.2016.10.019

      Abstract

      Background and purpose

      Multi-fraction high dose-rate (HDR) brachytherapy as monotherapy is safe and effective for low and intermediate risk prostate cancer. Two or single fraction regimens have some radiobiological rationale. The purpose is to determine toxicity and effect on health related quality of life (HRQOL) of single fraction 19 Gy or 13.5 Gy × 2.

      Materials and methods

      Eligible patients had low or intermediate risk prostate cancer, prostate volume <60 cc, and no androgen deprivation use. 170 patients were randomized to receive either a single 19 Gy or two fractions of 13.5 Gy 1 week apart. HRQOL was measured using the Expanded Prostate Index Composite (EPIC), toxicity with Common Terminology for Adverse Events (CTCAE) v4.0 and urinary symptoms with the International Prostate Symptom Score (IPSS).

      Results

      Median follow-up is 20 months. Grade 2 urinary toxicity occurred in 51% within the first 3 months and in 31% thereafter with no significant difference between treatment arms. Ten patients (6%) developed urinary retention in the acute phase, although only 4 (2.4%) required a catheter for more than 48 h. One Grade 3 acute (⩽3 months) and late (>3 months) urinary toxicity occurred. No more than 1% had any Grade 2 GI toxicity. The 2-fraction arm had a higher occurrence of grade 2 erectile dysfunction (29% vs. 11.5%, p = 0.0249) and higher IPSS scores for the first year. Mean EPIC urinary scores at 12 months decreased by 4.0 and 4.6, and sexual scores decreased by 8 and 15.9 (p = 0.035) in the single and 2-fraction arms, respectively. No change occurred in the bowel or hormonal domains.

      Conclusions

      Single 19 Gy and 13.5 Gy × 2 are both well tolerated. During the first 12 months, urinary symptoms and erectile dysfunction are more common in the 2-fraction arm.

      Keywords

      Brachytherapy using permanently implanted radioactive seeds as monotherapy is a well tolerated and effective treatment for men with low and intermediate-risk prostate cancer. High dose-rate brachytherapy (HDR) is most commonly combined with external beam radiotherapy as a boost to treat men with intermediate and high-risk disease, with excellent long term clinical results [
      • Morton G.C.
      High-dose-rate brachytherapy boost for prostate cancer: rationale and technique.
      ]. Prostate HDR has some potential advantages over permanent seed brachytherapy: because HDR is planned after catheter insertion, it avoids dose uncertainty due to seed movement or misplacement, and HDR may have radiobiological advantages in cancers with low alpha/beta ratios.
      Several institutional series report high cancer control rates for patients with low and intermediate risk disease following HDR monotherapy delivered in 4 or 6 fractions [
      • Demanes D.J.
      • Ghilezan M.I.
      High-dose-rate brachytherapy as monotherapy for prostate cancer.
      ]. Similar control rates are also reported from authors using 3 or 2 fraction regimens with a higher dose per fraction, although with shorter median length of follow-up. The 2016 NCCN Guidelines include a treatment protocol of 13.5 Gy × 2 fractions as a commonly used regimen for HDR monotherapy [
      • Mohler J.L.
      • Armstrong A.J.
      • Bahnson R.R.
      • et al.
      Prostate Cancer, Version 1.2016.
      ]. Based on radiobiological calculation with an alpha/beta ratio for prostate cancer of 1.5, 19 Gy as a single fraction would deliver a similar biologically equivalent dose to 13.5 Gy × 2, 11.5 Gy × 3 or 9.5 Gy × 4.
      Short-term clinical outcomes have been reported from several single-institution series using 19 Gy as a single fraction [
      • Prada P.J.
      • Jimenez I.
      • Gonzalez-Suarez H.
      • Fernandez J.
      • Cuervo-Arango C.
      • Mendez L.
      High-dose-rate interstitial brachytherapy as monotherapy in one fraction and transperineal hyaluronic acid injection into the perirectal fat for the treatment of favorable stage prostate cancer: treatment description and preliminary results.
      ,
      • Hoskin P.
      • Rojas A.
      • Ostler P.
      • et al.
      High-dose-rate brachytherapy alone given as two or one fraction to patients for locally advanced prostate cancer: acute toxicity.
      ,
      • Krauss D.J.
      • Martinez A.A.
      • Ye H.
      • et al.
      Highly favorable preliminary clinical and toxicity outcomes for low-and intermediate-risk prostate cancer patients treated with high-dose-rate brachytherapy in a single fraction of 19 Gy.
      ]. If effective and safe, single fraction HDR could present great advantages in terms of resource utilization, cost and patient convenience compared with more fractionated regimens.
      Given the potential advantages of single fraction HDR, we conducted a phase II randomized control trial of HDR delivered as either 13.5 Gy × 2 or as a single fraction of 19 Gy. Our hypothesis was that either treatment arm would be well tolerated and effective. Our primary objective was to determine the effect of both treatments on health-related quality of life at 12 months. Secondary objectives were to determine acute toxicity, late toxicity and biochemical and clinical disease control rates following these treatment protocols to help inform a subsequent larger phase III randomized trial.

      Materials and methods

      The clinical trial was registered on ClinicalTrials.gov (NCT01890096) and approved by the Sunnybrook Health Sciences Research Ethics Board. Eligible patients had histologically confirmed adenocarcinoma of the prostate, clinical stage T1c or T2a, with a Gleason Score of 6 or 7, and a serum prostate specific antigen (PSA) level of less than 20 ng/ml. Prostate volume had to be less than 60 cc as determined by ultrasound, CT or MRI prior to enrolment. Subjects had to give informed consent to participate and be able and willing to complete the Quality of Life Questionnaires. Exclusion criteria were: evidence of distant or nodal metastases, previous pelvic radiotherapy, previous trans-urethral resection of prostate, use of androgen deprivation therapy, an International Prostate Symptom Score (IPSS) of >18, connective tissue or inflammatory bowel disease, and significant medical co-morbidity rendering the patient unsuitable for general anaesthesia. Subjects were randomized to one of the two treatment arms using block randomization. Baseline evaluation included a physical examination, assessment of baseline toxicity using Common Terminology Criteria for Adverse Events (CTCAE) v4.0 and completion of the IPSS and Expanded Prostate Index Composite (EPIC) [
      • Wei J.T.
      • Dunn R.L.
      • Litwin M.S.
      • Sandler H.M.
      • Sanda M.G.
      Development and validation of the expanded prostate cancer index composite (EPIC) for comprehensive assessment of health-related quality of life in men with prostate cancer.
      ] questionnaires.
      Treatment consisted of HDR delivered as either 19 Gy as a single fraction, or two fractions of 13.5 Gy delivered 1 week apart (allowable range 5–10 days). Treatment was delivered as an outpatient using intra-operative trans-rectal ultrasound (TRUS)-based planning [
      • Morton G.C.
      Prostate high-dose-rate brachytherapy: transrectal ultrasound based planning, a technical note.
      ]. Following general anaesthetic, the patient was positioned in the dorsal lithotomy position. A 12-French urinary catheter was inserted to delineate the urethra. Flexible ProGuide needles (Elekta, Sweden) 24 cm in length were inserted as far as the base of the prostate using TRUS guidance. The rigid introducing stylets were removed and TRUS images were acquired and exported to Oncentra Prostate v 4.1.6 (SP1) (Elekta, Sweden). The prostate, outer surface of the urinary catheter and anterior rectal wall along the length of the prostate were contoured. The Clinical Target Volume was defined as the prostate with a 0–2 mm expansion based on disease parameters, so patients with palpable or visible disease generally had a CTV expansion around the nodule. No further margin was added for the Planning Target Volume (PTV). The prescription dose (13.5 Gy or 19 Gy) was prescribed to the PTV with the following planning objectives: PTV V100 > 95%, PTV V150 < 35%, PTV V200 < 12%; urethra maximum dose < 120% and urethra D10 < 115%; rectal maximal dose 90% and V80 < 0.2 cc (where Vx is the volume of that structure receiving x% of the prescribed dose and Dx is the dose to x% of the structure). Dwell time optimization was performed using inverse dose–volume histogram-based optimization (DVHO). Treatment was then delivered with the patient still under general anaesthesia in lithotomy position with the ultrasound probe in place. Following treatment, catheters were removed, the patient was awoken and discharged home once recovered from the anaesthetic – typically within 2 h. Subjects randomized to the 2-fraction arm returned a week later for the second fraction.
      Follow-up occurred at 6 weeks and 3 months, then 3-monthly for the first year, 6-monthly from year 1 to 3, and annually thereafter. Serum PSA, toxicity and IPSS were evaluated at every visit. EPIC questionnaires were completed by the patient at 6 months, 12 months and annually thereafter.

      Statistical considerations and sample size

      Simple descriptive statistics are used to describe baseline clinical, demographic and treatment planning parameters in each arm, and comparisons made using Wilcoxon’s rank-sum or Fisher’s exact test as appropriate. A two-sided p-value of <0.05 was considered significant. General linear regression analysis was used to investigate changes in EPIC and IPSS over time, with Bonferroni’s adjustment to account for multiple comparisons with a p-value of <0.025 considered significant. Acute toxicity was defined as toxicity occurring within the first 3 months of treatment.
      From our previous studies [
      • Morton G.C.
      • Loblaw D.A.
      • Chung H.
      • et al.
      Health-related quality of life after single-fraction high-dose-rate brachytherapy and hypofractionated external beam radiotherapy for prostate cancer.
      ] a rate for a >0.5 SD change in EPIC urinary domain score of up to 43% of patients was considered acceptable, with a rate ⩾63% specified as unacceptable. Similarly, a rate for a >0.5 SD change in EPIC bowel domain score of up to 41% was considered acceptable, with a rate ⩾61% unacceptable. Our hypothesis was that either treatment arm would be acceptable, and a sample size of 156 eligible patients (78 per arm) was required with 95% power and significance level 0.05 (two-sided test). Adjusting for 10% ineligibility, the required sample size was 174 patients (87 per arm).

      Results

      A total of 180 patients were accrued to the clinical trial between June 2013 and April 2015. Ten of these patients were withdrawn before treatment and were excluded from the analysis – 4 became ineligible on further staging and pathology review, 3 were deemed unsuitable due to pubic arch interference, 2 withdrew consent and chose alternative treatments and 1 was unable to have treatment due to an unrelated emergent medical event. Of the remaining 170, 87 were randomized to receive 19 Gy × 1 and 83 to receive 13.5 Gy × 2. Median follow-up is 20 months (range 6–37 months). Median age was 65 years (range 46–80 years) and median PSA was 6.33 ng/ml (range 1.12–16.01 ng/ml). Overall, 28% had Gleason 6, 60% Gleason 3 + 4 and 12% Gleason 4 + 3. No significant differences were found in baseline clinical parameters between subjects in either treatment arm (Table 1). A median of 16 catheters was used (range 12–18). Relative dosimetry was similar in both arms with a median V100 of 97%, median V200 of 11%, median D90 of 110% and median urethra maximal dose of 120% (Supplementary File 1). Within the two-fraction arm, prostate volume was on average 12% larger at the time of second implant.
      Table 1Baseline clinical factors in patients randomized to single 19 Gy or 13.5 Gy × 2.
      19 Gy × 1

      (n = 87)
      13.5 Gy × 2

      (n = 83)
      p-value
      Two-sided p-value was obtained by Wilcoxon’s rank-sum nonparametric test for continuous variables, or by Fisher’s exact test for categorical variables. p<0.05 was considered as statistical significance.
      Age (years)0.7364
       Mean ± SD64.5 ± 6.865.1 ± 6.8
       Median (Q1, Q3)65 (59, 70)65 (60, 70)
       Range46, 8049, 80
      Clinical stage0.8648
       T1c67 (77.0%)63 (75.9%)
       T2a20 (23.0%)20 (24.1%)
      PSA at baseline (ng/ml)0.9366
       Mean ± SD6.73 ± 2.876.86 ± 3.14
       Median (Q1, Q3)6.43 (4.71, 8.90)6.27 (4.64, 8.68)
      Gleason score categories0.0694
       3 + 328 (32.2%)19 (22.9%)
       3 + 445 (51.7%)57 (68.7%)
       4 + 314 (16.1%)7 (8.4%)
      NCCN Risk Group0.5295
       Intermediate risk64 (73.6%)67 (80.7%)
       Low risk23 (26.4%)16 (19.3%)
      Perineural invasion0.7276
       No65 (75.6%)60 (73.2%)
       Yes21 (24.4%)22 (26.8%)
      History of diabetes0.8274
       No74 (85.1%)72 (86.8%)
       Yes13 (14.9%)11 (13.2%)
      History of hypertension0.8779
       No47 (54.0%)43 (51.8%)
       Yes40 (46.0%)40 (48.2%)
      Receiving 5 alpha-reductase inhibitors0.6122
       No77 (88.5%)76 (91.6%)
       Yes10 (11.5%)7 (8.4%)
      Prostate volume at baseline (cc)0.8625
       Mean ± SD34.6 ± 10.035.7 ± 10.5
       Median (Q1, Q3)35 (27, 41)35 (27, 40)
       Range13, 5618, 62
      low asterisk Two-sided p-value was obtained by Wilcoxon’s rank-sum nonparametric test for continuous variables, or by Fisher’s exact test for categorical variables. p < 0.05 was considered as statistical significance.

      Acute toxicity

      Follow-up toxicity data are available on 166 patients at 6 weeks and 158 at 3 months. No significant acute gastro-intestinal (GI) toxicity occurred. The maximal reported acute toxicity was one case each of Grade 2 diarrhoea, constipation, proctitis and haemorrhoids, respectively. There was no difference in toxicity between treatment arms (Supplementary File 2). Genito-urinary (GU) toxicity was more common. In the acute phase, 10 patients developed acute urinary retention following discharge requiring catheterization – 6 in the single fraction arm and 4 in the 2-fraction arm, although the catheter was required for more than 48 h in only 4 of these cases, with no difference by treatment arm. One patient (in the single 19 Gy arm) developed acute Grade 3 haematuria immediately following the implant requiring overnight admission for bladder irrigation. The most common acute toxicity was Grade 2 frequency or retention (requiring use of alpha-blockers) occurring in 21% and 51% of patients, respectively. The only statistically significant difference in acute toxicity between arms was in fatigue – patients randomized to the 2-fraction arm were more likely to experience grade 1 fatigue (32% vs. 16%, p = 0.0286).

      Late toxicity

      Toxicity data are available at 6, 9, 12, 18 and 24 months on 153, 142, 138, 105 and 59 patients respectively. During this period 4 patients (3%) experienced any Grade 2 GI toxicity (2 proctitis, 1 constipation, 1 diarrhoea) with no Grade 3 GI toxicity (Supplementary File 2). Grade 3 urinary tract obstruction occurred in 1 patient in the single 19 Gy arm – stricture at the bladder neck requiring dilatation. No other Grade 3 toxicity has occurred. Grade 2 urinary retention continued beyond 3 months in 31% with no difference between treatment arms. Four patients had Grade 2 urinary tract pain and 3 had Grade 2 urinary urgency. Grade 2 erectile dysfunction occurred in 12% of patients in the single fraction arm and in 29% of those in the 2-fraction arm (p = 0.0249). No other difference was found in late toxicities between treatment arms.

      Urinary symptoms

      IPSS was available at baseline, 6 weeks, 3 months, 6 months, 9 months, 12 months, 18 months and 24 months for 169, 160, 154, 151, 142, 140, 105 and 63 patients, respectively, with respective median IPSS of 4, 9, 7, 7, 6, 6, 5 and 5. During the acute phase, there was a significant increase in IPSS between baseline and 6 weeks (p < 0.0001) and 3 months (p < 0.001). IPSS remained significantly higher than baseline at 6 months (p < 0.001), although differences did not reach statistical significance at later time points. A treatment arm effect was noted in IPSS scores, with patients in the 13.5 Gy × 2 arm reporting significantly higher IPSS in the first 3 months (p = 0.036) and also between 3 and 12 months (p = 0.044). No difference between treatment arms was found beyond 12 months. The proportion of patients reporting no or mild urinary symptoms (IPSS ⩽ 7) was significantly lower than baseline in both treatment arms for the first 12 months (Fig. 1).
      Figure thumbnail gr1
      Fig. 1Categorical IPSS by treatment arms in patients randomized to 19 Gy × 1 (A) or 13.5 Gy × 2 (B), where “mild” = IPSS ⩽ 7, “moderate” = IPSS between 8 and 19, and “severe” = IPSS ⩾ 20. The number at risk is indicated. In both arms, there was a significant decrease in the proportion of patients with “mild” symptoms for the first 12 months.

      Health related quality of life

      Over the first year in both arms, a significant decrease was observed in the mean EPIC Urinary (p = 0.0016) and Sexual (p < 0.001) Domain scores, with no significant change in the Bowel (p = 0.2513) or Hormonal (p = 0.4256) Domains (Fig. 2). This decrease occurred for Urinary Function (p = 0.006) and Bother (p = 0.0100) and for Sexual Function (p < 0.001) and Bother (p = 0.0006). No change occurred in Bowel or Hormonal sub-domains. At 12 months, the mean EPIC Urinary Domain scores decreased by 4.0 and 4.6 in the 19 Gy × 1 and in the 13.5 Gy × 2 arms, respectively. The Sexual Domain Scores decreased by 8.0 and 15.9, respectively. A greater decrease in Sexual Domain score was seen in the 13.5 Gy × 2 arm than in the single 19 Gy arm (p = 0.035). The minimally important difference in EPIC Score (0.5 S.D.) was 4.4 in the Urinary Domain, 3.1 in the Bowel Domain, 11.1 in the Sexual Domain, and 4.5 in the Hormonal Domain. At 12 months, the proportion of patients experiencing a decline >0.5 S.D. in the Urinary, Bowel, Sexual and Hormonal Domains was 42.9%, 17.4%, 33.9% and 32.4%, in the 19 Gy × 1 arm, and 39.4%, 26.8%, and 58.2% and 19.7% in the 13.5 Gy × 2 arm, respectively. Individual changes in EPIC domain scores at 12 months are depicted in Fig. 3.
      Figure thumbnail gr2
      Fig. 2Mean and Standard Error of each EPIC domain score over time by each treatment. Solid line = 19 Gy × 1; dashed Line = 13.5 Gy × 2. Patients in both arms had significantly lower EPIC urinary and sexual domain scores at month 6 (p < 0.0001) and at month 12 (p = 0.002 and <0.0001, respectively), compared with baseline scores.
      Figure thumbnail gr3
      Fig. 3Waterfall plot of changes in EPIC Domain scores relative to baseline at 12 months. Mean change by treatment arm is indicated for each Domain. Patients randomized to the 2-fraction arm had a greater decrease in Sexual Domain scores (p = 0.035). Dark Grey = single 19 Gy; Light Grey = 13.5 Gy × 2.

      Discussion

      Although most of the published data supporting the use of HDR as monotherapy has used 4 or more fractions, there is radiobiological rationale for investigating more hypofractionated regimens. To determine optimal HDR dose and fractionation, Mavroidis and colleagues conducted detailed radiobiological modelling of tumour control and normal tissue complication probability based on 3-dimensional dose–volume histograms of HDR implants using different fractionation schemes [
      • Mavroidis P.
      • Milickovic N.
      • Cruz W.F.
      • et al.
      Comparison of different fractionation schedules toward a single fraction in high-dose-rate brachytherapy as monotherapy for low-risk prostate cancer using 3-dimensional radiobiological models.
      ]. Using four fractions of 9.5 Gy as standard, their model predicted that either two fractions of 13.2–13.8 Gy or a single fraction dose of 19.2–19.7 Gy would have as good or better tumour control and lower normal tissue complications. They predicted that a single fraction of 19.5 Gy would result in a 0–2.6% higher tumour control and a 38–55% reduction in probability of complications compared to the standard 4-fraction regimen. These models, however have several limitations including an inability to account for a potential effect of hypoxia and reoxygenation.
      Mature clinical data are available on well fractionated HDR regimens. Delivering a median dose of 43.5 Gy in 6 fractions and median follow-up of 6.5 years, investigators at UCLA report a 10-year biochemical disease-free survival of 97.8% for 448 patients with low and intermediate risk disease [
      • Hauswald H.
      • Kamrava M.R.
      • Fallon J.M.
      • et al.
      High-dose-rate monotherapy for localized prostate cancer: 10-year results.
      ]. The authors found no grade 3 rectal toxicity and a 4.7% rate of grade 3 urinary toxicity. With a dose of 38 Gy in 4 fractions and a median follow-up of 5.5 years, investigators from William Beaumont Hospital report a 5-year biochemical disease-free survival of 97% in 319 low and intermediate risk patients [
      • Jawad M.S.
      • Dilworth J.T.
      • Gustafson G.S.
      • et al.
      Outcomes associated with 3 treatment schedules of high-dose-rate brachytherapy monotherapy for favorable-risk prostate cancer.
      ]. The rate of chronic urinary toxicity was 2%. The group also reported on more hypofractionated HDR regimens – 79 patients were treated to a dose of 24 Gy in 2 fractions and 96 patients to a dose of 27 Gy in 2 fractions. The median follow-up for the 2-fraction regimens was 3.5 and 2.9 years respectively with biochemical disease-free survival rates of 87% and 90%, respectively. The largest HDR monotherapy series in the literature comes from Offenbach, which included 492 patients treated to 38 Gy in 4 fractions and 226 treated to 34.5 Gy in 3 fractions [
      • Zamboglou N.
      • Tselis N.
      • Baltas D.
      • et al.
      High-dose-rate interstitial brachytherapy as monotherapy for clinically localized prostate cancer: treatment evolution and mature results.
      ]. Biochemical disease-free survival at 5 years was 98% and 95%, respectively. Although there was no reported clinical outcome difference between the two fractionation schemes, median follow up was only 25 months for the 3-fraction regimen and 59–92 months for the 4-fraction regimen.
      To date there is limited clinical data on more hypofractionated regimens, with somewhat conflicting results. Prada and colleagues were first to publish outcome data following single fraction 19 Gy as monotherapy in a series of 40 patients with low and intermediate-risk disease [
      • Prada P.J.
      • Jimenez I.
      • Gonzalez-Suarez H.
      • Fernandez J.
      • Cuervo-Arango C.
      • Mendez L.
      High-dose-rate interstitial brachytherapy as monotherapy in one fraction and transperineal hyaluronic acid injection into the perirectal fat for the treatment of favorable stage prostate cancer: treatment description and preliminary results.
      ]. No grade 2 or higher toxicity was observed and only one patient (2.5%) developed acute urinary retention requiring a catheter. An update of the series has been reported, now including 60 patients – 44 low-risk and 16 intermediate-risk [
      • Prada P.J.
      • Cardenal J.
      • Blanco A.G.
      • et al.
      High-dose-rate interstitial brachytherapy as monotherapy in one fraction for the treatment of favorable stage prostate cancer: toxicity and long-term biochemical results.
      ]. With a median follow-up of 72 months, the 6-year biochemical disease-free survival was only 66%. Implant dosimetry appeared cooler than in our current series – median V100 was 93%, median D90 was 103% and median V200 was 5%. While it may be hypothesized that the high biochemical failure rate was associated with cooler implants, the authors found no association between D90 and recurrence risk.
      Hoskin and colleagues have investigated progressively more hypofractionated HDR monotherapy regimens in patients with locally advanced prostate cancer, almost always combined with some duration of androgen deprivation therapy. An initial regimen of 10.5 Gy × 3 (n = 109) was compared with 13 Gy × 2 (n = 118) [
      • Hoskin P.
      • Rojas A.
      • Ostler P.
      • et al.
      High-dose-rate brachytherapy with two or three fractions as monotherapy in the treatment of locally advanced prostate cancer.
      ]. The two-fraction regimen was associated with lower grade 1 and 2 bowel and urinary toxicity. With a median follow-up of 71 months for the 3-fraction regimen and 31 months for the 2-fraction regimen, the 3-year biochemical failure-free survival was 97% and 93%, respectively. Hoskin also reported acute toxicity outcomes between patients treated to 13 Gy × 2 with a further 20 patients treated to 19 Gy × 1 and 26 patients treated to 20 Gy × 1 [
      • Hoskin P.
      • Rojas A.
      • Ostler P.
      • et al.
      High-dose-rate brachytherapy alone given as two or one fraction to patients for locally advanced prostate cancer: acute toxicity.
      ]. Patients treated to 20 Gy had more severe urinary symptoms at 2 weeks, and over the first 3 months patients treated with either of the single fraction regimens had a significant increase in catheter use. At 12 weeks, 8% of those following 19 Gy and 22% of those following 20 Gy were still using a catheter.
      Krauss and colleagues have also reported on a series of 58 low and intermediate risk patients treated with single 19 Gy monotherapy [
      • Krauss D.J.
      • Martinez A.A.
      • Ye H.
      • et al.
      Highly favorable preliminary clinical and toxicity outcomes for low-and intermediate-risk prostate cancer patients treated with high-dose-rate brachytherapy in a single fraction of 19 Gy.
      ]. With a median follow-up of 2.1 years, the incidence of acute and chronic grade 2 urinary toxicity was 12% and 14%, respectively, with no grade 3 urinary toxicity. The 3-year biochemical failure rate was 6%.
      We have found HDR monotherapy delivered either as a single fraction of 19 Gy or as two fractions of 13.5 Gy to be well tolerated acutely with only one case of acute grade 3 urinary toxicity and an absence of gastrointestinal toxicity. While ten (5.8%) patients developed urinary retention in our clinical trial during the acute phase, only 4 (2.4%) required use of a catheter for greater than 48 h. Beyond 3 months, a single patient experienced urinary retention related to an intraprostatic urethral stricture. Urinary symptoms were elevated for the first 6 months following treatment, being the highest at 6 weeks when the median IPSS was 5 points above baseline. A difference was found between treatment arms – patients treated with a single fraction of 19 Gy reported less urinary symptoms over the first year than those treated with two fractions of 13.5 Gy. Patients in the single fraction arm also had better preservation of potency as assessed by the EPIC sexual domain scores and by a lower occurrence of Grade 2 Erectile Dysfunction. It is unclear how much the increase in toxicity in the 2-fraction arm was related to the additional trauma of having two insertions rather than a dose effect. No difference was found by treatment arm in any other toxicity, EPIC domain or sub-domain at any time point.
      The proportion of patients that experienced a clinically significant decrease in the EPIC Urinary and Bowel domain scores was considered acceptable in either arm and less than our pre-defined limits. In our previous clinical trial in a similar patient cohort using 15 Gy HDR as a boost combined with EBRT to a dose of 37.5 Gy in 15 fractions, the mean EPIC Urinary, Bowel, Sexual and Hormonal Doman scores decreased by 9.9, 6.1, 16.7 and 1.4, respectively at 12 months [
      • Morton G.C.
      • Loblaw D.A.
      • Sankreacha R.
      • et al.
      Single-fraction high-dose-rate brachytherapy and hypofractionated external beam radiotherapy for men with intermediate-risk prostate cancer: analysis of short- and medium-term toxicity and quality of life.
      ]. This compares favourably with mean EPIC Domain decreases for all patients in the current clinical trial of 4.2, 1.1, 12.3 and 0.9, respectively. The proportion of patients experiencing a >0.5 SD decline in EPIC Urinary and Bowel Domains at 12 months in our previous HDR boost protocol was 53% and 51%, respectively [
      • Morton G.C.
      • Loblaw D.A.
      • Chung H.
      • et al.
      Health-related quality of life after single-fraction high-dose-rate brachytherapy and hypofractionated external beam radiotherapy for prostate cancer.
      ]. In the current clinical trial the proportions experiencing a >0.5 SD decrease in the single 19 Gy and 13.5 Gy × 2 arms were 42.9% and 39.4% (urinary) and 17.4% and 26.8% (bowel), respectively.
      Hypofractionated HDR monotherapy regimens are well tolerated acutely. Our data are not yet sufficiently mature to report on efficacy outcomes. While single fraction HDR is an attractive option for patients, further data on efficacy and late toxicity are required before it can be considered a standard treatment option.

      Conclusions

      Either 13.5 Gy × 2 or 19 Gy × 1 is well tolerated acutely over the first two years. The single fraction regimen is associated with fewer urinary symptoms and lower incidence of erectile dysfunction.

      Conflict of interest

      None of the authors have a conflict of interest to disclose.

      Acknowledgement

      This work was funded by an AbbVie-CARO Uro-Oncologic Radiation Award (ACURA), from the Canadian Association of Radiation Oncologists .

      Appendix A. Supplementary data

      • Supplementary File 2

        Highest grade of CTCAE v4 acute (within 3 months) and late (beyond 3 months) toxicities by treatment arm. Late Grade 2 erectile dysfunction was more common in the 2-fraction arm (p = 0.0249); no other significant difference was found.

      References

        • Morton G.C.
        High-dose-rate brachytherapy boost for prostate cancer: rationale and technique.
        J Contemp Brachytherapy. 2014; 6: 323-330
        • Demanes D.J.
        • Ghilezan M.I.
        High-dose-rate brachytherapy as monotherapy for prostate cancer.
        Brachytherapy. 2014; 13: 529-541
        • Mohler J.L.
        • Armstrong A.J.
        • Bahnson R.R.
        • et al.
        Prostate Cancer, Version 1.2016.
        J Natl Compr Canc Netw. 2016; 14: 19-30
        • Prada P.J.
        • Jimenez I.
        • Gonzalez-Suarez H.
        • Fernandez J.
        • Cuervo-Arango C.
        • Mendez L.
        High-dose-rate interstitial brachytherapy as monotherapy in one fraction and transperineal hyaluronic acid injection into the perirectal fat for the treatment of favorable stage prostate cancer: treatment description and preliminary results.
        Brachytherapy. 2012; 11: 105-110
        • Hoskin P.
        • Rojas A.
        • Ostler P.
        • et al.
        High-dose-rate brachytherapy alone given as two or one fraction to patients for locally advanced prostate cancer: acute toxicity.
        Radiother Oncol. 2014; 110: 268-271
        • Krauss D.J.
        • Martinez A.A.
        • Ye H.
        • et al.
        Highly favorable preliminary clinical and toxicity outcomes for low-and intermediate-risk prostate cancer patients treated with high-dose-rate brachytherapy in a single fraction of 19 Gy.
        Int J Radiat Oncol Biol Phys. 2015; 93: S122
        • Wei J.T.
        • Dunn R.L.
        • Litwin M.S.
        • Sandler H.M.
        • Sanda M.G.
        Development and validation of the expanded prostate cancer index composite (EPIC) for comprehensive assessment of health-related quality of life in men with prostate cancer.
        Urology. 2000; 56: 899-905
        • Morton G.C.
        Prostate high-dose-rate brachytherapy: transrectal ultrasound based planning, a technical note.
        Pract Radiat Oncol. 2015; 5: 238-240
        • Morton G.C.
        • Loblaw D.A.
        • Chung H.
        • 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
        • Mavroidis P.
        • Milickovic N.
        • Cruz W.F.
        • et al.
        Comparison of different fractionation schedules toward a single fraction in high-dose-rate brachytherapy as monotherapy for low-risk prostate cancer using 3-dimensional radiobiological models.
        Int J Radiat Oncol Biol Phys. 2014; 88: 216-223
        • Hauswald H.
        • Kamrava M.R.
        • Fallon J.M.
        • et al.
        High-dose-rate monotherapy for localized prostate cancer: 10-year results.
        Int J Radiat Oncol Biol Phys. 2016; 94: 667-674
        • Jawad M.S.
        • Dilworth J.T.
        • Gustafson G.S.
        • et al.
        Outcomes associated with 3 treatment schedules of high-dose-rate brachytherapy monotherapy for favorable-risk prostate cancer.
        Int J Radiat Oncol Biol Phys. 2016; 94: 657-666
        • Zamboglou N.
        • Tselis N.
        • Baltas D.
        • et al.
        High-dose-rate interstitial brachytherapy as monotherapy for clinically localized prostate cancer: treatment evolution and mature results.
        Int J Radiat Oncol Biol Phys. 2013; 85: 672-678
        • Prada P.J.
        • Cardenal J.
        • Blanco A.G.
        • et al.
        High-dose-rate interstitial brachytherapy as monotherapy in one fraction for the treatment of favorable stage prostate cancer: toxicity and long-term biochemical results.
        Radiother Oncol. 2016; 119: 411-416
        • Hoskin P.
        • Rojas A.
        • Ostler P.
        • et al.
        High-dose-rate brachytherapy with two or three fractions as monotherapy in the treatment of locally advanced prostate cancer.
        Radiother Oncol. 2014; 112: 63-67
        • Morton G.C.
        • Loblaw D.A.
        • Sankreacha R.
        • et al.
        Single-fraction high-dose-rate brachytherapy and hypofractionated external beam radiotherapy for men with intermediate-risk prostate cancer: analysis of short- and medium-term toxicity and quality of life.
        Int J Radiat Oncol Biol Phys. 2010; 77: 811-817