Salvage high-dose-rate brachytherapy for locally recurrent prostate cancer after primary radiotherapy failure

Radiotherapy and Oncology xxx (2016) xxx–xxx

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Original article

Salvage high-dose-rate brachytherapy for locally recurrent prostate cancer after primary radiotherapy failure Piotr Wojcieszek a,⇑, Marta Szlag b, Grzegorz Głowacki c, Agnieszka Cholewka b, Marzena Gawkowska-Suwin´ska d, Sylwia Kellas-S´le˛czka a, Brygida Białas a, Marek Fijałkowski a a Brachytherapy Department; b Radiotherapy and Brachytherapy Treatment Planning Department; c Radiotherapy Department; and Chemotherapy, MSC Memorial Cancer Centre and Institute of Oncology, Gliwice, Ul. Wybrzeze Armii Krajowej 15, 44-100 Gliwice, Poland

a r t i c l e

i n f o

Article history: Received 20 July 2015 Received in revised form 15 April 2016 Accepted 20 April 2016 Available online xxxx Keywords: Nadir PSA Temporary implant Salvage brachytherapy

d

III Department of Radiotherapy and

a b s t r a c t Background and purpose: To evaluate high-dose-rate brachytherapy (HDR BT) as a salvage modality for locally recurrent prostate cancer after primary radiotherapy failure. Materials and methods: Eighty-three prostate cancer patients, who locally relapsed after radiotherapy, were treated with salvage HDR BT. The schedule was three implantations, every two weeks, with 10 Gy per implant, to a total dose of 30 Gy. Acute and late toxicity rates were evaluated. Overall survival (OS) and biochemical control were calculated using Kaplan–Meier method. Results: Median follow-up after salvage HDR was 41 months. The 3-year and 5-year OS were 93% and 86%, respectively. The 3-year and 5-year biochemical disease-free survival (bDFS) were 76% and 67%, respectively. The single factor associated with biochemical control was time to achieve salvage PSA nadir (p-.006). OS was linked significantly with primary nadir level (p-.001) while primary biochemical relapse interval was of borderline significance (p-.07). Conclusions: Salvage HDR BT is a promising treatment option for patients with localized relapse of previously irradiated prostate cancer. Lower PSA nadir after primary radiotherapy and longer primary disease-free interval influence the outcome. Ó 2016 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology xxx (2016) xxx–xxx

Due to the increasing use of external beam radiotherapy (EBRT) the number of cured prostate cancer patients has grown significantly over the past two decades. However, even one third of them undergo biochemical failure after the primary radiotherapy [1–4], which may be linked to distant metastases, local failure or both [5,6]. Moreover prostate apex is more exposed for radiotherapy failure than other sections [7]. Therefore, an effective radical treatment is needed for patients suffering from localized prostate cancer relapse [8,9]. High-dose-rate brachytherapy (HDR BT), has gained much interest due to its ability to deliver localized radiation dose to the prostate gland while minimizing normal tissue exposure. The method provides ablative doses per fraction (i.e. >7.5 Gy) for the whole prostate gland with even higher doses reached inside the target (i.e. >100%). Another advantage is overall shorter treatment time, compared to conventional EBRT, which probably enhances the radiation effect inside the target volume. A number of studies present the efficacy and safety of the salvage HDR BT. The first published research conducted on a group ⇑ Corresponding author.

of 7 men brought results of 58-month median follow-up and 5year disease-free survival of 71% [10]. Chen et al. presented results for 52 patients with a median follow-up of 59.6 months, and 5-year overall survival (OS) and biochemical relapse-free survival (bDFS) of 92% and 51%, respectively [11]. Yamada et al. enrolled 42 patients into phase II prospective trial, and achieved 36-month median follow-up, 5-year OS of 79%, and 5-year bDFS of 68.5% [12]. Although Tharp et al. reported that only 1 of 7 patients suffered from grade 2 rectal injury, while 5 patients developed urethral strictures (grade 2) (including 2 patients with grade 3 urethral necrosis, and 2 with grade 3 perineal pain), the salvage HDR BT toxicity rates have improved significantly over the last few years. Recent studies report just mild to moderate (i.e. 6grade 2) acute GU toxicity in 78–98% of patients, and mild to moderate late GU toxicity in 86–98% of patients [11,12]. Similar trends are observed for acute and late GI toxicity, with no patients suffering from grade 4, and no more than 3% suffering from grade 3 toxicity. Given these benefits, HDR BT is becoming an attractive option for salvaging locally recurrent prostate cancer. The goal of this retrospective study is to evaluate salvage HDR BT of the recurrent prostate cancer on a large group (83) of previously irradiated patients. HDR BT boost was applied in prostate

E-mail address: [email protected] (P. Wojcieszek). http://dx.doi.org/10.1016/j.radonc.2016.04.032 0167-8140/Ó 2016 Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: Wojcieszek P et al. Salvage high-dose-rate brachytherapy for locally recurrent prostate cancer after primary radiotherapy failure. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.04.032

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Prostate cancer salvage brachytherapy

cancer treatment for the first time in our center in 2003. Due to an increasing number of patients with locally recurring prostate cancer, particularly after primary radiotherapy failure, a new approach for these men was needed immediately. We adapted our prostate cancer HDR monotherapy schedule with decreased dose per fraction (i.e. from 11 Gy to 10 Gy). The first salvage HDR BT implantation was performed in our center in 2008.

Table 2 Patient characteristics.

Materials and methods One hundred and three men were treated with salvage HDR BT between 08/04/2008 and 30/06/2014. To achieve the longest follow-up we analyzed only those, who finished brachytherapy before 31/12/2012. Eighty-three men were enrolled into the retrospective analysis. All data were collected from the retrospective chart review.

Primary treatment Fifty-one men (61%) were treated with external-beam radiotherapy (EBRT). Thirty-two patients (39%) were treated with EBRT combined with one fraction of HDR boost. Median primary PSA peak was 13.7 ng/ml. Median Gleason score was 6. Fifty-eight patients (70%) underwent adjuvant androgen deprivation therapy (ADT) after first prostate cancer diagnosis. Primary ADT duration ranged from one month (52 days) to over 6.5 years (Table 2). Two patients were treated with oral steroidal anti-androgens alone. Forty-seven EBRT patients (56%) were treated with conventional schedules. Median total dose was 74 Gy (52–76 Gy). Three patients received hypofractionated EBRT (i.e. dose per fraction 2.6 Gy). Five or four-field planning technique was used most often, in 11 and 9 plans, respectively (4–9 fields; median 5). HDR boost patients were treated with EBRT (54 Gy/27 fx) followed by HDR boost (10 Gy). Three-field planning technique was used in 17 patients. Prostate implant needles number ranged from 10 to 18 with a median of 15.

Primary follow-up Eighty-three patients (53–76 y.o.; median 63 y.o.) failed after primary irradiation. Three patients (4%) relapsed during adjuvant ADT. Twenty-two patients (26%) were diagnosed with local relapse with no prior biochemical relapse. Eighteen (22%) of them were diagnosed using MRI. Forty-four patients (53%) had ADT reassigned. Median time to relapse after primary radiotherapy was 67 months (22–124 months). Median relapse peak PSA was 3.1 ng/ml (0.065–19.9 ng/ml).

Local relapse confirmation Patients with biochemical recurrence or suspicious lesion in MRI underwent clinical evaluation. Local recurrence was verified in the 12 core biopsy, no earlier than 18 months after radiotherapy. MRI imaged relapses were additionally targeted and sampled (without TRUS/MRI fusion). For biopsies performed outside our center, a pathologist review was required. Gleason score was reported if available. Moreover immunohistochemistry was done (Alpha-methylacyl CoA racemase (AMACR) combined with p63) to confirm prostate cancer relapse. Patients diagnosed with radiation atypia only were excluded from the salvage HDR BT treatment. Gleason sum was available for 44 patients (53%) with a majority of 7 or below. Biochemical relapse patients with negative biopsy remained under active surveillance (i.e. MRI after 3–6 months, biopsy repeated after 6 months) until positive biopsy.

Characteristics

Median (range)

Primary treatment age Age at salvage HDR Primary peak PSA Primary T stage T1c T2 T3 n/d Primary PSA (ng/ml) <10 10–20 >20 n/d Primary Gleason sum 66 7 P8 n/d Primary D’Amico risk groups Low Intermediate High n/d Primary ADT Primary ADT duration (months) Primary prostate volume (cm3) EBRT 52 Gy/20 fx (EQD2Gy = 58.2 Gy)⁄ 70 Gy/35 fx 72 Gy/36 fx 74 Gy/37 fx 76 Gy/38 fx n/d EBRT + HDR 54 Gy/27 fx + 10 Gy (EQD2Gy = 80 Gy)⁄ Time to relapse (months) Primary biochemical relapse Relapse peak PSA (ng/ml) Relapse ADT Relapse Gleason sum 66 7 P8 n/d

63 (53–76) 70 (57–81) 13.7 (3.11–366)

n = 83 (100%) n

%

33 44 5 1

40 53 6 1

24 32 21 6

29 39 25 7

50 17 3 13

60 20 4 16

16 25 29 13 71

19 30 35 16 86

51 3 8 6 22 11 1 32

61 4 10 7 26 13 1 39

61

73

44

53

16 22 6 39

19 27 7 47

13 (1–82) 51.5 (17.8–119.9)

67 (22–124) 3.1 (0.065–19.9)

EQD2Gy for a/b = 3; EQD2Gy – equivalent dose in 2 Gy fractions; EBRT – external beam radiotherapy; HDR – high-dose-rate brachytherapy; ADT – androgen deprivation therapy; PSA – prostate-specific antigen.

⁄

Every patient was carefully examined after histological confirmation of the recurrence. X-ray chest, bone scan, TRUS, abdominal and pelvic ultrasound were obligatory at the beginning of salvage HDR BT. Later, as we gained more insight into salvage HDR BT we required abdominal and pelvic computed tomography. Additionally, for patients with suspicion of extraprostatic extension an MRI scan was performed. Patients who suffered from urge incontinence (pharmacoresistant), frequent urination (P6 times per night or hourly or more frequent) or gross hematuria were excluded from the study. Urodynamics testing was not routinely performed. Radical prostatectomy patients were excluded. Due to the salvage goal of HDR BT our decision was to treat patients with every prostate volume (i.e. including <15 ccm and >60 ccm) with no pubic interference. Written informed consent was required from every patient. Salvage HDR procedure Each qualified patient was planned for three fractions of HDR, 10 Gy each to a total dose of 30 Gy. Biologically equivalent doses

Please cite this article in press as: Wojcieszek P et al. Salvage high-dose-rate brachytherapy for locally recurrent prostate cancer after primary radiotherapy failure. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.04.032

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P. Wojcieszek et al. / Radiotherapy and Oncology xxx (2016) xxx–xxx

for a/b = 1.5 and a/b = 3 are 230 Gy and 130 Gy, respectively. Equivalent doses in 2 Gy fractions for a/b = 1.5 and a/b = 3 are 98.6 Gy and 78 Gy, respectively. Our schedule was to perform three implantations every two weeks over 28–30 days. All procedures were performed in an operational theater in our center’s Brachytherapy Department. Plastic 6F tubes implantation was performed under transrectal ultrasound guidance in the lithotomy position under epidural anesthesia. Virtual and real-time planning was done in the dedicated system (OncentraÒ Prostate, Elekta). Clinical target volume (CTV) included the whole prostate. The seminal vesicles were not included in the CTV. Urethra, rectal wall and catheter’s balloon (urinary bladder) were delineated. The goal was to achieve >90% of minimal peripheral dose in 100% of CTV (V100). Recommended and achieved dose–volume parameters are presented in Table 1. Brachytherapy was performed with 192Ir encapsulated radioactive source (MicroselectronÒ, Nucletron). Needles were removed immediately after irradiation. Patients were usually discharged a day after the procedure, however those with persistent hematuria remained under observation for 48– 72 h. Follow-up All patients were followed-up in our center. Every visit included history with urination frequency, digital rectal examination and current PSA level. Additional imaging was done if needed (i.e. PSA level increase, bone pain or abnormal mass in the digital rectal examination). Phoenix definition of biochemical relapse was used (i.e. PSA nadir + 2 ng/ml). Peak adverse events were reported. Acute and late toxicity were graded with Common Terminology Criteria for Adverse Events 4.0 (CTCAE 4.0). Time to peak toxicity was counted from start of the irradiation to the maximal intensity of the symptoms (acute 6 180 days; late > 180 days). Sexual function was not evaluated. Patients were evaluated preferably four weeks after finishing the treatment, then every 3 months over the first year, and every 6 months follow-up was planned later. Statistical analysis Statistical analysis, including survival analysis and Cox regression, was performed using Statistica 10, StatSoftÒ. OS, bDFS, metastatic disease-free survival and cause specific survival were calculated for 3 and 5 year actuarial using Kaplan–Meier method. Follow-up time was counted as time from the last fraction to an event (e.g. metastatic disease; death etc.), time to an adverse event was counted from day 1 of salvage HDR. Age, PSA peak, Gleason

score, ADT, primary radiotherapy biologically equivalent dose (BED1), prostate-specific antigen nadir (PSA nadir), PSA nadir interval, primary biochemical relapse interval were considered as potential predictors for bDFS and OS. Cox regression model and likelihood ratio test was used for univariate analyses. Value of p < .05 was set as statistically significant. Results Salvage HDR BT outcomes Median age at salvage HDR BT was 70 years (57–81). Median follow-up time was 41 months (11–76 months). The 3-year and 5-year OS was 93% and 86%, respectively (Fig. 1a). The 3-year and 5-year bDFS was 76% and 67%, respectively (Fig. 1b). Metastatic disease-free survival was 87% at 3 years and 79% at 5 years. The 5-year cause-specific survival was 87%. Single factor associated with biochemical control was time to achieve salvage PSA nadir (p-.006; HR-0.995; 95% CI 0.991–0.999) (Fig. 2). OS was linked significantly with primary nadir level (p-.001; HR-1.87; 95% CI 1.49– 2.25), while the link with primary biochemical relapse interval was of borderline significance (p-.07; HR-0.96; 95% CI 0.924–1.01). Median PSA at last follow-up was 0.358 ng/ml (0.008–2470 ng/ ml). Fifty men were still in ADT treatment during the last followup. Fourteen men finished ADT after salvage HDR BT.

Salvage HDR BT toxicity Median time to peak acute and late toxicity was 75 days (3– 182 days) and 267 days (181–1926 days), respectively. In five cases (6%) salvage HDR BT was stopped after the second fraction due to an acute urinary retention. One patient (1%) underwent urological intervention that was complicated by urinary incontinence (grade 3). Nine patients (11%) did not exhibit genitourinary (GU) toxicity symptoms. Grade 1 and 2 acute GU toxicities were observed in 43 (52%) and 29 (35%) men, respectively. Eleven (13%) patients suffered from late GU toxicity in grade 3. All of them underwent urological intervention (i.e. TURP or urethrotomy) due to urinary retention. One patient had urinary retention followed by suprapubic cystotomy. Eleven (13%) patients did not complain on any late GU events. Grade 1 late GU toxicity was observed in 27 (33%) men. Thirty-two (39%) patients were reported as grade 2 GU toxicity. Acute gastrointestinal (GI) toxicity grade 1 was reported in 5 (6%) patients. Also, five (6%) patients had late GI toxicity in grade 1 that caused rectal discomfort.

Table 1 Recommended and achieved dose–volume parameters for salvage HDR. Dose–volume parameters

Recommended

CTV (cm3)

–

Catheters

–

V100 (%)

P90

D90 (%)

P100

Urethra D10 (%)

6120

Rectum D10 (%)

670

Bladder D10 (%)

670

Achieved 1st fraction

2nd fraction

3rd fraction

25 (9.4–54.2) 14 (8–18) 91.6 (67.7–97.3) 102.3 (71.4–111.8) 118.8 (97.5–122.6) 64.3 (36–88.5) 58.1 (42.7–97.1)

26.8 (11.3–56) 14 (8–18) 90.7 (45.5–99.4) 100.8 (68.3–112.1) 118.8 (80–124.3) 64.1 (5.2–72.2) 59.2 (38.5–83.4)

26.5 (11–77.9) 14 (9–18) 92.3 (79–99.7) 102.9 (86.8–116.7) 118.6 (108.7–120.8) 64.8 (36.8–77.6) 59.2 (39.9–87.5)

All achieved parameters are presented as median (range).

Please cite this article in press as: Wojcieszek P et al. Salvage high-dose-rate brachytherapy for locally recurrent prostate cancer after primary radiotherapy failure. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.04.032

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Prostate cancer salvage brachytherapy

Fig. 1. Kaplan–Meier curves for salvage HDR BT patients: (a) overall survival (OS). (b) biochemical-relapse free survival (bDFS) using Phoenix definition of failure.

Fig. 2. Biochemical relapse-free survival according to time to achieve PSA nadir. Five-year estimates biochemical relapse-free survival for patients with time to nadir >238 days is 77% comparing to patients with time to nadir 6238 days, which is 56% (log-rank test p-.004).

No grade 4 acute or late GU or GI toxicities were observed. Acute and late toxicity rates are presented in Table 3.

Discussion Management of prostate cancer recurrence after primary failure radiotherapy is difficult, especially among men with long life expectancy. Throughout the years a range of treatment options such as salvage surgery, cryotherapy, High Focused Ultrasound (HiFU), and brachytherapy, were developed providing us with a range of options for prostate cancer treatment. However, when salvage therapy is considered, it should be focused primarily on the outcome rates with emphasis placed on the adverse event risk and quality of life after therapy.

Our results for 5-year bDFS and OS are in agreement with previously reported salvage HDR studies. The 5-year OS reported for HDR ranges from 70% to 92%, while 5-year bDFS values vary between 51% and 77% showing the potential of HDR BT as a salvage prostate cancer treatment option [10–15]. The therapy also seems to yield results comparable or better than other available treatments. Even though salvage prostatectomy series have long follow-up, often exceeding 5 years, the long-term (8–10 years) results in large series (i.e. P100 patients) are moderate with progression-free survival or bDFS between 43% and 63% [16–23]. Assessing the efficacy of cryoablation is difficult due to different biochemical relapse definitions used in the studies. However, reported data show the 5-year bDFS of 59% (ASTRO definition) or 10-year bDFS of 39% (Phoenix definition), which is comparable to salvage HDR BT [24–28]. High Focused Ultrasound (HiFU) is a relatively new method in the salvage of prostate cancer patients with little data (in terms of 5-years or longer bDFS and/or OS) available for comparison with results presented in this paper. Most of the series have median follow up below 24 months, and the 3-year bDFS of 53% or 2-year of 86–100%, for intermediate and low risk patients [29–33]. At the same time, a 2-year OS as low as 14% were shown for high-risk groups [33]. A rather large discrepancy in results is also presented for the salvage low dose rate (LDR) BT. According to some authors the 3–5 year bDFS or failure-free survival after LDR BT can reach values between 65% and 87%, while others report a 5-year bDFS below 40% [34–38]. A risk factor that has to be considered when applying any radiotherapy treatment is the possibility of severe toxicity. The HDR BT treatment schedule implement in this study yields very good acute and late toxicity results. With only one patient suffering from grade 3 acute GU toxicity, and eleven men from grade 3 late GU toxicity, our results are in agreement with previous studies that reported either acute or late GU toxicity mostly equal or below grade 2 [10–15]. Even a combination of salvage HDR BT and interstitial hyperthermia did not yield severe toxicity [14]. Neither acute nor late grade 4 toxicities were observed in any of the salvage HDR studies. At the same time, LDR BT exhibits a broad range

Table 3 Acute and late toxicity rates – maximal score. Toxicity (CTCAE 4.0) Acute GU (%) GI (%) Late GU (%) GI (%)

Grade 0

Grade 1

Grade 2

Grade 3

Grade 4

n/a

9(11) 77(93)

43(52) 5(6)

29(35) –

1(1) –

– –

1(1) 1(1)

11(13) 76(92)

27(33) 5(6)

32(39) –

11(13) –

– –

2(2) 2(2)

CTCAE – Common Terminology Criteria for Adverse Events; GU – Genitourinary; GI – gastrointestinal.

Please cite this article in press as: Wojcieszek P et al. Salvage high-dose-rate brachytherapy for locally recurrent prostate cancer after primary radiotherapy failure. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.04.032

P. Wojcieszek et al. / Radiotherapy and Oncology xxx (2016) xxx–xxx

of adverse toxicity events from zero to 47% for patients suffering from >grade 2 side effects [35–37]. This implies that with appropriate optimization and adaptation of dose that ensures excellent coverage of target volume, HDR BT is less harmful than LDR BT. The study confirms previously suggested effect of PSA nadir on biochemical control and OS. The longer the interval to achieve PSA nadir after salvage HDR, the stronger the biochemical control. It is comparable to recent results of Morris et al., who presented that longer time to PSA nadir in patients after EBRT combined with HDR BT boost is associated with higher bDFS rates [39]. Lower PSA nadir after primary radiotherapy had a strong positive effect on OS. Similarly, longer interval between primary radiotherapy and biochemical recurrence was connected with better outcomes. According to Chen et al. [11] longer time to biochemical relapse combined with lower nadir PSA level may suggest improved effect of primary treatment. Presumably it may be linked with localized relapse with lower likelihood of micrometastatic disease. The greatest disadvantage of HDR BT is an invasive implantation. The procedure requires anesthesia (general or epidural), which is sometimes impossible due to patient status. Also patient anatomy is crucial to make optimal multicatheter implant to treat target volume. Additionally, pubic interference or lack of proper patient positioning may disturb the implantation. In conclusion, salvage HDR schedule of total dose of 30 Gy in 3 fractions every 2 weeks is an efficient prostate cancer salvage treatment with acceptable toxicity rates. The outcome of the treatment depends on the PSA nadir level and primary disease-free interval after primary radiotherapy. Similarly, faster PSA drop after salvage HDR BT allows for better biochemical control. Although, the presented data concern a retrospective analysis it provides results from the biggest group available with median follow-up exceeding 40 months. Further development of the method should include: research with more restrictive patient selection to avoid unnecessary invasive intervention in patients with occult disease (e.g. PET-CT imaging), exploring the possibility to design schedules with less implantations, and comparison between salvage HDR and conservative management such as ADT or active surveillance. Conflict of interest There is no conflict of interest. Acknowledgments We would like to thank all Brachytherapy Department staff for their help in collecting data with special thanks to Anna Wielgus M.A. Also we would like to thank Andrzej Andrejczuk M.D. for his urological counseling. Special thanks to Dominika E. Wojcieszek for the invaluable feedback on the composition and style. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.radonc.2016.04. 032. References [1] Schreiber D, Rineer J, Weiss JP, Safdieh J, Weiner J, Rotman M, et al. Clinical and biochemical outcomes of men undergoing radical prostatectomy or radiation therapy for localized prostate cancer. Radiat Oncol J 2015;33:21–8. [2] Swisher-McClure S, Mitra N, Woo K, Smaldone M, Uzzo R, Bekelman JE. Increasing use of dose-escalated external beam radiation therapy for men with nonmetastatic prostate cancer. Int J Radiat Oncol Biol Phys 2014;89:103–12. [3] Zaorsky NG, Palmer JD, Hurwitz MD, Keith SW, Dicker AP, Den RB. What is the ideal radiotherapy dose to treat prostate cancer? A meta-analysis of biologically equivalent dose escalation. Radiother Oncol 2015.

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Please cite this article in press as: Wojcieszek P et al. Salvage high-dose-rate brachytherapy for locally recurrent prostate cancer after primary radiotherapy failure. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.04.032

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Prostate cancer salvage brachytherapy

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Please cite this article in press as: Wojcieszek P et al. Salvage high-dose-rate brachytherapy for locally recurrent prostate cancer after primary radiotherapy failure. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.04.032