Original article
HDR brachytherapy as a solution in recurrences of locally advanced prostate cancer

Purpose
HDR brachytherapy is already a well established and safe treatment for localized prostate cancer [1]. It allows precise delivery of very high doses of radiation in a very short treatment time and is more conformal than LDR brachytherapy with seeds or IMRT. The accuracy offered by HDR brachytherapy is especially attractive for salvage therapy because it permits protection of healthy structures around the prostate with full dose of external beam radiotherapy already received during primary treatment [2-4]. Lee et al. have recently reported that patients with rising PSA after definitive treatment (approximately 26%) have a local recurrence, where 47% of cases developed distant metastases within five years [5]. However, after radiation therapy for clinically localized disease (stage T1, T2), 5-year biochemical failure rates have been reported as 25% to 50%, and 10-year local recurrence rates have been reported as 13% to 35% [6-8]. The aim of our study was to evaluate the suitability and safety of salvage high-dose-rate (HDR) brachytherapy (SBR) for local recurrence of prostate cancer after external beam radiotherapy, after HDR brachytherapy, or after radical prostatectomy.

Material and methods
One hundred and fifteen patients who underwent SBR for locally recurrent prostate cancer treated between December 1999 and August 2008 were retrospectively analyzed. Patients with prostate-specific antigen (PSA) failure, as the local failure, without distant metastasis, after external beam radiation, HDR brachytherapy treatment, after radical prostatectomy or combination of them, with or without hormonal therapy, have been enrolled to SBR. All patients were treated with 10 Gy per fraction using three HDR prostate applications guided by transrectal ultrasound. The fractions was separated by 3 week gaps. Files of 115 patients from Centre of Oncology were investigated as well as patients sent for salvage treatment from other hospitals in Poland. For this reason some of them didn’t have the full set of clinical data, for instance in 19 patients the Gleason score was not defined. Among patients with Gleason score determined the distribution of the score values is presented in Fig. 1. The distribution of patients age at the time of primary treatment is presented in Fig. 2. Clinical and pathological data of 115 patients are summarized in Table 1. All patients before SBR treatment were treated by surgery, external beam radiotherapy or brachytherapy. Data of the former treatment modalities are presented in Table 2. External beam radiotherapy has been performed in 88 patients. The radiation energy was 15 MV in 53 cases, 25 MV in 1 case, 9 MV in 3 patients, 6 MV in 3 cases, 4 MV in 10 cases and Co-60 in 14 patients. For 4 patients the photon energy was unknown. Total dose ranged from 30 to 76 Gy, median 52 Gy and fraction dose – 1.6 to 2.6 Gy. The median total treatment time was 33 days (range 22-66 days). Brachytherapy as the primary treatment was performed in 26 patients. Three of them received 27 Gy at 9 Gy fractions with 2 week gaps, 23 patients received 2 fractions with 3 weeks gap, each fraction of 15 Gy. Doses from external beam radiotherapy and brachytherapy were recalculated to equivalent biological dose (BED) using LQ model for a/b value equal 10 and 3 Gy, with total treatment time TD taking into account. According to Fowler and others suggestions, this is the duration of treatment considering the first fraction given on day 0 [9-12].


BED = nd [1+d/(a/b)] – TD K

where: n – number of fractions, d – fraction dose, K – the loss of biological effectiveness per day as a result of proliferation depending not only on the rate of repopulation in tissue (doubling time) but also on its radiosensitivity (K has a unit Gy/day).The calculated values of BED for the primary treatment for a/b = 10 Gy ranged from 20 to 97.2 Gy with median 51.6 Gy, and for a/b = 3 Gy ranged from 77.6 to 227.7 Gy with median 105.1 Gy. For SBR treatments for a/b = 10 Gy, BED ranged from 20 to 51.7 Gy with median 34.2 Gy and for a/b = 3 Gy BED range from 43.3 Gy to 171.7 Gy with median 125.7 Gy.
Patients follow up data concerning the toxicity of SBR was collected from the patients files. Post treatment PSA levels, occurrence of treatment related symptoms and complications were investigated in order to evaluate and possibly modify the SBR procedure. Evaluation of complication from SBR required careful revision and analysis of a patient’s reports at follow-up visits in order to separate the toxic effects of the primary treatment from those of SBR.

Results
Taking into account the EORTC/RTOG scale of toxicity, acute urinary symptoms such as frequency, urgency, hesitancy and nocturia were common during the first 3 months after SBR. They were readily managed by prescribed alpha-blocker or cholinolytic treatment on a routine basis. In Figs. 3 and 4 the toxicity of SBR treatments for the bladder and rectum is presented respectively. Serious genitourinary complications such as uncontrolled hematuria were observed in 6 patients, urethral fistulas in 2, bladder outlet obstruction requiring permanent catheterization in 2, and complete urinary incontinence occurred in 4 patients. Effectiveness of SBR was assessed by PSA level after treatment. Follow-up examinations after SBR were performed during the first two years at 3 month intervals, during the next two years every 6 months, and every 6-12 months thereafter. In general, the first post SBR PSA level was measured after 3 months. Biochemical failure (BF) was defined as the nadir-plus 2 ng/mL or more than PSA nadir after SBR treatment. Figures 5 and 6 present the BF and survival data. Some of the patients were lost from observation during the first two years after treatment, mostly because they’ve lived in distant part of Poland and they considered the follow-up visits as complicated and costly. They were assumed as the BF. In Figure 5, according to Kaplan-Meier estimation, the PSA rising and stratified by PSA nadir (< 2 vs. ł 2 ng/mL) and Gleason score (2-6 vs. 7-10) are displayed. The independence from biochemical progression of our group of patients after retreatment was 46% of patients with PSA Ł 6 and 18% of patients with PSA > 6. Overall survival for patients with PSA Ł 6 is 86% and respectively 48% for patients with PSA > 6.

Discussion
Although salvage prostate brachytherapy demonstrated acceptable disease control without major complications, salvage brachytherapy should be limited only to patients with pathologically confirmed local recurrence. According to Allen and other authors, the base of selection of the future patients should be as follows: 1) clinical tumor status T1 or T2, 2) PSA Ł 10 ng/ml, 3) Gleason score Ł 6, 4) pretreatment PSA value of 2.0 ng/ml per year, 5) interval to PSA failure > 12 months, 6) PSA-DT (doubling time) > 12 months, 7) negative bone scan, 8) negative pelvic im-age studies, 9) positive re-biopsy [13, 14]. Additionally, younger patients with earlier-stage of a disease treated with radiation therapy are at higher risk for long-term biochemical failure compared to older patients [15]. A significant subset of these patients with recurrent disease will be candidates for curative salvage procedures [14]. Dose escalation with modern radiation therapy techniques based on 3D imaging shows the improvement of therapeutic ratio for patients with prostate cancer in recent years.

Conclusions
Salvage HDR prostate brachytherapy for biochemical failure after radiation therapy appears to be safe and well tolerated with promising results in carefully selected patients.

References
1. Martinez A, Gonzalez, Spencer W et al. Conformal high dose rate brachytherapy improves biochemical control and causes specific survival in patients with prostate cancer and poor prognostic factors. J Urol 2003; 169: 974-980.
2. Beyer DC. Brachytherapy for recurrent prostate cancer after radiation therapy. Semin Radiat Oncol 2003; 13: 158-165.
3. Tharp M, Hardacre M, Bennett R et al. Prostate high-dose rate brachytherapy as salvage treatment of local failure after previous external or permanent seed irradiation for prostate cancer. Brachytherapy 2008; 7: 231-236.
4. Niehoff P, Loch T, Nurnberg N et al. Feasibility and preliminary outcome of salvage combined HDR brachytherapy and external beam radiotherapy (EBRT) for local recurrences after radical prostatectomy. Brachytherapy 2005; 4: 141-145.
5. Lee B, Shinohara K, Weinberg V et al. Feasibility of high-dose rate brachytherapy salvage for local prostate cancer recurrence after radiotherapy: the University of California-San Francisco experience. Int J Radiat Oncol Biol Phys 2007; 67: 1106-1112.
6. Spiess PE, Lee AK, Leibovici D et al. Presalvage prostate-specific antigen (PSA) and PSA doubling time as predictors of biochemical failure of salvage cryotherapy in patients with locally recurrent prostate cancer after radiotherapy. Cancer 2006; 107: 275-280.
7. Consensus statement: guidelines for PSA following radiation therapy. American Society for Therapeutic Radiology and Oncology Consensus Panel. Int J Radiat Oncol Biol Phys 1997; 37: 1035-1041.
8. Pollack A, Zagars GK, Antolak JA et al. Prostate biopsy status and PSA nadir level as early surrogates for treatment failure: Analysis of a prostate cancer randomized radiation dose escalation trial. Int J Radiat Oncol Biol Phys 2002; 54: 677-685.
9. Fowler J, Chappell RC, Ritter MA. Is alpha/beta for prostate tumors really low? Int J Radiat Oncol Biol Phys 2001; 50: 1021-1031.
10. Wang JZ, Guerrero M, Allen X. How low is the alpha-beta ratio for prostate cancer. Int J Radiat Oncol Biol Phys 2003; 55: 194-203.
11. Williams SG, Taylor JM, Liu N et al. Use of individual fraction size data from 3,756 patients to directly determine the alpha/beta ratio of prostate cancer. Int J Radiat Oncol Biol Phys 2007; 68: 24-33.
12. Dasu A. Is the a/b value for prostate tumors low enough to be safely used in clinical trials. Clin Oncol 2007; 19: 289-301.
13. Chen BT, Wood DP Jr. Salvage prostatectomy in patients who have failed radiation therapy or cryotherapy as primary treatment for prostate cancer. Urology 2003; 62 Suppl 1: 69-78.
14. Allen GW, Howard AR, Jarrard DF et al. Management of prostate cancer recurrences after radiation therapy-brachytherapy as a salvage option. Cancer 2007; 110: 1405-1416.
15. Zelefsky MJ, Fuks Z, Hunt M et al. High-dose intensity modulated radiation therapy for prostate cancer: early toxicity and biochemical outcome in 772 patients. Int J Radiat Oncol Biol Phys 2002; 53: 1111-1116.