Clinical Investigations
Salvage brachytherapy for local recurrences of prostate cancer treated previously with radiotherapy

Purpose
Carcinoma of the prostate is one of the most common health problems among men [1]. In Poland the prostate cancer incidence rate is 28.3/100 000 [2] and it is the second leading cause of cancer-related deaths after lung carcinoma [3]. Radiation therapy for localized prostate cancer is a standard option of treatment. The risk of local recurrences depends on the initial stage, Gleason score and PSA level. Usually recurrences have ominous prognosis. The standard treatment is androgen deprivation therapy. Local recur-rences after EBRT are a difficult clinical problem [4]. Increasing PSA in patients after radical therapy may occur as a signal of local failure after initial local therapy or as a sign of dissemination [5]. The response to hormone therapy lasts about 2 years and then the disease progresses. Patients who do not have distant metastases potentially may be cured with a salvage local therapy [5, 6]. There is no standard treatment for locally relapsed prostate cancer after EBRT. Radical prostatectomy, brachytherapy (BT), cryotherapy and high-intensity focused ultrasound are currently used as local salvage treatments [5, 7].
Depending on initial prognostic factors, it is estimated that about 10-70% of patients who undergo definitive radiotherapy for prostate cancer may experience a bio-chemical recurrence [4, 8]. Post-radiotherapy increasing PSA level can predict tumour recurrence. It is estimated that 75% of patients will have clinically detectable recurrent prostatic cancer 5 years after a PSA elevation [9]. Patients with local-only recurrence after EBRT can be treated with a salvage therapy, and salvage HDR-BT is one of the most promising options. Prostatectomy and cryotherapy have very serious side effects and only some patients are eligible for the treatment [10]. High-intensity focused ultrasound is still an experimental method [11]. In MCS Memorial Institute of Oncology in Gliwice a research programme on salvage HDR-BT for local recurrences of prostate cancer treated previously with radiotherapy was started in February 2008. The aim of the study was to analyze early effects and toxicity of salvage high dose rate brachytherapy for local recurrences of prostate cancer after EBRT.

Material and methods
Eligibility criteria: confirmed local recurrence after radiotherapy for localized prostate cancer (transrectal ultrasound or MRI of the prostate, bone scan for occult metastases, biopsy of the prostate for histopathological confirmation of the recurrences). Time interval from radiotherapy had to be at least 2 years. Exclusion criteria were the same as for any HDR brachytherapy of the prostate: metastatic disease, volume > 60 cm³, TURP (transurethral resection of the prostate) within 6 months, infiltration of the external sphincter of the bladder neck, significant urinary obstructive symptoms, pubic arch interference, lithotomic position or anaesthesia not possible.
According to these criteria from February 2008 to October 2009 fifteen patients were enrolled, treated and analyzed in the Maria Skłodowska-Curie Memorial Cancer Centre and Institute of Oncology, Gliwice Branch.
It was an inhomogeneous group in terms of initial stage and treatment. The mean age was 67 years (range 62-81 yrs). According to NCCN 2008 before primary treatment five patients had low risk cancer, two intermediate risk, seven high risk and one with cancer of unknown risk. All patients were treated with EBRT: six patients had conventional EBRT (73-76 Gy), eight EBRT with HDR-BT boost (EBRT: 54 Gy plus 10 Gy Ir 192), one patient underwent hypofractionated EBRT (52 Gy, dose per fraction 2.6 Gy). 10/15 patients had whole pelvis irradiation (45-46 Gy) and 4/15 received adjuvant hormone therapy after the primary treatment. Mean time of follow-up after prior radiotherapy to salvage treatment was 4.5 years (range 2-9). PSA nadir range: 0.03-5.72 ng/ml (mean 1.42 ng/ml, median 0.24). PSA before salvage HDR-BT range 1.04-11.57 ng/ml (median 4.01 ng/ml; mean 5.07). All recurrences were confirmed by biopsy. Gleason score of recurrence ranged from 6 to 8 (in 6 patients only foci adenocarcinoma was noted). Three patients had perineural invasion. Four patients had hormone-resistant cancer. Eight were on androgen deprivation therapy before BT salvage (two on the second line).
HDR brachytherapy was delivered using an iridium-192 stepping source (MicroSelectron®, Nucletron NV). Treat-ment planning was performed intra-operatively based on real time rectal ultrasonography (Oncentra Prostate 3.0 by Nucletron BV®). Needle applications were performed during spinal anaesthesia. The treatment consisted of 3 fractions of 10 Gy each given every 14 days. The dose was calculated on the prostate capsule or 2-3 mm from it (depending on clinical case). Generally homogeneous needle distributions were applied, with a hot-spot planned in the case of a visible tumour. Maximal urethral doses (calculated at the centre of the urethral outline each 3 mm) were constrained to be 120% of the prescribed dose. Maximal bladder and rectum doses were constrained to be 70% of the prescribed dose. Mean V 100% of prostate was 95% of prescribe and mean D10 in urethra from all applications was 118.5% (Fig. 1). The mean follow-up period is 9 months (range: 3-15 months).
Acute and late radiation toxicity were evaluated according to the EORTC/RTOG scale [6]. Change in IPSS (International Prostate Symptoms Score) and in PSA level was analyzed. A statistical analysis of results was carried out using Statistica 7.0 software. Student’s t-test was used for statistical analysis.

Results
All patients completed the treatment without major complications. The most common early complications were: macroscopic haematuria, pain in lower part of the abdomen or transient dysuria. During the first week after the procedure a transient increase in IPSS score was noticed (Fig. 2). The Foley catheter was removed on day 2 to 5. No complications after spinal anaesthesia were observed.
Acute toxicity according to EORTC/RTOG was low. For the bladder EORTC/RTOG score ranged from 0 to 2. Only in two patients grade 1 toxicity for the rectum was observed.
One patient had developed late rectum toxicity grade 2 after 12 months post salvage HDR-BT. One patient had urethral stricture 9 months post salvage BT and two patients developed bone metastases (one after a major surgical procedure, orthopaedic surgery, performed one month after salvage BT, the second after TURP for urethral stricture that developed 9 months after salvage HDR-BT) (Fig. 3).
PSA levels at 3, 6 and 9 months after salvage HDR-BT were examined. A decrease in PSA level between PSA before the treatment and after the treatment (except two cases where dissemination was observed; in those two patients a rapid increase of PSA level was observed just after dissemination). Mean PSA level after 3 months in all patients was 10.7 ng/ml (median 1.3 ng/ml), and after 9 months median was 1.8 ng/ml) (Fig. 4). In the group of 13 patients without distant metastasis there was observed a statistically significant decrease in PSA level. Mean PSA level after 3 months in that group was 2.53 ng/ml (median 1.02 ng/ml), and after 9 months median was 0.9 ng/ml) (Fig. 5). In a group of 11 patients with the best prognostic factors, without distant metastasis, with hormone-responsive tumour the PSA level decrease was the most striking. Mean PSA level after 3 months in that group was 3.35 ng/ml (median 1.9 ng/ml), and after 9 months median was 0.2 ng/ml (Fig. 6). The PSA level before and after salvage HDR-BT was summarised in Table 1.

Discussion
The first salvage brachytherapy was performed 40 years ago. But only now HDR units for brachytherapy for prostate cancer are more extensively available. Brachytherapy shows advantages over external beam radiotherapy in terms of re-irradiation mainly by the chance to spare organs at risk [12, 13]. Experience in salvage brachytherapy is limited, in the literature about 370 cases have been reported [13, 14] and the biggest group was described by Łyczek et al. [14]. Unresolved questions concern: the maximal dose for rectum, urethra and bladder neck after previous irradiation, the optimal dose and scheme of fractionation, and optimal qualification (who really benefits from the procedures). The presented early results are encouraging. The treatment was generally well tolerated and the toxicity was acceptable, which is consistent with data from other authors [7, 13-16].
Our inclusion criteria are among the widest. We assume that low toxicity of the treatment allowed the procedure to be used even in patients with general poor prognosis, mainly as an attempt at palliative treatment (which still may give a chance to prolong life for patients who have failed hormonal manipulation). The small numbers of analyzed patients prevent us from drawing any hard conclusions, but there is a clear trend for PSA level to fall after the treatment. Among the 15 patients only 4 with hormone-responsive cancer had endocrine treatment, so the observed drop in PSA should be attributed to brachytherapy. The two patients who suffered from dissemination did not have any significant risk for dissemination before the procedure. What is striking is the fact that dissemination was observed soon (4 and 6 weeks) after surgical procedures. Another interesting observation is the development of grade 2 late rectum toxicity in patients who had pronounced acute and late toxicity during and after previous irradiation.

Conclusions
Salvage brachytherapy for localized prostate cancer (3 × 10 Gy every 14 days) seems to be a safe and well tolerated procedure. A significant decline in PSA level is seen in patients with hormone-responsive cancer. Long-term efficiency and toxicity of the procedure are yet to be established.

References
1. Chodak G. Prostate cancer: epidemiology, screening, and biomarkers. Rev Urol 2006; 8 (Suppl 2): S3-S8.
2. Krajowy Rejestr Nowotworów. Centrum Onkologii – Instytut im. Marii Skłodowskiej-Curie w Warszawie, 2007 [in Polish].
3. Williams H, Powell IJ. Epidemiology, pathology, and genetics of prostate cancer among African Americans compared with other ethnicities. Methods Mol Biol 2009; 472: 439-453.
4. Weber DC, Wang H, Cozzi L et al. RapidArc, intensity modulated photon and proton techniques for recurrent prostate cancer in previously irradiated patients: a treatment planning comparison study. Radiat Oncol 2009; 9: 34-39.
5. Moul JW, Banez LL, Freedland SJ. Rising PSA in nonmetastatic prostate cancer. Oncology 2007; 21: 1436-1445.
6. Nguyen PL, Chen MH, D’Amico AV et al. Magnetic Resonance Image-guided Salvage Brachytherapy After Radiation in Select Men Who Initially Presented With Favorable-risk Prostate Cancer. A Prospective Phase 2 Study. Cancer 2007; 110: 1485-1492.
7. De Cicco L, Vavassori A, Cattani F et al. Salvage high dose rate brachytherapy after primary external beam irradiation in localized prostate cancer: a case report. Tumori 2009; 95: 553-556.
8. Allen GW, Howard AR, Jarrard DF et al. Management of pros-tate cancer recurrences after radiation therapy – brachytherapy as a salvage option. Cancer 2007; 110: 1405-1416.
9. 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.
10. Pisters LL, Rewcastle JC, Donnelly BJ et al. Salvage prostate cryoablation: initial results from the cryo on-line data registry. J Urol 2008; 180: 559-63; discussion 563-564.
11. Chalasani V, Martinez CH, Lim D et al. Salvage HIFU for recurrent prostate cancer after radiotherapy. Prostate Cancer Prostatic Dis 2009; 12: 124-129.
12. Lee B, Shinohara K, Wienberg 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.
13. 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.
14. Łyczek J, Kawczyńska MM, Garmol M et al. HDR brachytherapy as a solution in recurrences of locally advanced prostate cancer. J Contemp Brachyther 2009; 1: 105-108.
15. Nguyen PL, D’Amico AV, Lee AK et al. Patient selection, cancer control, and complications after salvage local therapy for postradiation prostate-specific antigen failure: a systematic review of the literature. Cancer 2007; 110: 1417-1428.