http://informahealthcare.com/sju ISSN: 2168-1805 (print), 2168-1813 (electronic) Scand J Urol, 2014; 49(2): 115–119 2014 Informa Healthcare. DOI: 10.3109/21681805.2014.968869
ORIGINAL ARTICLE
Salvage cryotherapy for local recurrence after radiotherapy for prostate cancer Klara Kvorning Ternov1, Ane Krag Jakobsen2, Ola Bratt3 and Go€ran Ahlgren2 1
Medical School, Faculty of Health and Medical Science, University of Copenhagen, Denmark, 2Department of Urology, Skåne University Hospital Malmo €, Sweden, and 3Department of Urology, Helsingborg Hospital, Lund University, Sweden
Abstract
Keywords:
Objective. The aim of this study was to present the outcome of patients treated with salvage cryotherapy after radiotherapy for prostate cancer at one institution. Materials and methods. Consecutive patients treated between 2007 and 2013 with transperineal cryotherapy for biopsyverified local recurrence after radiotherapy were investigated. An external reviewer retrieved outcome data retrospectively from medical records. Complications were graded according to the Clavien classification. One patient with less than 1 year of follow-up was excluded from the analysis of side-effects. Results. Thirty patients were included, 29 of whom had a follow-up of at least 1 year. The median follow-up was 2.7 years (range 1–6.5 years). Eleven of the 23 patients without hormonal treatment at the time of cryotherapy reached a prostate-specific antigen (PSA) nadir of less than 0.5 ng/ml. At the end of follow-up five of these 23 patients still had a PSA below 0.5 ng/ml and 10 were free from recurrence according to the Phoenix definition. Clinical recurrence (verified with imaging or biopsies) was detected in 13 patients, six of which were local. One patient died from prostate cancer. Eleven patients had urinary incontinence grade 1–2 and three had grade 3–4, seven had pelvic pain, three had severe but transitory tissue sloughing, three developed a urethral stricture or had prolonged urinary retention, and one developed a urinary fistula 4.5 years after cryotherapy. Conclusions. Salvage cryotherapy should be considered as an alternative to hormonal treatment and surgery for local recurrence after radiotherapy for prostate cancer. The results compare well to those reported from centres with longer experience.
Cryotherapy, prostate cancer, salvage
Introduction Recurrence after radiotherapy for prostate cancer is common, affecting 20–50% of treated men [1]. Traditionally, patients have been managed with either observation or androgen deprivation therapy [1]. Salvage radical prostatectomy is rarely used because it is associated with a high risk of complications, especially in elderly patients [1–3]. Alternative local treatments have been investigated, such as cryotherapy, high-intensity focused ultrasound, photodynamic therapy, radiofrequency interstitial thermoablation, microwave thermoablation and brachytherapy [1,2]. Except for cryotherapy and prostatectomy, these local treatments are still considered experimental, according to the European Association of Urology Guidelines [4]. Early trials with cryotherapy in the 1980 and 1990s led to disappointing results. However, since the introduction of the third generation of cryotherapy equipment a growing body of evidence for its effectiveness has emerged [5]. The sideeffects of modern cryotherapy are acceptable [1,3,5]. Despite its increasing use worldwide, in Scandinavia salvage prostate cryotherapy is currently only preformed at Skåne University Hospital (SUS) in Malmo€, Sweden. The Correspondence: Go €ran Ahlgren, Urologiska kliniken, SUS Malmo€, SE-205 02 Malmo€, Sweden. Tel: +46 40 333753. E-mail: [email protected]
History Received 5 May 2014 Revised 28 July 2014 Accepted 4 September 2014
aim of this article was to critically evaluate the oncological outcome and side-effects for patients treated in an institution setting up cryotherapy for treatment of local recurrence after radiotherapy for prostate cancer.
Materials and methods From 2007 to 2013, 36 patients received cryotherapy for prostate cancer at SUS Malmo€, Sweden. Five of these patients received cryotherapy as the primary treatment, three of whom had been operated on and received radiotherapy for rectal cancer before their prostate cancer diagnosis. These patients were excluded. The remaining 31 patients were treated for local recurrence after primary radiotherapy; 25 were treated with external beam radiation therapy and six with low dose-rate brachytherapy (“seeds”). All 31 had a biopsy indicating local recurrence. However, for one of these patients a re-examination of the histopathological specimen after cryotherapy could not verify cancer in the biopsies. This patient was excluded from the present report, which thus includes 30 patients. Almost all patients had a positron emission tomography (PET), computed tomography (CT) or bone scan showing no evidence of metastatic disease. Patients with extensive local recurrence were not accepted for cryotherapy. In one patient, only one half of the prostate was treated (hemiablation) because of a previous extensive
116 K. Kvorning Ternov et al. transurethral resection of the prostate (TURP). Seven patients had ongoing hormonal treatment at the time of cryotherapy; these patients were not included in the analysis of biochemical recurrence.
Cryotherapy All procedures were performed by the same urologist (GA). A cystoscopy was performed and a suprapubic catheter inserted at the start of the procedure. The prostate was visualized by transrectal ultrasound (BK Medical, Herlev, Denmark). Three rows of four 17 G Iceseed cryoneedles (Galil Medical, Arden Hills, MN), placed with a margin to the rectum of 1 cm, were used for freezing and another two needles in the prerectal fat for warming. Argon gas was used for freezing and helium gas for thawing. A 17 G multipoint thermal sensor (Galil Medical, Arden Hills, MN) with four sensor points was placed in the prostate with the distal sensor at the sphincter level to ensure therapeutic freezing. Another temperature sensor needle was placed in the fat between the rectum and the prostate to control the temperature at the rectal wall. The SeedNet and later the Precise system (Galil Medical, Arden Hills, MN) were used for the cryotherapy. Two cycles of whole-gland treatment were given, with temperatures below –40 C in the midprostate and below –20 C in the apical region. A cystoscopy was performed after placing the needles to ensure that no needles were within the urethra. To preserve the urethral mucosa, a Urethral Warming Catheter (Galil Medical, Arden Hills, MN) was placed over a guidewire and circulated with water with a temperature of 40 C. The patients were discharged from the hospital on the day after cryotherapy. The suprapubic catheter was routinely open for at least 1 week. It was removed when convenient, depending on outflow obstruction and urgency. The patients were treated with an antibiotic from the time of cryotherapy until the suprapubic catheter was removed.
Scand J Urol, 2014; 49(2): 115–119
persistent if no explicit cessation was documented in the medical records. The severity of urinary incontinence was further described by the Common Terminology Criteria for Adverse Events (CTCAE), version 3.0: grade 1 = occasional, pads not indicated; grade 2 = pads indicated; grade 3 = interfering with activities of daily living and/or non-surgical intervention indicated; and grade 4 = operative intervention indicated. The oncological outcome for patients without hormonal treatment was evaluated according to two different definitions of biochemical recurrence: the Phoenix definition for recurrence after radiotherapy (PSA nadir +2 ng/ml), which commonly has been applied when reporting results of cryotherapy [7], and the recently suggested definition of an increasing PSA greater than 0.5 ng/ml [8–10]. Prostate biopsies or imaging were obtained after biochemical recurrence according to the Phoenix definition. Biochemical recurrencefree survival is presented as Kaplan–Meier plots produced by IBM SPSS Statistics program, version 22.
Results The characteristics of the prostate cancer before radiotherapy and before salvage cryotherapy are described in Table 1. The median age of the 30 patients was 70 years (range 61– 80 years) at the date for cryotherapy. The median time between primary radiotherapy and cryotherapy was 7 years (range 3–14 years). The patients were followed for up to 6.6 years from the date of cryotherapy, with a median
Table 1 Clinical characteristics before radiotherapy and before cryotherapy for 30 patients with prostate cancer treated with cryotherapy for local recurrence after radiotherapy at Skåne University Hospital in Malmo€, Sweden, between 2007 and 2014. Before Before radiotherapy (n) cryotherapy (n)
Follow-up The follow-up included a clinical examination and prostatespecific antigen (PSA) analysis at 3, 6, 12, 18 and 24 months after cryotherapy. From the third year the patients were evaluated with annual PSA tests only. The patients were instructed to contact their urologist if they experienced sideeffects beyond 2 years. The oncological outcome, complications and side-effects were assessed retrospectively through medical records by an external reviewer (KKT). Complications and side-effects were evaluated only for the patients with a follow-up of 1 year or more, and classified according to Clavien [6]: grade 1 = any deviation from the normal postoperative course without needing intervention; grade 2 = requiring pharmacological treatment; grade 3 = requiring surgical, endoscopic or radiological intervention (including catheterization) without (3a) or with (3b) general or spinal anaesthesia; and grade 4 = life threatening or lethal. Furthermore, the side-effect and complications were characterized as either early (onset 1 year). The side-effects were classified as
Clinical tumour stage T1–T2 16 T3 8 Unknown 6 Gleason score £6 2 7 9 8–10 16 Unknown 3 Prostate-specific antigen (PSA) 0.3, 0.4 or 0.5 ng/ml) reported values for 2 years’ recurrence-free survival from 19% to 51% [1]. One likely reason for the variable oncological outcome is differences in patient selection. Previous studies have established several predictors of poor outcome, such as advanced clinical tumour stage, high Gleason score, and high PSA levels and short PSA doubling time before cryotherapy [1,2,5,13,14,16]. With better patient selection, the risk of recurrence could probably be reduced. Suggested selection criteria for cryotherapy for recurrence after radiotherapy include preradiotherapy stage T1–2, Gleason score 7 or lower, precryotherapy PSA less than 5–10 ng/ml, non-apical recurrence and a recent negative metastatic investigation [1,8]. The two best documented local salvage treatments for recurrence following radiotherapy for prostate cancer are prostatectomy and cryotherapy [1,3]. According to a systematic review, the risks of urinary incontinence and serious complications are lower after cryotherapy than after prostatectomy [1]. Although cure is the principal aim of local
118 K. Kvorning Ternov et al.
Scand J Urol, 2014; 49(2): 115–119
Table 2. Side-effects and complications among 30 patients after cryotherapy for local recurrence after radiotherapy for prostate cancer, between 2007 and 2013 at Skåne University Hospital in Malmo€, Sweden.
a
Urinary incontinence Early/late Transitory/persistent Urinary urgency Early/late Transitory/persistent Urethral stricture Early/late Transitory/persistent Pelvic pain Early/late Transitory/persistent Severe sloughing Early/late Transitory/persistent Infection Early/late Transitory/persistent Fistula Early/late Transitory/persistent Erectile dysfunction
Total
Clavien 1
Clavien 2
Clavien 3a
Clavien 3b
Clavien 4
14 10/4 4/10 15 12/3 7/8 3 1/2b 2/1b 7 7/0 5/2 3 3/0 3/0 3 3/0 3/0 1 0/1 0/1
See Table 3
See Table 3
See Table 3
See Table 3
0
6
4
1
1
0
0
0
2
1b
0
0
5
0
0
0
2
0
0
1
0
0
3
0
0
0
0
0
0
0
1
Allc
For definitions of the Clavien grades, early versus late and transitory versus persistent, see Materials and Methods. Several side-effects could be registered for an individual patient. a See Table 3 for grading of urinary incontinence. bOne late urinary retention was more likely to be caused by local recurrence of the cancer. c Not assessed, but patients were told to expect erectile dysfunction.
salvage therapy, secondary aims include local cancer control with prevention of local complications, eradication of poorly differentiated cancer clones with metastatic capability, minimization of treatment-related morbidities, and maintenance of quality of life [8]. Although the effect of salvage treatment for local recurrence after radiotherapy has not been evaluated in randomized studies, the prevailing tradition of hormonal treatment only can be questioned. Cryotherapy may be an attractive alternative or complement to hormonal treatment only, especially for older patients who are not considered candidates for salvage prostatectomy. Almost half of the patients in the present treatment series experienced some urinary incontinence following cryotherapy. However, even though the median age at cryotherapy was as high as 70 years and two patients were as old as 80 years, only three out of 30 patients with more than 1 year of followup had severe incontinence (grade 3–4) (Table 3). One of Table 3. Grading of urinary incontinence among 30 patients after cryotherapy for local recurrence after radiotherapy for prostate cancer at Skåne University Hospital, Malmo€, Sweden. Grade
No.
No incontinence Grade 1: Occasional, pads not required Grade 2: Pads required, not interfering with daily living Grade 3: Interfering with daily living and/or minor intervention required Grade 4: Major intervention required, i.e. artificial sphincter
16 6 5 1 2
these patients had a TURP before radiotherapy, which makes urethral cooling ineffective, increasing the risk of sloughing. This patient underwent several transurethral resections after cryotherapy, which probably caused the incontinence. Seven patients (23%) had pelvic pain, three (10%) had prolonged problems with tissue sloughing, three (10%) developed a urethral stricture or had prolonged urinary retention, and one, who used intermittent self-catheterization, developed a urinary fistula 4.5 years after cryotherapy. A recent systematic review reported similar complication risks, with a mean of 16% urinary incontinence, 16% perianal pain, 12% urethral stricture/ retention, 8% tissue sloughing and 1.6% fistulae [1]. This illustrates that applying a local treatment to a tissue that has been radiated is associated with a high risk of complications. Most series do not report on erectile dysfunction after salvage cryotherapy. The patients in the present cohort were informed to expect erectile dysfunction. Some patients successfully used alprostadil injection after cryotherapy. This study is limited by the small number of treated patients and by the lack of prospective, patient-reported evaluation of the side-effects. The validity of the assessment of the side-effects is, however, strengthened by its having been performed by an external investigator. The retrospective collection of the data for side-effects may have led to overestimation of their duration, since they were categorized as persistent if no explicit documentation of their cessation was found in the medical records. Reliable, detailed documentation of symptoms and side-effects of the radiotherapy and other conditions before the cryotherapy was also lacking. In conclusion, cryotherapy is now a well-documented treatment for local prostate cancer recurrence after radiotherapy, with local efficacy and usually mild to moderate side-
Salvage cryotherapy
DOI: 10.3109/21681805.2014.968869
effects. The results from Skåne University Hospital in Malmo€ compare well with those reported from centres with longer experience. Proper patient selection is crucial for obtaining optimal results.
[7]
Acknowledgements This study was funded by a grant from the Swedish Cancer Foundation (2012/475). Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References [1]
[2]
[3]
[4]
[5] [6]
Parekh A, Graham PL, Nguyen PL. Cancer control and complications of salvage local therapy after failure of radiotherapy for prostate cancer: a systematic review. Semin Radiat Oncol 2013;23:222–34. Gravina GL, Tombolini V, Di Staso M, Franzese P, Bonfili P, Gennarelli A, et al. Advances in imaging and in non-surgical salvage treatments after radiorecurrence in prostate cancer: what does the oncologist, radiotherapist and radiologist need to know? Eur Radiol 2012;22:2848–58. Friedlander DF, Gu X, Prasad SM, Lipsitz SR, Nguyen PL, Trinh QD, et al. Population-based comparative effectiveness of salvage radical prostatectomy vs cryotherapy. Urology 2014;83:653–7. Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T, et al. EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol 2014;65:467–79. Mouraviev V, Spiess PE, Jones JS. Salvage cryoablation for locally recurrent prostate cancer following primary radiotherapy. Eur Urol 2012;61:1204–11. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of
[8] [9] [10]
[11]
[12] [13]
[14]
[15]
[16]
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6336 patients and results of a survey. Ann Surg 2004;240:205– 13. Roach M III, Hanks G, Thames H Jr, Schellhammer P, Shipley WU, Sokol GH, et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiol Biol Phys 2006;65:965–74. Heidenreich A. Locally recurrent prostate cancer following radiation therapy: to cut or to freeze? Eur Urol 2013;64:8–10. Levy DA, Pisters LL, Jones JS. Prognostic value of initial prostate-specific antigen levels after salvage cryoablation for prostate cancer. BJU Int 2010;106:986–90. Spiess PE, Given RW, Jones JS. Achieving the “bifecta” using salvage cryotherapy for locally recurrent prostate cancer: analysis of the Cryo On-Line Data (COLD) registry data. BJU Int 2012;110:217–20. Peters M, Moman MR, van der Poel HG, Vergunst H, de Jong IJ, Vijverberg PL, et al. Patterns of outcome and toxicity after salvage prostatectomy, salvage cryosurgery and salvage brachytherapy for prostate cancer recurrences after radiation therapy: a multi-center experience and literature review. World J Urol 2013;31:403–9. Philippou P, Yap T, Chinegwundoh F. Third-generation salvage cryotherapy for radiorecurrent prostate cancer: a centre’s experience. Urol Int 2012;88:137–44. Spiess PE, Levy DA, Mouraviev V, Pisters LL, Jones JS. Predictors of biochemical failure in patients undergoing prostate wholegland salvage cryotherapy: a novel risk stratification model. BJU Int 2013;112:E256–61. Spiess PE, Levy DA, Pisters LL, Mouraviev V, Jones JS. Outcomes of salvage prostate cryotherapy stratified by pre-treatment PSA: update from the COLD registry. World J Urol 2013;31:1321–5. Wenske S, Quarrier S, Katz AE. Salvage cryosurgery of the prostate for failure after primary radiotherapy or cryosurgery: longterm clinical, functional, and oncologic outcomes in a large cohort at a tertiary referral centre. Eur Urol 2013;64:1–7. Williams AK, Martinez CH, Lu C, Ng CK, Pautler SE, Chin JL. Disease-free survival following salvage cryotherapy for biopsyproven radio-recurrent prostate cancer. Eur Urol 2011;60:405–10.
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ORIGINAL ARTICLE
Salvage cryotherapy for local recurrence after radiotherapy for prostate cancer Klara Kvorning Ternov1, Ane Krag Jakobsen2, Ola Bratt3 and Go€ran Ahlgren2 1
Medical School, Faculty of Health and Medical Science, University of Copenhagen, Denmark, 2Department of Urology, Skåne University Hospital Malmo €, Sweden, and 3Department of Urology, Helsingborg Hospital, Lund University, Sweden
Abstract
Keywords:
Objective. The aim of this study was to present the outcome of patients treated with salvage cryotherapy after radiotherapy for prostate cancer at one institution. Materials and methods. Consecutive patients treated between 2007 and 2013 with transperineal cryotherapy for biopsyverified local recurrence after radiotherapy were investigated. An external reviewer retrieved outcome data retrospectively from medical records. Complications were graded according to the Clavien classification. One patient with less than 1 year of follow-up was excluded from the analysis of side-effects. Results. Thirty patients were included, 29 of whom had a follow-up of at least 1 year. The median follow-up was 2.7 years (range 1–6.5 years). Eleven of the 23 patients without hormonal treatment at the time of cryotherapy reached a prostate-specific antigen (PSA) nadir of less than 0.5 ng/ml. At the end of follow-up five of these 23 patients still had a PSA below 0.5 ng/ml and 10 were free from recurrence according to the Phoenix definition. Clinical recurrence (verified with imaging or biopsies) was detected in 13 patients, six of which were local. One patient died from prostate cancer. Eleven patients had urinary incontinence grade 1–2 and three had grade 3–4, seven had pelvic pain, three had severe but transitory tissue sloughing, three developed a urethral stricture or had prolonged urinary retention, and one developed a urinary fistula 4.5 years after cryotherapy. Conclusions. Salvage cryotherapy should be considered as an alternative to hormonal treatment and surgery for local recurrence after radiotherapy for prostate cancer. The results compare well to those reported from centres with longer experience.
Cryotherapy, prostate cancer, salvage
Introduction Recurrence after radiotherapy for prostate cancer is common, affecting 20–50% of treated men [1]. Traditionally, patients have been managed with either observation or androgen deprivation therapy [1]. Salvage radical prostatectomy is rarely used because it is associated with a high risk of complications, especially in elderly patients [1–3]. Alternative local treatments have been investigated, such as cryotherapy, high-intensity focused ultrasound, photodynamic therapy, radiofrequency interstitial thermoablation, microwave thermoablation and brachytherapy [1,2]. Except for cryotherapy and prostatectomy, these local treatments are still considered experimental, according to the European Association of Urology Guidelines [4]. Early trials with cryotherapy in the 1980 and 1990s led to disappointing results. However, since the introduction of the third generation of cryotherapy equipment a growing body of evidence for its effectiveness has emerged [5]. The sideeffects of modern cryotherapy are acceptable [1,3,5]. Despite its increasing use worldwide, in Scandinavia salvage prostate cryotherapy is currently only preformed at Skåne University Hospital (SUS) in Malmo€, Sweden. The Correspondence: Go €ran Ahlgren, Urologiska kliniken, SUS Malmo€, SE-205 02 Malmo€, Sweden. Tel: +46 40 333753. E-mail: [email protected]
History Received 5 May 2014 Revised 28 July 2014 Accepted 4 September 2014
aim of this article was to critically evaluate the oncological outcome and side-effects for patients treated in an institution setting up cryotherapy for treatment of local recurrence after radiotherapy for prostate cancer.
Materials and methods From 2007 to 2013, 36 patients received cryotherapy for prostate cancer at SUS Malmo€, Sweden. Five of these patients received cryotherapy as the primary treatment, three of whom had been operated on and received radiotherapy for rectal cancer before their prostate cancer diagnosis. These patients were excluded. The remaining 31 patients were treated for local recurrence after primary radiotherapy; 25 were treated with external beam radiation therapy and six with low dose-rate brachytherapy (“seeds”). All 31 had a biopsy indicating local recurrence. However, for one of these patients a re-examination of the histopathological specimen after cryotherapy could not verify cancer in the biopsies. This patient was excluded from the present report, which thus includes 30 patients. Almost all patients had a positron emission tomography (PET), computed tomography (CT) or bone scan showing no evidence of metastatic disease. Patients with extensive local recurrence were not accepted for cryotherapy. In one patient, only one half of the prostate was treated (hemiablation) because of a previous extensive
116 K. Kvorning Ternov et al. transurethral resection of the prostate (TURP). Seven patients had ongoing hormonal treatment at the time of cryotherapy; these patients were not included in the analysis of biochemical recurrence.
Cryotherapy All procedures were performed by the same urologist (GA). A cystoscopy was performed and a suprapubic catheter inserted at the start of the procedure. The prostate was visualized by transrectal ultrasound (BK Medical, Herlev, Denmark). Three rows of four 17 G Iceseed cryoneedles (Galil Medical, Arden Hills, MN), placed with a margin to the rectum of 1 cm, were used for freezing and another two needles in the prerectal fat for warming. Argon gas was used for freezing and helium gas for thawing. A 17 G multipoint thermal sensor (Galil Medical, Arden Hills, MN) with four sensor points was placed in the prostate with the distal sensor at the sphincter level to ensure therapeutic freezing. Another temperature sensor needle was placed in the fat between the rectum and the prostate to control the temperature at the rectal wall. The SeedNet and later the Precise system (Galil Medical, Arden Hills, MN) were used for the cryotherapy. Two cycles of whole-gland treatment were given, with temperatures below –40 C in the midprostate and below –20 C in the apical region. A cystoscopy was performed after placing the needles to ensure that no needles were within the urethra. To preserve the urethral mucosa, a Urethral Warming Catheter (Galil Medical, Arden Hills, MN) was placed over a guidewire and circulated with water with a temperature of 40 C. The patients were discharged from the hospital on the day after cryotherapy. The suprapubic catheter was routinely open for at least 1 week. It was removed when convenient, depending on outflow obstruction and urgency. The patients were treated with an antibiotic from the time of cryotherapy until the suprapubic catheter was removed.
Scand J Urol, 2014; 49(2): 115–119
persistent if no explicit cessation was documented in the medical records. The severity of urinary incontinence was further described by the Common Terminology Criteria for Adverse Events (CTCAE), version 3.0: grade 1 = occasional, pads not indicated; grade 2 = pads indicated; grade 3 = interfering with activities of daily living and/or non-surgical intervention indicated; and grade 4 = operative intervention indicated. The oncological outcome for patients without hormonal treatment was evaluated according to two different definitions of biochemical recurrence: the Phoenix definition for recurrence after radiotherapy (PSA nadir +2 ng/ml), which commonly has been applied when reporting results of cryotherapy [7], and the recently suggested definition of an increasing PSA greater than 0.5 ng/ml [8–10]. Prostate biopsies or imaging were obtained after biochemical recurrence according to the Phoenix definition. Biochemical recurrencefree survival is presented as Kaplan–Meier plots produced by IBM SPSS Statistics program, version 22.
Results The characteristics of the prostate cancer before radiotherapy and before salvage cryotherapy are described in Table 1. The median age of the 30 patients was 70 years (range 61– 80 years) at the date for cryotherapy. The median time between primary radiotherapy and cryotherapy was 7 years (range 3–14 years). The patients were followed for up to 6.6 years from the date of cryotherapy, with a median
Table 1 Clinical characteristics before radiotherapy and before cryotherapy for 30 patients with prostate cancer treated with cryotherapy for local recurrence after radiotherapy at Skåne University Hospital in Malmo€, Sweden, between 2007 and 2014. Before Before radiotherapy (n) cryotherapy (n)
Follow-up The follow-up included a clinical examination and prostatespecific antigen (PSA) analysis at 3, 6, 12, 18 and 24 months after cryotherapy. From the third year the patients were evaluated with annual PSA tests only. The patients were instructed to contact their urologist if they experienced sideeffects beyond 2 years. The oncological outcome, complications and side-effects were assessed retrospectively through medical records by an external reviewer (KKT). Complications and side-effects were evaluated only for the patients with a follow-up of 1 year or more, and classified according to Clavien [6]: grade 1 = any deviation from the normal postoperative course without needing intervention; grade 2 = requiring pharmacological treatment; grade 3 = requiring surgical, endoscopic or radiological intervention (including catheterization) without (3a) or with (3b) general or spinal anaesthesia; and grade 4 = life threatening or lethal. Furthermore, the side-effect and complications were characterized as either early (onset 1 year). The side-effects were classified as
Clinical tumour stage T1–T2 16 T3 8 Unknown 6 Gleason score £6 2 7 9 8–10 16 Unknown 3 Prostate-specific antigen (PSA) 0.3, 0.4 or 0.5 ng/ml) reported values for 2 years’ recurrence-free survival from 19% to 51% [1]. One likely reason for the variable oncological outcome is differences in patient selection. Previous studies have established several predictors of poor outcome, such as advanced clinical tumour stage, high Gleason score, and high PSA levels and short PSA doubling time before cryotherapy [1,2,5,13,14,16]. With better patient selection, the risk of recurrence could probably be reduced. Suggested selection criteria for cryotherapy for recurrence after radiotherapy include preradiotherapy stage T1–2, Gleason score 7 or lower, precryotherapy PSA less than 5–10 ng/ml, non-apical recurrence and a recent negative metastatic investigation [1,8]. The two best documented local salvage treatments for recurrence following radiotherapy for prostate cancer are prostatectomy and cryotherapy [1,3]. According to a systematic review, the risks of urinary incontinence and serious complications are lower after cryotherapy than after prostatectomy [1]. Although cure is the principal aim of local
118 K. Kvorning Ternov et al.
Scand J Urol, 2014; 49(2): 115–119
Table 2. Side-effects and complications among 30 patients after cryotherapy for local recurrence after radiotherapy for prostate cancer, between 2007 and 2013 at Skåne University Hospital in Malmo€, Sweden.
a
Urinary incontinence Early/late Transitory/persistent Urinary urgency Early/late Transitory/persistent Urethral stricture Early/late Transitory/persistent Pelvic pain Early/late Transitory/persistent Severe sloughing Early/late Transitory/persistent Infection Early/late Transitory/persistent Fistula Early/late Transitory/persistent Erectile dysfunction
Total
Clavien 1
Clavien 2
Clavien 3a
Clavien 3b
Clavien 4
14 10/4 4/10 15 12/3 7/8 3 1/2b 2/1b 7 7/0 5/2 3 3/0 3/0 3 3/0 3/0 1 0/1 0/1
See Table 3
See Table 3
See Table 3
See Table 3
0
6
4
1
1
0
0
0
2
1b
0
0
5
0
0
0
2
0
0
1
0
0
3
0
0
0
0
0
0
0
1
Allc
For definitions of the Clavien grades, early versus late and transitory versus persistent, see Materials and Methods. Several side-effects could be registered for an individual patient. a See Table 3 for grading of urinary incontinence. bOne late urinary retention was more likely to be caused by local recurrence of the cancer. c Not assessed, but patients were told to expect erectile dysfunction.
salvage therapy, secondary aims include local cancer control with prevention of local complications, eradication of poorly differentiated cancer clones with metastatic capability, minimization of treatment-related morbidities, and maintenance of quality of life [8]. Although the effect of salvage treatment for local recurrence after radiotherapy has not been evaluated in randomized studies, the prevailing tradition of hormonal treatment only can be questioned. Cryotherapy may be an attractive alternative or complement to hormonal treatment only, especially for older patients who are not considered candidates for salvage prostatectomy. Almost half of the patients in the present treatment series experienced some urinary incontinence following cryotherapy. However, even though the median age at cryotherapy was as high as 70 years and two patients were as old as 80 years, only three out of 30 patients with more than 1 year of followup had severe incontinence (grade 3–4) (Table 3). One of Table 3. Grading of urinary incontinence among 30 patients after cryotherapy for local recurrence after radiotherapy for prostate cancer at Skåne University Hospital, Malmo€, Sweden. Grade
No.
No incontinence Grade 1: Occasional, pads not required Grade 2: Pads required, not interfering with daily living Grade 3: Interfering with daily living and/or minor intervention required Grade 4: Major intervention required, i.e. artificial sphincter
16 6 5 1 2
these patients had a TURP before radiotherapy, which makes urethral cooling ineffective, increasing the risk of sloughing. This patient underwent several transurethral resections after cryotherapy, which probably caused the incontinence. Seven patients (23%) had pelvic pain, three (10%) had prolonged problems with tissue sloughing, three (10%) developed a urethral stricture or had prolonged urinary retention, and one, who used intermittent self-catheterization, developed a urinary fistula 4.5 years after cryotherapy. A recent systematic review reported similar complication risks, with a mean of 16% urinary incontinence, 16% perianal pain, 12% urethral stricture/ retention, 8% tissue sloughing and 1.6% fistulae [1]. This illustrates that applying a local treatment to a tissue that has been radiated is associated with a high risk of complications. Most series do not report on erectile dysfunction after salvage cryotherapy. The patients in the present cohort were informed to expect erectile dysfunction. Some patients successfully used alprostadil injection after cryotherapy. This study is limited by the small number of treated patients and by the lack of prospective, patient-reported evaluation of the side-effects. The validity of the assessment of the side-effects is, however, strengthened by its having been performed by an external investigator. The retrospective collection of the data for side-effects may have led to overestimation of their duration, since they were categorized as persistent if no explicit documentation of their cessation was found in the medical records. Reliable, detailed documentation of symptoms and side-effects of the radiotherapy and other conditions before the cryotherapy was also lacking. In conclusion, cryotherapy is now a well-documented treatment for local prostate cancer recurrence after radiotherapy, with local efficacy and usually mild to moderate side-
Salvage cryotherapy
DOI: 10.3109/21681805.2014.968869
effects. The results from Skåne University Hospital in Malmo€ compare well with those reported from centres with longer experience. Proper patient selection is crucial for obtaining optimal results.
[7]
Acknowledgements This study was funded by a grant from the Swedish Cancer Foundation (2012/475). Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References [1]
[2]
[3]
[4]
[5] [6]
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