Int Urol Nephrol (2015) 47:301–305 DOI 10.1007/s11255-014-0887-7
UROLOGY - ORIGINAL PAPER
Salvage cryosurgery for locally recurrent prostate cancer after primary cryotherapy Xiaofeng Chang · Tieshi Liu · Fan Zhang · Xiaozhi Zhao · Changwei Ji · Rong Yang · Weidong Gan · Gutian Zhang · Xiaogong Li · Hongqian Guo
Received: 21 June 2014 / Accepted: 16 November 2014 / Published online: 16 December 2014 © Springer Science+Business Media Dordrecht 2014
Abstract Objective To report our preliminary experience of salvage cryosurgery (SCS) for locally recurrent prostate cancer (PCa) after primary cryotherapy and determine the efficacy of cryoablation of the prostate in the salvage setting. Patients and methods We conducted a retrospective review of the records of all patients who underwent SCS for locally recurrent PCa after primary cryotherapy between February 2008 and March 2012. Patients were assessed after treatment by prostate-specific antigen (PSA) testing, transrectal ultrasonography, radiologic imaging, and biopsy. Biochemical failure was defined using the Phoenix criteria. Results Data from 12 patients who had undergone SCS were entered. Median age at SCS was 77.5 year. Before SCS, patients had a median PSA level of 2.5 ng/ml and median Gleason sum of 7. Patients underwent SCS at a median of 7.8 months after primary CS. Median PSA nadir after SCS was 1.32 ng/ml. The mean (range) follow-up was 33.5 months. Three patients were started on hormonal therapy for disease progression at a median post-SCS period of 12 months. Two patients underwent repeat cryoablation. Only one patient developed mild incontinence after
Xiaofeng Chang and Tieshi Liu have contributed equally to this work as co-first authors. X. Chang · T. Liu · F. Zhang · X. Zhao · C. Ji · R. Yang · W. Gan · G. Zhang · X. Li (*) · H. Guo (*) Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, Jiangsu, China e-mail: [email protected] H. Guo e-mail: [email protected]
SCS. Urethral sloughing occurred in one patient. Only two patients suffered from transient impotence. Conclusions It is feasible for patients with PCa to adopt SCS when primary cryotherapy has failed. The application of SCS also allows hormonal therapy to be deferred for a sufficient period of time. Keywords Prostatic neoplasms · Cryosurgery · Recurrence · Salvage · Focal therapy
Introduction Prostate cancer (PCa) is the most common male cancer in the Western countries, and there is an increasing incidence of PCa in Eastern countries including China. More than seventy percent of these cancers are discovered when they are still localized with the help of prostate-specific antigen (PSA) and early diagnosis [1]. Radical prostatectomy (RP), radiotherapy (RT), cryosurgery (CS), and active surveillance are all used as primary management modalities for localized PCa [2]. Biopsy and serum prostate-specific antigen (PSA) data after curative therapy suggest a significant clinical failure rate in these patients. Among patients who have undergone CS, failure rates range from 20 to 50 % [3–5]. There has been no consensus on optimal management for local recurrence after primary prostate cryotherapy. An alternative treatment is hormonal therapy, which has no curative potential. Salvage RP has curative potential but it is more technically challenging than primary RP and associated with high morbidity. Repeating RT is not successful, as these tumors are radio-resistant, and it is associated with a greater risk of complications. Salvage cryoablation has emerged as a potentially curative treatment option that maintains cancer control while minimizing treatment side
13
302
Int Urol Nephrol (2015) 47:301–305
effects. Many studies about salvage cryosurgery (SCS) in treating the prostate recurrence after RT with encouraging outcomes have been reported. The longest follow-up available demonstrated a 7-year biochemical disease-free rate of 59 % using a PSA threshold definition of biochemical failure (BF) of 0.5 ng/ml [6]. Several other recent publications have demonstrated an improvement in functional and oncologic outcomes with improved technology [7, 8]. However, there is little report about applying SCS to the treatment of recurrent prostate cryotherapy. In the present study, we report the oncological and functional outcomes of our preliminary experience with salvage cryoablation for locally recurrent PCa after primary CS.
Patients and methods This study was approved by the institutional review board of our center. We reviewed the records of all the patients who underwent SCS for locally recurrent PCa after primary cryotherapy between February 2008 and March 2012 at our hospital retrospectively. All men were identified as developing an isolated local recurrence after CS by a rising PSA level and a positive biopsy with a negative distant metastatic workup with abdominal and pelvic computed tomography (CT) and radionucleotide bone scan before treatment. Data collected included patient age, PSA levels before and after primary and salvage treatment, clinical stage, biopsy Gleason grade, follow-up PSA levels, and survival. Hormonal therapy use data before and after salvage cryoablation were also collected. Our technique of CS has been previously described [9]. All cryoablation procedures were performed using the Table 1 Patient demographics and tumor characteristics Number of patients (n) Median patient age (range, year) Median Gleason sum before CS (range) Median serum PSA before CS (range, ng/mL) Number of stage pre-CS (%) T2a T2b T3a Median serum nadir PSA after CS (range, ng/mL) Median pre-SCS Gleason sum (range) Median interval between CS and SCS (range, month) Median pre-SCS serum PSA (range, ng/mL) Median follow-up (mo)
12
Median PSA nadir after SCS (range, ng/mL)
1.32 (0.15–4.14)
77.5 (56–86) 7 (6–9) 26.04 (3.81–38.63) 4 (33.3 %) 6 (50.0 %) 2 (16.7 %) 0.08 (0.03–3.12) 7 (6–9) 7.8 (3–42) 2.5 (0.18–7.28) 33 (15–54)
CS cryosurgery, SCS salvage cryosurgery, PSA prostate-specific antigen
13
Cryo-Hit System (Galil Medical Ltd, Israel) by a single surgeon. Under general anesthesia with the patient in the modified lithotomic position, a urethral-warming catheter was placed in the bladder with warm saline circulating through it at a temperature of 40 °C. Under transrectal ultrasound (TRUS) guidance (BK 2202UV, Denmark), cryoprobes (two to four, depending on gland size) were placed into the prostate through the perineum using a brachytherapy grid. Temperature probes were then placed in Denonvilliers’ fascia in the treated side, the apex, the external sphincter, and the neurovascular bundle ipsilateral to the site of disease recurrence. After placement of all probes, warmed normal saline (40 °C) was circulated through a urethralwarming device, and two to four freeze thaw cycles were performed. Each freezing cycle continued until all temperature probes (except the one at the external sphincter) registered less than −20 °C. The urethral-warming catheter was exchanged for an 18F Foley catheter 30 min after completion of the procedure. The bladder was drained postoperatively with urethral Foley catheter for 1 day and a suprapubic cystostomy catheter for 3 weeks. The patients were followed up with physical examination and PSA measurement every 3 months, and with radiologic imaging (MRI, or CT) when clinically indicated. BF was defined according to the Phoenix definition (>2-ng/mL rise in PSA value above the post-cryotherapy nadir) [10], which had been reported as being preferable to the classic ASTRO definition (when there are three consecutive increases in the serum PSA following nadir) [11]. Prostate biopsies were performed routinely 6 months after treatment and/or on suspicious PSA findings. Bone scans were performed when necessary to rule out metastasis. Potency was defined as erections adequate for penetration in over half of attempts (score ≥3 in question 2 of the International Index of Erectile Function) [12]. Continence was defined as the use of no pads. Androgen deprivation therapy (ADT) was begun purely at the discretion of the treating physician; in no cases was ADT started before biochemical, histologic, or clinical recurrence.
Results The patient demographics and tumor characteristics are presented in Table 1. Overall, 12 patients, who had sufficient follow-up data to be included in the analysis, underwent SCS for biopsy proven locally recurrent PCa after CS between February 2008 and March 2012 at our hospital. All of them underwent a focal CS and SCS. Median age at SCS was 77.5 year (range 56–86 year). Patient characteristics prior to primary treatment included a median PSA level of 26.04 ng/ml (range 3.81–38.63 ng/ml) and median Gleason sum of 7 (range 6–9). After primary treatment, median PSA
Int Urol Nephrol (2015) 47:301–305
nadir was 0.08 ng/ml (range 0.03–3.12 ng/ml). Median time to recurrence was 7.8 months (range 3–42 months). Before SCS, patients had a median PSA level of 2.5 ng/ ml (range 0.18–7.28 ng/ml) and median Gleason sum of 7 (range 6–9). Patients underwent SCS at a median of 7.8 months (range 3–42 months) after primary CS. Median PSA nadir after SCS was 1.32 ng/ml (range 0.15–4.14 ng/ ml). The mean (range) follow-up was 33.5 (15–54) months; there were no operative or cancer-related deaths. All the 12 patients had a reduction in the PSA after the initial 3 months of SCS. There were seven patients, who did not suffer from biochemical or clinical recurrence, having a relatively stable and low PSA in the last follow-up. Among these seven patients, none of them received any hormonal therapy after SCS. A total of three patients were started on hormonal therapy for disease progression at a median postSCS period of 12 months (range 9–18 months). There were two patients who underwent repeat cryoablation for persistent disease without metastasis. Both of them had biopsyproven cancer (GS: 6 and 7, respectively) on the treated side, and the disease was under control after the secondary SCS without hormonal therapy. Complications resulting from cryoablation were as follows. While minor side effects were common in cryoablation, severe complications such as urethrorectal fistula and total urinary incontinence were rare. No urethral strictures, rectourethral fistulas, or chronic pelvic pain were reported in our cohort. No patients experienced urinary retention. Those with persistent lower urinary tract symptoms were treated adequately with symptomatic relief using α-blockers or anti-spasmodics depending on the urinary complaint. Only one patient (1/12, 8.3 %) who underwent a repeat therapy developed mild incontinence requiring 1–2 pads per day after SCS. Urethral sloughing occurred in one of the 12 patients (1/12, 8.3 %) and was resolved with short-term catheterization. Only two relatively young patients who were potent at the time of salvage cryoablation suffered from transient impotence immediately after the procedure because of the damage that occurred to the neurovascular bundles.
Discussion Currently, CS is offered as primary therapy for PCa, especially for those deemed medically unfit for surgery. However, complete ablation of the prostate is difficult to achieve with current cryoablation techniques. Chin et al. [13] found that after cryoablation up to 43 % of patients harbor residual viable benign glands at some point on follow-up biopsy. They also found that persistence or recurrence of PCa existed in 16.6 % of their patients [14]. More and more researchers have focused their attention on the
303
application of SCS in the treatment of locally recurrent PCa after primary RT. Pisters et al. [15] reported the results of 279 patients who had undergone salvage cryoablation that the 5-year actuarial biochemical disease-free rates were 58.9 ± 5.7 % (ASTRO) and 54.5 ± 4.9 % (Phoenix). They concluded that biochemical and local control rates supported the use of salvage cryoablation for localized recurrence following failed radiation therapy. Wenske et al. [16] conducted a sufficient follow-up of 328 patients and found that respective 5- and 10-year DFS was 63 and 35 %; OS: 74 and 45 %; and DSS: 91 and 79 %. Their analysis confirmed SCS as an effective treatment option for patients failing primary RT. However, there are few reports about SCS in the treatment of patients who had locally recurrent PCa after primary cryoablation. This study reports our preliminary results in patients with biopsy-proven local recurrence of PCa following primary cryoablation. Salvage cryoablation is most effective in patients who present with a low PSA at the time of the procedure. Conversely, salvage cryoablation has limited efficacy for patients who present with high PSA levels. Ng et al. [14] showed that the best outcomes were seen in patients who presented with a PSA
UROLOGY - ORIGINAL PAPER
Salvage cryosurgery for locally recurrent prostate cancer after primary cryotherapy Xiaofeng Chang · Tieshi Liu · Fan Zhang · Xiaozhi Zhao · Changwei Ji · Rong Yang · Weidong Gan · Gutian Zhang · Xiaogong Li · Hongqian Guo
Received: 21 June 2014 / Accepted: 16 November 2014 / Published online: 16 December 2014 © Springer Science+Business Media Dordrecht 2014
Abstract Objective To report our preliminary experience of salvage cryosurgery (SCS) for locally recurrent prostate cancer (PCa) after primary cryotherapy and determine the efficacy of cryoablation of the prostate in the salvage setting. Patients and methods We conducted a retrospective review of the records of all patients who underwent SCS for locally recurrent PCa after primary cryotherapy between February 2008 and March 2012. Patients were assessed after treatment by prostate-specific antigen (PSA) testing, transrectal ultrasonography, radiologic imaging, and biopsy. Biochemical failure was defined using the Phoenix criteria. Results Data from 12 patients who had undergone SCS were entered. Median age at SCS was 77.5 year. Before SCS, patients had a median PSA level of 2.5 ng/ml and median Gleason sum of 7. Patients underwent SCS at a median of 7.8 months after primary CS. Median PSA nadir after SCS was 1.32 ng/ml. The mean (range) follow-up was 33.5 months. Three patients were started on hormonal therapy for disease progression at a median post-SCS period of 12 months. Two patients underwent repeat cryoablation. Only one patient developed mild incontinence after
Xiaofeng Chang and Tieshi Liu have contributed equally to this work as co-first authors. X. Chang · T. Liu · F. Zhang · X. Zhao · C. Ji · R. Yang · W. Gan · G. Zhang · X. Li (*) · H. Guo (*) Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, Jiangsu, China e-mail: [email protected] H. Guo e-mail: [email protected]
SCS. Urethral sloughing occurred in one patient. Only two patients suffered from transient impotence. Conclusions It is feasible for patients with PCa to adopt SCS when primary cryotherapy has failed. The application of SCS also allows hormonal therapy to be deferred for a sufficient period of time. Keywords Prostatic neoplasms · Cryosurgery · Recurrence · Salvage · Focal therapy
Introduction Prostate cancer (PCa) is the most common male cancer in the Western countries, and there is an increasing incidence of PCa in Eastern countries including China. More than seventy percent of these cancers are discovered when they are still localized with the help of prostate-specific antigen (PSA) and early diagnosis [1]. Radical prostatectomy (RP), radiotherapy (RT), cryosurgery (CS), and active surveillance are all used as primary management modalities for localized PCa [2]. Biopsy and serum prostate-specific antigen (PSA) data after curative therapy suggest a significant clinical failure rate in these patients. Among patients who have undergone CS, failure rates range from 20 to 50 % [3–5]. There has been no consensus on optimal management for local recurrence after primary prostate cryotherapy. An alternative treatment is hormonal therapy, which has no curative potential. Salvage RP has curative potential but it is more technically challenging than primary RP and associated with high morbidity. Repeating RT is not successful, as these tumors are radio-resistant, and it is associated with a greater risk of complications. Salvage cryoablation has emerged as a potentially curative treatment option that maintains cancer control while minimizing treatment side
13
302
Int Urol Nephrol (2015) 47:301–305
effects. Many studies about salvage cryosurgery (SCS) in treating the prostate recurrence after RT with encouraging outcomes have been reported. The longest follow-up available demonstrated a 7-year biochemical disease-free rate of 59 % using a PSA threshold definition of biochemical failure (BF) of 0.5 ng/ml [6]. Several other recent publications have demonstrated an improvement in functional and oncologic outcomes with improved technology [7, 8]. However, there is little report about applying SCS to the treatment of recurrent prostate cryotherapy. In the present study, we report the oncological and functional outcomes of our preliminary experience with salvage cryoablation for locally recurrent PCa after primary CS.
Patients and methods This study was approved by the institutional review board of our center. We reviewed the records of all the patients who underwent SCS for locally recurrent PCa after primary cryotherapy between February 2008 and March 2012 at our hospital retrospectively. All men were identified as developing an isolated local recurrence after CS by a rising PSA level and a positive biopsy with a negative distant metastatic workup with abdominal and pelvic computed tomography (CT) and radionucleotide bone scan before treatment. Data collected included patient age, PSA levels before and after primary and salvage treatment, clinical stage, biopsy Gleason grade, follow-up PSA levels, and survival. Hormonal therapy use data before and after salvage cryoablation were also collected. Our technique of CS has been previously described [9]. All cryoablation procedures were performed using the Table 1 Patient demographics and tumor characteristics Number of patients (n) Median patient age (range, year) Median Gleason sum before CS (range) Median serum PSA before CS (range, ng/mL) Number of stage pre-CS (%) T2a T2b T3a Median serum nadir PSA after CS (range, ng/mL) Median pre-SCS Gleason sum (range) Median interval between CS and SCS (range, month) Median pre-SCS serum PSA (range, ng/mL) Median follow-up (mo)
12
Median PSA nadir after SCS (range, ng/mL)
1.32 (0.15–4.14)
77.5 (56–86) 7 (6–9) 26.04 (3.81–38.63) 4 (33.3 %) 6 (50.0 %) 2 (16.7 %) 0.08 (0.03–3.12) 7 (6–9) 7.8 (3–42) 2.5 (0.18–7.28) 33 (15–54)
CS cryosurgery, SCS salvage cryosurgery, PSA prostate-specific antigen
13
Cryo-Hit System (Galil Medical Ltd, Israel) by a single surgeon. Under general anesthesia with the patient in the modified lithotomic position, a urethral-warming catheter was placed in the bladder with warm saline circulating through it at a temperature of 40 °C. Under transrectal ultrasound (TRUS) guidance (BK 2202UV, Denmark), cryoprobes (two to four, depending on gland size) were placed into the prostate through the perineum using a brachytherapy grid. Temperature probes were then placed in Denonvilliers’ fascia in the treated side, the apex, the external sphincter, and the neurovascular bundle ipsilateral to the site of disease recurrence. After placement of all probes, warmed normal saline (40 °C) was circulated through a urethralwarming device, and two to four freeze thaw cycles were performed. Each freezing cycle continued until all temperature probes (except the one at the external sphincter) registered less than −20 °C. The urethral-warming catheter was exchanged for an 18F Foley catheter 30 min after completion of the procedure. The bladder was drained postoperatively with urethral Foley catheter for 1 day and a suprapubic cystostomy catheter for 3 weeks. The patients were followed up with physical examination and PSA measurement every 3 months, and with radiologic imaging (MRI, or CT) when clinically indicated. BF was defined according to the Phoenix definition (>2-ng/mL rise in PSA value above the post-cryotherapy nadir) [10], which had been reported as being preferable to the classic ASTRO definition (when there are three consecutive increases in the serum PSA following nadir) [11]. Prostate biopsies were performed routinely 6 months after treatment and/or on suspicious PSA findings. Bone scans were performed when necessary to rule out metastasis. Potency was defined as erections adequate for penetration in over half of attempts (score ≥3 in question 2 of the International Index of Erectile Function) [12]. Continence was defined as the use of no pads. Androgen deprivation therapy (ADT) was begun purely at the discretion of the treating physician; in no cases was ADT started before biochemical, histologic, or clinical recurrence.
Results The patient demographics and tumor characteristics are presented in Table 1. Overall, 12 patients, who had sufficient follow-up data to be included in the analysis, underwent SCS for biopsy proven locally recurrent PCa after CS between February 2008 and March 2012 at our hospital. All of them underwent a focal CS and SCS. Median age at SCS was 77.5 year (range 56–86 year). Patient characteristics prior to primary treatment included a median PSA level of 26.04 ng/ml (range 3.81–38.63 ng/ml) and median Gleason sum of 7 (range 6–9). After primary treatment, median PSA
Int Urol Nephrol (2015) 47:301–305
nadir was 0.08 ng/ml (range 0.03–3.12 ng/ml). Median time to recurrence was 7.8 months (range 3–42 months). Before SCS, patients had a median PSA level of 2.5 ng/ ml (range 0.18–7.28 ng/ml) and median Gleason sum of 7 (range 6–9). Patients underwent SCS at a median of 7.8 months (range 3–42 months) after primary CS. Median PSA nadir after SCS was 1.32 ng/ml (range 0.15–4.14 ng/ ml). The mean (range) follow-up was 33.5 (15–54) months; there were no operative or cancer-related deaths. All the 12 patients had a reduction in the PSA after the initial 3 months of SCS. There were seven patients, who did not suffer from biochemical or clinical recurrence, having a relatively stable and low PSA in the last follow-up. Among these seven patients, none of them received any hormonal therapy after SCS. A total of three patients were started on hormonal therapy for disease progression at a median postSCS period of 12 months (range 9–18 months). There were two patients who underwent repeat cryoablation for persistent disease without metastasis. Both of them had biopsyproven cancer (GS: 6 and 7, respectively) on the treated side, and the disease was under control after the secondary SCS without hormonal therapy. Complications resulting from cryoablation were as follows. While minor side effects were common in cryoablation, severe complications such as urethrorectal fistula and total urinary incontinence were rare. No urethral strictures, rectourethral fistulas, or chronic pelvic pain were reported in our cohort. No patients experienced urinary retention. Those with persistent lower urinary tract symptoms were treated adequately with symptomatic relief using α-blockers or anti-spasmodics depending on the urinary complaint. Only one patient (1/12, 8.3 %) who underwent a repeat therapy developed mild incontinence requiring 1–2 pads per day after SCS. Urethral sloughing occurred in one of the 12 patients (1/12, 8.3 %) and was resolved with short-term catheterization. Only two relatively young patients who were potent at the time of salvage cryoablation suffered from transient impotence immediately after the procedure because of the damage that occurred to the neurovascular bundles.
Discussion Currently, CS is offered as primary therapy for PCa, especially for those deemed medically unfit for surgery. However, complete ablation of the prostate is difficult to achieve with current cryoablation techniques. Chin et al. [13] found that after cryoablation up to 43 % of patients harbor residual viable benign glands at some point on follow-up biopsy. They also found that persistence or recurrence of PCa existed in 16.6 % of their patients [14]. More and more researchers have focused their attention on the
303
application of SCS in the treatment of locally recurrent PCa after primary RT. Pisters et al. [15] reported the results of 279 patients who had undergone salvage cryoablation that the 5-year actuarial biochemical disease-free rates were 58.9 ± 5.7 % (ASTRO) and 54.5 ± 4.9 % (Phoenix). They concluded that biochemical and local control rates supported the use of salvage cryoablation for localized recurrence following failed radiation therapy. Wenske et al. [16] conducted a sufficient follow-up of 328 patients and found that respective 5- and 10-year DFS was 63 and 35 %; OS: 74 and 45 %; and DSS: 91 and 79 %. Their analysis confirmed SCS as an effective treatment option for patients failing primary RT. However, there are few reports about SCS in the treatment of patients who had locally recurrent PCa after primary cryoablation. This study reports our preliminary results in patients with biopsy-proven local recurrence of PCa following primary cryoablation. Salvage cryoablation is most effective in patients who present with a low PSA at the time of the procedure. Conversely, salvage cryoablation has limited efficacy for patients who present with high PSA levels. Ng et al. [14] showed that the best outcomes were seen in patients who presented with a PSA
