Cytoreductive cryosurgery in patients with bone metastatic prostate cancer: A retrospective analysis

+

MODEL

Kaohsiung Journal of Medical Sciences (2017) xx, 1e7

Available online at www.sciencedirect.com

ScienceDirect journal homepage: http://www.kjms-online.com

Original Article

Cytoreductive cryosurgery in patients with bone metastatic prostate cancer: A retrospective analysis Ming-Xiong Sheng a, Ling-Ling Wan a, Chang-Ming Liu a, Chun-Xiao Liu b,*, Shu-Shang Chen c a

Department of Urology, Mindong Hospital Affiliated to Fujian Medical University, Fuan, Fujian, People’s Republic of China b Department of Urology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guang Dong, People’s Republic of China c Department of Urology, Fuzhou General Hospital, Xiamen University, Fuzhou, Fujian, People’s Republic of China Received 10 January 2017; accepted 27 June 2017

KEYWORDS Androgen deprivation; Bone metastasis; Cryosurgery; Progression-free survival; Prostate cancer

Abstract The current study is a retrospective analysis of 49 patients with bone metastatic prostate cancer: 26 receiving androgen deprivation therapy (ADT) alone versus 23 receiving cytoreductive cryosurgery of the primary tumor plus ADT treatment. Progression-free survival (PFS) was the primary outcome variable, and Cox proportional hazards regression analysis was used to identify predictors for PFS. The baseline characteristics were generally comparable between the 2 groups. Median follow-up time was 41 months (range 24e56) and 37 months (range 19e53) in ADT alone group and cryosurgery groups, respectively. Patients receiving cryosurgery had significantly longer PFS (35 vs 25 months, P Z 0.0027) and time to castration resistance (36 vs 25 months, P Z 0.0011). Cox multivariate analysis associated longer PFS with the following factors: cryosurgery (HR0.207, 95% CI 0.094e0.456), lower prostate specific antigen at diagnosis (100 ng/ml, HR0.235, 95% CI 0.072e0.763) and lower Gleason score (7, HR0.195, 95% CI 0.077e0.496). Cryosurgery reduced the risk of progression by 79.3%. In conclusion, cytoreductive cryosurgery of the primary tumor in patients with bone metastatic prostate cancer could reduce the risk of progression and delay time to castration-resistant prostate cancer. Copyright ª 2017, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/).

Conflicts of interest: All authors declare no conflicts of interest. * Corresponding author. C.-X. Liu, Department of Urology, Zhujiang Hospital of Southern Medical University, No 253, Industrial Rd., Guangzhou, Guangdong, 510282, People’s Republic of China. E-mail address: [email protected] (C.-X. Liu). http://dx.doi.org/10.1016/j.kjms.2017.07.002 1607-551X/Copyright ª 2017, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Sheng M-X, et al., Cytoreductive cryosurgery in patients with bone metastatic prostate cancer: A retrospective analysis, Kaohsiung Journal of Medical Sciences (2017), http://dx.doi.org/10.1016/j.kjms.2017.07.002

+

MODEL

2

Introduction Androgen deprivation therapy (ADT) is the recommended treatment for patient with metastatic prostate cancer (mPCa) [1]. Unfortunately, many patients eventually develop castration-resistant prostate cancer (CRPC) within two to three years [1]. And more than one third of patients without local treatment to the primary tumors will experience local complications due to local progression of prostate cancer (PCa) [2,3]. Recent studies have suggested patients with mPCa would benefit from local treatment to the primary tumor [4e6]. Fossati et al. found that the benefits of local treatment of the primary tumor in mPCa patients (either with radical prostatectomy or radiation therapy) depend on tumor characteristics [4]. Heidenreich et al. showed that cytoreductive radical prostatectomy could reduce the risk of locally recurrent PCa and local complications in mPCa patients who respond well to neoadjuvant ADT [3]. Traditionally, local treatments to the primary tumor in mPCa included radical prostatectomy or external beam radiation therapy [2]. There are limited available data on the outcomes of cryosurgery for mPCa. Cryosurgery has been increasingly used for localized prostate cancer [6], mostly due to less blood loss and minimal invasion [7]. We speculate that cryosurgery could reduce local complications and/or improve progression-free survival (PFS) in patients with mPCa. In this study, we retrospectively analyzed a group of patients with bone mPCa receiving cytoreductive cryosurgery on a background of ADT vs. a group of patients receiving ADT only. Cox proportional hazards regression analysis was used to identify predictors for PFS. Prostate specific antigen (PSA) kinetics after the surgery was also examined.

Methods Study design and patients The current retrospective study was approved by the Ethics Committee. A total of 49 mPCa subjects receiving ADT, with or without cytoreductive cryosurgery, during a period from September 2010 to July 2014 were included in the analysis. 23 patients received cytoreductive cryosurgery plus ADT (the cryosurgery group); the remaining 26 patients received ADT alone (the control). The following set of criteria was used to identify these cases: 1. A diagnosis of PCa based on transperiaeum prostate needle biopsy under transrectal ultrasound (TRUS) guidance; 2. Metastasis to the bone, as confirmed by radionuclide bone scan; 3. Absence of visceral metastases; 4. Clinical stage cT3a; 5. Prostate volume 50 ml; 6. PSA decrease to 1.0 ng/ml within 6 months of ADT; 7. Written informed consents. Cases with severe comorbid diseases and expected survival at <1 year were excluded.

Project of cryosurgery plus ADT Neoadjuvant and adjuvant ADT Upon a definitive diagnosis, bicalutamide (50 mg/d, p.o.) was initiated. Leuprolide (3.75 mg, s.c.; once every month)

M.-X. Sheng et al. was added 2 weeks later. PSA and serum testosterone were measured at 4 weeks, 3 and 6 months. Radiographic assessment was made at 6 months to evaluate the treatment response. Patients with a PSA decrease to less than 1.0 ng/ml within 6 months, remission or stable disease of osseous metastases and without the development of new lymph node or visceral metastases were considered candidates for cryosurgery. The patients received cryosurgery at 6 months after ADT. Adjuvant ADT after cytoreductive cryosurgery was identical to the neoadjuvant treatment. Cryosurgery Cryosurgery was carried out by the same surgeon using a CRYO care system (Endocare, USA) in all cases. Thirty minutes after administration of pethidine (75e100 mg) and phenergan (25 mg), patients were placed in the dorsal lithotomy position and received local infiltration anesthesia with 10-ml 1% lidocaine. A warming catheter was inserted into the bladder to protect the urethra. A real-time biplanar TRUS probe was used to visualize the insertion of cryoprobes and temperature probes and monitor the freezeethaw cycles. 17-G cryoprobes were inserted under TRUS guidance and spaced approximately 1.0 cm apart. The needles were placed according to prostate size and shape. Warm saline irrigation was started through the warming unit in a continuous-flow manner to avoid urethral freezing. Two freezeethaw cycles were performed. After surgery, the urethral warming unit was kept in place for 5 min. Bladder irrigation continued for 24 h. The Foley catheter was removed 1e2 weeks later. Project of ADT alone The patients in the control received ADT alone. Upon a definitive diagnosis, bicalutamide (50 mg/d, p.o.) was initiated. Leuprolide (3.75 mg, s.c.; once every month) was added 2 weeks later. Follow-up Patients were followed up at 1-month interval in the first year, at 3-month interval during the next 2 years, and once every year thereafter. Follow-up examinations included serum PSA, testosterone, creatinine, alanine aminotransferase and alkaline phosphatase, as well as digital rectal examination. Prostate magnetic resonance imaging (MRI) and radionuclide bone scan were performed every 6 months. Outcomes Biochemical progression was defined as 3 consecutive PSA increases, 1 week apart, resulting in 50% increases over the nadir. Clinical progression was defined as the onset of new symptoms due to local progression, lymphonodular or systemic metastases. PFS was defined as the time from the initiation of ADT to the first evidence of biochemical or clinical progression. Time to CRPC was defined as the time from the initiation of ADT to confirmed biochemical progression in the presence of castrate serum testosterone levels (&50 ng/dl). Nadir PSA after cryosurgery was defined as PSA decreased to nadir level firstly after cryosurgery. In subjects receiving cryosurgery, time to nadir PSA and time to PSA progression was calculated from the time of cryosurgery.

Please cite this article in press as: Sheng M-X, et al., Cytoreductive cryosurgery in patients with bone metastatic prostate cancer: A retrospective analysis, Kaohsiung Journal of Medical Sciences (2017), http://dx.doi.org/10.1016/j.kjms.2017.07.002

+

MODEL

Cryosurgery for bone metastatic prostate cancer Statistical analysis Demographic features were summarized using conventional descriptive statistics. Continuous variables were analyzed using independent-samples Student’s t-test. Categorical variables were analyzed using chi square test. Wilcoxon Rank sum test was used to analyze ranked variables. PFS and time to CRPC were compared by log-rank test after KaplaneMeier analysis. The primary outcome was PFS. A Cox proportional hazards regression model was used to predict PFS; hazard ratios (HRs), 95% CIs, and Wald chisquare test P values were reported. Statistical significance was defined as P < 0.05 (2-sided). All analyses were carried out with SPSS for Windows (version 11.0.1).

Results Baseline characteristics Patient age did not differ between the 2 groups: 68.1 years (range 57e83) in the cryosurgery group vs. 72.0 years (range 63e84) in patients receiving ADT alone (Table 1). Clinical features, including prostate volume, AJCC clinical stage, PSA at diagnosis, and biopsy Gleason score, also did not differ significantly. PSA at 6 months after ADT (PSA response to ADT) did not differ significantly too.

Features specific to cryosurgery Before surgery, the prostate volume was measured again by TRUS. The prostate volume immediately prior to the surgery decreased to 27.35  6.15 ml (range 15e38) because the patients received 6-months neoadjuvant ADT. Average

Table 1

3 operation time was 92.6  21.4 min. No severe complications (e.g., rectal injury, infection, perineum hematoma and urethra-rectal fistula) occurred in any case. Three patients (13.0%) experienced stress incontinence; symptoms dissipated in 2 cases within 3 months and within 12 months in the remaining case. All patients (including 3 patients with preoperative urinary retention) could urinate after the catheter was removed.

Outcomes Cytoreductive cryosurgery plus ADT The median follow-up time was 37 months (range 19e53). Three patients (13.0%) died during the follow-up: 1 (4.3%) of hepatic metastasis, and 2 (8.7%) of acute myocardial infarction. Median time to CRPC was 36 months (range 23e48; Fig. 1). Median PFS was 35 months (range 14e48). One patients later received palliative surgical intervention (percutaneous nephrostomy for unilateral hydronephrosis) due to local progression. In the 20 patients who developed CRPC, 14 (70.0%) patients were without second line treatment, and 6 patients (30.0%) received chemotherapy with docetaxel. PSA at the time of cryosurgery was 0.58  0.28 ng/ml (range 0e0.95) (Table 2). Nadir PSA after cryosurgery was 0.07  0.05 ng/ml (range 0e0.17). Median time to nadir PSA after cryosurgery was 3 months (range 1e6). Median time to PSA progression after cryosurgery was 30 months (range 19e42). ADT alone The median follow-up time was 41 months (range 24e56). A total of 7 (26.9%) patients died during the follow-up:

Baseline patient characteristics of the two groups.

Age at diagnosis (year) 60 60e70 >70 PSA at diagnosis (ng/ml) Biopsy Gleason score 6 or less 7 8 or greater Prostate volume (ml) Clinical stage cT2c cT3a Lymph nodes status N0 N1 Bone metastases 5 5e10 >10 PSA at 6 months after ADT (ng/ml)

Cryosurgery plus ADT (n Z 23)

ADT alone (n Z 26)

P value

68.1  9.9 (range 57e83) 8 (34.8%) 5 (21.7%) 10 (43.5%) 110.10  35.02 (range 25.00e149.30)

72.0  4.7 (range 63e84) 0 (0%) 12 (46.2%) 14 (53.8%) 98.42  44.17 (range 12.20e149.21)

0.081 0.084

4 (17.4%) 5 (21.7%) 14 (60.9%) 37.74  6.14 (range 25e48)

5 (19.2%) 7 (26.9%) 14 (53.8%) 40.53  6.37 (range 30e50)

0.661

15 (65.2%) 8 (34.8%)

16 (61.5%) 10 (38.5%)

0.792

16 (69.6%) 7 (30.4%)

18 (69.2%) 8 (30.8%)

0.980

11 (47.8.%) 10 (43.5%) 2 (8.7%) 0.58  0.28 (range 0e0.95)

13 (50.0%) 10 (38.5%) 3 (11.5%) 0.52  0.26 (range 0e0.95)

0.973

0.315

0.125

0.416

*: Continuous variables are presented as mean  SD; categorical variables are presented with number and percentage.

Please cite this article in press as: Sheng M-X, et al., Cytoreductive cryosurgery in patients with bone metastatic prostate cancer: A retrospective analysis, Kaohsiung Journal of Medical Sciences (2017), http://dx.doi.org/10.1016/j.kjms.2017.07.002

+

MODEL

4

M.-X. Sheng et al. retention and 3 (11.5%) received percutaneous nephrostomy for unilateral hydronephrosis. In the 24 subjects who developed CRPC, 12 (50%) patients were without second line treatment, 9 (37.5%) patients underwent chemotherapy with docetaxel and 3 (12.5%) patients received abiraterone. Regression analyses of PFS A univariate analysis indicated an association of the following factors with longer PFS: lower clinical AJCC staging, Gleason score at 7, lower PSA at diagnosis, and cytoreductive cryosurgery (Table 3). A multivariate analysis confirmed the association of longer PFS with: cytoreductive cryosurgery (HR 0.207, 95% CI 0.094e0.456), lower PSA at diagnosis (100 ng/ml, HR0.235, 95% CI 0.072e0.763) and lower biopsy Gleason score (7, HR0.195, 95% CI 0.077e0.496) (Table 4). Cryosurgery reduced the risk of progression by 79.3%.

Discussion

Figure 1. A, Time to castration-resistant prostate cancer in patients with vs without cryosurgery (P Z 0.0011). B, Progression-free survival in patients with vs without cryosurgery (P Z 0.0027).

4 (15.4%) of prostate cancer progression, 2 (7.6%) of myocardial infarction and 1 (3.8%) of stroke. Median time to CRPC was 25 months (range 19e50; Fig. 1). Median PFS was 25 months (range 16e48). Five (19.2%) patients received palliative transurethral resection of the prostate for urine

Table 2

PSA kinetics in subjects receiving cryosurgery.

Variable

Value

PSA at diagnosis (ng/ml)

110.10  35.02 (range 25.00e149.30) 0.58  0.28 (range 0e0.95) 0.07  0.05 (range 0e0.17) 3 (range 1e6)

Mean  SD PSA at cryosurgery (ng/ml) Mean  SD Nadir PSA after cryosurgery (ng/ml) Median time to nadir PSA after cryosurgery (mos) Median time to PSA progression after cryosurgery (mos)

30 (range 19e42)

The current study suggested potential benefits of cytoreductive cryosurgery in prostate cancer patients with bone metastasis. To our best knowledge, this is the first report of better prognosis in mPCa patients receiving cytoreductive cryosurgery plus ADT vs. ADT alone. Several important caveats in the current study require considerations. Firstly, all subjects receiving cryosurgery responded to neoadjuvant ADT (PSA decrease to <1.0 ng/ml within 6 month). PSA response to ADT is a reliable predictor of survival in patients with bone PCa presenting with extremely high PSA levels [8]. Non-responsiveness to neoadjuvant ADT is associated with poorer survival; such patients are clearly not good candidates for local treatment with cryosurgery. Secondly, clinical stage was cT3a in all cases in the current study. When the primary lesions invade prostate capsula and/or surrounding tissues, the local lesion is difficult to manage. Recent studies have indicated that prostate cancer with bulk tumor outside the prostate capsula are not suitable candidates for cryosurgery, and those with small tumor outside the prostate capsula could be treated with cryoablation in combination with neoadjuvant ADT [9e11]. Limiting the subjects to patients with cT3a disease probably has contributed to minimal complications associated with cryosurgery. Thirdly, prostate volume is also an important concern. In order to ensure that the iceball could cover the whole prostate gland, prostate volume in subjects receiving cryosurgery was relatively small (range 25e48). The prostate volume at immediately prior to the surgery decreased to 27.35  6.15 ml (range 15e38) because the patients received 6-months neoadjuvant ADT. A previous study recommended that prostate volume should be <40 ml to be considered for cryosurgery in patients with organ-confined PCa [12]. Subjects not meeting this criterion should be treated with ADT to reduce the prostate volume to <40 ml prior to cryosurgery [12]. Won et al. reported 35% bladder outlet obstruction and 15.2% ureteric obstruction in CRPC patients [2]. They also reported that primary treatment of the prostate by either radical prostatectomy or external beam radiation therapy could reduce the rate of these local complications [2]. In

Please cite this article in press as: Sheng M-X, et al., Cytoreductive cryosurgery in patients with bone metastatic prostate cancer: A retrospective analysis, Kaohsiung Journal of Medical Sciences (2017), http://dx.doi.org/10.1016/j.kjms.2017.07.002

+

MODEL

Cryosurgery for bone metastatic prostate cancer Table 3

5

Univariate analyses of progression-free survival.

Variable Cryosurgery

Yes No 70 >70 7 >8 cT2c >cT2c N0 N1 5 >5 100 >100 40 >40

Age (years) Biopsy Gleason score T staging N staging M staging PSA at diagnosis (ng/ml) Prostate volume (ml)

Table 4 survival.

Multivariate

analyses

of

progression-free

Variable

HR

95% CI

P value

Prostate cryosurgery (Yes) Biopsy Gleason score (7) T staging (cT2c) N staging (N0) M staging (5) PSA at diagnosis (100 ng/ml)

0.207

0.094e0.456

0.000

0.195

0.077e0.496

0.001

0.649 1.036 0.573 0.235

0.157e2.691 0.271e3.952 0.173e1.870 0.072e0.763

0.552 0.959 0.356 0.016

the current study, considerably less patients in the cryosurgery group (4.3% vs. 19.2% in subjects receiving ADT alone) required palliative surgery after the cytoreduction, suggesting a benefit of cytoreductive cryosurgery in reducing local complications. Consistent with the EAU guideline [1], we confirmed an association of longer PFS with lower PSA and Gleason score upon diagnosis. A key finding in the current study is the association of longer PFS with cytoreductive cryosurgery. Specifically, the risk of progression was decreased by 79.3%. Such a finding is consistent with the results of a SEERMedicare Analysis, in which local therapy with radical prostatectomy and intensity modulated radiation therapy was associated with a decrease in the risk of prostate cancer specific mortality by 52% (HR 0.48, 95% CI 0.27e0.85) and 62% (HR 0.38, 95% CI 0.24e0.61), respectively [13]. We failed to find an association of prognosis with TNM staging, possibly due to limited sample size. A feasibility and caseecontrol study by Heidenreich et al. demonstrated that mPCa patients treated by radical prostatectomy and adjuvant ADT had significantly longer median time to CRPC (40 months vs 29 months), clinical PFS (38.6 vs 26.5 months, P Z 0.032), cancer specific survival

n

Median progressionfree survival (mos)

P value

23 26 25 24 21 28 31 18 34 15 24 25 18 31 27 22

35 25 35 24 36 25 35 23 35 23 36 25 36 25 35 24

0.0027

(range (range (range (range (range (range (range (range (range (range (range (range (range (range (range (range

14e48) 16e48) 25e46) 14e48) 30e48) 14e48) 24e48) 14e48) 24e48) 14e30) 25e48) 14e35) 27e48) 14e36) 25e46) 14e48)

0.2151 0.0000 0.0000 0.0000 0.0000 0.0002 0.1588

rate (95.6% vs 84.2%, P Z 0.043) and local complications than ADT alone [3]. In a study that included 8185 mPCa patients receiving definitive treatment of the prostate, both the 5-year overall survival and disease-specific survival were significantly improved in patients undergoing radical prostatectomy (67.4% and 75.8%, respectively) or brachytherapy (52.6 and 61.3%, respectively) in comparison to no surgery or radiation therapy patients (22.5% and 48.7%, respectively) [5]. Our study differs in that the patients received local treatment with cryosurgery. Cryosurgery is generally safer and better tolerated [3,14e16]. A previous study suggested that cryosurgery could achieve similar short-term outcomes in comparison with other methods [17]. A notable benefit with cryosurgery is higher life quality after operation [18]. Although the current study indicated that the cytoreductive cryosurgery treatment reduces the risk of progression, the mechanism and underlying tumor biology remain unknown. Satkunasivam et al. [13] have summarized the following hypotheses to explain a survival benefit from local treatment with radical prostatectomy or intensity modulated radiation therapy in patients with mPCa: 1. Eradicating the primary tumor may eliminate the source of cytokine signaling which prepares microenvironments for eventual sites of metastasis and promotes their progress [19]. 2. The primary tumor may serve as a source of circulating tumor cells which are capable of self-seeding the primary organ [20]. 3. Local treatment may decrease self-renewing progenitor cells still persisting after ADT, which have an androgen receptor-low immature luminal phenotype and propagate adenocarcinoma [21]. These hypotheses might been used to explain why cryosurgery might reduce the risk of progression. In addition, anti-tumor immune responses induced by cryosurgery may play an important role. Cryosurgery destroys tumor tissue in situ by freezing, which leaves tumor proteins and tumorassociated antigens intact. The presence of residual tumor antigens in an inflammatory microenvironment can induce anti-tumor immune responses. Thus, cryosurgery

Please cite this article in press as: Sheng M-X, et al., Cytoreductive cryosurgery in patients with bone metastatic prostate cancer: A retrospective analysis, Kaohsiung Journal of Medical Sciences (2017), http://dx.doi.org/10.1016/j.kjms.2017.07.002

+

MODEL

6 has the potential to reducing the recurrence in distant organs as the systemic treatment [22]. Si T et al. found that cryosurgery in PCa could induce limited tumor-specific cytotoxic T-cell stimulation [23]. Machlenkin et al. demonstrated that the cryoimmunological response could be enhanced by the intratumor administration of dendritic cells [24]. However, some studies showed that cryosurgery induced only a partial systemic response which had no effect on metastasis [25e27]. So far, the existence of a cryoimmunological response remains controversial, and the mechanisms how a cryoimmunological response is induced remain unclear. In a phase 3 randomized trial of South European Uroncological Group (SEUG) 9401, 312 patients with locally advanced or mPCa were treated with continuous ADT alone [28]. The death rate was 65 (20.8%) from PCa, 19 (6.1%) from second primary cancer, 52 (16.7%) from cardiovascular diseases (CVD) and 33 (10.6%) from others, respectively [28]. Patients on continuous ADT were more likely to die from CVD or other causes than patients receiving intermittent ADT [19]. A systematic review of observational studies on more than 80,000 patients with prostate suggested a 17% increase in cardiovascular mortality by ADT [29]. Cardiovascular disease, rather than PCa itself, is the most common cause of mortality in older men with early stage prostate cancer [30]. In our study, four (15.4%) of the patients treated with ADT alone died of prostate cancer progression, 2 (7.6%) of myocardial infarction and 1 (3.8%) of stroke, respectively. Our result is similar to the SEUG study in death structure as well as the increasing risk of cardiovascular event. Apparently, the potential risk of ADT on cardiovascular events needs to be carefully considered. As a retrospective analysis, the current study has limitations that apply to all retrospective analyses. The sample size is also relatively limited. The follow-up is relatively short, with only a few deaths. Considering such a limitation, we choose PFS as the primary outcome variable. Regardless, the results showed an association of cytoreductive cryosurgery with improved outcomes. In conclusion, using cytoreductive cryosurgery to manage the primary lesions in prostate cancer patients could reduce the risk of progression and delay time to CRPC.

Acknowledgments This research was supported by grants from the Natural Science Foundation of Fujian Province, China (No. 2016J01661) and National Natural Science Foundation of China (No. 81402107).

References [1] 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;65:467e79. [2] Won AC, Gurney H, Marx G, De Souza P, Patel MI. Primary treatment of the prostate improves local palliation in men who ultimately develop castrate-resistantprostate cancer. BJU Int 2013;112:E250e5.

M.-X. Sheng et al. [3] Heidenreich A, Pfister D, Porres D. Cytoreductive radical prostatectomy in patients with prostate cancer and low volume bone metastases: results of a feasibility and case-control study. J Urol 2015;193:832e8. [4] Fossati N, Trinh QD, Sammon J, Sood A, Larcher A, Sun M, et al. Identifying optimal candidates for local treatment of the primary tumor among patients diagnosed with metastatic prostate cancer: a SEER-based study. Eur Urol 2015;67:3e6. [5] Culp SH, Schellhammer PF, Williams MB. Might men diagnosed with metastatic prostate cancer benefit from definitive treatment of the primary tumor? A SEER-based study. Eur Urol 2014;65:1058e66. [6] Sverrisson E, Jones JS, Pow-Sang JM. Cryosurgery for prostate cancer: a comprehensive review. Arch Esp Urol 2013;66:546e56. [7] Al Ekish S, Nayeemuddin M, Maddox M, Pareek G. The role of cryosurgery of the prostate for nonsurgical candidates. JSLS 2013;17:423e8. [8] Koo KC, Park SU, Kim KH, RHa KH, Hong SJ, Yang SC, et al. Predictors of survival in prostate cancer patients with bone metastasis and extremely high prostate-specific antigen levels. Prostate Int 2015;3:10e5. [9] Chin JL, Al-Zahrani AA, Autran-Gomez AM, Williams AK, Bauman G. Extended followup oncologic outcome of randomized trial between cryoablation and external beam therapy for locally advanced prostate cancer (T2c-T3b). J Urol 2012;188:1170e5. [10] Ukimura O, de Castro Abreu AL, Hung AJ, Gill IS. Cryosurgery for clinical T3 prostate cancer. BJU Int 2014;113:684e5. [11] Ward JF, DiBlasio CJ, Williams C, Given R, Jones JS. Cryoablation for locally advanced clinical stage T3 prostate cancer: a report from the Cryo-On-Line Database (COLD) Registry. BJU Int 2014;113:714e8. [12] Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T, et al. EAU guidelines on prostate cancer. Part1: screening, diagnosis, and local treatment with curative intentdupdate 2013. Eur Urol 2014;65:124e37. [13] Satkunasivam R, Kim AE, Desai M, Nguyen MM, Quinn D, Leslie B, et al. Radical prostatectomy or external beam radiationtherapy vs no local therapy for survival benefit in metastatic prostate cancer:A SEER-medicare analysis. J Urol 2015;194:378e85. [14] Cho S, Kang SH. Current status of cryotherapy for prostate and kidney cancer. Korean J Urol 2014;55:780e8. [15] Wilt TJ, MacDonald R, Rutks I, Shamliyan TA, Taylor BC, Kane RL. Systematic review: comparative effectiveness and harms of treatments for clinically localized prostate cancer. Ann Intern Med 2008;148:435e48. [16] Govorov AV, Vasil’ev AO, Ivanov VIu, Kovylina MV, Prilepskaia EA, Pushkar’ D Iu. Treatment of prostate cancer using cryoablation: a prospective study. Urologiia 2014;6: 69e72, 74 [In Russian, English abstract]. [17] Ritch CR, Katz AE. Prostate cryotherapy: current status. Curr Opin Urol 2009;19:177e8. [18] Govorov AV, Vasil’ev AO, Pushkar DJ. Quality of life in patients undergoing prostate cryoablation. Urologiia 2015;3:43e8 [In Russian, English abstract]. [19] Psaila B, Lyden D. The metastatic niche:adapting the foreign soil. Nat Rev Cancer 2009;9:285e93. [20] Kim MY, Oskarsson T, Acharyya S, Nguyen DX, Zhang XH, Norton L, et al. Tumor self-seeding by circulating cancer cells. Cell 2009;139:1315e26. [21] Stoyanova T, Cooper AR, Drake JM, Liu X, Armstrong AJ, Pienta KJ, et al. Prostate cancer originating in basal cells progresses to adenocarcinoma propagated by luminal-like cells. Proc Natl Acad Sci U S A 2013;110:20111e6. [22] Sabel MS. Cryo-immunology: a review of the literature and proposed mechanisms for stimulatory versus suppressive effects of cryoablation on the immune response. Cryobiology 2009;58:1e11.

Please cite this article in press as: Sheng M-X, et al., Cytoreductive cryosurgery in patients with bone metastatic prostate cancer: A retrospective analysis, Kaohsiung Journal of Medical Sciences (2017), http://dx.doi.org/10.1016/j.kjms.2017.07.002

+

MODEL

Cryosurgery for bone metastatic prostate cancer [23] Si T, Guo Z, Hao X. Immunologic response to primary cryoablation of high-risk prostate cancer. Cryobiology 2008;57:66e71. [24] Machlenkin A, Goldberger O, Tirosh B, Paz A, Volovitz I, BarHaim E, et al. Combined dendritic cell cryotherapy of tumor induces systemic antimetastatic immunity. Clin Cancer Res 2005;11:4955e61. [25] Redondo P, del Olmo J, Lo ´pez-Diaz de Cerio A, Inoges S, Marquina M, Melero I, et al. Imiquimod enhances the systemic immunity attained by local cryosurgery destruction of melanoma lesions. J Invest Dermatol 2007;127:1673e80. [26] Hoffmann NE, Coad JE, Huot CS, Swanlund DJ, Bischof JC. Investigation of the mechanism and the effect of cryoimmunology in the Copenhagen rat. Cryobiology 2001;42: 59e68. [27] Udagawa M, Kudo-Saito C, Hasegawa G, Yano K, Yamamoto A, Yaguchi M, et al. Enhancement of immunologic tumor

7 regression by intratumoral administration of dendritic cells in combination with cryoablative tumor pretreatment and Bacillus Calmette-Guerin cell wall skeleton stimulation. Clin Cancer Res 2006;12:7465e75. [28] Calais da Silva FE, Bono AV, Whelan P, Brausi M, Queimadelos M, Martin JA, et al. Intermittent androgen deprivation for locally advanced and metastatic prostate cancer: results from a randomised phase 3 study of the South European Uroncological Group. Eur Urol 2009;55:1269e77. [29] Taylor LG, Canfield SE, Du XL. Review of major adverse effects of androgen-deprivation therapy in men with prostate cancer. Cancer 2009;115:2388e99. [30] Ketchandji M, Kuo YF, Shahinian VB, Goodwin JS. Cause of death in older men after the diagnosis of prostate cancer. J Am Geriatr Soc 2009;57:24e30.

Please cite this article in press as: Sheng M-X, et al., Cytoreductive cryosurgery in patients with bone metastatic prostate cancer: A retrospective analysis, Kaohsiung Journal of Medical Sciences (2017), http://dx.doi.org/10.1016/j.kjms.2017.07.002