Disease-Free Survival Following Salvage Cryotherapy for Biopsy-Proven Radio-Recurrent Prostate Cancer

EUROPEAN UROLOGY 60 (2011) 405 410 available at www.sciencedirect.com journal homepage: www.europeanurology.com Platinum Priority Prostate Cancer Editorial by J. Stephen Jones on pp. 411 412 of this issue Disease-Free Survival Following Salvage Cryotherapy for Biopsy-Proven Radio-Recurrent Prostate Cancer Andrew K. Williams a, Carlos H. Martínez a, Chen Lu a, Chee Kwan Ng b, Stephen E. Pautler a, Joseph L. Chin a, * a Departments of Urology and Oncology, University of Western Ontario, London, Ontario, Canada b Department of Urology, Tan Tock Seng Hospital, Singapore Article info Article history: Accepted December 10, 2010 Published online ahead of print on December 21, 2010 Keywords: Prostate cancer Cryotherapy Radiation Recurrence Abstract Background: The optimum treatment of prostate cancer recurrence following radiation therapy (RT) remains controversial due to the lack of long-term data. Objective: Our aim was to review the survival of patients who underwent salvage cryotherapy to the prostate gland for biopsy-proven recurrent prostate cancer and establish prognostic indicators. Design, setting, and participants: A retrospective analysis was performed on all patients undergoing salvage cryotherapy at an academic urology unit for biopsyproven locally recurrent prostate cancer after RT from 1995 to 2004. Patients preoperative, perioperative, and postoperative data were reviewed and recorded. Intervention: Two freeze-thaw cycles of transperineal cryotherapy were performed under transrectal ultrasound guidance by a single surgeon. Measurements: The primary outcome was survival. Secondary outcomes were disease-free survival (DFS), metastasis-free survival, and progression to androgen-deprivation therapy. Results and limitations: Of 187 patients, 176 had records available for follow-up (follow-up rate: 94%). Mean follow-up was 7.46 yr (range: 1 14 yr). Fifty-two patients were followed for >10 yr. DFS at 10 yr was 39%. Risk factors for recurrence were presalvage prostate-specific antigen (PSA), preradiation, and presalvage Gleason score. A PSA nadir >1.0 ng/dl was highly predictive of early recurrence. Conclusions: Salvage cryotherapy led to an acceptable 10-yr DFS. Presalvage PSA and Gleason score were the best predictors of disease recurrence. A PSA nadir >1 ng/dl following cryotherapy indicated a poor prognosis, and recurrence of disease was universal in these patients. # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Urology, London Health Sciences Centre, 800 Commissioners Rd, London, Ontario, Canada N6AAG5. Tel. +1 519 685 8451; Fax: +1 519 685 8455. E-mail address: joseph.chin@lhsc.on.ca (J.L. Chin). 0302-2838/$ see back matter # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2010.12.012

406 EUROPEAN UROLOGY 60 (2011) 405 410 1. Introduction Prostate cancer recurrence following radiation therapy (RT) remains a common but difficult treatment scenario. An estimated 32% patients fail RT [1], and most commonly they receive androgen-deprivation treatment (ADT) with a very few offered salvage treatments [2]. Salvage radical prostatectomy (RP) has been regarded as a relatively morbid procedure with high rates of incontinence and a significant risk of rectal injury. These concerns have resulted in the use of salvage cryotherapy and, more recently, high-intensity focused ultrasound (HIFU) to reduce this morbidity. There are data suggesting that local salvage procedures can achieve disease-free survival (DFS) rates of up to 50 60% at 5 yr [3]. Cryotherapy was reported to have a 5-yr DFS of 56% at 5 yr [4]. We present our results of salvage cryotherapy dating back to 1994 in biopsy-proven radio-recurrent prostate cancer and identify risk factors for recurrence as well as markers that may predict DFS. 2. Materials and methods 2.1. Patient recruitment All patients who underwent salvage cryotherapy between 1994 and 2004 at the University of Western Ontario by a single surgeon (JC) were included in this study. All patients except two had histologic confirmation of local recurrence, and all patients had negative metastatic screening with abdominal and pelvic computed tomography (CT) and radionucleotide bone scan. 2.2. Treatment Cryotherapy was performed using the Candella system (Candella, Wayland, MA, USA) for the first 11 patients followed by the Cryo-Care system (Endocare Inc, Irvine, CA, USA) for the subsequent 176 patients. In most patients five or six cryoprobes were placed transperineally, guided via transrectal ultrasound (TRUS). A Saldinger technique was used to place the cryotherapy probes with two freeze-thaw cycles. Monitoring was by visualization of the ice ball on ultrasound as well as three thermocouples positioned at the left and right neurovascular bundles and midline apex. Urethral warming was achieved using a Cook urethral warming catheter (Cook Medical, Bloomington, IN, USA). A suprapubic Foley catheter was placed intraoperatively and left in place for 3 wk. Following 10 cases using the Cryo-Care system, the treatment was standardized. No changes in the technique occurred following that point. 2.3. Follow-up Patients were initially followed up at our institution with TRUS-guided biopsy at 6, 12, and 24 mo. Biopsies were taken from four quadrants as well as from any areas of clinical concern. Prostate-specific antigen (PSA) was measured at 3, 6, and 12 mo and then every 6 mo thereafter unless otherwise clinically indicated. After 24 mo, patients were followed up at our institution or by their local urologist. Follow-up data were attained either through clinical records or by contacting the patients local urologist or family practitioner. All TRUS, PSA, bone scan, and CT results were collected as well as any change in clinical status. Recurrence was defined using the Phoenix definition of nadir plus 2 ng/ml as well as any radiologic, histologic, or clinical evidence of recurrent prostate cancer. DFS was defined as the time period from salvage treatment to the date of recurrence. ADT was begun purely at the discretion of the treating physician; in no cases was ADT started before biochemical, histologic, or clinical recurrence. 2.4. Statistics Statistics were prepared by a qualified biostatistician using SAS/STAT software (SAS Institute Inc, Cary, NC, USA). Chi-square tests were used for grouped data and Student t tests for continuous data. 3. Results Of the 187 patients initially included in the study, 176 had data available for inclusion (follow-up rate: 94%). Mean follow-up was 7.46 yr; 52 patients were followed up >10 yr. One hundred and seventy-two patients underwent externalbeam radiation therapy, and four patients had brachytherapy. Tables 1 and 2 describe the preradiation treatment and presalvage characteristics, respectively. Overall survival was 95%, 91%, and 87% at 5, 8, and 10 yr, respectively. However, overall DFS was 47%, 39%, and 39% (Fig. 1). Metastasis-free survival was 87%, 83%, and 82%. Sixty-eight patients (38.6%) went on to be treated with ADT at a mean of 2.83 yr following salvage treatment. Mean time to recurrence was 2.3 yr. As part of our follow-up protocol, 95.6% of patients underwent at least one biopsy, with 57.2% completing the full biopsy protocol of three biopsies. Thirty-one patients (17.6%) had a positive postsalvage prostate biopsy. Specific risk factors statistically correlated with disease recurrence were preradiation PSA, presalvage PSA, and a presalvage Gleason score of 8. Patients with a presalvage PSA <5 ng/dl had a 10-yr DFS rate of 64% versus patients with a presalvage PSA of >10 ng/dl who had a 10-yr DFS rate of only 6.7% (Fig. 1). A 54% 10-yr DFS was noted with Gleason score 6 prostate cancer on presalvage biopsy. A presalvage Gleason score of 8 was associated with a 1.92 relative risk (RR) ( p = 0.03) of disease recurrence as compared with Gleason score 6 disease; presalvage Gleason 7 disease was not statistically different from Table 1 Preradiotherapy characteristics Clinical T score No. of patients Relative risk for recurrence (95% confidence interval) T1 25 1 T2 93 1.69 (0.85 3.33) T3 or 4 19 1.62 (0.67 3.90) Gleason score 6 63 1 7 35 0.97 (0.52 1.81) 8 7 1.63 (0.57 4.77) PSA, ng/dl <5 17 1 5 10 40 4.987 (1.1 21.1) >10 73 5.527 (1.3 22.8) Age at time of primary treatment, yr <65 63 1.17 (0.73 1.89) >65 78 1 Range: 48 76; IQR: 59 71 IQR = interquartile range; PSA = prostate-specific antigen.

EUROPEAN UROLOGY 60 (2011) 405 410 407 Table 2 Presalvage characteristics Presalvage Gleason score Before RT Relative risk for recurrence (95% confidence interval) 6 38 1 7 50 1.69 (0.91 3.11) 8 57 1.92 (1.06 3.49) Presalvage PSA, ng/dl <5 84 1 5 10 56 2.8 (1.7 4.7) >10 34 5.1 (3.0 8.7) Age at time of salvage treatment, yr <70 83 1.45 (0.96 2.2) >70 92 1 Range: 54 82, IQR: 65 74 Time between primary and salvage treatments, yr <5 85 1.05 (0.81 1.13) >5 56 1 IQR = interquartile range; PSA = prostate-specific antigen; RT, radiation therapy. Gleason 6 disease (Fig. 3). However, patients with Gleason 7 disease had similar 10-yr survival to those with Gleason 8 disease (both 33%). Postsalvage PSA nadir was strongly associated with disease recurrence. A PSA nadir of >1 ng/dl had a RR ratio of 6.63 ( p < 0.001) for recurrence (95% confidence interval, 4.1 10.6) and was associated with disease-free rates of 3%, 0%, and 0% at 5, 8, and 10 yr, respectively. In contrast, PSA nadir <1 ng/dl was associated with a DFS of 56%, 46%, and 46%, respectively (Fig. 4). 4. Discussion This study reports the intermediate-term results in patients with biopsy-proven local recurrence of prostate cancer following RT. We are limited as always by the retrospective nature of studies such as this and the evolution to newer technologies that inevitably occurs over a period of followup. It is likely that morbidity has reduced and efficacy has increased with newer technologies, but it will take at least 10 yr for validation. It is difficult to correlate our work with the only previously large cohort of salvage cryotherapy patients [5] due to the heterogeneity in a multi-institutional database. Our study was limited to patients with biopsyproven cancer who underwent a method of standardized screening for localized disease, and follow-up biopsies were performed in 95.7% versus 16.5% from the Cyro On-Line Database registry. As demonstrated in the Kaplan-Meier curves, this study indicates DFS rates with very little change to the survival between 8 and 10 yr despite the fact that median follow-up of the 176 patients was nearly 8 yr and 52 patients were followed >10 yr. A recent HIFU study on establishing a definition for recurrence [6] highlighted the high sensitivity and low specificity of the American Society for Therapeutic Radiology and Oncology (ASTRO) definition versus the low sensitivity and high specificity of the Phoenix definition. This likely applies in analyzing cryotherapy data. Pisters et al [7] describe inferior recurrence-free survival with cryotherapy using a variety of definitions. However, notably [()TD$FIG] _ Fig. 1 Kaplan-Meier curve for presalvage prostate-specific antigen (PSA; nanograms per deciliter) with corresponding n values.

408 [()TD$FIG] EUROPEAN UROLOGY 60 (2011) 405 410 Fig. 2 Kaplan-Meier curve for prostate-specific antigen (PSA) nadir (nanograms per deciliter) with corresponding n values. no analysis was shown using the Phoenix definition of PSA nadir plus 2 ng/ml, and they described recurrence rates that are significantly higher than our series. From our experience we have seen significantly higher biochemical recurrence rates in this cohort using the ASTRO definition [8] that do not seem to translate to an increased recurrence rate with time under the Phoenix definition. This highlights the fact that with a lack of a validated standard definition of failure, [()TD$FIG] long-term follow-up is required. Comparisons between treatment modalities can be heavily influenced by the definitions used. Regardless, we have demonstrated a significant overall recurrence-free survival that can be optimized with appropriate stringent patient selection. We acknowledge that we have not proven any survival benefit for this treatment given the absence of any control arm. A trial of salvage versus observation, however, is unlikely to 100 % Disease Free 80 60 40 < 7 7 > 7 20 0 0 12 24 36 48 60 72 84 96 108 120 Time (Months) Mo 0 24 48 72 96 120 Gleason <7 38 36 34 30 18 8 Gleason 7 50 47 39 33 28 18 Gleason >7 57 46 39 35 29 18 Fig. 3 Kaplan-Meier curve for presalvage Gleason scores with corresponding n values.

[()TD$FIG] EUROPEAN UROLOGY 60 (2011) 405 410 409 100 80 % Surviving 60 40 20 Overall Survival Disease Free Survival 0 0 12 24 36 48 60 72 84 96 108 120 Time (Months) Mo 0 24 48 72 96 120 No. of patients 176 156 134 113 88 52 Fig. 4 Kaplan-Meier curve for overall and disease-free survival with corresponding n values. be palatable to patients. It could be argued it would be unethical in the context of documented 10-yr biochemical recurrence-free survival rates of 39%. Salvage cryotherapy was shown to have incontinence rates of 36% and fistula rates of 2.6% across studies in comparison with salvage RP with incontinence rates of 41% and rectal injury rates of 2 15% [3]. The complication rates of the current cohort were previously described [4] and are consistent with the literature [9,10]. This cohort had 37% mild and 3% severe incontinence rates, along with a 2% fistula rate that we find acceptable in a salvage setting. We believe that just as primary treatment needs to be tailored to the individual, so does salvage treatment. Although no randomized head-to-head comparison exists, this study reaffirms that salvage cryotherapy is a reasonable alternative to salvage RP, particularly in patients with significant medical comorbidity but a significant life expectancy. We believe that RP still plays a role in the management of radiorecurrent prostate cancer. However, it requires a motivated and younger patient with few comorbidities who is willing to accept the associated morbidity. It has become increasingly apparent that ADT is associated with a significant increase in non prostate-related diseases such as cardiovascular disease and osteoporosis [11], albeit not without some debate [12 14]. These results show that with a mean follow-up of nearly 8 yr, only 38.6% of patients went on to ADT, which leads to a well-documented reduction in quality of life. Keating et al [15] demonstrated that gonadotropin-releasing hormone agonist treatment led to an increased rate of myocardial infarction, stroke, diabetes, and sudden cardiac death in a cohort of 37 443 patients. It is important to note that these data only had a short median follow-up of 2.6 yr, and it would be reasonable to suggest the risk of cardiovascular disease continues with ongoing ADT. In addition to the obvious financial benefit, we also speculate that we may delay the development of androgen resistance. It is unlikely there will ever be randomized studies to compare mortality rates between patients undergoing salvage treatment (who we must acknowledge are likely to have fewer comorbidities) with patients receiving ADT, and therefore it is observational data we must rely on. This study has shown that patients with presalvage PSA >10 ng/dl had very high recurrence rates and tended to recur early, and we do not believe they are good candidates for salvage cryotherapy. This concurs with other salvage studies that have shown this effect at the 5-yr mark [9,16]. Our data also highlight the role of rebiopsy and Gleason score in predicting response to subsequent salvage cryotherapy. Presalvage biopsies obviously must be viewed with some caution, given the changes induced by radiation. However, these were able to predict prognosis, whereas preradiation Gleason scores had no predictive value in our cohort. Patients with Gleason 7 disease on presalvage biopsy had a higher risk of recurrence that was not statistically different from patients with Gleason 8 disease. The recurrence rates in patient with Gleason 7, 8, or 9 disease was still acceptable at 33%. Given the theoretical benefit of cryotherapy being cytocidal regardless of tumor grade, we believe the presence of high-grade cancer should not exclude a patient with otherwise favorable features, most notably a low PSA, from salvage treatment. We therefore believe patients should not be excluded based on a higher Gleason score on preradiation biopsy but should be counseled about a higher risk of recurrence. We suggest any patient with a presalvage PSA >10 ng/dl is a poor candidate for salvage cryoablation, and patients with a PSA between 5 and 10 ng/dl should be counseled about their increased risk of recurrence. We found no correlation in the time between initial and salvage treatment to higher recurrence rates.

410 EUROPEAN UROLOGY 60 (2011) 405 410 Patients with a high PSA nadir following salvage cryotherapy are at an increased risk of recurrence [17,18]. The question has really been how high this risk of recurrence is. Fig. 2 shows the poor prognosis for DFS in these patients. Patients with a PSA nadir >1 ng/dl are likely to harbor metastatic disease at the time of treatment. 5. Conclusions This study clearly delineates the prognostic variables associated with salvage cryotherapy for biopsy-proven recurrence. We have established the prognostic variables for patients who wish to consider undergoing salvage cryotherapy so an educated decision can be made regarding the appropriateness of treatment. We believe 10-yr diseasefree recurrence rates between 39% and 64% are a more than acceptable return on the morbidity of salvage cryotherapy. Coupled with these DFS rates, a significant proportion of our cohort (61%) did not progress to ADT during the study period, indicating a secondary benefit of salvage cryotherapy in reducing the use of ADT. Salvage cryotherapy is not a treatment for all patients but is a suitable alternative to salvage RP in a group of patients either unwilling or inappropriate for major surgery but who have a significant life expectancy. Author contributions: Joseph L. Chin had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Williams, Ng, Pautler, Chin. Acquisition of data: Williams, Ng. Analysis and interpretation of data: Williams, Ng, Lu, Martinez. Drafting of the manuscript: Williams. Critical revision of the manuscript for important intellectual content: Williams, Ng, Pautler, Chin, Lu, Martinez. Statistical analysis: None. Obtaining funding: Chin. Administrative, technical, or material support: None. Supervision: None. Other (specify): None. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None. References [1] Zietman AL, Bae K, Slater JD, et al. Randomized trial comparing conventional-dose with high-dose conformal radiation therapy in early-stage adenocarcinoma of the prostate: long-term results from Proton Radiation Oncology Group/American College of Radiology 95-09. J Clin Oncol 2010;28:1106 11. [2] Agarwal PK, Sadetsky N, Konety BR, Resnick MI, Carroll PR, Cancer of the Prostate Strategic Urological Research Endeavor (CaPSURE). 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