Ann Surg Oncol (2015) 22:1612–1617 DOI 10.1245/s10434-014-3942-9
ORIGINAL ARTICLE – UROLOGIC ONCOLOGY
Predictors of Prostate-Specific Antigen Biochemical Recurrence in Patients Undergoing Primary Whole-Gland Prostate Cryoablation Yi Yang Liu, MD, Po Hui Chiang, MD, PhD, Yao Chi Chuang, MD, Wei Ching Lee, MD, Yuan Tso Cheng, MD, and Hung Jen Wang, MD Department of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
ABSTRACT Purpose. Cryoablation has been proven as a less invasive, safe, and effective treatment for localized prostate cancer. We attempted to identify the predictors of biochemical recurrence after prostate cryoablation for localized prostate cancer in this study. Methods. We reviewed 114 patients who underwent primary whole-gland prostate cryoablation for localized prostate cancer from October 2008 to March 2013. The perioperative parameters included age [70 years, initial prostate-specific antigen (PSA), preoperative prostate volume, Gleason score, T stage, D’Amico risk group, postoperative PSA nadir, time to PSA nadir, and PSA biochemical recurrence, defined by Phoenix definition (nadir plus 2 ng/mL). Receiver operating characteristic (ROC) analysis was used for the best cutoff value of PSA nadir for PSA biochemical recurrence. The parameters were analyzed in binary logistic regression and Kaplan– Meier analysis for PSA biochemical recurrence. Results. A total of 31.6 % (N = 36) patients had PSA biochemical recurrence during the median follow-up of 34.87 ± 16.49 months. ROC analysis revealed that the best cutoff value for biochemical recurrence prediction was when the PSA nadir = 0.3 ng/mL. On multivariate analysis and Kaplan–Meier analysis, the D’Amico high-risk group [hazard ratio (HR) 6.552; p = 0.014], PSA nadir [0.3 ng/mL (HR 34.062; p \ 0.001), and time to PSA
Po Hui Chiang and Yi Yang Liu contributed equally to this paper. Ó Society of Surgical Oncology 2014 First Received: 14 December 2013; Published Online: 7 October 2014 P. H. Chiang, MD, PhD e-mail: [email protected]
nadir \3 months (HR 4.144; p = 0.021) were statistically significant for PSA biochemical recurrence. Conclusions. The D’Amico high-risk group, postoperative PSA nadir [0.3 ng/mL, and time to PSA nadir \3 months predict biochemical recurrence in primary whole-gland prostate cryoablation.
Prostate cryoablation was first introduced for prostate cancer in the 1960s.1 With the improvement of instruments and techniques such as the Argon/Helium system, urethra warming catheter, and multipoint thermal sensors, fourthgeneration cryoablation has been proven as a less invasive, safe, and effective treatment for localized prostate cancer.2 Prostate-specific antigen (PSA) biochemical recurrence is a surrogate for true biopsy-proven prostate cancer recurrence or metastasis disease.3 The predictors of PSA biochemical recurrence after definitive treatments of localized prostate cancer can help us select suitable candidates for preoperative treatment and detect earlier any possible prostate cancer recurrence postoperatively. To date, the definition and predictors of PSA biochemical recurrence in radical prostatectomy and radiotherapy have been well established and studied. For cryoablation, the RTOG-ASTRO Phoenix definition has been proven more predictive for true biopsyproven recurrence after prostate cryoablation than strict PSA levels or traditional ASTRO definition.4 However, in comparison with radical prostatectomy and radiotherapy, there is no consensus on the predictors of post-cryoablation PSA biochemical recurrence, especially for Asian patients. In previous studies, preoperative PSA, Gleason score, D’Amico risk group, clinical stage, PSA nadir, and PSA doubling time (PSAdt) were identified as the predictors.3,5,6 In this study, we attempted to find the clinical predictive factors of PSA biochemical recurrence after primary whole-gland prostate cryoablation for localized prostate
Predictors of Cryoablation PSA Recurrence
cancer. The results may provide useful information for clinical urological oncologists. MATERIALS AND METHODS From October 2008 to March 2013, 138 patients who underwent prostate cryoablation for prostate cancer at Kaohsiung Chang Gung Memorial Hospital were retrospectively reviewed under the approval of the Institutional Review Board. All patients were treated by fourth-generation cryosurgical technology (Endocare Cryocare Surgical System, Heathtronics Inc., Austin, TX, USA). The operations were performed under the Argon/Helium system with two freeze–thaw cycles, urethral warming catheters, and multipoint thermal sensors. We selected 114 patients who underwent primary whole-gland prostate cryoablation for localized prostate cancer after exclusion of focal therapy (N = 7), salvage therapy (N = 11), pathology other than adenocarcinoma (N = 2, all were urothelial carcinoma), and advanced prostate cancer (N = 4, T stage [T3a or Nstage positive or M-stage positive). The perioperative parameters such as age, initial PSA (iPSA), preoperative prostate volume, Gleason score, T stage, D’Amico risk group, postoperative PSA nadir, time to PSA nadir, and PSA biochemical recurrence defined by Phoenix definition (PSA nadir plus 2 ng/mL) were collected. Patients were classified into two groups according to the existence of PSA biochemical recurrence. These two groups were compared using Student’s t test for continuous variables, and Chi square test for categorical variables. Receiver operating characteristic (ROC) analysis was used to detect the best predictive value of PSA nadir for PSA biochemical recurrence. All variables were analyzed with postoperative PSA biochemical recurrence in univariate binary logistic regression. The variables with statistical significance on univariate analysis were chosen for multivariate analysis and further Kaplan–Meier analysis. All analyses were performed using SPSS Statistics version 17.0 (SPSS Inc., Chicago, IL, USA). p values\0.05 were considered significant. RESULTS Patient characteristics are listed in Table 1. A total of 31.6 % (N = 36) of patients had PSA biochemical recurrence after cryoablation during the median follow-up of 34.87 ± 16.49 months. The PSA biochemical recurrence rate in the D’Amico high-, intermediate- and low-risk group patients were 42.3 % (N = 30), 12.5 % (N = 3), and 15.8 % (N = 3), respectively. The median PSA biochemical recurrence-free survival and time to PSA biochemical recurrence was 27.19 ± 18.10 and 15.07 ± 15.12 months, respectively. Intergroup comparison was demonstrated in
1613 TABLE 1 Patient characteristics Variable
(N = 114)
Age, years, men (mean ± SD)
69.76 ± 6.49
Prostate volume, cc (mean ± SD)
36.71 ± 16.94
iPSA, ng/mL [N (%)] Mean ± SD
26.76 ± 49.33
B10
39 (34.2)
10–20
39 (34.2)
C20
36 (31.6)
Gleason score [N (%)] B6 7 C8 T stage (N (%)]
41 (36.0) 38 (33.3) 35 (30.7)
\T2b
52 (45.6)
T2b
16 (14.0)
[T2b
46 (40.4)
D’Amico risk group [N (%)] Low
19 (16.7)
Intermediate
24 (21.1)
High
71 (62.3)
PSA nadir, ng/mL (mean ± SD)
0.81 ± 2.29
Time to PSA nadir, months (mean ± SD)
3.40 ± 3.29
SD standard deviation, iPSA initial PSA, PSA prostate-specific antigen
Table 2. The proportion of iPSA (p = 0.004), Gleason score (p = 0.023), D’Amico risk group (p = 0.007), PSA nadir (p = 0.002), and time to PSA nadir (p = 0.005) revealed significant difference between these two groups. ROC analysis showed the area under the curve (AUC) of PSA nadir for PSA biochemical recurrence prediction was 0.882, indicating good predictive power. We then used different cutoff values of PSA nadir (0.2, 0.3, 0.5, 0.6, 0.8, 1.0 ng/mL) for ROC analysis. PSA of 0.3 ng/mL revealed the best AUC (0.818) in sensitivity (0.778) and specificity (0.859) for PSA biochemical recurrence. On univariate analysis, Gleason score C8 [hazard ratio (HR) 2.982; p = 0.011], D’Amico high-risk group (HR 4.750; p = 0.002), PSA nadir [0.3 ng/mL (HR 21.318; p \ 0.001) and time to PSA nadir \3 months (HR 3.737; p = 0.003) were considered significant (Table 3). These four parameters were selected for multivariate analysis. On multivariate analysis, D’Amico high-risk group (HR 6.552; p = 0.014), PSA nadir[0.3 ng/mL (HR 34.062; p \ 0.001) and time to PSA nadir \3 months (HR 4.144; p = 0.021) were statistically significant for PSA biochemical recurrence. Kaplan–Meier analysis with log-rank test also demonstrated a significant difference (for D’Amico high-risk group, p \ 0.001; for PSA nadir[0.3 ng/mL, p \ 0.001; for time to PSA nadir\3 months, p = 0.001) (Fig. 1).
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TABLE 2 Intergroup comparison Variable
Biochemical recurrence-free (N = 78)
Biochemical recurrence (N = 36)
p value
Age, year, men (mean ± SD)
69.76 ± 6.79
69.76 ± 5.86
1.000
Prostate volume, cc (mean ± SD)
37.99 ± 18.36
TABLE 3 Univariate and multivariate analysis of perioperative parameters for PSA biochemical recurrence Hazard ratio (95 % CI)
p value
Univariate analysis
33.92 ± 13.17
0.181
iPSA, ng/mL (N (%)] Mean ± SD
23.18 ± 54.16
34.50 ± 36.26
0.192
B10
31 (39.7)
8 (22.2)
0.004
10–20
30 (38.5)
9 (25.0)
C20
17 (21.8)
19 (52.8)
Gleason score [N (%)]
Age [ 70 years
1.099 (0.498–2.427)
0.815
iPSA C 20 ng/mL
1.004 (0.996–1.013)
0.307
Prostate volume [ 50 cc
0.449 (0.139–1.445)
0.179
Gleason score C 8
2.982 (1.288–6.908)
0.011
T stage [ T2b
1.786 (0.802–3.976)
0.156
D’Amico high-risk group PSA nadir [ 0.3 ng/mL Time to PSA nadir \3 months
0.023
B6
33 (42.3)
8 (22.2)
D’Amico high-risk group
7
27 (34.6)
11 (30.6)
PSA nadir [ 0.3 ng/mL
C8
18 (23.1)
17 (47.2)
Time to PSA nadir \3 months 0.085
\T2b
41 (52.6)
11 (30.6)
T2b
9 (11.5)
7 (19.4)
[T2b
28 (35.9)
18 (50.0)
D’Amico risk group [N (%)]
0.007
Low Intermediate
16 (20.5) 21 (26.9)
High
3 (8.3) 3 (8.3)
41 (52.6)
30 (83.3)
PSA nadir, ng/mL (mean ± SD)
0.17 ± 0.33
2.20 ± 3.72
0.002
Time to PSA nadir, months (mean ± SD)
3.85 ± 3.74
2.42 ± 1.60
0.005
SD standard deviation, iPSA initial PSA, PSA prostate-specific antigen
Due to the high proportion of D’Amico high- and intermediate-risk groups (83.3 %) in this study, we further analyzed these patients in univariate and multivariate studies (Table 4). The results showed that PSA nadir [0.3 ng/mL (HR 33.893; p \ 0.001) and time to PSA nadir \3 months (HR 4.150; p = 0.042) were still predictive for PSA biochemical recurrence. DISCUSSION The mechanisms of definitive treatments for localized prostate cancer—radical prostatectomy, radiotherapy, and cryoablation—are different. The differences among these three treatments result in different definitions, rates, and predictors of PSA biochemical recurrence. Radical prostatectomy is total surgical removal of prostate tissue. Theoretically, postoperative PSA will
0.002 \0.001
3.737 (1.585–8.811)
0.003
1.293 (0.345–6.851)
0.703
6.552 (1.453–29.535)
0.014
Multivariate analysis Gleason score C 8
T stage [N (%)]
4.750 (1.778–12.689) 21.318 (7.750–58.642)
34.062 (9.264–125.237) \0.001 4.144 (1.240–13.847)
0.021
PSA prostate-specific antigen, CI confidence interval, iPSA initial PSA
become undetectable in the first month if there is no residual tumor or prostate tissue.7 Therefore, the definition of PSA biochemical recurrence after radical prostatectomy is strict (two consecutive PSA values [0.2 ng/mL).8 The 10-year PSA biochemical recurrence-free survival varies from 60 to 75 % in different case series.9 Due to available pathological specimen, the predictors of PSA biochemical recurrence after radical prostatectomy include not only clinical parameters (clinical stage, preoperative PSA, and Gleason score) but also pathological parameters (tumor volume, surgical margin, perineural or vascular invasion, and neuroendocrine differentiation).10 The mechanism of radiotherapy is to create reactive oxygen species and damage double-strand DNA of targeted cells. If the extent of damage becomes too much to repair, target-cell death will be induced by necrosis, autography, or apoptosis.11 The cell-death process is slow so that postradiation PSA will reach the nadir gradually after a mean interval of 1–2 years.7 The definition of PSA biochemical recurrence after radiotherapy is PSA [ (nadir ? 2) ng/mL in consideration of possible residual prostate tissue after non-surgical treatment of prostate cancer.12 The 10-year PSA biochemical recurrence-free survival varies from 49 to 62 % in different case series.13,14 Unlike radical prostatectomy, there are no postoperative pathological parameters after radiotherapy, but the concepts of PSA nadir and PSA kinetic change are applied for the prediction of PSA biochemical recurrence. Some studies reveal parameters such as preoperative PSA, Gleason score, PSA nadir, time to PSA nadir, and PSAdt are the key factors for PSA biochemical recurrence after radiotherapy.15,16
Predictors of Cryoablation PSA Recurrence
B
Time to PSA biochemical recurrence
A
Time to PSA biochemical recurrence
1.0
1.0
0.8
0.8
Survival rate
Survival rate
1615
0.6
0.6
0.4
0.4 D Amico intermediate or low risk
PSA nadir ≤ 0.3 ng/mL
0.2
PSA nadir > 0.3 ng/mL
D Amico high risk
0.2
PSA nadir ≤ 0.3 ng/mL-censored
D Amico intermediate or low risk-censored D Amico high risk-censored 0.00
12.00
24.00
PSA nadir > 0.3 ng/mL-censored
0.0
36.00
48.00
60.00
72.00
0.00
12.00
Biochemical free survival(m)
24.00
36.00
48.00
60.00
72.00
Biochemical free survival(m) Time to PSA biochemical recurrence
C 1.0
Survival rate
0.8
0.6
0.4
Time to PSA nadir ≥ 3 months
0.2
Time to PSA nadir < 3 months Time to PSA nadir ≥ 3 months-censored Time to PSA nadir < 3 months-censored
0.0 0.00
12.00
24.00
36.00
48.00
60.00
72.00
Biochemical free survival(m)
FIG. 1 Kaplan–Meier PSA biochemical recurrence-free survival stratified by a D’Amico high risk, b PSA nadir[0.3 ng/mL, and c time to PSA nadir \3 months. PSA prostate-specific antigan
Cryoablation destructs prostate cancer cells by (1) ice crystal with intracellular dehydration and metabolic disturbance; (2) ice crystal-induced mechanical cell membrane disruption; (3) vascular stasis and thrombosis after thawing with tissue ischemia; and (4) molecularbased cancer cell apoptosis.17,18 Post-cryoablation PSA will reach the nadir after a mean interval of 3 months.19 Although the time to PSA nadir interval for cryoablation is shorter than radiotherapy, it may still indicate persistent postoperative immune response for further cancer cell
death. The 10-year PSA biochemical recurrence-free survival after cryoablation is 62.36 % in a case series.20 Similar to radiotherapy, preoperative PSA, Gleason score, D’Amico risk group, clinical stage, PSA nadir, and PSAdt have been identified as the predictors of PSA biochemical recurrence after cryoablation in different studies.3,5,6 In the present study, we found three important predictors of PSA biochemical recurrence after cryoablation— D’Amico high-risk group, PSA nadir \0.3 ng/mL, and time to nadir \3 months. After D’Amico risk stratification,
1616
Y. Y. Liu et al.
TABLE 4 Univariate and multivariate analysis of perioperative parameters for PSA biochemical recurrence in D’Amico high- and intermediate-risk patients Hazard ratio (95 % CI)
p value
Univariate analysis Age [ 70 years
0.648 (0.276–1.518)
0.317
iPSA C 20 ng/mL Prostate volume [ 50 cc
3.592 (1.479–8.727) 0.520 (0.155–1.745)
0.005 0.290
Gleason score C 8
2.812 (1.165–6.792)
0.022
T stage [ T2b
1.457 (0.624–3.404)
0.384
D’Amico high-risk group
5.500 (1.505–20.097)
0.010
PSA nadir [ 0.3 ng/mL
29.167 (9.155–92.923)
\0.001
4.327 (1.686–11.105)
0.002
Time to PSA nadir \3 months Multivariate analysis iPSA C 20 ng/mL
2.775 (0.615–12.512)
0.184
Gleason score C 8
2.343 (0.542–10.130)
0.254
2.417 (0.321–18.173)
0.391
D’Amico high-risk group PSA nadir [ 0.3 ng/mL Time to PSA nadir \3 months
33.893 (8.289–138.585) \0.001 4.150 (1.052–16.376)
0.042
PSA prostate-specific antigen, CI confidence interval, iPSA initial PSA
PSA biochemical recurrence-free survival rate in low-, intermediate-, and high-risk groups was 84.2 % (16 of 19 patients), 87.5 % (21 of 24 patients), and 51.7 % (41 of 71 patients), respectively. On multivariate analysis, D’Amico high-risk group was predictive for PSA biochemical recurrence (HR 6.552; p = 0.014). For other studies of primary prostate cryoablation, the 5-year PSA biochemical recurrence-free survival by ASTRO or Phoenix definition in D’Amico low-, intermediate-, and high-risk groups was 85–92, 73–89, and 62–89 %, respectively.21–23 In addition, the 10-year PSA biochemical recurrence-free survival by Phoenix definition in D’Amico low-, intermediate-, and high-risk groups was 80.56, 74.16, and 45.54 %, respectively.20 These results were compatible with our study, indicating the importance of the D’Amico high-risk group for PSA biochemical recurrence after cryoablation. High PSA biochemical recurrence rate in the D’Amico high-risk group may be related to occult micrometastases, which cannot be detected by either bone scan or magnetic resonance imaging (MRI).24 Therefore, the updated European Association of Urology (EAU) guidelines suggest the best potential candidates for prostate cryoablation are the D’Amico low- and intermediate-risk group patients.9 We obtained the best predictive PSA cutoff value of 0.3 ng/mL for PSA biochemical recurrence in the study. Also, PSA nadir [0.3 ng/mL revealed significance in multivariate analysis (HR 34.062; p \ 0.001) for PSA biochemical recurrence. According to the updated EAU guidelines, post-cryoablation PSA nadir may have a prognostic value.9 The PSA nadir after cryoablation is commonly
contributed by possibly residual periurethral prostate tissue and median lobe, which may contain residual tumor cells.23 Levy et al. reported that post-cryoablation PSA nadir [0.6 ng/mL predicts the PSA biochemical recurrence rate at 24 months.3 Our results echoed this finding, and confirmed PSA nadir [0.3 ng/mL is an important predictor for PSA biochemical recurrence after cryoablation. Time to PSA nadir has been proven as a predictor for PSA biochemical recurrence after radiotherapy and highintensity focused ultrasound.16,25,26 Ray et al. reported that a shorter time to PSA nadir is associated with decreased PSA biochemical recurrence-free survival, regardless of the PSA nadir after radiotherapy.16 They also confirmed that PSA nadir \12 months predicts PSA biochemical recurrence after radiotherapy.25 In other words, time to PSA nadir is inversely proportional to PSA biochemical recurrence-free survival after radiotherapy. This can be explained by persistent cancer cell death during gradual, unsuccessful mitosis. A shorter time to PSA nadir means insufficient time to complete the response, indicating possible treatment failure. Similarly, Sung et al. reported that time to PSA nadir is a significant predictor of PSA biochemical recurrence in patients undergoing primary prostate high-intensity focused ultrasound.26 In our study, time to PSA nadir \3 months was significant in multivariate analysis (HR 4.144; p = 0.021) for PSA biochemical recurrence. This finding was similar to the findings in radiotherapy and high-intensity focused ultrasound. It can also be explained by post-cryoablation vascular thrombosis with tissue ischemia and molecular-based cancer cell apoptosis associated with immune response-induced persistent cancer cell death.18 Therefore, persistent PSA decrease [3 months implies complete response and favorable PSA biochemical recurrence-free survival. To the best of our knowledge, this is the first article discussing time to PSA nadir in patients undergoing primary prostate cryoablation. We may hypothesize that indirect and persistent prostate cancer cell death is the key point to successful treatment in radiotherapy, cryoablation, and highintensity focused ultrasound. This important result would help us understand the trend of postoperative PSA change after non-surgical treatment. In addition, it is worthwhile to confirm the validity of this novel finding in further, larger database studies. There were some limitations to this study. First, it was a retrospective, single-institutional study. In addition, the follow-up was relatively shorter (median 34.87 ± 16.49 months) than other studies. However, Shinohara et al. reported that the majority of post-cryoablation PSA biochemical recurrence (96 %) was detected within the first 12 months.27 Thus, the median 34.87 months of follow-up would be sufficient for evaluation of postcryoablation PSA biochemical recurrence. However, long-
Predictors of Cryoablation PSA Recurrence
term data still need to be assessed. In addition, a high proportion of D’Amico high-risk group patients might influence the characteristics of the patient group. In fact, PSA screening for prostate cancer in Taiwan is not as popular as in Western countries; therefore, patients with prostate cancer are often not diagnosed earlier. Furthermore, radical prostatectomy may tend to be performed for D’Amico low- or intermediate-risk patients if indicated. For the above reasons, D’Amico high-risk patients contributed the most overall and this may result in some selection bias. Finally, we could not analyze the correlation between PSA biochemical recurrence and true biopsyproven recurrence due to lack of routine prostate biopsy after PSA biochemical recurrence. CONCLUSIONS In this study, we confirmed that the D’Amico high-risk group, PSA nadir [0.3 ng/mL, and time to PSA nadir \3 months are independent predictors of PSA biochemical recurrence in primary whole-gland prostate cryoablation. These results provide useful information for preoperative patient selection and postoperative follow-up. ACKNOWLEDGMENT
None.
DISCLOSURES Yi Yang Liu, Po Hui Chiang, Yao Chi Chuang, Wei Ching Lee, Yuan Tso Cheng, and Hung Jen Wang certify that there are no conflicts of interest with any financial organization regarding the material discussed in the manuscript.
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1617 10. Kotb AF, Elabbady AA. Prognostic factors for the development of biochemical recurrence after radical prostatectomy. Prostate Cancer. 2011;2011:485189. 11. Zimmerman MA, Huang Q, Li F, Liu X, Li CY. Cell deathstimulated cell proliferation: a tissue regeneration mechanism usurped by tumors during radiotherapy. Semin Radiat Oncol. 2013;23(4):288–295. 12. Roach M 3rd, Hanks G, Thames H Jr, 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 Radiat Oncol Biol Phys. 2006;65(4): 965–974. 13. Zietman AL, Chung CS, Coen JJ, Shipley WU. 10-year outcome for men with localized prostate cancer treated with external radiation therapy: results of a cohort study. J Urol. 2004;171(1): 210–214. 14. Zelefsky MJ, Kattan MW, Fearn P, et al. Pretreatment nomogram predicting ten-year biochemical outcome of three-dimensional conformal radiotherapy and intensity-modulated radiotherapy for prostate cancer. Urology. 2007;70(2):283–287. 15. Lee AK, Levy LB, Cheung R, Kuban D. Prostate-specific antigen doubling time predicts clinical outcome and survival in prostate cancer patients treated with combined radiation and hormone therapy. Int J Radiat Oncol Biol Phys. 2005;63(2):456–462. 16. Ray ME, Thames HD, Levy LB, et al. PSA nadir predicts biochemical and distant failures after external beam radiotherapy for prostate cancer: a multi-institutional analysis. Int J Radiat Oncol Biol Phys. 2006;64(4):1140–1150. 17. Gage AA, Baust J. Mechanisms of tissue injury in cryosurgery. Cryobiology. 1998;37(3):171–186. 18. Baust JG, Gage AA, Robilottto AT, Baust JM. The pathophysiology of thermoablation: optimizing cryoablation. Curr Opin Urol. 2009;19(2):127–132. 19. Wieder J, Schmidt JD, Casola G, Sonnenberg E, Stainken BF, Parsons CL. Transrectal ultrasound-guided transperineal cryoablation in the treatment of prostate carcinoma: preliminary results. J Urol. 1995;154(2):435–441. 20. Cohen JK, Miller RJ Jr, Ahmed S, Lotz MJ, Baust J. Ten-year biochemical disease control for patients with prostate cancer treated with cryosurgery as primary therapy. Urology. 2008;71(3):515–518. 21. Prepelica KL, Okeke Z, Murphy A, Katz AE. Cryosurgical ablation of the prostate: high risk patient outcomes. Cancer. 2005;103(8):1625–1630. 22. Bahn DK, Lee F, Badalament R, Kumar A, Greski J, Chernick M. Targeted cryoablation of the prostate: 7-year outcomes in the primary treatment of prostate cancer. Urology. 2002;60(2 Suppl 1): 3–11. 23. Jones JS, Rewcastle JC, Donnelly BJ, Lugnani FM, Pisters LL, Katz AE. Whole gland primary prostate cryoablation: initial results from the cryo on-line data registry. J Urol. 2008;180(2):554–558. 24. Cresswell J, Asterling S, Chaudhary M, Sheikh N, Greene D. Third-generation cryotherapy for prostate cancer in the UK: a prospective study of the early outcomes in primary and recurrent disease. BJU Int. 2006;97(5):969–974. 25. Ray ME, Levy LB, Horwitz EM, et al. Nadir prostate-specific antigen within 12 months after radiotherapy predicts biochemical and distant failure. Urology. Dec 2006;68(6):1257–1262. 26. Sung HH, Jeong BC, Seo SI, Jeon SS, Choi HY, Lee HM. Seven years of experience with high-intensity focused ultrasound for prostate cancer: advantages and limitations. Prostate. 2012;72(13): 1399–1406. 27. Shinohara K, Rhee B, Presti JC Jr, Carroll PR. Cryosurgical ablation of prostate cancer: patterns of cancer recurrence. J Urol. 1997;158(6):2206–2209; discussion 2209–2210.
ORIGINAL ARTICLE – UROLOGIC ONCOLOGY
Predictors of Prostate-Specific Antigen Biochemical Recurrence in Patients Undergoing Primary Whole-Gland Prostate Cryoablation Yi Yang Liu, MD, Po Hui Chiang, MD, PhD, Yao Chi Chuang, MD, Wei Ching Lee, MD, Yuan Tso Cheng, MD, and Hung Jen Wang, MD Department of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
ABSTRACT Purpose. Cryoablation has been proven as a less invasive, safe, and effective treatment for localized prostate cancer. We attempted to identify the predictors of biochemical recurrence after prostate cryoablation for localized prostate cancer in this study. Methods. We reviewed 114 patients who underwent primary whole-gland prostate cryoablation for localized prostate cancer from October 2008 to March 2013. The perioperative parameters included age [70 years, initial prostate-specific antigen (PSA), preoperative prostate volume, Gleason score, T stage, D’Amico risk group, postoperative PSA nadir, time to PSA nadir, and PSA biochemical recurrence, defined by Phoenix definition (nadir plus 2 ng/mL). Receiver operating characteristic (ROC) analysis was used for the best cutoff value of PSA nadir for PSA biochemical recurrence. The parameters were analyzed in binary logistic regression and Kaplan– Meier analysis for PSA biochemical recurrence. Results. A total of 31.6 % (N = 36) patients had PSA biochemical recurrence during the median follow-up of 34.87 ± 16.49 months. ROC analysis revealed that the best cutoff value for biochemical recurrence prediction was when the PSA nadir = 0.3 ng/mL. On multivariate analysis and Kaplan–Meier analysis, the D’Amico high-risk group [hazard ratio (HR) 6.552; p = 0.014], PSA nadir [0.3 ng/mL (HR 34.062; p \ 0.001), and time to PSA
Po Hui Chiang and Yi Yang Liu contributed equally to this paper. Ó Society of Surgical Oncology 2014 First Received: 14 December 2013; Published Online: 7 October 2014 P. H. Chiang, MD, PhD e-mail: [email protected]
nadir \3 months (HR 4.144; p = 0.021) were statistically significant for PSA biochemical recurrence. Conclusions. The D’Amico high-risk group, postoperative PSA nadir [0.3 ng/mL, and time to PSA nadir \3 months predict biochemical recurrence in primary whole-gland prostate cryoablation.
Prostate cryoablation was first introduced for prostate cancer in the 1960s.1 With the improvement of instruments and techniques such as the Argon/Helium system, urethra warming catheter, and multipoint thermal sensors, fourthgeneration cryoablation has been proven as a less invasive, safe, and effective treatment for localized prostate cancer.2 Prostate-specific antigen (PSA) biochemical recurrence is a surrogate for true biopsy-proven prostate cancer recurrence or metastasis disease.3 The predictors of PSA biochemical recurrence after definitive treatments of localized prostate cancer can help us select suitable candidates for preoperative treatment and detect earlier any possible prostate cancer recurrence postoperatively. To date, the definition and predictors of PSA biochemical recurrence in radical prostatectomy and radiotherapy have been well established and studied. For cryoablation, the RTOG-ASTRO Phoenix definition has been proven more predictive for true biopsyproven recurrence after prostate cryoablation than strict PSA levels or traditional ASTRO definition.4 However, in comparison with radical prostatectomy and radiotherapy, there is no consensus on the predictors of post-cryoablation PSA biochemical recurrence, especially for Asian patients. In previous studies, preoperative PSA, Gleason score, D’Amico risk group, clinical stage, PSA nadir, and PSA doubling time (PSAdt) were identified as the predictors.3,5,6 In this study, we attempted to find the clinical predictive factors of PSA biochemical recurrence after primary whole-gland prostate cryoablation for localized prostate
Predictors of Cryoablation PSA Recurrence
cancer. The results may provide useful information for clinical urological oncologists. MATERIALS AND METHODS From October 2008 to March 2013, 138 patients who underwent prostate cryoablation for prostate cancer at Kaohsiung Chang Gung Memorial Hospital were retrospectively reviewed under the approval of the Institutional Review Board. All patients were treated by fourth-generation cryosurgical technology (Endocare Cryocare Surgical System, Heathtronics Inc., Austin, TX, USA). The operations were performed under the Argon/Helium system with two freeze–thaw cycles, urethral warming catheters, and multipoint thermal sensors. We selected 114 patients who underwent primary whole-gland prostate cryoablation for localized prostate cancer after exclusion of focal therapy (N = 7), salvage therapy (N = 11), pathology other than adenocarcinoma (N = 2, all were urothelial carcinoma), and advanced prostate cancer (N = 4, T stage [T3a or Nstage positive or M-stage positive). The perioperative parameters such as age, initial PSA (iPSA), preoperative prostate volume, Gleason score, T stage, D’Amico risk group, postoperative PSA nadir, time to PSA nadir, and PSA biochemical recurrence defined by Phoenix definition (PSA nadir plus 2 ng/mL) were collected. Patients were classified into two groups according to the existence of PSA biochemical recurrence. These two groups were compared using Student’s t test for continuous variables, and Chi square test for categorical variables. Receiver operating characteristic (ROC) analysis was used to detect the best predictive value of PSA nadir for PSA biochemical recurrence. All variables were analyzed with postoperative PSA biochemical recurrence in univariate binary logistic regression. The variables with statistical significance on univariate analysis were chosen for multivariate analysis and further Kaplan–Meier analysis. All analyses were performed using SPSS Statistics version 17.0 (SPSS Inc., Chicago, IL, USA). p values\0.05 were considered significant. RESULTS Patient characteristics are listed in Table 1. A total of 31.6 % (N = 36) of patients had PSA biochemical recurrence after cryoablation during the median follow-up of 34.87 ± 16.49 months. The PSA biochemical recurrence rate in the D’Amico high-, intermediate- and low-risk group patients were 42.3 % (N = 30), 12.5 % (N = 3), and 15.8 % (N = 3), respectively. The median PSA biochemical recurrence-free survival and time to PSA biochemical recurrence was 27.19 ± 18.10 and 15.07 ± 15.12 months, respectively. Intergroup comparison was demonstrated in
1613 TABLE 1 Patient characteristics Variable
(N = 114)
Age, years, men (mean ± SD)
69.76 ± 6.49
Prostate volume, cc (mean ± SD)
36.71 ± 16.94
iPSA, ng/mL [N (%)] Mean ± SD
26.76 ± 49.33
B10
39 (34.2)
10–20
39 (34.2)
C20
36 (31.6)
Gleason score [N (%)] B6 7 C8 T stage (N (%)]
41 (36.0) 38 (33.3) 35 (30.7)
\T2b
52 (45.6)
T2b
16 (14.0)
[T2b
46 (40.4)
D’Amico risk group [N (%)] Low
19 (16.7)
Intermediate
24 (21.1)
High
71 (62.3)
PSA nadir, ng/mL (mean ± SD)
0.81 ± 2.29
Time to PSA nadir, months (mean ± SD)
3.40 ± 3.29
SD standard deviation, iPSA initial PSA, PSA prostate-specific antigen
Table 2. The proportion of iPSA (p = 0.004), Gleason score (p = 0.023), D’Amico risk group (p = 0.007), PSA nadir (p = 0.002), and time to PSA nadir (p = 0.005) revealed significant difference between these two groups. ROC analysis showed the area under the curve (AUC) of PSA nadir for PSA biochemical recurrence prediction was 0.882, indicating good predictive power. We then used different cutoff values of PSA nadir (0.2, 0.3, 0.5, 0.6, 0.8, 1.0 ng/mL) for ROC analysis. PSA of 0.3 ng/mL revealed the best AUC (0.818) in sensitivity (0.778) and specificity (0.859) for PSA biochemical recurrence. On univariate analysis, Gleason score C8 [hazard ratio (HR) 2.982; p = 0.011], D’Amico high-risk group (HR 4.750; p = 0.002), PSA nadir [0.3 ng/mL (HR 21.318; p \ 0.001) and time to PSA nadir \3 months (HR 3.737; p = 0.003) were considered significant (Table 3). These four parameters were selected for multivariate analysis. On multivariate analysis, D’Amico high-risk group (HR 6.552; p = 0.014), PSA nadir[0.3 ng/mL (HR 34.062; p \ 0.001) and time to PSA nadir \3 months (HR 4.144; p = 0.021) were statistically significant for PSA biochemical recurrence. Kaplan–Meier analysis with log-rank test also demonstrated a significant difference (for D’Amico high-risk group, p \ 0.001; for PSA nadir[0.3 ng/mL, p \ 0.001; for time to PSA nadir\3 months, p = 0.001) (Fig. 1).
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Y. Y. Liu et al.
TABLE 2 Intergroup comparison Variable
Biochemical recurrence-free (N = 78)
Biochemical recurrence (N = 36)
p value
Age, year, men (mean ± SD)
69.76 ± 6.79
69.76 ± 5.86
1.000
Prostate volume, cc (mean ± SD)
37.99 ± 18.36
TABLE 3 Univariate and multivariate analysis of perioperative parameters for PSA biochemical recurrence Hazard ratio (95 % CI)
p value
Univariate analysis
33.92 ± 13.17
0.181
iPSA, ng/mL (N (%)] Mean ± SD
23.18 ± 54.16
34.50 ± 36.26
0.192
B10
31 (39.7)
8 (22.2)
0.004
10–20
30 (38.5)
9 (25.0)
C20
17 (21.8)
19 (52.8)
Gleason score [N (%)]
Age [ 70 years
1.099 (0.498–2.427)
0.815
iPSA C 20 ng/mL
1.004 (0.996–1.013)
0.307
Prostate volume [ 50 cc
0.449 (0.139–1.445)
0.179
Gleason score C 8
2.982 (1.288–6.908)
0.011
T stage [ T2b
1.786 (0.802–3.976)
0.156
D’Amico high-risk group PSA nadir [ 0.3 ng/mL Time to PSA nadir \3 months
0.023
B6
33 (42.3)
8 (22.2)
D’Amico high-risk group
7
27 (34.6)
11 (30.6)
PSA nadir [ 0.3 ng/mL
C8
18 (23.1)
17 (47.2)
Time to PSA nadir \3 months 0.085
\T2b
41 (52.6)
11 (30.6)
T2b
9 (11.5)
7 (19.4)
[T2b
28 (35.9)
18 (50.0)
D’Amico risk group [N (%)]
0.007
Low Intermediate
16 (20.5) 21 (26.9)
High
3 (8.3) 3 (8.3)
41 (52.6)
30 (83.3)
PSA nadir, ng/mL (mean ± SD)
0.17 ± 0.33
2.20 ± 3.72
0.002
Time to PSA nadir, months (mean ± SD)
3.85 ± 3.74
2.42 ± 1.60
0.005
SD standard deviation, iPSA initial PSA, PSA prostate-specific antigen
Due to the high proportion of D’Amico high- and intermediate-risk groups (83.3 %) in this study, we further analyzed these patients in univariate and multivariate studies (Table 4). The results showed that PSA nadir [0.3 ng/mL (HR 33.893; p \ 0.001) and time to PSA nadir \3 months (HR 4.150; p = 0.042) were still predictive for PSA biochemical recurrence. DISCUSSION The mechanisms of definitive treatments for localized prostate cancer—radical prostatectomy, radiotherapy, and cryoablation—are different. The differences among these three treatments result in different definitions, rates, and predictors of PSA biochemical recurrence. Radical prostatectomy is total surgical removal of prostate tissue. Theoretically, postoperative PSA will
0.002 \0.001
3.737 (1.585–8.811)
0.003
1.293 (0.345–6.851)
0.703
6.552 (1.453–29.535)
0.014
Multivariate analysis Gleason score C 8
T stage [N (%)]
4.750 (1.778–12.689) 21.318 (7.750–58.642)
34.062 (9.264–125.237) \0.001 4.144 (1.240–13.847)
0.021
PSA prostate-specific antigen, CI confidence interval, iPSA initial PSA
become undetectable in the first month if there is no residual tumor or prostate tissue.7 Therefore, the definition of PSA biochemical recurrence after radical prostatectomy is strict (two consecutive PSA values [0.2 ng/mL).8 The 10-year PSA biochemical recurrence-free survival varies from 60 to 75 % in different case series.9 Due to available pathological specimen, the predictors of PSA biochemical recurrence after radical prostatectomy include not only clinical parameters (clinical stage, preoperative PSA, and Gleason score) but also pathological parameters (tumor volume, surgical margin, perineural or vascular invasion, and neuroendocrine differentiation).10 The mechanism of radiotherapy is to create reactive oxygen species and damage double-strand DNA of targeted cells. If the extent of damage becomes too much to repair, target-cell death will be induced by necrosis, autography, or apoptosis.11 The cell-death process is slow so that postradiation PSA will reach the nadir gradually after a mean interval of 1–2 years.7 The definition of PSA biochemical recurrence after radiotherapy is PSA [ (nadir ? 2) ng/mL in consideration of possible residual prostate tissue after non-surgical treatment of prostate cancer.12 The 10-year PSA biochemical recurrence-free survival varies from 49 to 62 % in different case series.13,14 Unlike radical prostatectomy, there are no postoperative pathological parameters after radiotherapy, but the concepts of PSA nadir and PSA kinetic change are applied for the prediction of PSA biochemical recurrence. Some studies reveal parameters such as preoperative PSA, Gleason score, PSA nadir, time to PSA nadir, and PSAdt are the key factors for PSA biochemical recurrence after radiotherapy.15,16
Predictors of Cryoablation PSA Recurrence
B
Time to PSA biochemical recurrence
A
Time to PSA biochemical recurrence
1.0
1.0
0.8
0.8
Survival rate
Survival rate
1615
0.6
0.6
0.4
0.4 D Amico intermediate or low risk
PSA nadir ≤ 0.3 ng/mL
0.2
PSA nadir > 0.3 ng/mL
D Amico high risk
0.2
PSA nadir ≤ 0.3 ng/mL-censored
D Amico intermediate or low risk-censored D Amico high risk-censored 0.00
12.00
24.00
PSA nadir > 0.3 ng/mL-censored
0.0
36.00
48.00
60.00
72.00
0.00
12.00
Biochemical free survival(m)
24.00
36.00
48.00
60.00
72.00
Biochemical free survival(m) Time to PSA biochemical recurrence
C 1.0
Survival rate
0.8
0.6
0.4
Time to PSA nadir ≥ 3 months
0.2
Time to PSA nadir < 3 months Time to PSA nadir ≥ 3 months-censored Time to PSA nadir < 3 months-censored
0.0 0.00
12.00
24.00
36.00
48.00
60.00
72.00
Biochemical free survival(m)
FIG. 1 Kaplan–Meier PSA biochemical recurrence-free survival stratified by a D’Amico high risk, b PSA nadir[0.3 ng/mL, and c time to PSA nadir \3 months. PSA prostate-specific antigan
Cryoablation destructs prostate cancer cells by (1) ice crystal with intracellular dehydration and metabolic disturbance; (2) ice crystal-induced mechanical cell membrane disruption; (3) vascular stasis and thrombosis after thawing with tissue ischemia; and (4) molecularbased cancer cell apoptosis.17,18 Post-cryoablation PSA will reach the nadir after a mean interval of 3 months.19 Although the time to PSA nadir interval for cryoablation is shorter than radiotherapy, it may still indicate persistent postoperative immune response for further cancer cell
death. The 10-year PSA biochemical recurrence-free survival after cryoablation is 62.36 % in a case series.20 Similar to radiotherapy, preoperative PSA, Gleason score, D’Amico risk group, clinical stage, PSA nadir, and PSAdt have been identified as the predictors of PSA biochemical recurrence after cryoablation in different studies.3,5,6 In the present study, we found three important predictors of PSA biochemical recurrence after cryoablation— D’Amico high-risk group, PSA nadir \0.3 ng/mL, and time to nadir \3 months. After D’Amico risk stratification,
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Y. Y. Liu et al.
TABLE 4 Univariate and multivariate analysis of perioperative parameters for PSA biochemical recurrence in D’Amico high- and intermediate-risk patients Hazard ratio (95 % CI)
p value
Univariate analysis Age [ 70 years
0.648 (0.276–1.518)
0.317
iPSA C 20 ng/mL Prostate volume [ 50 cc
3.592 (1.479–8.727) 0.520 (0.155–1.745)
0.005 0.290
Gleason score C 8
2.812 (1.165–6.792)
0.022
T stage [ T2b
1.457 (0.624–3.404)
0.384
D’Amico high-risk group
5.500 (1.505–20.097)
0.010
PSA nadir [ 0.3 ng/mL
29.167 (9.155–92.923)
\0.001
4.327 (1.686–11.105)
0.002
Time to PSA nadir \3 months Multivariate analysis iPSA C 20 ng/mL
2.775 (0.615–12.512)
0.184
Gleason score C 8
2.343 (0.542–10.130)
0.254
2.417 (0.321–18.173)
0.391
D’Amico high-risk group PSA nadir [ 0.3 ng/mL Time to PSA nadir \3 months
33.893 (8.289–138.585) \0.001 4.150 (1.052–16.376)
0.042
PSA prostate-specific antigen, CI confidence interval, iPSA initial PSA
PSA biochemical recurrence-free survival rate in low-, intermediate-, and high-risk groups was 84.2 % (16 of 19 patients), 87.5 % (21 of 24 patients), and 51.7 % (41 of 71 patients), respectively. On multivariate analysis, D’Amico high-risk group was predictive for PSA biochemical recurrence (HR 6.552; p = 0.014). For other studies of primary prostate cryoablation, the 5-year PSA biochemical recurrence-free survival by ASTRO or Phoenix definition in D’Amico low-, intermediate-, and high-risk groups was 85–92, 73–89, and 62–89 %, respectively.21–23 In addition, the 10-year PSA biochemical recurrence-free survival by Phoenix definition in D’Amico low-, intermediate-, and high-risk groups was 80.56, 74.16, and 45.54 %, respectively.20 These results were compatible with our study, indicating the importance of the D’Amico high-risk group for PSA biochemical recurrence after cryoablation. High PSA biochemical recurrence rate in the D’Amico high-risk group may be related to occult micrometastases, which cannot be detected by either bone scan or magnetic resonance imaging (MRI).24 Therefore, the updated European Association of Urology (EAU) guidelines suggest the best potential candidates for prostate cryoablation are the D’Amico low- and intermediate-risk group patients.9 We obtained the best predictive PSA cutoff value of 0.3 ng/mL for PSA biochemical recurrence in the study. Also, PSA nadir [0.3 ng/mL revealed significance in multivariate analysis (HR 34.062; p \ 0.001) for PSA biochemical recurrence. According to the updated EAU guidelines, post-cryoablation PSA nadir may have a prognostic value.9 The PSA nadir after cryoablation is commonly
contributed by possibly residual periurethral prostate tissue and median lobe, which may contain residual tumor cells.23 Levy et al. reported that post-cryoablation PSA nadir [0.6 ng/mL predicts the PSA biochemical recurrence rate at 24 months.3 Our results echoed this finding, and confirmed PSA nadir [0.3 ng/mL is an important predictor for PSA biochemical recurrence after cryoablation. Time to PSA nadir has been proven as a predictor for PSA biochemical recurrence after radiotherapy and highintensity focused ultrasound.16,25,26 Ray et al. reported that a shorter time to PSA nadir is associated with decreased PSA biochemical recurrence-free survival, regardless of the PSA nadir after radiotherapy.16 They also confirmed that PSA nadir \12 months predicts PSA biochemical recurrence after radiotherapy.25 In other words, time to PSA nadir is inversely proportional to PSA biochemical recurrence-free survival after radiotherapy. This can be explained by persistent cancer cell death during gradual, unsuccessful mitosis. A shorter time to PSA nadir means insufficient time to complete the response, indicating possible treatment failure. Similarly, Sung et al. reported that time to PSA nadir is a significant predictor of PSA biochemical recurrence in patients undergoing primary prostate high-intensity focused ultrasound.26 In our study, time to PSA nadir \3 months was significant in multivariate analysis (HR 4.144; p = 0.021) for PSA biochemical recurrence. This finding was similar to the findings in radiotherapy and high-intensity focused ultrasound. It can also be explained by post-cryoablation vascular thrombosis with tissue ischemia and molecular-based cancer cell apoptosis associated with immune response-induced persistent cancer cell death.18 Therefore, persistent PSA decrease [3 months implies complete response and favorable PSA biochemical recurrence-free survival. To the best of our knowledge, this is the first article discussing time to PSA nadir in patients undergoing primary prostate cryoablation. We may hypothesize that indirect and persistent prostate cancer cell death is the key point to successful treatment in radiotherapy, cryoablation, and highintensity focused ultrasound. This important result would help us understand the trend of postoperative PSA change after non-surgical treatment. In addition, it is worthwhile to confirm the validity of this novel finding in further, larger database studies. There were some limitations to this study. First, it was a retrospective, single-institutional study. In addition, the follow-up was relatively shorter (median 34.87 ± 16.49 months) than other studies. However, Shinohara et al. reported that the majority of post-cryoablation PSA biochemical recurrence (96 %) was detected within the first 12 months.27 Thus, the median 34.87 months of follow-up would be sufficient for evaluation of postcryoablation PSA biochemical recurrence. However, long-
Predictors of Cryoablation PSA Recurrence
term data still need to be assessed. In addition, a high proportion of D’Amico high-risk group patients might influence the characteristics of the patient group. In fact, PSA screening for prostate cancer in Taiwan is not as popular as in Western countries; therefore, patients with prostate cancer are often not diagnosed earlier. Furthermore, radical prostatectomy may tend to be performed for D’Amico low- or intermediate-risk patients if indicated. For the above reasons, D’Amico high-risk patients contributed the most overall and this may result in some selection bias. Finally, we could not analyze the correlation between PSA biochemical recurrence and true biopsyproven recurrence due to lack of routine prostate biopsy after PSA biochemical recurrence. CONCLUSIONS In this study, we confirmed that the D’Amico high-risk group, PSA nadir [0.3 ng/mL, and time to PSA nadir \3 months are independent predictors of PSA biochemical recurrence in primary whole-gland prostate cryoablation. These results provide useful information for preoperative patient selection and postoperative follow-up. ACKNOWLEDGMENT
None.
DISCLOSURES Yi Yang Liu, Po Hui Chiang, Yao Chi Chuang, Wei Ching Lee, Yuan Tso Cheng, and Hung Jen Wang certify that there are no conflicts of interest with any financial organization regarding the material discussed in the manuscript.
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