The Effect of Time to Castration Resistance on Overall Survival and Success of Docetaxel Treatment in Castration Resistant Prostate Cancer Patients Evren Suer1, Nurullah Hamidi2, Cagri Akpinar1*, Mehmet Ilker Gokce1, Omer Gulpinar1, Kadir Turkolmez1, Yasar Beduk1, Sumer Baltaci1. Purpose: To investigate the prognostic role of time to castration resistance(TTCR) in patients who have received solely Docetaxel chemotherapy regimen(DCR) for castration resistant prostate cancer(CRPC). Methods: Between Jan 2004 and Dec 2015, data of 162 patients who have received DCR for CRPC were gath- ered. Patients were divided into three groups according to TTCR: Group 1(≤ 12 months), group 2(13-24 months), and group 3(>24 months). Data of age, clinical stage, Gleason grade(GG), previous treatments, site of metastases, Prostate-specific antigen (PSA) values, TTCR, overall survival, biochemical progression free survival(PFS) and PSA response to docetaxel were recorded. Result: The mean age of the 162 patients was 74.4 ± 8.5 years. Data on mean age, type of castration, adding estra- mustine to docetaxel, secondary hormonal manipulation, Gleason grade, clinical T stage at initial diagnosis and site of metastases were comparable between three groups. PSA values were higher in group 1 than other groups. PSA response to docetaxel was 59.2% in all patient and it was worse in group 1 than other groups (P = .009). Two years overall survival rates were 7.6%, 25% and 32.3% in group 1, 2 and 3, respectively. Median survival rates were 7, 14 and 23 months in group 1, 2 and 3, respectively, and this difference was statistically significant (P=.016). On multivariate analysis, TTCR was found to be independent prognostic factor for overall survival and response to docetaxel treatment. Conclusion: TTCR appears to be an independent prognostic factor for patients who are candidates for DCR. Keywords: castration; chemotherapy; docetaxel; prostate cancer; survival INTRODUCTION Androgen deprivation therapy (ADT) is the main treatment option for metastatic prostate cancer.(1) After an initial response, resistance to ADT occurs in most patients, with the result that the median survival among patients with metastatic prostate cancer is ap- proximately 3 years.(2) Eventually most of the patients will progress to castration resistant prostate cancer (CRPC). Previously docetaxel chemotherapy regimen (DCR) was the mainstay treatment for CRPC patients. (3) The therapeutic armamentarium for metastatic CRPC has rapidly expanded in recent years. Recently new agents with diverse mechanisms of action (sip- uleucel-T, abiraterone acetate, enzalutamide and radi- um-223) were shown to prolongoverall survival.(4-7) Al- though abiraterone and enzalutamide are widely used, cytotoxics continue to play an important role in the manage¬ment of metastatic CRPC. The best timing for the use of cytotoxic chemotherapy remains questiona- ble and varies among patients. In patients with disease progres¬sion and who are symptomatic or harbour vis- ceral metastases, cytotoxic chemo¬therapy may have a role to play earlier in the dis¬ease course. 1 Ankara University School of Medicine, Department of Urology, Ankara, TURKEY. 2Ankara Atatürk Research and Training Hospital, Department of Urology, Ankara, TURKEY. *Correspondence: Ankara University School of Medicine, Department of Urology, Ankara, TURKEY Tel: +90 541 738 76 38, Fax: +90 (312) 508 21 47. akpinar.cagri89@gmail.com. Received March 2018 & Accepted September 2018 Due to emerging treatment options for CRPC, it is important to define predictive markers to categorise patients suitable for DCR and prevent the ineffective- ness, costs and side effects of this treatment. Time to castration resistance (TTCR) was defined as a pre- dictive factor for secondary endocrine treatment and mixed chemotherapy regimens in previous studies.(8,9) We aimed to investigate the prognostic role of TTCR in patients who have received solely DCR for CRPC. MATERIALS AND METHODS In this retrospective study we have evaluated our met- astatic prostate cancer database. Between Jan 2004 and Dec 2015, a total of 211 patients who have received DCR for CRPC were detected. To prevent the flare up phenomenon, antiandrogen was started 10 days before LHRH agonist started and then patients received only LHRH agonist therapy. PSA and testosterone levels were measured once every 3 months during ADT ther- apy. CRPC was defined as biochemical or radiological disease progression on ADT with castrate testosterone levels (< 50 ng/dL). Biochemical progression was de- fined as a 50% increase in two of three consecutive PSA UROLOGICAL ONCOLOGY Urology Journal/Vol 16 No. 5/ September-October 2019/ pp. 453-457. [DOI: 10.22037/uj.v0i0.4497] measurements taken at 1 week intervals, provided that the PSA value was > 2 ng/mL. Forty nine patients were excluded from the study due to; indeterminate starting dates for primary ADT or chemotherapy (n=24), dis- continuation of chemotherapy due to patient incompli- ance or preference (n=11), significant lack of follow-up data (n=10) and multiple cancer diagnosis (n=4). There- fore, the remaining 162 patients were eligible for the final analysis. Clinical T stage at initial diagnosis was evaluated in patients and is shown in Table 2. Docetaxel was administered I.V. at the standard dose of 75 mg/m2 every 3 weeks as a 1-h infusion with dex- amethasone prophylaxis and oral prednisolone 5 mg twice daily as described previously.(3) Prostate specif- ic antigen (PSA) response rates were measured using Prostate Cancer Working Group (PCWG) 2 criteria.(9) As recommended by the PCWG 2, PSA response was defined as 50% declines from baseline and a 25% in- crease confirmed with a second PSA reading a mini- mum of 3 weeks later was used to determine PSA pro- gression and response duration. Blood tests, including PSA, were measured every three weeks, and radiologi- cal assessments, including computed tomography scans of the thorax, abdomen and pelvis and bone scans, were Table 1. Patient characteristics and comparison of patient characteristics of three groups Patient characteristics Age, mean ± std 74.4 ± 8.5 Median follow up time, , month (Median(range) and IQR) 40 (9-120) , 36 Gleason grade at initial diagnosis, n(%) <8 18 (11) ≥8 144 (89) Clinical T stage at initial diagnosis, n(%) ≤T2 44 (27.2) T3-4 118 (72.8) Type of castration, n(%) Medical 114 (70.3) Surgical 48 (29.7) Adding estramustine to docetaxel, n(%) 33 (20.3) Secondary hormonal manipulation, n(%) None 82 (50.6) Anti-androgen withdrawal 38 (23.4) Switch to another anti-androgen 42 (26) Presence of bone metastases, n(%) 149 (92) Presence of lymph node metastases, n(%) 62 (38.3) Presence of liver metastases, n(%) 18 (11) Presence of lung metastases, n(%) 18 (11) Time to castration resistance, month (Median(range) and IQR) 18 (3-86) , 23 Parameters Group 1 (n=52) Group 2 (n=48) Group 3 (n=62) P value Age, mean ± std 75.7 ± 8.2 73.3 ± 8.5 74.2 ± 8.8 0.84 Gleason grade at initial diagnosis, n(%) 0.21 <8 6 (11.5) 2 (4.2) 10 (16.2) ≥8 46 (88.5) 46(95.8) 52 (83.8) Clinical T stage at initial diagnosis, n(%) 0.72 ≤T2 15 (29.8) 14 (29.2) 16 (25.9) T3-4 37 (71.2) 34 (70.8) 46 (74.1) Type of castration, n(%) 0.25 Medical 32 (61.5) 34 (70.8) 48 (77.4) Surgical 20 (38.5) 14 (29.2) 14 (22.6) Adding estramustine to docetaxel, n(%) 10 (19.2) 11 (22.9) 12 (19.3) 0.78 Secondary Hormonal manipulation, n(%) 0.48 None 28 (53.8) 23 (47.9) 33 (53.2) Anti-androgen withdrawal 11 (21.2) 10 (20.7) 16 (25.8) Switch to another anti-androgen 13 (25) 15 (31.2) 13 (21) Metastases 0.64 M1b Presence of bone metastases , n(%) 48 (92.3) 47 (97) 54 (87) 0.62 M1a, Presence of lymph node metastases, n(%) 26 (50) 10(20.8) 26 (42) 0.54 M1c, Presence of liver metastases, n(%) 4 (7.6) 4 (8.3) 10 (16.1) 0.68 Presence of lung metastases, n(%) 6 (11.5) 4 (8.3) 8 (13) 0.72 Median follow-up,month 46 43 47 0.58 Median nadir PSA value during ADT, (range) 17.7 (0.12-150) 2.3 (0.03-19) 1.2 (0.008-7.3) *0.014 Median PSA value immediately before docetaxel, (range) 93.4 (4-526) 63.7(4.42-196) 78.1(1.5-1092) *0.024 Median nadir PSA value during docetaxel, (range) 65.9 (0.7-400) 34.8 (0.03-161) 18 (0.3-120) *0.026 Median highest PSA value after starting docetaxel, (range) 153 (4-617) 102.7 (3.2-231) 88.2 (5-490) *0.037 Median OS, month(range) 7 (3-26) 14(8-38) 23(6-39) *0.016 2 years OS rate, % 7.6 25 32.2 *0.029 Median biochemical PFS, month(range) 3(1-7) 6(1-13) 10(2-19) *0.04 PSA response to docetaxel, n(%) 16(30.7) 32(66.6) 44(71) *0.009 Abbreviations: ADT, Androgen deprivation therapy; OS, Overall survival; PFS, Progression free survival; PSA, Prostate specific antigen *Statistically significant Time to castration resistance and survival in CRPC-Suer et al. Urological Oncology 454 carried out after PSA progression were detected. Fol- low-up data, including time to biochemical progression and date of death, were available for all patients. Time to castration resistance (TTCR) was calculated from the time of ADT initiation irrespective of stage until confir- mation of CRPC. Data on patient and characteristics, were collected from a retrospective review of medical records. The follow- ing variable were recorded for analysis; age, stage, Gleason grade(GG), previous treatments, site of me- tastases, PSA value and TTCR. Biochemical progres- sion and death due to any reason were considered as events. Kaplan Meier analysis were performed to ob- tain estimates for overall survival (OS) (Figure 1). Cox regression analysis was performed to define independ- ent prognostic factors. Variables that were significant in univariate analysis or close to p value 0,05 although not statistically significant, were included in the cox regression analysis. P value < 0.05 was accepted the statistical significance criteria. SPSS 17.0 was used for the analysis. RESULTS The mean age of the 162 patients was 74.4±8.5 years. Patient characteristics are listed in Table 1. Thirty men (18.5 %) had received prior local therapy for prostate cancer with curative intent. Of these 30 men, 20 and 10 had received radical prostatectomy and radiothera- py, respectively. Median nadir PSA value during ADT, median PSA value immediately before docetaxel, me- dian nadir PSA value during docetaxel, median high- est PSA value after starting docetaxel were 3.2 (range: 0.008-150), 78.7 (range: 1.5- 1092), 38.4 (0.03-400), 113.3 (range: 3.2-617), respectively. Median survival (minimum survival was 3 months and maximum sur- vival 39 months. When this data is ranked from lowest to highest, the median value in the middle is the median value, which is calculated 15) and 2 years survival rate were 15 month and 18.5%, respectively. PSA response to docetaxel was 59.2%. Patients were divided into three groups according to TTCR: Group 1(≤12 months), group 2(13-24 months), and group 3(> 24 months). Data on patient and disease characteristics of three groups were compared. Data on mean age, type of castration, adding estramustine to docetaxel, secondary hormonal manipulation, Gleason grade,clinical T stage at initial diagnosis and site of me- tastases were comparable between three groups (Table 1). Median nadir PSA value during ADT (P = .014), median PSA value immediately before docetaxel (P =.024), median nadir PSA value during docetaxel (P = .026), and median highest PSA value after starting docetaxel (P =.037) were statistically significant high- er in group 1 than other groups. Median survival rates were 7, 14 and 23 months in group 1, 2 and 3, respec- tively, and this difference was statistically significant (P = .016). PSA response to docetaxel treatment were worse in group 1 than other groups (P = .009). Medi- an biochemical PFS rates were 3, 6, and 10 months in group 1, 2 and 3 respectively, and this difference was statistically significant (P =.04). There was no statis- tically significant difference between the 3 groups in terms of the median follow-up time (Table 1). All comparisons were detailed in Table 2. Two years OS rates were 7.6%, 25% and 32.3% in group 1, 2 and 3, respectively (Table 1) and in the Kaplan Meier anal- ysis found overall survival in group 1 was statistically significant worse than group 2 and group 3 (Figure 1). On multivariate analysis, TTCR was found to be in- dependent prognostic factor for overall survival (95% CI: 1.924-3.282, HR = 2.8 P = .001,) and response to docetaxel treatment (95% CI: 1.156-4.086, HR= 1.9, P = .001) (Table 2). DISCUSSION DCR was established as the standard care in CRPC after the outcomes of two randomized studies.(3,10) The results of these two phase III studies showed that Time to castration resistance and survival in CRPC-Suer et al. Table 2. Multivariate analysis for prediction of overall survival and response to docetaxel treatment Variables Overall survival Response to docetaxel treatment HR 95% CI p value HR 95% CI P value ≥8 Gleason grade at initial diagnosis 2.2 1.230-3.547 .001 1.8 1.486-4.342 .003 Higher median nadir PSA value during ADT 0.9 0.702-1.131 0.54 0.9 0.842-1.236 0.5 Higher median PSA value immediately before docetaxel 1.2 0.562-1.634 0.31 1.2 0.674-1.938 0.3 Higher median nadir PSA value during docetaxel 2.3 1.288-5.142 .01 1.9 1.084-4.046 .02 Visceral metastasis 3 1.062-4.328 .001 3.2 1.812-6.326 .001 Time to resistance to ADT 2.8 1.924-3.282 .001 2.2 1.156-4.086 .001 Abbreviations: ADT, Androgendeprivationtherapy; PSA, Prostate-specificantigen Figure 1. Kaplan Meier curves for overall survival Two years OS rates were 7.6%, 25% and 32.3% in group 1, 2 and 3, respectively. Kaplan-Meier analysis showed statistically signif- icant difference between OS rates of three groups (P < .001 for comparison of group 1 and 2; P <.001 for group 1 and 3; P =.038 for group 2 and 3). Vol 16 No 04 September-October 2019 455 docetaxel in a 3-weekly regimen improved OS, which was the primary endpoint of both trials. Additionally, DCR offered better palliation and quality of life. How- ever, the side effects of chemotherapy and the relatively elder CRPC population was the basis for tailoring the therapy. A nomogram was formed using independent prognostic factors in TAX 327 study to simplify impor- tant clinical decisions such as when to start cytotoxic chemotherapy. These prognostic factors were presence of liver metastases, number of metastatic sites, clinical- ly significant pain, Karnofsky performance status, type of progression, pretreatment PSA doubling time, base- line PSA, tumor grade, baseline alkaline phosphatase, and baseline hemoglobin.(11) Furthermore, in the TAX 327 secondary analysis study, four independent risk factors were defined, risk groups were developed and validated for predicting PSA decline and OS in men with mCRPC. These independent risk factors are pain, visceral metastases, anaemia, and bone scan progres- sion.(12) The approval of abiraterone and enzalutamide in pre-docetaxel setting enhanced the need for the iden- tification of patients who may have greater benefit by the use of chemotherapy. High Gleason score at the time of diagnosis and patients who had a short response to prior ADT (<16 months) had poor PSA responses when treated with secondary hormonal therapies such as abiraterone and enzalutamide.(13,14) Loriot et al. eval- uated median duration of response to initial ADT in patients treated with androgen receptor axis targeted drugs. In this study patients who had longer initial ADT response demonstrated better responses for secondary treatments and 12 months was the cut-off.(9) Bellmunt et al. examined COU-AA-301 and COU-AA-302 pa- tients and demonstrated the positive effects of longer exposure to prior ADT on survival.(15) However, the clinical benefit of abiraterone was maintained in all groups. Zheng et al. evaluated the prognostic effects of circulating tumor cells (CTC). In this meta-analysis demonstrated that CTC positivity indicates poor prog- nosis in patients with CRPC and can be used as an in- dependent prognostic factor of survival rate in patients with CRPC.(16) Also a case of penic metastasis in a 70-year-old geriatric male patient with prostatic adeno- carcinoma is reported. who was treated with cabazitaxel chemotherapy beyond 20 cycles with a good response and acceptable minimal toxicity.(17) In an era of shifting paradigms in CRPC with multi- ple options becoming available prior to DCR, prior response to ADT may serve to discriminate between patients who benefit most from docetaxel chemother- apy as first-line treatment. The cell cycle is important because many chemotherapy drugs work only on cells that are actively reproducing. Docetaxel is a mitotic in- hibitor and based on this information we expected bet- ter responses in shorter TTCR. However,in our study shorter TTCR was associated with lower PSA response and survival. Particularly in patients who have TTCR < 12 months demonstrated the worse prognosis. Shorter TTCR is also associated with short doubling time and fast cell cycle, which is also a poor prognostic parame- ter.(18) The outcomes of this study confirm the previous study published by Bournakis et al.(8) In a series which have included docetaxel and non-docetaxel regimens, they have demonstrated < 2 year of TTCR as an inde- pendent prognostic factor for PFS and OS. According to these results we can accept TTCR as a prognostic factor, without relating to any therapy. The process for the secondary therapy must concern quality of life and side effects of the therapy. This study has several limitations. In this retrospec- tive study we did not have adequate data to evaluate radiological PFS and pain scores. Although all of the patients were treated with DCR, a significant number of patients received estramustin in their regimen which causes some heterogeneity. Due to the health insurance restriction, none of our patients were treated in pre- DCR setting with novel drugs such as abiraterone ace- tate and enzalutamide. Only the minority of the patients received abiraterone acetate after the development of unresponsiveness of chemotherapy. CONCLUSIONS TTCR appears to be an independent prognostic factor for patients who are candidates for DCR. Although utilizing chemotherapy instead of secondary hormonal treatments seem to be reasonable in patients who have developed early castration resistance , the patients must be informed of the lower response rates for chemother- apy. ACKNOWLEDGEMENT Thanks are due to Ankara University Health Research and Practice Center support for the preparing of this manuscript. CONFLICT OF INTEREST The authors have declared no conflict of interest. REFERENCES 1. Horwich A, Hugosson J, de Reijke T, Wiegel T, Fizazi K, Kataja V. Prostate cancer: ESMO Consensus Conference Guidelines 2012. Ann Oncol. 2013;24:1141-62. 2. Tangen CM, Hussain MH, Higano CS, et al. Improved overall survival trends of men with newly diagnosed M1 prostate cancer: a SWOG phase III trial experience (S8494, S8894 and S9346). J Urol. 2012;188:1164-9. 3. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502-12. 4. Beer TM, Armstrong AJ, Sternberg CN, et al. Enzalutamide in men with chemotherapy- naive metastatic prostate cancer (mCRPC): Results of phase III PREVAIL study. J Clin Oncol. 2014;32:LBA1-LBA. 5. Fizazi K, Scher HI, Molina A, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012;13:983-92. 6. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration- resistant prostate cancer. N Engl J Med. 2010;363:411-22. 7. Sartor O, Coleman R, Nilsson S, et al. Effect of radium-223 dichloride on symptomatic Time to castration resistance and survival in CRPC-Suer et al. Urological Oncology 456 Vol 16 No 04 September-October 2019 457 skeletal events in patients with castration- resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol. 2014;15:738- 46. 8. Bournakis E, Efstathiou E, Varkaris A, et al. Time to castration resistance is an independent predictor of castration-resistant prostate cancer survival. Anticancer Res. 2011;31:1475-82. 9. Loriot Y, Eymard JC, Patrikidou A, et al. Prior long response to androgen deprivation predicts response to next-generation androgen receptor axis targeted drugs in castration resistant prostate cancer. Eur J Cancer. 2015;51:1946- 52. 10. Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351:1513-20. 11. Armstrong AJ, Garrett-Mayer ES, Yang YC, de Wit R, Tannock IF, Eisenberger M. A contemporary prognostic nomogram for men with hormone-refractory metastatic prostate cancer: a TAX327 study analysis. Clin Cancer Res. 2007;13:6396-403. 12. Armstrong AJ, Tannock IF, de Wit R, George DJ, Eisenberger M, Halabi S. The development of risk groups in men with metastatic castration-resistant prostate cancer based on risk factors for PSA decline and survival. Eur J Cancer. 2010;46:517-25. 13. Heidenreich A, Pfister D. Treatment decisions for metastatic castration-resistant prostate cancer progressing after docetaxel chemotherapy: the role of cabazitaxel in the continuum of care. Eur Urol. 2012;62:1201-4. 14. Loriot Y, Massard C, Albiges L, et al. Personalizing treatment in patients with castrate-resistant prostate cancer: A study of predictive factors for secondary endocrine therapies activity. J Clin Oncol. 2012;30:213. 15. Bellmunt J, Kheoh T, Yu MK, et al. Prior Endocrine Therapy Impact on Abiraterone Acetate Clinical Efficacy in Metastatic Castration-resistant Prostate Cancer: Post-hoc Analysis of Randomised Phase 3 Studies. Eur Urol. 2016;69:924-32. 16. Zheng Y, Zhang C, Wu J, et al. Prognostic Value of Circulating Tumor Cells in Castration Resistant Prostate Cancer: A Meta-analysis. Urol J. 2016;13:2881-8. 17. Atag E, Semiz HS, Kazaz SN, et al. Response to Cabazitaxel Beyond 20 Cycles in A Patient with Penile Metastasis of Prostate Cancer: A Case Report. Urol J. 2017;14:2985-8. 18. Stewart AJ, Scher HI, Chen MH, et al. Prostate-specific antigen nadir and cancer- specific mortality following hormonal therapy for prostate-specific antigen failure. J Clin Oncol. 2005;23:6556-60. Time to castration resistance and survival in CRPC-Suer et al.