Prognostic factors in locally advanced prostate cancer as determined by biochemistry, imaging studies and pathology

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1 Prognostic factors in locally advanced prostate cancer as determined by biochemistry, imaging studies and pathology Authors Key words C.Y. Hsu, S. Joniau, R. Oyen, T. Roskams, H. Van Poppel Prognostic factors, prostate cancer Summary In his doctoral thesis, Dr. Chao-Yu Hsu investigated possible prognostic factors in locally advanced prostate cancer. These prognostic factors were determined using biochemistry, imaging studies and pathology. Dr. Hsu conducted his research at the University Hospitals Gasthuisberg in Leuven under the promotership of professor Hendrik Van Poppel. He presented his thesis on June 16 th, (BJMO 2009;Vol 3;6: ) Introduction Locally advanced prostate cancer is defined as cancer that has extended clinically beyond the prostatic capsule with invasion of the pericapsular tissue, apex or seminal vesicle (T3) or of the sphincter or bladder neck (T4), but without lymph node involvement or distant metastases. T3a prostate cancer is an extracapsular extension (ECE), either unilateral or bilateral, and T3b is seminal vesicles invasion (SVI). 1 It is important to identify T3 tumors before treatment. Overstaging is not an exception but understaging is more frequent. In order to improve the diagnostic accuracy of the digital rectal examination (DRE), transrectal ultrasound (TRUS) can be helpful in recognizing ECE or SVI. Magnetic resonance imaging (MRI) is also helpful in recognizing SVI and a contrast-enhanced computed tomography (CT) scan will help in recognizing enlarged nodes. In the first chapter, the ability of imaging in improving the accuracy of the detection of an extracapsular extension was evaluated. Partin tables, combination of preoperative serum PSA, biopsy Gleason score (Gl.S), and clinical stage are the most widely used tools to predict final histopathology after radical prostatectomy (RP) for stage ct1c to ct2c. 2 The tables help the urologists to counsel the patient before surgery and to make an optimal treatment decision for organ-confined prostate cancer. For patients with ct3a prostate cancer, no such table is available. In the second chapter, such a pretreatment table to predict the final pathology is presented. The surgical procedure for localized prostate cancer was described by Walsh et al. 3 The surgical technique of RP for locally advanced T3 cancer is different from that applied in locally confined tumors. Since many urologists are treating ct3 patients with hormones and radiotherapy, the technique of RP for this stage of the disease was not properly described. Therefore the surgical technique was detailed in chapter 3. Not all patients that undergo surgery for ct3 prostate cancer can be cured by surgery alone. Those that prove to be pt2 and those with limited pt3a with only a limited ECE will be cured, but many patients with more advanced ct3 will eventually need adjuvant radiotherapy (RT) or androgen-deprivation therapy (ADT). However, it has become more and more obvious that surgery has an important role as initial treatment for locally advanced T3 prostate cancer. In chapter 4, the reports on RP in multi- B E L G I A N J O U R N A L O F M E D I C A L O N C O L O G Y v o l. 3 i s s u e

2 modality setting with radio- and hormonotherapy in the current literature were summarized and our results were presented. 4-8 The application of hormonal manipulation before RP has been quite extensively investigated in ct2 and much less in ct3 prostate cancer. All reports clearly showed that in the ct2 cancers, the number of positive margins was dramatically decreased, although this had no effect on the ultimate outcome. 9 For locally advanced prostate cancer there could be an advantage for high risk patients, with a high PSA or with poorly differentiated tumors. Our findings on this are described in chapter 5. Materials and methods Between 1987 and 2004, a total of 2,273 patients underwent RP at our institution. Two hundred and thirty-five patients (10.3%) were assessed as unilateral ct3 disease by DRE. They were selected for surgery on the basis of limited, unilateral ct3a, any Gl.S, any PSA, and ECOG performance status 0-1. Thirtyfive patients received neoadjuvant treatment before surgery. Two hundred patients were included in the analysis and underwent RP and bilateral pelvic lymphadenectomy. The mean follow-up was 70.6 months (range 7 to 177). The data were retrieved from patient files and from general practitioners by phone for the latest data on clinical and biochemical recurrence. Added value of transrectal ultrasound in the staging of clinical T3a prostate cancer Next to DRE and PSA testing, TRUS is the most common modality to evaluate prostate cancer. According to previous reports, there was a significant difference in biochemical progression-free survival (bpfs) between unilateral pt3a and bilateral pt3a. Therefore, T3a was considered as operable disease and bilateral T3a as advanced disease where surgery is not very beneficial. 10 It was demonstrated that TRUS can be used to refine the clinical staging in unilateral ct3a prostate cancer. In the case TRUS indicates advanced disease, it might be wise to trust the TRUS staging rather than the DRE. 11 A pretreatment table for the prediction of final histopathology after radical prostatectomy in unilateral ct3a prostate cancer The predicted probabilities of the tumor, being pt2, pt3a, pt3b or pt4 by just using preoperative PSA Figure 1. Dr. Chao-Yu Hsu (right) and Prof. Dr. Hendrik Van Poppel (left) and biopsy Gl.S, are depicted in Table 1, page 272. In Table 2, page 272, the number and percentage of patients with positive lymph nodes and positive surgical margins, again using different PSA and biopsy Gl.S intervals, are summarized. Radical prostatectomy for locally advanced prostate cancer Description of surgical technique A radical prostatectomy (RP) for ct3 prostate cancer includes an extended lymph node dissection, not limited to the oturator fossa but including the internal and external iliac and presacral nodes, a broad resection of the neurovascular bundle at least at the tumor-bearing side, a complete extirpation of the seminal vesicles, and in most cases the resection of a bladder neck. 13 Outcomes of RP for ct3a prostate cancer At 5 and 10 years, bpfs rates were 59.5% and 51.1% respectively, cpfs (clinical progression free survival) rates were 95.9% and 85.4%, CSS (cancer specific survival) rates were 98.7% and 91.6%, and OS (overall survival) rates were 95.9% and 77.0%. 14 Univariate Cox proportional hazard analysis revealed that from all the parameters (final Gl.S, margin status, nodal status, pathological stage, preoperative PSA, and cancer volume), only final Gl.S was not significantly correlated with bpfs. Furthermore, final Gl.S and preoperative PSA were not significantly correlated with cpfs (Table 3, 272). The Kaplan- Meier analysis further confirmed that there was a significant difference between pt3a and pt3b-4 in bpfs and cpfs, whereas there were no differences in bpfs and cpfs between pt2 and pt3a. Multivari- 271 v o l. 3 i s s u e B E L G I A N J O U R N A L O F M E D I C A L O N C O L O G Y

3 Table 1. Predicted probabilities of the tumor being pt2, pt3a, pt3b, or pt4 using only preoperative PSA and biopsy Gleason score. Biopsy Gl.S Histopathological results PSA 10 PSA >10-20 PSA >20 7(3+4) 7(4+3) organ confined pt2 extraprostatic extension pt3a + seminal vesicle pt3b + adjacent structure pt4 organ confined pt2 extraprostatic extension pt3a + seminal vesicle pt3b + adjacent structure pt4 29 (20-39) 65 (55-74) 5 (2-10) 1 (0-2) 31 (15-46) 54 (37-71) 12 (4-25) 3 (0-10) 21 (12-33) 63 (49-76) 14 (5-24) 2 (0-8) 20 (7-36) 47 (30-65) 26 (12-46) 7 (0-17) 14 (5-27) 46 (30-62) 32 (18-48) 8 (0-16) 9 (2-21) 23 (9-43) 44 (19-69) 24 (0-55) Table 2. The number and percentage of patients with positive lymph nodes and positive surgical margins again using different PSA and biopsy Gl.S intervals. Biopsy Gl.S 7 (3+4) (N=152) 7 (4+3) (N=48) Histopathological results + lymph node + surgical margin + lymph node + surgical margin PSA 10 (n=98) 4.0% (n=3) 18.7% (n=14) (n=75) 8.7% (n=2) 34.8% (n=8) (n=23) PSA >10-20 (n=58) 9.5% (n=4) 33.3% (n=14) (n=42) 12.5% (n=2) 43.8% (n=7) (n=16) PSA >20 (n=44) 11.4% (n=4) 54.3% (n=19) (n=35) 22.2% (n=2) 55.6% (n=5) (n=9) Table 3. Cox univariate and multivariate regression analysis of histopathological parameters and preoperative PSA. A p-value of less than 0.05 is considered significant. PSA, biopsy Gl.S and cancer volume are coded as continuous variables. Univariate analysis Multivariate analysis Survival Covariate HR 95% CI p-value HR 95% CI p-value final Gleason score bpfs margin < <0.001 node < pathological stage < preoperative PSA < cancer volume < final Gleason score cpfs margin node pathological stage preoperative PSA cancer volume < ate Cox proportional hazard analysis revealed that the status of surgical margin was a significant independent factor for bpfs. Furthermore, cancer volume was a significant independent factor in cpfs. It was shown that in a well-selected patient group with locally advanced prostate cancer, RP with adjuvant or salvage treatment at biochemical relapse can yield very high long-term cancer control and B E L G I A N J O U R N A L O F M E D I C A L O N C O L O G Y v o l. 3 i s s u e

4 Key messages for clinical practice 1. TRUS can be used to refine clinical staging in unilateral ct3a prostate cancer. 2. Combining preoperative PSA and biopsy Gleason score to predict pathological stage in unilateral ct3a prostate cancer can facilitate treatment decisions in unilateral ct3a prostate cancer. 3. Radical prostatecomy, with adjuvant or salvage treatment when needed, can yield very high long-term cancer specific survival rates. 4. Neoadjuvant hormone therapy can decrease the tumor size, but it does not reduce the positive surgical margin rate and it does not improve the survival. survival rates. Margin status and cancer volume are significant predictors of outcome after RP. 14 Neoadjuvant androgen-deprivation therapy in the treatment of T3a prostate cancer The mean cancer volume decreased from 6.6 ml in patients without hormone therapy to 4.0 ml in those with neoadjuvant treatment. In patients without neoadjuvant treatment, the positive surgical margin rate was 33.5%. After neoadjuvant therapy, the positive surgical margin rate was 57.1%, probably because of underestimation of the tumor extent after hormone therapy. The Kaplan-Meier analysis showed that there was no significant difference in overall survival between patients who did and those that did not receive neoadjuvant hormonotherapy. 15 Conclusions TRUS can be used to refine clinical staging in unilateral ct3a prostate cancer. When TRUS indicates locally advanced disease, it might be wise to trust the TRUS staging rather than the DRE. The table combining preoperative PSA and biopsy Gleason score to predict pathological stage in unilateral ct3a prostate cancer can help to make an optimal decision for treating unilateral ct3a prostate cancer. In a well-selected patient group with locally advanced prostate cancer, radical prostatectomy, with adjuvant or salvage treatment when needed, can yield very high long-term cancer specific survival rates. Margin status and cancer volume are independent predictors of outcome after RP. Neoadjuvant hormone therapy can decrease the tumor size, but it does not reduce the positive surgical margin rate and it does not improve the survival. References 1. Sobin LH, Wittekind C. TNM Classification of prostate cancer. 6th ed. New York: Wiley-Liss; p Partin AW, Kattan MW, Subong EN, Walsh PC, Wojno KJ, Oesterling JE, et al. Combination of prostate-specific antigen, clinical stage and Gleason score to predict patological stage of localized prostate cancer. A multi-institutional update. JAMA 1997;277: Walsh PC. Radical prostatectomy: a procedure in evolution. Semin Oncol 1994;21(5): Yamada AH, Lieskovsky G, Petrovich Z, et al. Results of radical prostatectomy and adjuvant therapy in the management of locally advanced, clinical stage TC, prostate cancer. Am J Clin Oncol 1994;17(4): Gerber GS, Thisted RA, Chodak GW, Schroder FH, Frohmuller HGW, Scardino PT, et al. Results of radical prostatectomy in men with locally advanced prostate cancer: multi-institution pooled analysis. Eur Urol 1997;32: Van den Ouden D, Hop WC, Schroder FH. Progression in and survival of patients with locally advanced prostate cancer (T3) treated with radical prostatectomy as monotherapy. J Urol 1998;160: Martinez de la Riva SI, Lopez-Tomasety JB, Dominguez RM, Cruz EA, Blanco PS. Radical prostatectomy as monotherapy for locally advanced prostate cancer (T3a): 12 years follow-up. Arch Esp Urol 2004;(7): Ward JF, Slezak JM, Blute ML, Bergstralh EJ, Zincke H. Radical prostatectomy for clinically advanced (ct3) prostate cancer since the advent of prostate-specific antigen testing: 15-year outcome. BJU International 2005;95: Aus G, Abrahamsson PA, Ahlgren G, Hugosson J, Lundberg S, Schain M, et al. Three-month neoadjuvant hormonal therapy before radical prostatectomy: a 7-year follow-up of a randomized controlled trial. BJU International 2002;90: Van Poppel H, Goethuys H, Callewaert P, Vanuytsel L, Van de Voorde W, Baert L. Radical prostatectomy can provide a cure for well-selected clinical stage T3 prostate cancer. Eur 273 v o l. 3 i s s u e B E L G I A N J O U R N A L O F M E D I C A L O N C O L O G Y

5 Urol 2000;38: Hsu CY, Joniau S, Oyen R, Roskams T, Van Poppel H. Transrectal ultrasound in the staging of clinical T3a prostate cancer. Eur J Surg Oncol 2007;33(1): Joniau S, Hsu CY, Lerut E, Van Baelen A, Haustermans K, Roskams T, et al. A pretreatment table for the prediction of final histopathology after radical prostatectomy in clinical unilateral T3a prostate cancer. Eur Urol 2007;51(2): Hsu CY, Joniau S, Van Poppel H. Radical prostatectomy for locally advanced prostate cancer: technical aspects of radical prostatectomy. EAU Update Series 2005;3: Hsu CY, Joniau S, Oyen R, Roskams T, Van Poppel H. Outcome for clinical unilateral T3a prostate cancer: a singleinstitution experience. Eur Urol 2007;51(1): Hsu CY, Joniau S, Roskams T, Oyen R, Van Poppel H. Comparing results after surgery in patients with clinical unilateral T3a prostate cancer treated with or without neoadjuvant androgen-deprivation therapy. BJU Int 2007;99(2): Related BJMO articles - Denis L. Active Surveillance in prostate cancer. BJMO 2007;1: Soete G. Technical and clinical evaluation of image guided conformal Arc radiotherapy for localised prostate cancer. BJMO 2007;1: Peeters S. High-dose radiotherapy in localized prostate cancer: a randomized phase III trial. BJMO 2008;2: Salembier C, Rijnders A. Permanent seed brachytherapy for low- and intermediate risk prostate cancer. BJMO 2009;3: Van Poppel H, Bangma C. PSA based screening reduces the rate of prostate cancer death by 20%. BJMO 2009;3: C o r r e s p o n d e n c e a d d r e s s Authors: C.Y. Hsu, S. Joniau, R. Oyen, T. Roskams, H. Van Poppel Please send all correspondence to: University Hospitals Gasthuisberg, Leuven, Belgium Prof. Dr. H. Van Poppel Department of Urology University Hospitals Leuven Herestraat Leuven Belgium [email protected] Conclicts of interest: the authors have nothing to disclose and indicate no potential conflicts of interest. B E L G I A N J O U R N A L O F M E D I C A L O N C O L O G Y v o l. 3 i s s u e