PROGNOSTIC FACTORS OF BIOCHEMICAL RECURRENCE AFTER RADICAL PROSTATECTOMY FOR LOCALIZED AND LOCALLY-ADVANCED PROSTATE CANCER

Purpose. To reveal prognostic factors of PSA-failure following radical prostatectomy in patients with localized and locally-advanced prostate cancer.

Materials and methods. Medical data of 386 consecutive patients with localized and locally-advanced prostate cancer who underwent radical prostatectomy from 1997 to 2011 were analyzed. Median age was 61.0 years. Median PSA before surgery – 10.3 ng/ml. Plasma levels of VEGF, VEGFR2, VEGFR3, TGF-β1, CD105, IL-6 were measured using Enzyme Linked-Immuno-Sorbent Assay (ELISA) before radical prostatectomy in 77 patients. Postoperatively the tumours were categorized as pT2 in 288 (59.1 %), pT3 – in 144 (37.3 %), pT4 – in 14 (3.6); pN+ – in 34 (8.8 %) cases. Gleason score < 7 was present in 254 (65.8 %),  7 – in 132 (34.2 %) specimens. Perineural invasion was identified in 188 (48.7 %), angiolymphatic invasion – in 126 (32.6) cases.

Results. Biochemical recurrence occurred in 64 (16.6 %) out of 386 patients at a median follow-up of 30.5 (12−164) months. Independent predictors of biochemical recurrence were PSA (HR 0.161 (95% CI:0.058−0.449); р = 0.001), Gleason sum in surgical specimens (HR 0.496 (95 % CI:0.268−0.917); p = 0.025), pN (HR 0.415 (95 % CI:0.181−0.955); p = 0.039). The patients were divided into 3 prognostic groups: good (0 factor), intermediate (1 factor), poor (2 factors) and very poor (3 factors) (AUC – 0.720 (95% CI: 0.656−0.784)). High preoperative levels VEGF ( 67 pg/ml) (р = 0.005), VEGFR2 ( 3149 pg/ml) (р = 0.036), VEGFR3 ( 2268 pg/ml) (р = 0.001), TGF-β1 ( 14473 pg/ml) (р = 0.052) were identified as unfavorable prognostic factors for survival without PSA-failure.

Conclusion. Independent prognostic factors of biochemical recurrence after prostatectomy were PSA, Gleason sum and pN. Joint effect of the factors allows to predict PSA-relapse with accuracy 0.720. Preoperative serum levels VEGF, VEGFR2, VEGFR3, TGF-β1 potentially are perspective markers for PSA-failure after surgical treatment prostate cancer, further trials are needed.

1. Stephenson A.J., Scardino P.T., Eastham J.A. et al. Postoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy. J Clin Oncol 2005;23:7005−12.

2. D'Amico A.V., Moul J., Carroll P.R. et al. Prostate specific antigen doubling time as a surrogate end point for prostate cancer specific mortality following radical prostatectomy or radiation therapy. J Urol 2004;172(5 Pt 2):42−6.

3. Kattan M.W., Wheeler T.M., Scardino P.T. Postoperative nomogram for disease recurrence after radical prostatectomy for prostate cancer. J Clin Oncol 1999;17: 1499−507.

4. Stephenson A.J., Scardino P.T., Eastham J.A. et al. Preoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy. J Natl Cancer Inst 2006; 98:715−17.

5. Stephenson A.J., Scardino P.T., Eastham J.A. et al. Postoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy, J Clin Oncol 2005; 23:7005−12.

6. Bianco F.J. Jr., Kattan M.W., Scardino P.T. et al. Radical prostatectomy nomograms in black American men: accuracy and applicability. J Urol 2003;170: 73−6.

7. Shahrokh F. Shariat, Jose A. Karam, JochenWalz et al. Improved prediction of disease relapse after radical prostatectomy through a panel of preoperative blood-based biomarkers. Clin Cancer Res 2008;14(12).

8. Schroder F.H. Management of locally advanced prostate cancer. Staging, natural history, and results of radical surgery. World J Urol 2000;18(3):194−203.

9. Wheeler T.M., Dillioglugil O., Kattan M.W. et al. Clinical and pathological significance of the level and extent of capsular invasion in clinical stage T1-2 prostate cancer. Hum Pathol 1998;29(8):856−62.

10. Hull G.W., Rabbani F., Abbas F. et al. Cancer control with radical prostatectomy alone in 1,000 consecutive patients. J Urol 2002;167(2 Pt 1):528−34.

11. de la Taille A., Rubin M.A., Buttyan R. et al. Is microvascular invasion on radical prostatectomy specimens a useful predictor of PSA recurrence for prostate cancer patients? Eur Urol 2000;38:79−84.

12. May M., Kaufmann O., Hammermann F. et al. Prognostic impact of lymphovascular invasion in radical prostatectomy specimens. BJU 2006;99:539−44.

13. Maru N., Villers A., McNeal J.E. et al. The role of perineural space invasion in the local spread of prostatic adenocarcinoma. J Urol 1989;142:763−8.

14. Faruk Ozcan. Correlation of perineural Invasion on radical prostatectomy specimens with other pathologic prognostic factors and PSA failure. Eur Urol 2001;40:308−12.

15. Shelley M.D., Kumar S., Wilt T. et al. A systematic review and meta-analysis of randomized trials of neo-adjuvant hormone therapy for localised and locally advanced prostate carcinoma. Cancer Treat Rev 2009;35:19−7.

16. Bianco F.J., Grignon D.J., Sakr W.A. et al. Radical prostatectomy with bladder neck preservation: impact of a positive margin. Eur Urol 2003;43(5):461−6.

17. Ward J.F., Zincke H., Bergstralh E.J. et al. The impact of surgical approach (nerve bundle preservation versus wide local excixion) on surgical margins and biochemical recurrence following radical prostatectomy. J Urol 2004; 172:1328−32.

18. Simon M.A., Kim S., Soloway M.S. Prostate specific antigen recurrence rates are low after radical retropubic prostatectomy and positive margins. J Urol 2006;175(1):140−4.

19. Wright J.L., Dalkin B.L., True L.D. et al. Positive surgical margins at radical prostatectomy predict prostate cancer specific mortality. J Urol 2010;183(6):2213−8.

20. Alkhateeb S., Alibhai S., Fleshner N. et al. Impact of positive surgical margins after radical prostatectomy differs by disease risk group. J Urol 2010;183(1):145−50.

21. Shikanov S., Song J., Royce C. et al. Length of positive surgical margin after radical prostatectomy as a predictor of biochemical recurrence. J Urol 2009;182(1):139−44.

22. Albadine R., Hyndman M.E., Chaux A.et al. Characteristics of positive surgical margins in robotic-assisted radical prostatectomy, open retropubic radical prostatectomy, and laparoscopic radical prostatectomy: a comparative histopathologic study from a single academic center. Hum Pathol 2012;43(2):254−60.

23. Shariat S.F., Menesses-Diaz A., Kim I.Y.et al. Tissue expression of transforming growth factor-h1 and its receptors: correlation with pathologic features and biochemical progression in patients undergoing radical prostatectomy. Urology 2004;63:1191−7.

24. Kattan M.W., Shariat S.F., Andrews B. et al. The addition of interleukin-6 soluble receptor and transforming growth factor beta1 improves a preoperative nomogram for predicting biochemical progression in patients with clinically locali-zed prostate cancer. J Clin Oncol 2003;21:3573.