1. Memorial Sloan-Kettering Cancer Center
Radical Prostatectomy in the Treatment of High-Risk but Clinically Localized Prostate Cancer
James A. Eastham, MD
Memorial Sloan-Kettering Cancer Center
353 East 68th Street
New York, NY 10021, USA
NOTE: The following slides are to be used for medical education purposes only. Copyright belongs to Prous Science and Prous Science is not responsible for any modification or change made by the users to these slides.

2. Radical Prostatectomy in the Treatment of High-Risk but Clinically Localized Prostate Cancer
INDEX
Defining high-risk but clinically localized prostate cancer
Outcomes after radical prostatectomy (RP) based on the definition used to define high-risk patients
Efforts to improve outcomes in high-risk patients
Key Words: prostate cancer, radical prostatectomy, risk assessment

3. Established Factors that Characterize Prostate Cancer Risk
Extent ~ Clinical/path stage (TNM)
Grade ~ Gleason patterns (1-5)
Volume ~ Serum PSA level
Each is an independent predictor of risk, but when combined the predictive accuracy increases
There are no standardized criteria to define high-risk prostate cancer

4. Predicting Risk for Prostate Cancer
At diagnosis
Partin tables
Risk groups
Pre-treatment nomograms
After radical prostatectomy
Pathological features
Post-treatment nomograms

5. Radical Prostatectomy for Clinically Localized, High-Risk Prostate Cancer: Critical Analysis of Risk Assessment Methods1
Analyze outcomes for patients classified as high risk by various definitions that are in use in the medical literature, using adverse pathological features and BCR as endpoints

6. Study Cohort
5840 patients undergoing RP between 6/83-12/04 for clinical stage T1-T3 N0M0 adenocarcinoma of the prostate
Excluded :
790 patients - neoadjuvant hormonal treatment
25 patients - neoadjuvant chemotherapy
31 patients - adjuvant radiation therapy
286 patients - missing data (stage, grade or PSA)
Final study population: 4708 patients with complete clinical, pathological and outcome data

7. Preoperative Patient Characteristics
No. Patients (%)
Median age at surgery, years (IQR)
61 (56, 65)
Median preoperative PSA, ng/ml (IQR)
6.19 (4.40, 9.10)
Median preoperative PSA velocity, ng/ml/y (IQR)*
1.08 (-0.99, 3.58)
Biopsy Gleason Sum
2-6
3194 (68)
7 (3+4)
903 (19)
7 (4+3)
337 (7)
8-10
274 (6)
1992 TNM Clinical Stage
T1AB
110 (2)
T1C
2148 (46)
T2A
1048 (22)
T2B
823 (18)
T2C
435 (9) T3
144 (3)

8. High-Risk Definitions Based on Preoperative Variables
1) Biopsy Gleason Score (bGS) ≥ 8
Reference 2
2) Preoperative PSA ≥ 20
3) TNM stage T3
Reference 3
4) PSA ≥ 20 or ≥ cT2C or bGS ≥ 8
References 4, 5
5) 5-year PFP < 50% (nomogram)
Reference 6
6) PSA ≥ 20 or ≥ cT3 or bGS ≥ 8
Reference 7
7) PSA ≥ 15 or ≥ cT2B or bGS ≥ 8
References 8, 9
8) PSA velocity > 2 ng/ml/y
Reference 10

9. Number (%) of Patients in Study Population According to Definition of High Risk1
1) Biopsy Gleason Score (bGS) ≥ 8
274 (6%)
2) Preoperative PSA ≥ 20
275 (6%)
3) TNM stage T3
144 (3%)
4) PSA ≥ 20 or ≥ cT2C or bGS ≥ 8
957 (20%)
5) 5-year PFP < 50% (nomogram)
391 (8%)
6) PSA ≥ 20 or ≥ cT3 or bGS ≥ 8
605 (13%)
7) PSA ≥ 15 or ≥ cT2B or bGS ≥ 8
1752 (37%)
8) PSA velocity > 2 ng/ml/y
952 (38%)*
* Percentage of the 2521 patients with calculable preoperative PSA velocity

10. Pathological Features Based on Definition of High-Risk Prostate Cancer
High-Risk Definition
No.
GS 8-10
n=321
ECE
n=1331 1
Biopsy Gleason Score (bGS) 8-10
274
143 (52)
163 (60) 2
Preoperative PSA ≥ 20
275
44 (16)
168 (61) 3
1992 TNM cT3
144
40 (28)
103 (71) 4
PSA ≥ 20 or ≥ 1992 TNM cT2C or bGS 8-10
957
200 (21)
505 (53) 5
Nomogram 5-year PFP ≤ 50%
391
104 (27)
266 (68) 6
PSA ≥ 20 or ≥ 1992 TNM cT3 or bGS 8-10
605
183 (30)
362 (59) 7
PSA ≥ 15 or ≥ 1992 TNM cT2B or bGS 8-10
1752
254 (14)
797 (46) 8
Preoperative PSA velocity > 2 ng/ml/y
952
96 (10)
332 (35)

11. Pathological Features Based on Definition of High-Risk Prostate Cancer
High-risk definition
PSM
n=951
SVI
n=382
LNI
n=182 OC
n=3280
Biopsy Gleason Score (bGS) 8-10
81 (30)
69 (25)
52 (19)
96 (35)
Preoperative PSA ≥ 20
126 (46)
91 (33)
40 (15)
90 (33)
1992 TNM cT3
38 (26)
45 (31)
33 (23)
32 (22)
PSA ≥ 20 or ≥ 1992 TNM cT2C or bGS 8-10
275 (29)
203 (21)
111 (12)
407 (43)
Nomogram 5-year PFP ≤ 50%
149 (38)
117 (30)
71 (18)
109 (28)
PSA ≥ 20 or ≥ 1992 TNM cT3 or bGS 8-10
208 (34)
166 (24)
95 (16)
205 (34)
PSA ≥ 15 or ≥ 1992 TNM cT2B or bGS 8-10
474 (27)
281 (16)
147 (8)
892 (51)
Preoperative PSA velocity > 2 ng/mL/y
209 (22)
94 (10)
62 (7)
598 (63)
PSM: positive surgical margin; SVI: seminal vesicle invasion;
LNI: lymph node invasion; OC: organ-confined

12. High-Risk Prostate Cancer: Progression-free Probability (PFP) by Definition

13. High-Risk Prostate Cancer: 5- and 10-year PFP
High Risk Definition
BCR / No. patients
5-year PFP* (95% CI)
10-year PFP* (95% CI)
Biopsy Gleason 8-10
109 / 274
53 (46, 60)
42 (38, 56)
Preoperative PSA ≥ 20
121 / 275
56 (50, 62)
47 (40, 54)
1992 TNM stage T3
62 / 144
49 (39, 58)
41 (29, 53)
PSA ≥ 20 or ≥ T2C or GS ≥ 8
299 / 957
68 (65, 71)
59 (55, 63)
Nomo 5-year PFP ≤ 50%
180 / 391
53 (47, 57)
43 (36, 49)
PSA ≥ 20 or ≥ T3 or GS ≥ 8
234 / 605
57 (53, 62)
50 (44, 55)
PSA ≥ 15 or ≥ T2B or GS ≥ 8
466 / 1752
73 (71, 75)
65 (62 ,68)
PSA velocity > 2 ng/ml/y
161 / 952
80 (77, 83)
74 (70, 78)

14. High-Risk Prostate Cancer: 5- and 10-year PFP
Depending on the definition of high-risk, the:
5-year PFP ranges from 49% to 80%
10-year PFP ranges from 41% to 74%

15. All hazards ratios significant at the 0.0005 level
High-Risk Prostate Cancer – Hazard Ratios for Biochemical Recurrence (BCR) Compared to Non-High-Risk Patients
High Risk Definition
BCR / No. Patients
HR (95% CI)
Biopsy Gleason Score 8-10
109 / 274
4.3 (3.5, 5.3)
Preoperative PSA ≥ 20
121 / 275
3.8 (3.2, 4.7)
1992 TNM stage T3
62 / 144
4.4 (3.4, 5.7)
PSA ≥ 20 or ≥ T2C or bGS ≥ 8
299 / 957
3.3 (2.8, 3.8)
Nomogram 5-year PFP ≤ 50%
180 / 391
4.8 (4.1, 5.7)
PSA ≥ 20 or ≥ T3 or bGS ≥ 8
234 / 605
4.4 (3.7, 5.1)
PSA ≥ 15 or ≥ T2B or bGS ≥ 8
466 / 1752
3.8 (3.2, 4.4)
PSA velocity > 2 ng/ml/y
161 / 952
1.8 (1.5, 2.3)
All hazards ratios significant at the level

16. High-Risk Prostate Cancer – Hazard Ratios for Biochemical Recurrence (BCR) Compared to Non-High-Risk Patients
All high-risk definitions select men more likely to experience BCR than non-high-risk patients
However, depending on the definition, the risk of BCR ranges from 1.8 to 4.8 times

17. High-Risk Prostate Cancer: Cancer-Specific Survival

18. High-Risk Prostate Cancer: Estimated 12-Year Disease-Specific Survival (DSS) after RP
High Risk Definition
12-year DSS (95% CI)
Biopsy Gleason 8-10
80 (69, 91)
Preoperative PSA ≥ 20
86 (76, 96)
1992 TNM stage T3
78 (69, 89)
PSA ≥ 20 or ≥ T2C or GS ≥ 8
93 (89, 97)
Nomogram 5-year PFP ≤ 50%
90 (84, 96)
PSA ≥ 20 or ≥ T3 or GS ≥ 8
91 (86, 96)
PSA ≥ 15 or ≥ T2B or GS ≥ 8
94 (92, 96)
PSA velocity > 2 ng/ml/y
94 (90, 98)

19. High-Risk Prostate Cancer – Cancer-Specific Survival
Regardless of the definition of high-risk prostate cancer, men treated with radical prostatectomy have an excellent cancer-specific survival at 10 to 15 years after surgery

20. Identifying and Treating Men with High-Risk but Clinically Localized Prostate Cancer
Predictive tools have been developed to identify the risk that a patient will fail definitive local therapy (either surgery or radiation)
The risk will depend on the definition used
While radical prostatectomy or radiation can cure some men with high-risk disease, local therapy alone is often inadequate for patients with high-risk prostate cancer
Based on this assessment, patients can be identified to participate in trials examining multimodal therapy for clinically localized but high-risk prostate cancer

21. Multimodal Treatment is the Standard of Care for Many Cancers
Testis
Bladder
Breast
Colon
Lung
Surgery + Radiation + Chemotherapy + Hormonal Therapy
This strategy requires effective local and systemic therapy

22. Multimodal Treatment in Prostate Cancer
Local treatment effectively eradicates local disease
Radiation plus hormonal therapy has been demonstrated to improve survival in men with high-risk prostate cancer compared to radiation alone, but many men still experience cancer recurrence11
Survival outcomes after radical prostatectomy have not been improved with hormonal therapy except in men with node-positive disease12
More effective systemic therapy is needed in prostate cancer

23. A Reason For Optimism?
Two randomized, phase III trials have demonstrated a survival advantage of approximately 20% in men with hormone-refractory prostate cancer treated with docetaxel chemotherapy13, 14

24. Implications of these Studies
The 20% improvement in survival is similar to other studies in metastatic solid tumors (breast, colon) that have shown a survival benefit when moving therapy earlier
Because of the results from these studies, neoadjuvant and adjuvant trials using docetaxel in high-risk prostate cancer have been opened
Should result in a new treatment paradigm for high-risk, but localized prostate cancer

25. Conclusions
Patients diagnosed with high-risk cancers do not uniformly have poor prognosis after RP but can be selected based on the features of their cancer
Overall risk of locally advanced or occult metastatic disease and incidence of PSA relapse may vary greatly depending on the definition used
Experience in other cancers demonstrates that multimodal strategies improve patient outcomes
Support Clinical Trials!

26. References
1. Yossepowitch, O., Eggener, S.E., Bianco, F.J., Jr., Carver, B.S., Serio, A., Scardino, P.T., Eastham, J.A. Radical prostatectomy for clinically localized, high risk prostate cancer: Critical analysis of risk assessment methods. J Urol 2007, 69(6):
2. Donohue, J.F., Bianco, F.J., Jr, Kuroiwa, K., Vickers, A.J., Wheeler, T.M., Scardino, P.T., Reuter, V.A., Eastham, J.A. Poorly differentiated prostate cancer treated with radical prostatectomy: long-term outcome and incidence of pathological downgrading. J Urol 2006, 176:
3. Ward, J.F., Slezak, J.M., Blute, M.L., Bergstralh, E.J., Zincke, H. Radical prostatectomy for clinically advanced (cT3) prostate cancer since the advent of prostate-specific antigen testing: 15-year outcome. BJU Int 2005, 95:

27. References
D'Amico, A.V., Whittington, R., Malkowicz, S.B. et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998, 280:
5. Grossfeld, G.D., Chang, J.J., Broering, J.M., Li, Y.P., Lubeck, D.P., Flanders, S.C., Carroll, P.R. Under staging and under grading in a contemporary series of patients undergoing radical prostatectomy: results from the Cancer of the Prostate Strategic Urologic Research Endeavor database. J Urol 2001, 165:
6. Kattan, M.W., Eastham, J.A., Stapleton, A.M., T.M. Wheeler, T.M., Scardino, P.T. A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J Natl Cancer Inst 1998, 90:

28. References
7. Scardino, P. Update: NCCN prostate cancer Clinical Practice Guidelines. J Natl Compr Canc Netw 2005, 3 (Suppl): S29.
8. Clark, P.E., Peereboom, D.M., Dreicer, R., Levin, H.S., Clark, S.B., Klein, E.A. Phase II trial of neoadjuvant estramustine and etoposide plus radical prostatectomy for locally advanced prostate cancer. Urology 2001, 57:
9. Dreicer, R., Magi-Galluzzi, C., Zhou, M., Rothaermel, J., Reuther , A., Ulchaker, J., Zippe, C., Fergany, A., Klein, E.A. Phase II trial of neoadjuvant docetaxel before radical prostatectomy for locally advanced prostate cancer. Urology 2004, 63:
10. D'Amico, A.V., Chen, M.H., Roehl, K.A., Catalona, W.J. Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med 2004, 351:

29. References
11. Bulla, M., Collette, L., Blank, L. et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002, 360(9327):
12. Messing, E., Manola, J., Yao, J., Kiernan, M., Crawford, D., Wilding, G., di'SantAgnese, P., Trump, D. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol 2006, 7(6):
13. Petrylak, D.P., Tangen, C.M., Hussain, M.H. et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004, 351:1513–20.
14. Tannock, I.F., de Wit, R., Berry, W.R. et al.; TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004, 351:1502–12.