1. Is there a role for adjuvant/neoadjuvant chemotherapy in High risk prostate cancer? Giuseppe Procopio Fondazione IRCCS Istituto Nazionale Tumori Milano

2. PROSTATE CANCER USA prostate cancer incidence/mortality: 218.890 new cases /27.050 deaths in 2007 Androgen deprivation is the mainstay of therapy in advanced disease After failure of initial androgen ablation, median survival is usually < 18 months The role of cytotoxic chemotherapy is evolving

3. As a result of widespread PSA testing, most patients are diagnosed with asymptomatic, clinically localized cancer

4. OPTIMAL TREATMENT OF PROSTATE CANCER REQUIRES ASSESMENT OF RISK How likely is a given cancer to be confined to the prostate or to spread to the regional lymph-nodes? How likely is the cancer to progress or metastasize after the first treatment?

5. PREDICTIVE PROGNOSIS IS ESSENTIAL FOR PATIENT DECISION- MAKING, TREATMENT DECISION AND ADJUVANT THERAPY NCCN Guidelines incorporate a risk stratification scheme to assign patient to risk groups that predicts the probability of biochemical failure after definitive local therapy. D’ Amico et al. JCO1999

6. The nomogram is a predictive instrument that takes a set of imput data and makes predictions about an outcome. Nomograms predict more accurately for the individual patient their risk group, because they combine the relevant prognostic variables regardless of value

7. The choice of initial treatment is highly influenced by estimated life expectancy, comorbidities, potential therapy side effects and patient preference

8. KATTAN’S POSTOPERATIVE NOMOGRAM Preoperative PSA Gleason score Surgical margins, capsule and seminal vescicles invasion Lymph node invasion  60-months recurrence free prob

9. LOW RISK T1-T2a gleason score 6 or less PSA < 10 ng/mL INTERMEDIATE RISK T2b-T2c Gleason score 7 or PSA 10-20 ng/mL

10. HIGH RISK T3a or Gleason score 8-10 or PSA>20 ng/mL LOCALLY ADVANCED T3b-T4 METASTATIC Any T, N1 Any t, Any N, M1 Bolla et al. NEJM 1997

11. Very high risk patients are not considered candidates for radical prostatectomy Currently the gold standard for high risk patients is 3D-CRT in conjunction with ADT for at least 2-3 years Bolla et al. NEJM 1997

12. Radical prostatectomy with pelvic limph node dissection remains an option in selected patients with low tumor volume and no fixation to adjacent organs T3b or T4; nonlocalized cancer are not considered candidates for radical prostatectomy.

13. Adjuvant therapy RT adjuvant can be used after a radical prostatectomy in selected cases. Adjuvant ADT is recommended for patients with positive lymph nodes found during surgery.

14. HIGH-RISK prostate cancer 5 years > 50 % biochemical relapse

15. CHEMOTHERAPY Mitoxantrone Docetaxel Vinorelbine Satraplatino Patupilone

16. Pts: 161 PREDNISONE: 10 mg 81 pts 81 pts P<0.01 PDN DHAD PDN  PAIN 29% 12% P=0.025 Analgesic use 38% 21% Time 18 wks 43 wks P=0.001 (Tannock et al., JCO 1996) 80 pts 80 pts DHAD: 12 mg/mq/iv HORMONE-REFRACTORY PROSTATE CANCER CHEMOTHERAPY

17. HORMONE-REFRACTORY PROSTATE CANCER VINORELBINE (Abratt, Ann Oncol, 2004)

18. PROSTATE CANCER: TAX 327 Study design RANDOMIZE Docetaxel 75mg/m 2 Q3 wks+ Prednisone 5 mg bid Docetaxel 30mg/m 2 wkly 5 of 6 wks+ Prednisone 5 mg bid Mitoxantrone 12mg/m 2 Q3 wks+ Prednisone 5 mg bid Treatment duration in all 3 arms= 30 wks Stratification Pain level PPI >2 or AS >10 vs PPI <2 or AS <10 Kanofsky 80 80

19. PROSTATE CANCER: TAX 327 Overall Survival

20. Taxotere 3 wks A 18.94835 Taxotere w B 17.44531 Mitoxantrone C 16.53222 (Eisenberger et al. Proc ASCO, 2004) OS(months)Biochemical Responses (%) Symptomatic Arm PROSTATE CANCER: TAX 327 Results

21. A randomized phase 3 study….CALGB 90213 Radical Estramusrine and vs Docetaxel x 6 cycles Prostatectomy followed by Prostatectomy The main endpoints are Recurrence rates at 5 years Safety Pathological tumor stage Time to disease recurrence Overall survival Eastham et al. Urology 2003

22. Phase 2 trial of neoadjuvant Docetaxel in locally advanced prostate cancer Weekly Docetaxel x 6 weeks for T2b and PSA 15 or greater GPS 8 or more and no metastatic disease.  Biochemical response 79% with chemotherapy, good tolerability At 23 months of follow up 20/29 pts were disease free with no additional therapy. Dreier et al. Urology 2004

23. Neoadjuvant chemohormonal in high risk prostate cancer 21 pts treated with LH-RH analogue until the PSA nadir Estramustine and Docetaxel Prostatectomy The treatment was well tolerated The rate of pathological organ confined disease was higher then expected and responding patients had an 85% disease free survival rate at 5 years Prayer Galetti et al. BJU Int 2007

24. Neoadjuvant docetaxel treatment for locally advanced prostate cancer: a clinic pathologic study 20 pts treated at the Cleveland Clinic : none achieved a complete pathologic responce. At a median follow up of 49.5 months 12 pts (43%) remained clinically and biochemically free of disease with no additional therapy. 57% biochemical failure. Magi – Galluzzi et al. Cancer 2007

25. Neoadjuvant docetaxel before prostatectomy in patients with high risk PC 19 patients treated Docetaxel 6 months Prostatectomy Results : PSA and tumor volume reduction No complete response Febbo et al. Clin Cancer Res 2005

26. Chemo-radiotherapy in locally advanced prostate cancer (Southwest Oncology Group Study 9024) RT 70 Gy + 5-FU continous weekly infusion 30 pts treated PSA response (43%) Negative biopsy (33%) CR (20%) The treatment was feasible but is necessary to use a better chemotherapy regimen to improve the results. Swanson et al. J Urol 2006

27. Overall: In summary the data of neoadjuvant chemotherapy in high risk patients Very limited Has little value No evidence of complete response Currently it is possible to use neoadjuvant chemotherapy only in clinical trials.

28. Pilot trial of adjuvant paclitaxel plus estramustine in high risk PC Prostatectomy Paclitaxel weekly x 3 cycles 17 pts The median time to PSA failure was 19 months. A statistically significant difference was noted comparing the expected rate of PSA failure. Catmar JP Urology 2008

29. A multicenter, phase III trial comparing immediate adjuvant hormonal therapy in combination with taxotere administered every three weeks versus hormonal therapy alone versus deferred therapy followed by the same therapeutic options in patients at high risk of relapse after radical prostatectomy

30. Study Rationale Radical Prostatectomy or Radiotherapy 3-5 ys 40% PD HRPC: what is the best after RP/RT? Observation ? Adjuvant Hormonal therapy? Or Chemotherapy ??

31. TAXOTERE TAX 327 and SWOG 99-16: potential role of Taxotere in both extending the lives of men with hormone-refractory prostate cancer and relieving distressing symptoms such as bone pain

32. Treatment Plan 1 Radical Prostatectomy ARM 1 ARM 2 Taxotere q21 x 6 cycles + Leuprolide leuprolide acetate for 18 months for 18 months ARM 3 Observation

33. Treatment Plan 2 PD (ARM 3) Taxotere q21 x 6 cycles + Leuprolide acetate leuprolide acetate for 18 months for 18 months

34. Inclusion criteria Pathologically confirmed adenocarcinoma of the prostate Less than 12 weeks from prostatectomy and lymphadenectomy. Not prior RT or systemic treatment for prostate cancer or other malignancy Predicted probability of 5-ys PFS<60% (by the Kattan’s nomogram) Normal cardiac, renal, hepatic and bone marrow function and PS = 0-1 Life expentancy > 5 ys Undetectable PSA at least 2 months after radical prostatectomy Written informed consent

35. Study objectives PRIMARY OBJECTIVE: - PFS on Taxotere + Leuprolide given immediately after radical prostatectomy versus deferred therapy. SECONDARY OBJECTIVES: - PFS on Taxotere + Leuprolide versus Leuprolide alone - OS and DFS - QoL

36. Conclusions The Chemotherapy demonstrated a benefit in OS and PFS in HRPC. Better results reported in metastatic, symptomatic patients. To improve the prognosis of high risk patient it is necessary to evaluate in clinical trials the activity of different drugs,also chemotherapy regimen.

37. Conclusions Predictive models for response and toxicity can help to choose the best treatment for our patients. Currently no data supports the use of adjuvant/neoadjuvant chemotherapy in high risk prostate cancer. The preliminary results of neoadjuvant chemotherapy reported no complete pathological responses.

38. Take-home message It is necessary to evaluate the role of a chemotherapy in high risk prostate cancer in a randomized study having as mean goals the progression free and overall survival.

39. High risk prostate cancer Arm A Arm B Arm C Hormonal therapy Chemotherapy Locoregional treatment Locoregional treatment Locoregional Chemo-hormonal treatment therapy Hormonal therapy