PROSTATA MULTIDISCIPLINARITA IN URO-ONCOLOGIA INTEGRAZIONE TERAPIA SISTEMICA-TRATTAMENTO LOCALE. Dr.ssa Ori Ishiwa Dr Sergio Bracarda

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1 15 anno di fondazione del GUONE MULTIDISCIPLINARITA IN URO-ONCOLOGIA Aviano, 10 settembre 2010 INTEGRAZIONE TERAPIA SISTEMICA-TRATTAMENTO LOCALE PROSTATA Dr.ssa Ori Ishiwa Dr Sergio Bracarda UOC Oncologia Medica Arezzo

2 Locally advanced prostate cancer (T3-T4, Nx-1, M0)

3 Patients affected by locally advanced prostate cancer present an high risk of relapse or death after exclusive local treatment, especially if: - Clinical stage T3 - PSA > 20 ng/ml - Gleason Score 8-10 Standard Txt: - RRP - RT+ adj ADT D Amico JCO 2002 EORTC T3-T4 o N1: RT ±3 yr OT (goserelin): > OS (Bollà, Lancet 2002) RTOG T3-T4 o N+: RT ± OT fino a PD: > OS (Pilepich, Int J Radiat Oncol Biol Phys 2005)

4 But recent increasing evidence for harmful effects of long-term ADT!"

5 ? Which is the optimal duration for ADT combined with RT?

6 EORTC 22961, Bolla, ASCO 2007 # $%#$&%#& # $&#$'(#&( )*+%,(-. &! &! Non-inferiority Trial "#$%/$ * 0#1" $ 2#134#5

7 RESULTS: significant differences in OS between treatment arms OS!! p = Long Term ADT >>> Short Term ADT

8 And in PFS any clinical progression in 20.1 vs 8.2%

9 La Chemioterapia, come la Terapia Ormonale, è una terapia sistemica. Potrebbe avere un ruolo nella gestione della malattia Loc-Avanzata? No, nessuno.. Non ora, per lo meno... tuttavia..

10 From 2004 DCT standard CT approach in CRPC Overall. More than met CRPC pts treated!! Treatment of Choice for CRPC since 2004: Docetaxel (>OS)

TAX-327 OS = +2.5m Docetaxel 3-Weekly, significantly improves: - OS (18.9 vs 16.5 m) p =.009) (24% in the risk of death, HR=0.76, 95% CI 0.62-0.94) - PSA response: 45 vs. 32%, p =.

11 TAX-327 OS = +2.5m Docetaxel 3-Weekly, significantly improves: - OS (18.9 vs 16.5 m) p =.009) (24% in the risk of death, HR=0.76, 95% CI ) - PSA response: 45 vs. 32%, p = Objective response: 12 vs 7%, p = Pain response: 35 vs. 22%, p =.01 - Quality of Life (FACT-P): 22 vs 13%, p = Safe but with toxicity (Grade 3/4 neutropenia: 32 vs 21.%)

SWOG 99-16 OS = +2m Docetaxel 3-W plus Estramustine Ph. significantly improves: - OS (17.5 vs 15.6 m) p = 0.02 (20% in the risk of death. HR = 0.80 (95% CI, 0.67-0.

12 SWOG OS = +2m Docetaxel 3-W plus Estramustine Ph. significantly improves: - OS (17.5 vs 15.6 m) p = 0.02 (20% in the risk of death. HR = 0.80 (95% CI, ) - PSA response: 50 vs 27%, p< Objective response: 17 vs 11%, p= PFS: +27% (95% CI, 14 to 37%; p< But also toxicity, even if without differences in toxic death rates

14 2007 Updated OS Analysis of TAX-327 Study Initial report with 557 of 1006 pts died. Survival updated to Jan 2007 (by contacting investigators at each site by mail, or phone). 310 additional deaths recorded resulting in a total of 867 deaths

15 Comparison of initial and updated OS data Median OS 2003 Data p-value Update 2007 p-value - DCT Q3w 18.9 ( ) ( ) DCT wk 17.4 ( ) 17.8 ( ) - Mitox ( ) 16.3 ( ) * 95% confidence interval indicated Survival > 3 years Docetaxel Q3W (n=335) Docetaxel Weekly (n=334) Mitoxantrone (n=337) 3-yr survival rate 17.9% 16.7% 13.7% Propotion Alive Docetaxel 3-Weekly Docetaxel Weekly Mitoxantrone Years

16 Questi dati sono applicabili solo all CRPC?

17 a "Proof of Principle : evidence of docetaxel activity also in HDPC. "Effect of Docetaxel in Pts With Hormone-Dependent PSA Progression After Local Therapy for Prostate Cancer" Goodin, et Al. JCO pts with PSA relapse after RP (14), RT (6), RP+RT (5) - Median baseline PSA 31.5 ( ) - Median Gleason Score 7 (6-9) PSA response in 10/23 ev. pts (43%) PSA nadir 5m - Testosterone level: not affected (Docetaxel plus Pdn active in HDPC and not influencing the hormonal status) (not affecting eventual HT)...

18 Local therapy Hormonal therapy Chemotherapy

19 Local therapy ADJUVANT CHEMOTHERAPY Hormonal therapy Chemotherapy

20 Adjuvant Chemotherapy Trials Only 1 modern randomized trial Of 93 patients enrolled, only 38 had T3/T4 disease No radiotherapy administered! Randomized to leuprolide vs leuprolide + mitoxantrone x 4 cycles (not an actual standard) Wang BJU Int 2000

21 '"()*+#, P=0.044 Wang BJU Int 2000

22 SWOG 9921: HT vs HT+CT after RP (n = 1360) High Risk after RP R A N D O M I Z E Hormonal therapy x 2 yr Hormonal therapy x 2 yrs Mitoxantrone + Prednisone x 6 cycles Adjuvant CT trials ongoing or closed Primary Endpoint: OS RP TAX (2.172 pts) R a n d o m i z a t i o n Observation ADT ADT+Taxotere P r o g r e s i o n ADT LH-RH x 18 mos Taxotere- 75mg/m2 q.3wks x 6 cycles ADT ADT + Taxotere 2 nd Pr og re ss io n P r o g r e s i o n

23 NEOADJUVANT CHEMOTHERAPY Local therapy ADJUVANT CHEMOTHERAPY Hormonal therapy Chemotherapy

24 Why Neoadjuvant Therapy? Well characterized high risk groups Ability to assess in vivo chemosensitivity Early treatment of micrometastases Ability to assess molecular determinants of response in pathologic specimens Rapid ability to assess effect of new agents compared with adjuvant trials

25 Neoadjuvant Docetaxel Prior To Radical Prostatectomy Phase II trial Up to 6 months of weekly docetaxel prior to RP in high risk localized prostate cancer Monthly PSA, DRE assessments Endorectal coil MRI at 0, 2, and 6 months Primary endpoint: Pathologic CR Febbo Clin Cancer Res 2005

26 Clinical Response PSA decline > 50% in 11/19 (58%) Measurable tumor response by ermri > 25% in 13/19 (68%) Toxicity Overall well tolerated Most common side effect: grade 1-2 fatigue No neutropenia or thrombocytopenia No serious N/V, neuropathy, diarrhea, infection Unusual side effects: nail changes, excess tearing Pathology Results (N=16) Pathologic Stage # Patients (%) pt0 0 pt2 6 (38%) pt3a 2 (13%) pt3b 7 (44%) pt4 1 (6%) N (+) 0

27 Neoadjuvant CT trials ongoing CALGB 90203: Neoadjuvant CT In High Risk Prostate Cancer (n = 610) High Risk 40% DFS R A N D O M I Z E RP Docetaxel x 6 cycles RP (n = 610) Primary Endpoint: 5 yr DFS

28 CONCLUSIONI La chemioterapia sistemica precoce potrebbe essere un approccio potenzialmente vantaggioso (ritardato sviluppo di cloni CRPC). Tale approccio, tuttavia, va ancor oggi impiegato solo nell ambito di protocolli di ricerca clinica. La RT+HT (trattamento integrato) rimane ancor oggi lo standard terapeutico ottimale del Ca. Prostatico Loc. Avanzato

Rationale for Multimodality Therapy for High Risk Localized Prostate Cancer

Rationale for Multimodality Therapy for High Risk Localized Prostate Cancer 100 80 60 Cancer Death Rates for Men, US 1930-2002 Rate Per 100,000 Lung William K. Oh, M.D. 40 Stomach Colon & rectum Prostate