MON 2011 - Slide 1 - K. Fizazi - Spotlight session - New developments in the treatment of prostate cancer

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MON 2011 - Slide 1 - K. Fizazi - Spotlight session - New developments in the treatment of prostate cancer

  1. 1. Localized prostate cancer Karim Fizazi, MD, PhD Department of Cancer Medicine Institut Gustave Roussy Villejuif, France
  2. 2. Localized prostate cancer <ul><li>#1 cancer in most Western countries (before breast cancer) </li></ul><ul><li>Rapidly increasing incidence in the last 15 y </li></ul><ul><li>Debate on (PSA) screening </li></ul><ul><li>Currently, newly diagnosed CaP: </li></ul><ul><ul><li>~ 80% localized </li></ul></ul><ul><ul><li>10-20% metastatic </li></ul></ul>
  3. 3. 3 important prognostic factors <ul><li>Disease extension: </li></ul><ul><ul><li>T3: extra-capsular invasion </li></ul></ul><ul><li>Gleason score: Histoprognostic score: </li></ul><ul><ul><li>6: good </li></ul></ul><ul><ul><li>7: intermediate </li></ul></ul><ul><ul><li>8-10: agressive </li></ul></ul><ul><li>Serum PSA (<10; >20 ng/mL) </li></ul>
  4. 4. Radical prostatectomy Resection of the prostate + seminal vesicles +/- pelvic lymph node dissection
  5. 5. Laparoscopic prostatectomy
  6. 6. Conformal radiotherapy
  7. 7. Collimateur Multi Lames
  8. 8. Brachytherapy <ul><li>Active treatment: < 3% cancer deaths </li></ul><ul><li>- Limited toxicity </li></ul><ul><li>20 years experience (> 500 000 pts treated - Indicated in good risk disease (T1-2, Gleason < 6 et PSA < 10) </li></ul>
  9. 10. Localized prostate cancer: Prognosis and treatment Good prognosis Intermediate prognosis « High risk » PSA < 10 Gleason <7 T1 T2 10 < PSA < 20 Gleason  7 T1 T2 PSA > 20 Gleason  8 T3 Treatment options: - Prostatectomy - Radiotherapy - Brachytherapy - Active surveillance <ul><li>Options: </li></ul><ul><li>- Prostatectomy </li></ul><ul><li>Radiotherapy </li></ul><ul><li>(+ short-term ADT) </li></ul>RXT + Endocrine therapy Specific death: 0-5% 10-20% 30%
  10. 11. Mr Leo, 68 year old <ul><li>Systematic serum PSA= 28 ng/mL </li></ul><ul><li>Confirmed twice </li></ul><ul><li>Moderate increase in night mictions </li></ul><ul><li>Minor erection troubles in the last year </li></ul>
  11. 12. Mr Leo, 68 year old <ul><li>No previous medical history </li></ul><ul><li>Married, 2 children </li></ul><ul><li>Normal physical examination (except digital examination) </li></ul><ul><li>Mother (89 year) and father (91 year) alive </li></ul>Mr Leo’s dad, 91
  12. 13. He meets the urologist <ul><li>Serum PSA= 28 ng/mL </li></ul><ul><li>Likely clinical T3 </li></ul><ul><li>Biopsy: Adenocarcinoma Gleason 8 (4+4) </li></ul><ul><li>6/12 positive biopsies </li></ul>
  13. 14. Radiologic assessment Bone scan? Yes : high risk of bone metastases CT scan of the abdomen/pelvis? Yes : Lymph nodes MRI of the prostate? To be discussed if changes treatment decision
  14. 15. Prostate MRI for capsular invasion <ul><li>Sensitivity  60% </li></ul><ul><li>Specificity  80% </li></ul>T1 T2
  15. 16. Preoperative Kattan nomogram Stephenson, JNCI 2006, 98: 715-7
  16. 17. Nomogram for patients receiving RT + Hormone therapy Parker CC, Br J Cancer 2002, 86: 686-91
  17. 18. What to do? You should have a prostatectomy ! No ! Radiation therapy ! Yes, but they also talk about hormones
  18. 19. Prostatectomy? Radiotherapy? Hormone therapy? Chemotherapy? Pelvic lymph node dissection? High risk localized prostate cancer
  19. 20. Prostatectomy? Radiotherapy? Hormone therapy? Chemotherapy? Pelvic lymph node dissection? High risk localized prostate cancer
  20. 21. Pelvic lymph nodes dissection <ul><li>Potential role: </li></ul><ul><ul><li>Powerful prognostic factor </li></ul></ul><ul><ul><li>Treatment: Irradiation of the pelvis if pN+? </li></ul></ul><ul><li>Incidence of pN+ according to LND extent (classical LND vs extended LND): </li></ul><ul><ul><li>7% vs 23% (Stone 1997) </li></ul></ul><ul><ul><li>14% vs 26% (Heidenreich 2002) </li></ul></ul>
  21. 22. Prostatectomy? Radiotherapy? Hormone therapy? Chemotherapy? Pelvic lymph node dissection? High risk localized prostate cancer
  22. 23. Radical prostatectomy in high risk localized prostate cancer <ul><li>Classically not recommended because of high failure rate (+ margins, relapse) </li></ul><ul><li>Currently re-assessed in « minimal » cT3 patients + low Gleason score + low PSA : </li></ul><ul><ul><li>Van den Ouden 1998 (n=83) </li></ul></ul><ul><ul><li>Van Poppel 2006 (n=40) EORTC </li></ul></ul><ul><ul><li>Mayo Clinic experience (n= 661) Ward 2005 </li></ul></ul><ul><li>Cannot be compared with other modalities due to high patient selection </li></ul><ul><li>No available large prospective randomized trial </li></ul>
  23. 24. Prostatectomy? Radiotherapy? Hormone therapy? Chemotherapy? Pelvic lymph node dissection? High risk localized prostate cancer
  24. 25. Radiotherapy as the only local treatment <ul><li>Reference treatment in high risk CaP </li></ul><ul><li>Currently combined to hormone therapy </li></ul><ul><li>Target: pelvis or prostate? </li></ul><ul><li>Dose escaladation </li></ul>Pollack A. Int J Radiat Oncol Biol Phys 2002, 53: 1097-1105 Metastases-free Survival
  25. 26. Should radiotherapy be added if endocrine therapy is used?
  26. 27. Should Radiotherapy be added to Endocrine Therapy? <ul><li>SPCG-7/SFUO-3 trial: 875 pts T3 (PSA<70, N0,M0) </li></ul><ul><li>Randomization: </li></ul><ul><ul><li>Endocrine therapy (leuprorelin 3 months + Flutamide life-long) </li></ul></ul><ul><ul><li>vs same endocrine therapy + RT (70 Gy) </li></ul></ul><ul><li>Follow-up: 7.6 years </li></ul><ul><li>PSA relapse: 75% vs 26% (p< 0.0001) </li></ul><ul><li>Specific mortality: 24% vs 12% (RR: 0.44 [0.30-0.66] </li></ul><ul><li>Mortality: 39% vs 29% (RR: 0.68 [0.52-0.89] </li></ul>Widmark et al. Lancet 2009; 373: 274-6
  27. 28. SPCG-7— Endocrine Therapy Alone Versus Endocrine Therapy Plus Radiotherapy HR: 0.44 (0.3 – 0.6) P < .001 HR: 0.68 (0.5 – 0.9) P < .001 Widmark et al. Lancet 2009; 373: 274-6 Death from prostate cancer Overall mortality
  28. 29. NCIC CTG PR.3/ MRC PR07/ SWOG JPR3: OS Warde ASCO 2010 320 Deaths, 175 ADT alone, 145 RT+ADT HR=0.77 (95% C.I. 0.61-0.98) P=0.0331 # at Risk ADT ADT+RT ADT ADT+RT Percentage 0 20 40 60 80 100 0 3 6 9 602 603 509 512 Time (Years) 213 232 51 60 7 yr OS 74% 7 yr OS 66%
  29. 30. Should radiotherapy be used if the primary local treatment is radical prostatectomy?
  30. 31. Radiotherapy as adjuvant to radical prostatectomy 3 randomized phase III trials showing a benefit on PFS German trial (Wiegel T, ASCO 2005) EORTC 22 911 trial (Bolla, Lancet 2005, 366: 572-8) SWOG trial (Thompson, JAMA 2006, 296: 2329-35) Met-free: 83% vs 61% (at 10y) OS : HR 0.76
  31. 32. Prostatectomy? Radiotherapy? Hormone therapy? Chemotherapy? Pelvic lymph node dissection? High risk localized prostate cancer
  32. 33. Androgen deprivation (ADT) in high risk prostate cancer? <ul><li>> 3 large trials with prolonged ADT: </li></ul><ul><ul><li>EORTC (Bolla 2002) </li></ul></ul><ul><ul><li>RTOG 85-31 (Pilepitch 2005) </li></ul></ul><ul><ul><li>RTOG 92-2 (Hanks 2003) </li></ul></ul><ul><li>3 trials of short-term ADT </li></ul><ul><ul><li>RTOG 86-10 (Mack Roach 2008) </li></ul></ul><ul><ul><li>D’Amico 2004 </li></ul></ul><ul><ul><li>Denham 2005 </li></ul></ul>
  33. 34. Bolla M, Lancet 2002, 360: 103-108 EORTC trial 22863 PFS OS <ul><li>415 patients, mostly T3 (82%) </li></ul><ul><li>RT= 70 Gy </li></ul><ul><li>Gosereline 3 years vs no ADT </li></ul><ul><li>5-year OS: 78% vs 62% </li></ul>
  34. 35. Short-term or Long-term ADT combined with radiotherapy?
  35. 36. Long-Term ADT prolongs clinical PFS Long-term ADT (n = 487) Short-term ADT (n = 483) Time, years 0 1 2 3 4 5 6 7 8 9 0 10 20 30 40 50 60 70 80 90 100 HR= 1.93, P <.0001 Patients alive, % Bolla, ASCO 2007, Abstr 5014
  36. 37. Long-Term ADT prolongs OS Time, years 0 1 2 3 4 5 6 7 8 9 0 10 20 30 40 50 60 70 80 90 100 Long-term ADT (n = 487) Short-term ADT (n = 483) P = .019 (H0: Long ADT superior) HR: 1.43 P = .6543 (H0: Short ADT non-inferior) Patients alive, % Bolla, ASCO 2007, Abstr 5014
  37. 38. Prostatectomy? Radiotherapy? Hormone therapy? Chemotherapy? Pelvic lymph node dissection? High risk localized prostate cancer
  38. 39. Tannock IF: NEJM 351:1502-12, 2004 Fizazi K: Lancet Oncol 2007; 8: 994-1000 <ul><li>Docetaxel: established standard </li></ul><ul><li>in metastatic prostate cancer </li></ul>Rationale for chemotherapy in localized CaP <ul><li>Docetaxel + Estramustine </li></ul><ul><li>may be even more active </li></ul><ul><li>than docetaxel alone </li></ul><ul><li>In Oncology, minor OS benefit in the metastatic setting </li></ul><ul><li>usually transfers in higher benefit in localized disease </li></ul><ul><li>(breast, colon, etc) </li></ul>HR= 19%, p= 0.02
  39. 40. High risk prostate cancer GETUG 12 trial ADT (3 years) + RXT Docetaxel + Estramustine (4 cycles) RANDOMI ZE Primary endpoint: Progression-free survival n = 413/400 pts Stratification - Gleason  8 - PSA>20 - T3 - pN+ / pN- ADT (3 years) + RXT
  40. 41. Phase III trials of Docetaxel in localized prostate cancer Ongoing 636 RP Montgomery (USA) VA # 553 CAP Early enrolment termination 228 /1700 RP M. Eisenberger (USA) TAX 3501 Accrual completed 600 XRT H. Sandler (USA) RTOG 0521 Ongoing 396 RP Ahlgren (Sweden) AdPro Accrual completed 413 / 400 XRT K. Fizazi (France) GETUG 12 Ongoing 350 XRT A. D’Amico (USA) DOCET-L-02357 Ongoing 750 RP Eastham (USA) CALGB 90203 Ongoing 924 XRT Kellokumpu-Lehtinen (Fin) AdRad Status # patients ( enrolled /planned) Local treatment PI Study name
  41. 42. Mr Leo tolerated well his treatment… … but he’s getting upset … with treatment-induced erectile dysfunction … and his wife as well. Coming back to our patient
  42. 43. Treatment of erectile dysfunction in Oncology <ul><li>Oral drugs: phosphodiesterase 5 inhibitors (tadalafil, sildenafil citrate, etc) </li></ul><ul><li>Intra-cavernosal injections (Prostaglandin E1) </li></ul>
  43. 44. Conclusions: High risk localized prostate cancer <ul><li>Validated prognostic factors/nomograms </li></ul><ul><li>Responsible for most deaths from originally localized CaP </li></ul><ul><li>Current recommended management: </li></ul><ul><ul><li>Pelvic LND: better N staging </li></ul></ul><ul><ul><li>Standard: Androgen deprivation + Radiotherapy </li></ul></ul><ul><li>Currently under investigation: </li></ul><ul><ul><li>Role of radical prostatectomy? </li></ul></ul><ul><ul><li>Role of docetaxel-based chemotherapy? </li></ul></ul>
  44. 45. Thank you !

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