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

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

    • Localized prostate cancer Karim Fizazi, MD, PhD Department of Cancer Medicine Institut Gustave Roussy Villejuif, France
    • Localized prostate cancer
      • #1 cancer in most Western countries (before breast cancer)
      • Rapidly increasing incidence in the last 15 y
      • Debate on (PSA) screening
      • Currently, newly diagnosed CaP:
        • ~ 80% localized
        • 10-20% metastatic
    • 3 important prognostic factors
      • Disease extension:
        • T3: extra-capsular invasion
      • Gleason score: Histoprognostic score:
        • 6: good
        • 7: intermediate
        • 8-10: agressive
      • Serum PSA (<10; >20 ng/mL)
    • Radical prostatectomy Resection of the prostate + seminal vesicles +/- pelvic lymph node dissection
    • Laparoscopic prostatectomy
    • Conformal radiotherapy
    • Collimateur Multi Lames
    • Brachytherapy
      • Active treatment: < 3% cancer deaths
      • - Limited toxicity
      • 20 years experience (> 500 000 pts treated - Indicated in good risk disease (T1-2, Gleason < 6 et PSA < 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
      • Options:
      • - Prostatectomy
      • Radiotherapy
      • (+ short-term ADT)
      RXT + Endocrine therapy Specific death: 0-5% 10-20% 30%
    • Mr Leo, 68 year old
      • Systematic serum PSA= 28 ng/mL
      • Confirmed twice
      • Moderate increase in night mictions
      • Minor erection troubles in the last year
    • Mr Leo, 68 year old
      • No previous medical history
      • Married, 2 children
      • Normal physical examination (except digital examination)
      • Mother (89 year) and father (91 year) alive
      Mr Leo’s dad, 91
    • He meets the urologist
      • Serum PSA= 28 ng/mL
      • Likely clinical T3
      • Biopsy: Adenocarcinoma Gleason 8 (4+4)
      • 6/12 positive biopsies
    • 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
    • Prostate MRI for capsular invasion
      • Sensitivity  60%
      • Specificity  80%
      T1 T2
    • Preoperative Kattan nomogram Stephenson, JNCI 2006, 98: 715-7
    • Nomogram for patients receiving RT + Hormone therapy Parker CC, Br J Cancer 2002, 86: 686-91
    • What to do? You should have a prostatectomy ! No ! Radiation therapy ! Yes, but they also talk about hormones
    • Prostatectomy? Radiotherapy? Hormone therapy? Chemotherapy? Pelvic lymph node dissection? High risk localized prostate cancer
    • Prostatectomy? Radiotherapy? Hormone therapy? Chemotherapy? Pelvic lymph node dissection? High risk localized prostate cancer
    • Pelvic lymph nodes dissection
      • Potential role:
        • Powerful prognostic factor
        • Treatment: Irradiation of the pelvis if pN+?
      • Incidence of pN+ according to LND extent (classical LND vs extended LND):
        • 7% vs 23% (Stone 1997)
        • 14% vs 26% (Heidenreich 2002)
    • Prostatectomy? Radiotherapy? Hormone therapy? Chemotherapy? Pelvic lymph node dissection? High risk localized prostate cancer
    • Radical prostatectomy in high risk localized prostate cancer
      • Classically not recommended because of high failure rate (+ margins, relapse)
      • Currently re-assessed in « minimal » cT3 patients + low Gleason score + low PSA :
        • Van den Ouden 1998 (n=83)
        • Van Poppel 2006 (n=40) EORTC
        • Mayo Clinic experience (n= 661) Ward 2005
      • Cannot be compared with other modalities due to high patient selection
      • No available large prospective randomized trial
    • Prostatectomy? Radiotherapy? Hormone therapy? Chemotherapy? Pelvic lymph node dissection? High risk localized prostate cancer
    • Radiotherapy as the only local treatment
      • Reference treatment in high risk CaP
      • Currently combined to hormone therapy
      • Target: pelvis or prostate?
      • Dose escaladation
      Pollack A. Int J Radiat Oncol Biol Phys 2002, 53: 1097-1105 Metastases-free Survival
    • Should radiotherapy be added if endocrine therapy is used?
    • Should Radiotherapy be added to Endocrine Therapy?
      • SPCG-7/SFUO-3 trial: 875 pts T3 (PSA<70, N0,M0)
      • Randomization:
        • Endocrine therapy (leuprorelin 3 months + Flutamide life-long)
        • vs same endocrine therapy + RT (70 Gy)
      • Follow-up: 7.6 years
      • PSA relapse: 75% vs 26% (p< 0.0001)
      • Specific mortality: 24% vs 12% (RR: 0.44 [0.30-0.66]
      • Mortality: 39% vs 29% (RR: 0.68 [0.52-0.89]
      Widmark et al. Lancet 2009; 373: 274-6
    • 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
    • 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%
    • Should radiotherapy be used if the primary local treatment is radical prostatectomy?
    • 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
    • Prostatectomy? Radiotherapy? Hormone therapy? Chemotherapy? Pelvic lymph node dissection? High risk localized prostate cancer
    • Androgen deprivation (ADT) in high risk prostate cancer?
      • > 3 large trials with prolonged ADT:
        • EORTC (Bolla 2002)
        • RTOG 85-31 (Pilepitch 2005)
        • RTOG 92-2 (Hanks 2003)
      • 3 trials of short-term ADT
        • RTOG 86-10 (Mack Roach 2008)
        • D’Amico 2004
        • Denham 2005
    • Bolla M, Lancet 2002, 360: 103-108 EORTC trial 22863 PFS OS
      • 415 patients, mostly T3 (82%)
      • RT= 70 Gy
      • Gosereline 3 years vs no ADT
      • 5-year OS: 78% vs 62%
    • Short-term or Long-term ADT combined with radiotherapy?
    • 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
    • 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
    • Prostatectomy? Radiotherapy? Hormone therapy? Chemotherapy? Pelvic lymph node dissection? High risk localized prostate cancer
    • Tannock IF: NEJM 351:1502-12, 2004 Fizazi K: Lancet Oncol 2007; 8: 994-1000
      • Docetaxel: established standard
      • in metastatic prostate cancer
      Rationale for chemotherapy in localized CaP
      • Docetaxel + Estramustine
      • may be even more active
      • than docetaxel alone
      • In Oncology, minor OS benefit in the metastatic setting
      • usually transfers in higher benefit in localized disease
      • (breast, colon, etc)
      HR= 19%, p= 0.02
    • 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
    • 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
    • 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
    • Treatment of erectile dysfunction in Oncology
      • Oral drugs: phosphodiesterase 5 inhibitors (tadalafil, sildenafil citrate, etc)
      • Intra-cavernosal injections (Prostaglandin E1)
    • Conclusions: High risk localized prostate cancer
      • Validated prognostic factors/nomograms
      • Responsible for most deaths from originally localized CaP
      • Current recommended management:
        • Pelvic LND: better N staging
        • Standard: Androgen deprivation + Radiotherapy
      • Currently under investigation:
        • Role of radical prostatectomy?
        • Role of docetaxel-based chemotherapy?
    • Thank you !