Locally advanced Prostate cancer

Management of Locally Advanced Prostate Cancer John Fitzpatrick School of Medicine & Medical Science Mater Misericordiae University Hospital & University College Dublin, Ireland Locally Advanced Prostate Cancer Definition  Clinical diagnosis whereby the tumor has extended beyond the capsule with no evidence of nodal or distant metastatic spread Oh WK et al. JCO 1999; 17: 3664–75 Prostate Cancer Stage at Diagnosis (1988-1998) 60 50 40 % 30 20 10 0 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 T1a+b T1c T2 T3+4 Metastatic T3+T4 Year 2042 patients with newly diagnosed PC at Walter Reed Army Medical Center Paquette EL et al. Urology 2002; 60: 756–759 Cancer-Specific Survival by T Stage in Men with M0 Prostate Cancer T1a T2a T2b-T3 T4 T1b Risk of death due to PC:  T1a: 10% Cumulative percentage  T2a: 52%  T1b: 47%  T2b-T3: 53%  T4: 70% Years 514 Swedish men with M0 prostate cancer treated with either deferred or immediate hormonotherapy Aus et al. J. Urol. 1995; 154, 460-465 Cancer-Specific Survival by Grade in Men with M0 Prostate Cancer Cumulative percentage G1 Risk of death due to PC:  G1: 43%  G2: 48%  G3: 60% G2 G3 Years 514 Swedish men with M0 prostate cancer treated with either deferred or immediate hormonotherapy Aus et al. J. Urol. 1995; 154, 460-465 5-Year PSA Outcome - D’Amico Risk Stratification  Low risk: <25% PSA failure1 • ≤T2a and Gleason ≤6 and PSA <10 ng/mL  Intermediate risk: 25%–50% PSA failure1 • T2b or Gleason 7 or PSA 10–20 ng/mL  High risk: >50% PSA failure • T2c or Gleason 8–10 or PSA >20 ng/mL1 • T3-T4 may also be included in the high risk group2 D’Amico, et al. JAMA 1998, 280: 969-974 Cooperberg et al, J. Urol. 2003, 170: S21-S27 CaPSURE Registry: Time Trends in Prostate Cancer Risk Stratification at Diagnosis 8685 men with prostate cancer in US Cooperberg et al, J. Urol. 2003, 170: S21-S27 Outcome of Men with High Risk Prostate Cancer  Biochemical relapse in 80% of men within 10 years after definitive local therapy1  Prostate cancer specific mortality: relative risk x 14 times that of the low risk group2 1Nakabayashi 2D’Amico M et al. BJU Int 2006; 97: 679–683 AV et al. JCO 200321: 2163-72 Clinically Localized Prostate Cancer Managed Conservatively: 20-Year Outcome  Low grade (Gleason 2-4) • Minimal risk of prostate cancer death during 20-years follow-up  Intermediate grade (Gleason score 5-6) • Intermediate risk of prostate cancer death  High grade (Gleason 7-10) • High risk of death with 10 years of diagnosis Albertsen P. JAMA 2005, 291: 2095-2101 Survival Non prostate cancer mortality Non prostate cancer mortality Albertsen P JAMA 2005 291: 2095-2101 Management of Locally Advanced Prostate Cancer  Deferred treatment Deferred Treatment Adolfsson et al. J. Urol. 1999, 161: 505-508 Deferred Treatment (J. Adolfsson)  50 selected asymptomatic patients: • median age 71 years • T3 M0, highly or moderately differentiated  Follow-up >144 months  Cancer-specific survival rates at 5 and 10 years of 90% and 74%, respectively  Likehood of being without treatment at 5 and 10 years of 40% and 30%, respectively  Deferred treatment an option for selected patients with well differentiated T3 tumors and short life expectancy? Adolfsson et al. J. Urol. 1999, 161: 505-508 Deferred versus Early Hormonal Treatment Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council trial THE MEDICAL RESEARCH COUNCIL PROSTATE CANCER WORKING PARTY INVESTIGATORS GROUP MRC. Br. J. Urol. 1997, 79: 235-246 Deferred versus Early Hormonal Treatment (MRC trial)  938 patients with locally advanced or asymptomatic metastatic PC randomized to immediate versus deferred hormonal treatment (orchiectomy or LHRH analogue)  Worse outcome for deferred treatment (greater mortality due to PC, more rapid local metastatic progression)1  On longer follow-up (up to 15 years), no significant difference in overall survival2 1MRC. Br. J. Urol. 1997, 79: 235-246 2Kirk D. Br. J. Urol. 2000, 86 (suppl. 3): S220 Deferred versus Early Hormonal Treatment Studer et al. JCO. 2006, 24: 1868-76 Deferred versus Early Hormonal Treatment (EORTC 30891)  985 patients with T0-4, N0-2, M0 PC randomized to immediate versus deferred androgen deprivation (orchiectomy or LHRH analogue/cyproterone acetate)  In the deferred group, the median time to start treatment was 7 years and 1 out 4 men died without needing treatment  Overall survival slightly better in case of immediate androgen deprivation but no difference in prostate cancer mortality and symptom-free survival. Studer et al. JCO. 2006, 24: 1868-76 Management of Locally Advanced Prostate Cancer  Deferred treatment  Radical prostatectomy Radical Prostatectomy  Few published reports on outcomes  Surgical treatment of clinical stage T3 traditionally discouraged, mainly because of an increased risk of positive margins and both lymph node metastases or distant relapse1-2 1van den Ouden et al. Brit. J. Urol. 1993, 72: 489 2Hodgston et al. Urol. Oncol. 1998, 4: 3-12 Radical Prostatectomy Lerner et al. J.Urol. 1995, 154: 1447-52 Radical Prostatectomy (Lerner)  812 patients (mean age 65 y.) with clinical T3, low co-morbidity and a 10-year life expectancy  Radical prostatectomy (+ external beam irraditation 7%, androgen deprivation 43%, or both 10%)  Follow-up: median 3.3 years (mean 4.5 years)  17% of clinical T3 overstaged  Cancer-specific survival rates at 5, 10 and 15 years of 90%, 80% and 69%, respectively  Good outcome in overstaged patients and Gleason <7 Lerner et al. J.Urol. 1995, 154: 1447-52 Radical Prostatectomy (Lerner) Prostate cancer-specific survival rate by clinical stage Prostate cancer-specific survival rate by Gleason score Years after surgery Years after surgery Lerner et al. J.Urol. 1995, 154: 1447-52 Radical Prostatectomy Ward et al. BJU Int. 2005, 95: 751-756 Radical Prostatectomy (Ward)  Retrospective analysis of 5652 patients (median 66 years) with clinical T2 (4810, 85%) or T3 (842, 15%) prostate cancer treated by radical prostatectomy  Follow-up: median 10.3 years  27% of hormone-naive patients overstaged  Cancer-specific survival of 95%, 90% and 79% at 5, 10 and 15 years, respectively without major difference between cT2 and cT3  Increased risk of relapse for Gleason ≥ 7, positive margins and non diploid chromatin Ward et al. BJU Int. 2005, 95: 751-756 Cancer-Specific Survival: cT2 vs cT3 cT2 cT3 cT3: Cancer-Specific Survival: 90% and 79% at 10 and 15 years cT2: Cancer-Specific Survival: 96% and 92% at 10 and 15 years Ward et al. BJU Int. 2005, 95: 751-756 Cancer-Specific Survival by Final Stage pT2 N0 pT3-4 N0 pTx N+ pT3-4: Cancer-Specific Survival: 89% and 80% at 10 and 15 years Ward et al. BJU Int. 2005, 95: 751-756 Morbidity of Radical Prostatectomy for cT3 Similar to cT2 Incidence (%) Rectal injury Intra-operative haemorrhage Hospitalized blood transfusion Hernia Bladder neck contracture Lymphocele Urethral stricture Deep vein thrombosis Pulmonary embolism Erectile dysfunction Incontinence * 6% had severe incontinence 0.5% required artificial sphincter 1.6% 1.8% 29% 2.6% 11.2% 1% 3.2% 8% 1.2% 75.3% 21%* Ward et al. BJU Int. 2005, 95: 751-756 Radical Prostatectomy & Neoadjuvant Hormonal Therapy Soloway MS et al. J Urol 2002, 167: 112-116 Radical Prostatectomy & Neoadjuvant Hormonal Therapy  Multicenter, prospective randomized trial  303 patients with clinical T2b prostate cancer randomized to receive 3 months of leuprolide + flutamide before RRP versus RRP alone  5-year follow-up Soloway MS et al. J Urol 2002, 167: 112-116 Radical Prostatectomy & Neoadjuvant Hormonal Therapy  Neoadjuvant therapy: • Reduced positive margins • Reduced capsular invasion • Reduced tumour at urethral margin  But: • Similar seminal vesicle invasion • Similar lymph node metastasis • Similar 5-year biochemical recurrence rate of 65% Soloway MS et al. J Urol 2002, 167: 112-116 Radical Prostatectomy: Predictors of Early PSA Failure D’Amico et al. JCO 2000, 18: 3240-3246 Radical Prostatectomy: Predictors of Early PSA Failure P value PSA (vs ≤ 10) • > 10 to 20 ng/ml • > 20 ng/ml 0.01 0.009 Positive biopsies • 34 to 50% (vs <34) • > 50% Positive margins (vs negative) Stage (vs T2) Grade (vs 2-6) • T3a • T3b • Gleason 7 • Gleason 8-10 0.009 0.0001 0.0001 NS 0.02 NS 0.04 D’Amico et al. JCO 2000, 18: 3240-3246 Cox regression multivariable analysis Radical Prostatectomy  May be an option in selected patients: • clinically overstaged patients (pT2) • Patients with clinical T3a, Gleason <8, PSA < 20 ng/ml and life expectancy ≥ 10 years Management of Locally Advanced Prostate Cancer  Deferred treatment  Radical prostatectomy  Radiation therapy Radiation Therapy Alone  Clinical T3 treated by RT alone (60-70 Gy): • 10-year overall survival ranging from 31% to 46% • 10-year cancer-specific survival from 44% to 64%  Clinical T4 treated by RT alone: • Overall survival at 10 years of only 15%  When PSA used as an indicator of recurrence: • only 18% of clinical T3-T4 treated by RT alone are biochemically free of relapse at 10 years Hodgson et al. Urol Oncol 1998, 4: 3-12 Radiation Therapy: Dose-Escalation to 78 Gy Seems of Benefit Pollack A. et al. Int J Radiat Oncol Biol Phys 2002, 53: 1097-1105 Radiation Therapy: Dose-Escalation to 78 Gy Seems of Benefit  305 patients with clinical T1-T3 randomized to radiation therapy dose-escalation to 78 Gy versus 70 Gy.  No neoadjuvant or adjuvant androgen ablation (except 2 protocol violations)  Median follow-up: 60 months Pollack A. et al. Int J Radiat Oncol Biol Phys 2002, 53: 1097-1105 Radiation Therapy: Dose-Escalation to 78 Gy Seems of Benefit Clinical and/or biochemical relapse for PSA > 10 ng/ml Distant metastasis for PSA > 10 ng/ml 305 stage T1-T3 patients Pollack A. et al. Int J Radiat Oncol Biol Phys 2002, 53: 1097-1105 Dose-Escalation 78 vs 70 Gy: Morbidity  Rectal complications ≥ Grade 2* at 6 years: • 12% for 70 Gy • 26% for 78 Gy (p=0.006)  Bladder complications ≥ Grade 2* at 6 years: • 8% for 70 Gy • 13% for 78 Gy (p=ns) * Grade 2: symptoms respond to simple outpatient management Grade 3: distressing symptoms Grade 4: symptoms require major surgical intervention Pollack A. et al. Int J Radiat Oncol Biol Phys 2002, 53: 1097-1105 Combination of External Beam Therapy and Brachytherapy Demanes D. et al. Int J Radiat Oncol Biol Phys 2005, 61: 1306-1316 External Beam Therapy & Brachytherapy Efficacy  209 consecutive patients with T2-T3 prostate cancer and no prior androgen suppression  Median follow-up: 7.25 years (range 5-12)  Results: • General clinical control: 90% • Overall survival rate: 79% • Cancer-specific survival rate: 97% • PSA progression-free survival of 90%, 87% and 69% at 10 years for low, intermediate and high risk patients Demanes D. et al. Int J Radiat Oncol Biol Phys 2005, 61: 1306-1316 Combination of External Beam Therapy and Brachytherapy: Morbidity  Morbidity at 10 years: • Grade 2: 7.7% (proctitis…) • Grade 3: 6.7% (bulbomembranous stricture in 13/14 cases) • Grade 4: 1% • Incontinence: 3.8% • Erectile dysfunction: 39% Demanes D. et al. Int J Radiat Oncol Biol Phys 2005, 61: 1306-1316 Radiation Therapy & Adjuvant Hormonal Therapy (RTOG 85-31)  977 patients with stage T3-4 N0-1 M0 or pT3 after radical prostatectomy  RT and hormonal therapy (goserolin acetate) started last week of RT and continued until relapse versus RT alone (with hormonal therapy in case of relapse)  Median follow-up 7.3 years  Results in favor of immediate hormonal therapy: • Overall survival at 5 years of 76% vs 71% • Overall survival at 10 years of 53% vs 38% • Cancer-specific survival at 10 years of 83% vs 78% Pilepich MV, JCO 2003, 22: 381 (abstract 1530) Radiation Therapy & Neoadjuvant Hormonal Therapy Pilepich et al. Int J Radiat Oncol Biol Phys 2001, 50: 1243-1252 Radiation Therapy & Neoadjuvant Hormonal Therapy (RTOG 86-10)  471 patients with stage T2-4 N0-X M0 (T2 32%, T3-4 70%, N0 91%)  RT + hormonal therapy (eulexine + goserolin acetate) started 2 months before RT and maintained during RT versus RT alone (with hormonal therapy in case of relapse)  At 8 years, neoadjuvant hormonal therapy associated with better local control (42% vs 30%, p=0.016), disease-free survival (33% vs 21%, p=0.004) and biochemical disease-free survival (PSA <1.5 ng/ml, 24% vs 10%, p<0.0001) Pilepich et al. Int J Radiat Oncol Biol Phys 2001, 50: 1243-1252 Radiation Therapy & Adjuvant Hormonal Therapy Bolla et al. Lancet 2002, 360: 103-108 EORTC Study (22863)  415 patients (mean age 70 y.) with T1-2 WHO grade 3 or T3-4 N0-1 M0 prostate cancer  RT (70 Gy) + immediate androgen suppression (goserolin for 3 years + cyproterone acetate for 1 month) versus RT alone  Follow-up: median 66 months  Results in favor of combined treatment: • Clinical disease-free survival rate at 5 years of 74% vs 40%, respectively (p=0.0001) • Overall survival at 5 years of 78% vs 62% (p=0.0002) • Cancer-specific survival at 5 years of 94% vs 79% Bolla et al. Lancet 2002, 360: 103-108 EORTC Study (22863) Overall survival rate Biochemically defined disease-free survival Bolla et al. Lancet 2002, 360: 103-108 EORTC Study (22863): Late Toxicity % with ≥ grade 2 22.8% 4.7% 4.7% 7.1% Overall toxicity Cystitis Haematuria Urinary stricture Urinary incontinence Proctitis Chronic diarrhoea Small bowel obstruction Leg oedema 5.3% 8.2% 3.7% 0.5% 1.5% Ataman et al. Eur J Cancer 2004, 40: 1674-1681 Radiation Therapy & Neoadjuvant + Adjuvant Hormonal Therapy Hanks GE JCO 2003, 21: 3972-3978 RTOG Study (92-02)  1554 patients with clinical T2c to T4  RT + long-term hormone therapy (before, during and 2 years after RT) versus RT + short-term hormone therapy (2 mo before and during RT)  Follow-up: median 5.8 years  Long-term hormone therapy significantly improved all efficacy end-points (biochemical freedom of disease, distant metastatic failure, local control, disease-free survival) except 5-year overall survival (80% vs 78.5%, p=0.73).  Survival advantage of RT+ long-term hormonal therapy for Gleason 8-10 Hanks GE JCO 2003, 21: 3972-3978 RTOG Study (92-02) - Outcomes at 5 Years for Gleason 8-10 p<0.01 100 80 p<0.05 93% 82% p<0.0001 RT + short-term hormone therapy RT + long-term hormone therapy 81% 71% p<0.0001 Estimated rate 65% 60 42% 40 20 0 p<0.01 33% 27% 19% 15% p<0.05 18% 9% Disease-Free Overall Survival Survival Cancer Biochemical Distant Local Specific Failure Metastasis Progression Survival Hanks GE JCO 2003, 21: 3972-3978 Radiation Therapy  Standard radiation to 70 Gy not effective enough  Dose-escalation studies to 78 Gy seem to be of benefit  External beam therapy only or combination of external beam and brachytherapy  Combination hormonal treatment in patients with high Gleason score is of benefit. Management of Locally Advanced Prostate Cancer  Deferred treatment  Radical prostatectomy  Radiation therapy  Hormonal therapy Immediate vs Deferred Hormonal Treatment Medical Research Council  938 patients with locally advanced or asymptomatic metastatic prostate cancer  Initial survival benefit with immediate hormonal treatment compared to deferred therapy1  On longer follow-up (up to 15 years), no significant difference in overall survival2 1MRC. Br. J. Urol. 1997, 79, 235-246 2Kirk D. Br. J. Urol. 2000, 86 (suppl. 3): S220 Immediate vs Deferred Hormonal Therapy (SAKK 08-88) Studer et al. JCO 2004, 22, 4109-4118 Immediate vs Deferred Hormonal Therapy (SAKK 08-88)  197 patients with locally advanced (T3-4 67%, N+ 20%) or metastatic (22%) prostate cancer  Immediate versus deferred orchiectomy  Immediate therapy associated with significantly longer time to onset of first pain, ureteric obstruction and/or documented metastases  But no difference in overall symptom free interval and overall survival up to 14 years Studer et al. JCO 2004, 22: 4109-4118 Immediate vs Deferred Hormonal Therapy (SAKK 08-88) Time to first pain, ureteric obstruction and/or new metastases Overall survival rate Studer et al. JCO 2004, 22: 4109-4118 Immediate vs Deferred Hormonal Therapy (EORTC 30891)  985 patients with T0-4, N0-2, M0 PC randomized to immediate versus deferred androgen deprivation (orchiectomy or LHRH analogue/cyproterone acetate)  Overall survival slightly better in case of immediate androgen deprivation (fewer deaths not related to PC)  No difference in prostate cancer mortality, symptom-free survival and time to progression to HRPC Studer et al. JCO. 2006, 24: 1868-76 Immediate vs Deferred Hormonal Therapy (EORTC 30891) Overall survival Prostate cancer mortality Immediate Deferred Deferred Immediate Studer et al. JCO. 2006, 24: 1868-76 Immediate Hormonal Therapy Iversen et al. J.Urol. 2004, 172: 1871-76 Immediate hormonal Therapy (SPCG-6 Study)  1,218 patients with T1-4 M0, any N prostate cancer including 505 (41.5%) locally advanced (T3-4 M0 any N, or any T M0 N+)  Bicalutamide (150mg) or placebo until failure, in addition to standard care (RP, RT or WW – 81% untreated)  At a median 5.3 years of follow-up: • Improved overall survival with bicalutamide in locally advanced PC but decreased survival in localized PC • Improved progression-free survival by 43% versus placebo, with greatest benefits in locally advanced PC Iversen et al. J.Urol. 2004, 172: 1871-76 Immediate Hormonal Therapy McLeod et al. BJU Int. 2005, 97: 247-54 Bicalutamide EPC Program  Combined analysis of 3 double-blind, placebocontrolled studies  8,113 men with T1-4 M0, any N prostate cancer including 2681 (33.0%) with locally advanced PC  Bicalutamide or placebo in addition to standard care (RP 55%, RT 17%, WW 28%)  At a median 5.4 years of follow-up: • Improved overall survival with bicalutamide in locally advanced disease treated by WW (not RP/RT) but decreased survival in localized disease • Improved progression-free survival by 27% compared to placebo, with greatest benefits in locally advanced PC McLeod et al. BJU Int. 2005, 97: 247-54 Bicalutamide EPC Program Overall Survival Favors bucalutamide + standard care ALL Radical prostatectomy Favors standard care • Localized disease • Locally advanced disease Radiotherapy • Localized disease • Locally advanced disease [0.65, 0.44–0.95] Watchful waiting • Localized disease • Locally advanced disease 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 McLeod et al. BJU Int. 2005, 97: 247-54 Bicalutamide EPC Program Progression-Free Survival Favors bucalutamide + standard care ALL Radical prostatectomy • Localized disease Favors standard care • Locally advanced disease Radiotherapy • Localized disease • Locally advanced disease Watchful waiting • Localized disease • Locally advanced disease 0.25 0.50 0.75 1.00 1.25 [0.75, 0.61–0.91] [0.56, 0.40–0.78] [0.60, 0.49–0.73] 1.50 1.75 2.00 McLeod et al. BJU Int. 2005, 97: 247-54 Bicalutamide EPC Program: Safety Bicalutamide (n=4,022) 28.7% 73.6% 68.3% 10.9% 9.2% 9.2% 3.1% Placebo (n=4,031) 9.8% 7.6% 8.3% 7.8% 5.3% 6.5% 1.7% Drop-outs for AE Breast pain Gynecomastia Asthenia Hot flashes Impotence Abnormal liver function McLeod et al. BJU Int. 2005, 97: 247-54 Hormonal Therapy: The Dilemna…  Immediate hormonal therapy may delay disease progression in locally advanced PC but does not improve overall survival  Potential benefits of immediate hormonal therapy must be balanced with: • the significant side-effect profile associated with hormonal therapy • The inevitable progression to hormone refractary disease within 2 or 3 years Management of Locally Advanced Prostate Cancer  Deferred treatment  Radical prostatectomy  Radiation therapy  Hormonal therapy  Chemotherapy? Rationale for Chemotherapy in Locally Advanced Prostate Cancer  Definitive treatment (RP or RT) is not able to eradicate all clones of PC in high risk patients  Two phase III trials (TAX 327, SWOG 9916) with docetaxel-based chemotherapy have shown for the 1st time a survival benefit in metastatic HRPC1-2  By analogy with other tumors (breast, lung, colorectal), chemotherapy in combination with other treatments may be of benefit at an earlier stage (i.e. lower tumor burden) in high risk patients3. 1Tannock 2Petrylak IF et al. N Engl J Med 2004, 351: 1502–1512 DP et al. New Engl J Med 2004, 351: 1513–1520 3Gleave M et al. JCO 2006, 23, 8186-91 Development of Docetaxel in Earlier Stages Relapsed/ Newly diagnosed M+/ Rising PSA Localised Disease M+ Hormone Refractory PC Adjuvant TAX3501 study (Eisenberger): (Docetaxel + ADT vs ADT given immediately after RP or at the time of progression) VA cooperative study 553 (RP  Docetaxel + Prednisone vs RP  Observation) RTOG 0521: (AD + RT  Docetaxel vs AD + RT) Neoadjuvant CALGB 90203 study: (Docetaxel + AD  RP vs AD  RP) D’Amico study (Docetaxel + AS + RT vs AS + RT) GETUG 12 (Docetaxel + estramustine + AD vs AD  Local therapy +AD) Adjuvant Treatment in High Risk Localized Prostate Cancer - TAX-3501 (Eisenberger) Deferred arm ADT 18 months RANDOMIZATION Observation ADT 18 months + Docetaxel RP Immediate arm ADT 18 months ADT 18 months + Docetaxel Primary end-point: progression-free survival Docetaxel: 75 mg/m2 every 3 weeks x 6 cycles N=1689 men at high risk of progression (predicted recurrence-free survival at 5 years ≤ 60% - Kattan nomogram) PROGRESSION 2ND PROGRESSION Adjuvant Treatment in High Risk Localized Prostate Cancer - VA cooperative study 553 R A N D O M I Z E P R O G R E S S I O N RP + high risk localized PC Docetaxel + prednisone (4 months) Observation Primary end-point: progression-free survival Docetaxel: 75 mg/m2 every 3 weeks N= 636 men at high rish of relapse (pT3b or T4, pT3a + Gleason ≥ 7, PSA > 20ng/ml, risk of PSA progression > 50% at 5 years – Kattan nomogram) Adjuvant Treatment in High Risk Localized Prostate Cancer – RTOG 0521 R A N D O M I Z E ADT° + RT°° (7275.6 Gy) High risk localized PC Docetaxel + prednisone ADT* + RT** (72-75.6 Gy) Observation P R O G R E S S I O N Primary end-point: overall survival Docetaxel: 75 mg/m2 every 3 weeks x 6 cycles °LHRH agonist + antiandrogen; °°3DCRT/IMRT N= 600 men at high risk of relapse (Gleason ≥ 9, PSA ≤ 150ng/ml, any T or Gleason 8, PSA ≤ 20ng/ml, ≥ T2 or Gleason 7-8, PSA >20-150 ng/ml, any T) Neoadjuvant Treatment in High Risk Localized Prostate Cancer - CALGB 90203 RANDOMIZE High risk localized CaP Docetaxel 70 mg/m2 D2 + prednisone x 6 cycles and ADT* (4 months) ADT* (4 months) Radical Prostatectomy Radical Prostatectomy Primary end-point: 5-year progression-free survival N= 750 men with localized PC at high risk of relapse (Pre-operative estimate of biochemical relapse-free survival ≤ 60% - Kattan nomogram) *AD: LH-RH agonist Neoadjuvant Treatment in High Risk Prostate Cancer – D’Amico study (US) R A N D O M I Z E ADT (6-month) Docetaxel 60 mg/m2 q3wks X 3 cycles  Docetaxel 20 wkly x 7 and RT (70 Gy) High-risk localized or locally advanced PC ADT (6-month) and RT 70 Gy Primary end-point: overall survival N= 350 men at high risk of relapse Treatment of Locally Advanced Prostate Cancer – Importance of QoL Issues … O’Connor & Fitzpatrick BJU Int. 2005, 97: 22-28 Conclusions (1)  Currently no consensus for the treatment of locally advanced prostate cancer  importance of quality of life issues  Watchful waiting rarely advocated  Radical prostatectomy may be an option in selected patients (T3a, Gleason <8, PSA<20 ng/ml, life expectancy ≥10 years)  Radiotherapy should be escalated above 70 Gy Conclusions (2)  Hormonal treatment delays disease progression but does not improve overall survival  Place of chemotherapy to be confirmed by clinical trials  Multidisciplinary approach for combined treatments needed in high risk patients+++