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Is there a role for adjuvant/neoadjuvant
chemotherapy in High risk prostate cancer?
Giuseppe ProcopioFondazione IRCCS
Istituto Nazionale Tumori Milano
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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
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As a result of widespread PSA testing, most patients are diagnosed
with asymptomatic, clinically localized cancer
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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?
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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
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• 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
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The choice of initial treatment is highly influenced by estimated life expectancy, comorbidities, potential therapy side effects and patient preference
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KATTAN’S POSTOPERATIVE NOMOGRAM
• Preoperative PSA
• Gleason score
• Surgical margins, capsule and seminal vescicles invasion
• Lymph node invasion
60-months recurrence free prob
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LOW RISK T1-T2a gleason score 6 or lessPSA < 10 ng/mL
INTERMEDIATE RISKT2b-T2c Gleason score 7 orPSA 10-20 ng/mL
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HIGH RISK T3a or Gleason score 8-10 or PSA>20 ng/mL
LOCALLY ADVANCEDT3b-T4
METASTATICAny T, N1
Any t, Any N, M1
Bolla et al. NEJM 1997
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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
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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.
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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.
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HIGH-RISK prostate cancer
5 years
> 50 % biochemical relapse
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CHEMOTHERAPYCHEMOTHERAPY
• Mitoxantrone
• Docetaxel
• Vinorelbine
• Satraplatino
• Patupilone
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Pts: 161Pts: 161
PREDNISONE: 10 mgPREDNISONE: 10 mg
81 81 ptspts
P<0.01P<0.01
PDNPDN
DHADDHAD
PDNPDN
PAINPAIN
29%29%
12%12%
P=0.025P=0.025
Analgesic useAnalgesic use
38%38%
21%21%
TimeTime
18 wks18 wks
43 wks43 wks
P=0.001P=0.001
(Tannock et al., JCO 1996)(Tannock et al., JCO 1996)
80 80 ptspts
DHAD: 12 mg/mq/ivDHAD: 12 mg/mq/iv
HORMONE-REFRACTORY PROSTATE HORMONE-REFRACTORY PROSTATE CANCERCANCER
CHEMOTHERAPYCHEMOTHERAPY
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HORMONE-REFRACTORY PROSTATE HORMONE-REFRACTORY PROSTATE CANCERCANCER
VINORELBINEVINORELBINE
(Abratt, Ann Oncol, 2004)(Abratt, Ann Oncol, 2004)
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PROSTATE CANCER: PROSTATE CANCER: TAX 327 Study designTAX 327 Study design
RRAANNDDOOMMIIZZEE
Docetaxel 75mg/mDocetaxel 75mg/m22 Q3 wks+ Q3 wks+Prednisone 5 mg bidPrednisone 5 mg bid
Docetaxel 30mg/mDocetaxel 30mg/m22 wkly 5 of 6 wks+ wkly 5 of 6 wks+Prednisone 5 mg bidPrednisone 5 mg bid
Mitoxantrone 12mg/mMitoxantrone 12mg/m22 Q3 wks+ Q3 wks+Prednisone 5 mg bidPrednisone 5 mg bid
Treatment duration in all 3 arms= 30 wks
StratificationStratification
Pain levelPain levelPPI PPI >>2 or AS 2 or AS >>1010
vsvsPPI <2 or AS <10PPI <2 or AS <10
KanofskyKanofsky<<70 vs 70 vs >>8080
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PROSTATE CANCER: PROSTATE CANCER: TAX 327 Overall SurvivalTAX 327 Overall Survival
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Taxotere 3 wks A Taxotere 3 wks A 18.918.9 4848 3535
Taxotere w Taxotere w B B 17.417.4 4545 3131
Mitoxantrone C Mitoxantrone C 16.516.5 3232 2222
(Eisenberger et al. Proc ASCO, 2004)(Eisenberger et al. Proc ASCO, 2004)
OSOS(months)(months)
BiochemicalBiochemicalResponses (%)Responses (%)
SymptomaticSymptomaticResponses (%)Responses (%)ArmArm
PROSTATE CANCER: PROSTATE CANCER: TAX 327 ResultsTAX 327 Results
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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
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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
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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
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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
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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
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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
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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.
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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
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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
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Study RationaleStudy Rationale
Radical Prostatectomy or Radiotherapy
3-5 ys
40% PD
HRPC: what is the best after RP/RT?
Observation ? Adjuvant Hormonal therapy? Or Chemotherapy ??
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TAXOTERETAXOTERE
TAX 327 and SWOG 99-16: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
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Treatment Plan 1Treatment Plan 1
Radical Prostatectomy
ARM 1 ARM 2Taxotere q21 x 6 cycles + Leuprolide leuprolide acetate for 18 months for 18 months
ARM 3 Observation
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Treatment Plan 2Treatment Plan 2
PD (ARM 3)
Taxotere q21 x 6 cycles + Leuprolide acetate
leuprolide acetate for 18 months
for 18 months
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Inclusion criteriaInclusion 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
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Study objectivesStudy objectives
PRIMARY OBJECTIVE:PRIMARY OBJECTIVE:
- PFS on Taxotere + Leuprolide given immediately after - PFS on Taxotere + Leuprolide given immediately after radical prostatectomy versus deferred therapy.radical prostatectomy versus deferred therapy.
SECONDARY OBJECTIVES:SECONDARY OBJECTIVES:
- PFS on Taxotere + Leuprolide versus Leuprolide alone- PFS on Taxotere + Leuprolide versus Leuprolide alone
- OS and DFSOS and DFS
- QoLQoL
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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.
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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.
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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.
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High risk prostate cancer
Arm A Arm B Arm CHormonal therapy Chemotherapy Locoregional
treatment
Locoregional treatment Locoregional Chemo-hormonal
treatment therapy
Hormonal therapy Hormonal therapy