Is there a role for adjuvant/neoadjuvant

chemotherapy in High risk prostate cancer?

Giuseppe ProcopioFondazione IRCCS

Istituto Nazionale Tumori Milano

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

As a result of widespread PSA testing, most patients are diagnosed

with asymptomatic, clinically localized cancer

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?

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

• 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

The choice of initial treatment is highly influenced by estimated life expectancy, comorbidities, potential therapy side effects and patient preference

KATTAN’S POSTOPERATIVE NOMOGRAM

• Preoperative PSA

• Gleason score

• Surgical margins, capsule and seminal vescicles invasion

• Lymph node invasion

60-months recurrence free prob

LOW RISK T1-T2a gleason score 6 or lessPSA < 10 ng/mL

INTERMEDIATE RISKT2b-T2c Gleason score 7 orPSA 10-20 ng/mL

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

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

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.

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.

HIGH-RISK prostate cancer

5 years

> 50 % biochemical relapse

CHEMOTHERAPYCHEMOTHERAPY

• Mitoxantrone

• Docetaxel

• Vinorelbine

• Satraplatino

• Patupilone

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

HORMONE-REFRACTORY PROSTATE HORMONE-REFRACTORY PROSTATE CANCERCANCER

VINORELBINEVINORELBINE

(Abratt, Ann Oncol, 2004)(Abratt, Ann Oncol, 2004)

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

PROSTATE CANCER: PROSTATE CANCER: TAX 327 Overall SurvivalTAX 327 Overall Survival

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

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

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

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

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

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

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

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.

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

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

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 ??

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

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

Treatment Plan 2Treatment Plan 2

PD (ARM 3)

Taxotere q21 x 6 cycles + Leuprolide acetate

leuprolide acetate for 18 months

for 18 months

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

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

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.

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.

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.

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