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Chemotherapy for Androgen-Independent Prostate Cancer. Daniel P. Petrylak Director, Genitourinary Oncology Program New York Presbyterian Medical Center New York, NY-USA. Advanced Prostate Cancer: Treatment.
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Chemotherapy for Androgen-Independent Prostate Cancer Daniel P. PetrylakDirector, Genitourinary Oncology Program New York Presbyterian Medical CenterNew York, NY-USA
Advanced Prostate Cancer: Treatment • Androgen ablation has been the standard treatment for advanced prostate cancer for 40 years • Despite rapid and dramatic responses, almost all patients progress • No agent or combination treatment has proven to prolong survival once patients are refractory to androgen ablation
Hormone Refractory Prostate Cancer: Characteristics • Median survival of 9-12 months • Bone only disease in 60% • PSA doubling time of 1-2 months, range 12-15 months • Spinal cord compression, pathological fracture in 30% • Anemia, cachexia, bone pain, sepsis, death
Problems with Traditional End Points in Prostate Cancer Trials • Survival duration/median survival time • need very active agents • need large, randomized studies to document small benefit in both hormone sensitive and insensitive patients • Tumor response difficult to measure • only 20% to 30% of patients have measurable disease • response of bone metastases difficult to quantify • interpretation of PSA response is controversial
Problems with Interpretation of Some Phase II Chemotherapy Trials • Antiandrogen withdrawal and concurrent steroid use may produce benefit independent of chemotherapy effect • Unique patient selection based on motivation to join a trial (e.g. ability to travel to specialty center, ability to tolerate therapy) • High socio-economic status and educational level are predictors for better survival and may explain good results in phase II trials
Prostate Cancer Chemotherapy Trials • 22 single agent trials between 1988-91 • CR + PR=8.8%, 95% CI=6.4-9.0%
Mitoxantrone + Corticosteroids Canadian CALBG Mitoxantrone 12mg/m2q 3wks 14 mg/m2 Prednisone 10 mg/day Hyrdrocortisone 40 mg/day 161 243 Palliation Survival Symptomatic disease required Not required Crossover allowed Not allowed Median age 68 years 72 years
Mitoxantrone Phase III Canadian Trial Mitoxantrone + Prednisone Prednisone (n = 80) (n = 81)Response n % n % P Value Primary 23 29 10 12 .011 Secondary 7 7 Total palliative 30 38 17 21 .025
Mitoxantrone: Phase III CALGB Study9182 • PSA decline >75%: 14% vs 7% • Impact on frequency and severity of pain favored mitoxantrone + hydrocortisone; however results were not statistically significant • No statistically significant difference in survival • Improved time to progression (218 vs 122 days; p=0.005) • Toxicities • Grade 1 and 2 comparable • Cardiac function abnormalities in 16% of patients treated with mitoxantrone and hydrocortisone vs. 1% in patients treated with hydrocortisone
Role of Bcl-2 in Prostate Cancer • 65% HRPC specimens overexpress Bcl-2 • Bcl-2 inactivation via phosphorylation • Docetaxel in vitro has 100 fold greater potency in inactivating Bcl-2 phosphorylation than paclitaxel
Inhibition of Polymerization: • colchicine • vinca alkaloids • Inhibition of Polymerization: • taxoids Mechanism of Action
Estramustine Phosphate • Synthesized 25 years ago • Estradiol + non-nitrogen mustard linked via a carbamate • Cytotoxic interaction mediated by interaction with microtubules, not hormonal or alkylating activity
Estramustine Phosphate (EMP): Phase II Summary • A non-nitrogen mustard - estradiol conjugate • intact molecule inhibits microtubule function and mitosis • estrogenic metabolites induce castrate levels of testosterone • no alkylating activity • Efficacy • 5 objective PR in 262 patients treated in five National Prostatic Cancer Project trials • 14% response rate (n = 44) using PSA and other criteria • Toxicity • nausea/vomiting • fluid retention • other estrogenic effects (e.g. gynecomastia) • Oral administration two or three times daily Yagoda: J Urol. 1991.
Estramustine-based Antimicrotubule Combinations: Rationale • Combine agents that target microtubule proteins at different loci • Additive or greater antitubule effects in vitro for • estramustine + vinblastine • estramustine + paclitaxel • estramustine + docetaxel • estramustine + etoposide
Taxol:Hormone-RefractoryProstate Cancer • Taxol 24 hour infusion 135-170 mg/m2 Q 21 days • 23 patients, bidimensionally measurable disease • 1 PR (4.3%), accompanied by a >75% reduction in PSA • 61% Grade 4 leukopenia, 26% granulocytopenic fever, 2 toxic deaths
Docetaxel Single-Agent Efficacy: HRPC Efficacy Parameter Response Rate >50% decline in PSA 46% (16/35) Partial Response >80% PSA decline, plus >50% reduction in measurable disease 28% (7/25) Substantial Response >40% PSA reduction, plus >50% reduction in measurable disease 38% (17/35) Median Overall Survival 12 months Picus et al ASCO 99
Regimen 2 mg/m IV Overall No. of Line of q week or Response Patients Therapy 6 of 8 weeks Rate Burstein et al 29 First - line 40 over 1 hour 41% J Clin Oncol 2000; (37%) or q 6/8 weeks 18:1212 - 9 higher Climent et al 14 Second - line 35 over 1 hour 36% Proc Am Soc C lin or higher x 16 weeks Oncol 1999; 18:119a (Abstract #453) Leoffler et al 43 Second - line 40 over 15 - 30 minutes 50% Br Ca Res Treat 1999; or higher q 6/8 weeks 57:125 (Abstract #527) Scholz et al 31 First - line 30 - 45 over 1 hour 19% Br Ca R es Treat 1998; (35%) or 50:262 (Abstract #228) higher Weekly Taxotere: Phase II Studies
Paclitaxel + Estramustine: Phase II Trials • EMP 600 mg/m2 /day starting 24 hours prior to paclitaxel • Paclitaxel 120mg/m2 by CI over 96 hrs • Treatment repeated every 3 weeks • Delay treatment if WBC<3000 or AGC <200 or platelet count<100,000
Paclitaxel + Estramustine: Response • 34 patients entered • Bidimensionally measurable disease: 4/9 had a PR • 32 patients had an elevated PSA • 50% PSA decline 17/32 (52%) • 75% PSA decline 9/32 (28%)
Estramustine + Paclitaxel: Toxicities Toxicity Grade 3/4 Leukopenia 21.2% Anemia 18.1% Edema 15.2% Nausea 6.1% Anorexia 21.1% Vascular events 6.1%
Taxotere + Estramustine: Treatment Regimen • Estramustine: 280 mg PO tid 1 hr before or 2 hr after meals days 1 to 5 • Decadron: 20mg PO at midnight, 6 AM, and just prior to Taxotere on day 2 • Taxotere: IV day 2; dosage levels 40,60, 70 or 80mg/m2 • Treatment repeated every 21 days
Taxotere + Estramustine: Declines in Prostate Specific Antigen *1 pt with ductal adenocarcinoma of the prostate and PSA of 1.7 not included in response analysis
Taxotere + Estramustine: Disease Correlated with PSA Decline
Taxotere + Estramustine: Pain Response • 15 patients had symptomatic bone pain requiring narcotic analgesics • After treatment, 8 (53%) discontinued narcotic analgesic for a median of 6 weeks (range 1-29 weeks) One patient reduced his narcotic • analgesic requirement by > 50%
Docetaxel + Estramustine (Kreis et al)Treatment Regimen • Estramustine: 14mg/kg PO tid 1 hr before or 2 hr after meals • Dexamethasone: 8mg PO bd, starting 24 hrs prior to Taxotere and contd. For a total of 5 days • Taxotere: IV; dosage levels 40,60, 70 or 80mg/m2 • Treatment repeated every 21 days
Docetaxel + estramustine (Kreis et al)Patient Characteristics
Docetaxel + estramustine (Kreis et al)Worst Grade 3/4 Hematological Toxicity
Docetaxel + Estramustine (Kreis et al)Efficacy • A total of 82% of patients achieved > 50% PSA decline, with a duration of 1-11+ months • At the suggested phase II dose level (docetaxel 70mg/m2): • 33% pts had PSA normalization • additionally, 33% pts had > 75% PSA decline
What is the contribution of Dexamethasone to the response rate of Docetaxel + Estramustine?
Decadron Lead In Trial: Patient Characteristics Entered 12 Median Age 74 (Range 48-81) Median PSA (Entry) 69.5 (Range 8.7-818) Bone metastases 11 Measurable disease 4 Bone Pain 5
Decadron Lead In Trial: Dexamethasone Treatment • Median # dexamethasone cycles = 1 (range 1-5) • 11 patients progressed by PSA, 1 by measurable disease • 0/12 patients demonstrated a > 50 PSA decline
Docetaxel + Estramustine: Treatment PSA at Docetaxel/Emcyt 171 (13-826) Number of treatments 119 Median cycles per patient 9 (4-16) Dose reductions 6 Treatment delays 4
Docetaxel + Estramustine: Response after Dexamethasone PSA decline >50% 11 (92%) PSA decline >75% 7 (58%) PSA Normalization 5 (41%) 50% decline at week 9 9 (75%) Soft tissue Response: 3 PR
What is the optimal dose of Estramustine? Is Estramustine necessary?
Alleviation of Estramustine side effects • Reduced dose • Low molecular weight heparin • Intravenous preparation
Reduced Dose Estramustine • Estramustine 280 mg PO Q6 X 5 doses • Docetaxel 70 mg/m2 over 1 hour 12 hrs after Estramustine • Coumadin 2 mg PO QD x 6 doses Sinibaldi et al Proc ASCO 2000
Reduced Dose Estramustine Entered 36 Evaluable 33 PSA >50% 14(42%) Measurable 4/18(22%) Pain/Sx 9/15(60%) Sinibaldi et al Proc ASCO 2000
Reduced Dose Estramustine:Toxicities Toxicity Grade 3 Grade 4 Fatigue 14 0 Fever 0 2 Vascular events 0 0 Local skin reactions 2 0 Sinibaldi et al Proc ASCO 1999
Weekly Estramustine/Docetaxel: NYPH Phase I study Dose Schedule: Estramustine Docetaxel 1000 20 1500 20 1500 30 2000 25 2000 30
EM 2 Taxotere (70 mg/m ) I.V. Cycle repeats Days: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Estramustine (EM) (280 mg) p.o., t.i.d. x 5 days Dexamethasone (20 mg) p.o., 12 hours, 6 hours, and immediately prior to each Taxotere infusion Taxotere/Estramustine in HRPC Patients (Petrylak): Treatment Schedule Petrylak, Proc Am Soc Clin Oncol 2000; 19: 334a (Abstract #1312)
Phase II summary Regimen N PSA>50% Measurable Estramustine 10 mg/kg/day 40 69% 33% days 1-5 Docetaxel 70 mg/m2 Hydrocortisone 30 mg/day Estramustine 280 TID D1-5 37 68% 55% Docetaxel 70 mg/m2
Taxotere + Estramustine in HRPC Conclusions • Docetaxel exhibits high activity both as a single agent and combined with estramustine • Question of duration and dosage for estramustine administration (or if necessary) • Manageable toxicities • Further studies needed to assess 1 hour or 15 minute weekly docetaxel • Phase III studies planned
SWOG 9916A Multicenter, Randomized Phase III Study of Docetaxel + Estramustine versus Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer Taxotere 60 mg/m2 d2 + Estramustine 280 mg TID d1-5 Q 3 Weeks Hormone-Refractory Advanced Prostate Cancer RANDOMIZE Mitoxantrone 12 mg/m2 d1 + Prednisone 5 mg BID d1-21 Q 3 Weeks 620 Patients to be entered to detect a 33% survival difference
Future Directions • How do we improve on the response duration? • Triplet regimens? • Addition of biologicals, ZD1839, Herceptin? • Toxicity • Earlier treatment??
Future Directions • How do we improve on the response duration? • Triplet regimens? • Addition of biologicals, ZD1839, Herceptin? • Toxicity • Earlier treatment??