1 / 160

Chemotherapy for Androgen-Independent Prostate Cancer

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.

pules
Download Presentation

Chemotherapy for Androgen-Independent Prostate Cancer

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Chemotherapy for Androgen-Independent Prostate Cancer Daniel P. PetrylakDirector, Genitourinary Oncology Program New York Presbyterian Medical CenterNew York, NY-USA

  2. 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

  3. 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

  4. 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

  5. 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

  6. Prostate Cancer Chemotherapy Trials • 22 single agent trials between 1988-91 • CR + PR=8.8%, 95% CI=6.4-9.0%

  7. 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

  8. 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

  9. 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

  10. 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

  11. Inhibition of Polymerization: • colchicine • vinca alkaloids • Inhibition of Polymerization: • taxoids Mechanism of Action

  12. 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

  13. 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.

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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%)

  20. 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%

  21. 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

  22. Taxotere + Estramustine: Patient Characteristics (cont)

  23. Taxotere + Estramustine: Patient Characteristics

  24. Taxotere + Estramustine: Grade 3 / 4 Toxicities

  25. 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

  26. Taxotere + Estramustine: Disease Correlated with PSA Decline

  27. 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%

  28. Petrylak Phase I Dose Escalation Trial Survival Curve

  29. Prostate Cancer Clinical Trials: Survival

  30. 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

  31. Docetaxel + estramustine (Kreis et al)Patient Characteristics

  32. Docetaxel + estramustine (Kreis et al)Worst Grade 3/4 Hematological Toxicity

  33. 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

  34. What is the contribution of Dexamethasone to the response rate of Docetaxel + Estramustine?

  35. 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

  36. 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

  37. 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

  38. 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

  39. What is the optimal dose of Estramustine? Is Estramustine necessary?

  40. Alleviation of Estramustine side effects • Reduced dose • Low molecular weight heparin • Intravenous preparation

  41. 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

  42. 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

  43. 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

  44. Weekly Estramustine/Docetaxel: NYPH Phase I study Dose Schedule: Estramustine Docetaxel 1000 20 1500 20 1500 30 2000 25 2000 30

  45. 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)

  46. 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

  47. 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

  48. 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

  49. Future Directions • How do we improve on the response duration? • Triplet regimens? • Addition of biologicals, ZD1839, Herceptin? • Toxicity • Earlier treatment??

  50. Future Directions • How do we improve on the response duration? • Triplet regimens? • Addition of biologicals, ZD1839, Herceptin? • Toxicity • Earlier treatment??

More Related