1. CARCINOMA DELLA PROSTATA

2. PROSTATE CANCER Prostate Anatomy

3. Prostate cancer is a disease predominantly of the older male population. Autopsy series have indicated that 15% to 30% of men older than the age 50 years have histologic evidence of prostate cancer

4. PROSTATE CANCER DEATHS BY AGE PROSTATE CANCER DEATHS BY AGE

9. Risk Factors for Prostate Cancer Age – Found mainly in men over age 55. Average age of diagnosis is 70 Family History – Men’s risk is higher if father or brother is diagnosed before the age of 60 Race – Prostate cancer is found more often in African American men then White men. It is less common in Asian and American Indian men Dietary factors – Evidence suggests that a diet high in fat may increase the risk of prostate cancer and diets high in fruits and vegetables decrease the risk

10. Risk for Developing Prostate Cancer

11. Genetic alterations associated with progression of prostate cancer

12. Hypothalamus pituitary testicular axis

13. Detailed schematic: Lateral section of a normal prostate

14. PROSTATE CANCER Stage A : Deep tumor: may not be detected by digital- rectal exam Stage B: Tumor may be detected by DRE or ultrasound Stage C: Spread to surrounding tissue Stage D: Metastasis to bone and lymph nodes

16. The Gleason grading system is used to evaluate or grade prostate cancer cells obtained by needle biopsy. The cells are assigned a number between 1 and 5 nearly normal cells are grade 1, and the most abnormal are grade 5. The scores of the two most common cell patterns are added together. Gleason scores range from 2 to 10. The higher the grade, the more aggressive the cancer. The Gleason scoring system for prostate cancer.

18. Prostatic Intraepithelial Neoplasia 85% carcinomas have associated PIN High grade PIN has 30- 50% risk of CA on subsequent biopsies cf 13% in controls PIN does not cause elevated PSA Atypical foci in 3-5% of biopsies, 50% risk of cancer on repeat biopsy

19. Symptoms of Prostate Cancer Frequent urination Inability to urinate Trouble starting and stopping urination Blood in the urine or semen Painful ejaculation Painful or burning urination

20. Screening for Prostate Cancer Prostate-Specific Antigen Blood Test (PSA) – Measures substance made by the prostate gland Digital Rectal Exam (DRE) – Physical exam of the Prostate Gland Transrectal Ultrasound (TRUS) – Uses sound waves to make an image of the prostate on a video screen

21. Screening … For & Against Organ confined prostate cancer is curable Advanced prostate cancer is incurable Screening offers earlier diagnosis Early detection is our only hope for mortality reduction More men die with Prostate cancer than of it PSA test not accurate enough Biopsy and treatment may cause morbidity No trial to show mortality reduction

24. Factors Increasing PSA Cycling Prostate massage Cystoscopy Ejaculation Prostate biopsy Transrectal Ultrasound Prostate disease

25. Percentage risk of CaP PSA < 4 (%) 4-10 (%) >10 (%) DRE neg 9 20 31 DRE pos 17 45 77

26. Screening - Improving the PSA PSA Velocity > 0.75 ng/ml/yr PSA Density Age adjusted PSA Molecular forms- free / total PSA

27. PSA Isoforms Free and complexed PSA - ACT FREE / TOTAL ratio < 10% suggestive Complex now measurable

28. Digital Rectal Exam for Prostate Tumors

29. Transrectal ultrasound-guided biopsy of the prostate

31. Management Alternatives Expectant -- Watchful Waiting Radical Prostatectomy Radiation Therapy -- EBRT, 3D - CRT, Brachytherapy: HDR, Seed Hormonal -- Mono Rx, MAB Combination

32. Trans-urethral Resection

34. Prostate Cancer Treatment Paradigms Clinically Localized Hormone Refractory Local treatmentEndocrine Chemotherapy Relapsed and Newly diagnosed M+

35. Prostate Cancer Treatment Background 50% fail after local treatment 10-15% have distant metastasis at presentation Virtually all progress after endocrine treatment Chemotherapy used for symptomatic control –No survival advantage in phase-III trials

36. Endocrine control of prostate cancer

37. Strategies for Androgen Deprivation LHRH = Luteinizing hormone-releasing hormone 5 R = 5-alpha reductase. LH = Luteinizing hormone AR = Androgen receptor T = Testosterone DHT = Dihydrotestosterone.

38. Types of Androgen Deprivation Monotherapy Bilateral orchiectomy Medical castration Estrogen LHRH agonist: leuprolide, goserelin Steroidal antiandrogens Megesterol acetate Cyproterone acetate Nonsteroidal antiandrogens Flutamide Bicalutamide Nilutamide Primary gonadal suppression + antiandrogen

39. Side Effects of Androgen Deprivation Impotence: 75%-100% Hot flashes: 60% Accelerated osteoporosis,  muscle mass GI upset, weight gain, leg edema, gynecomastia Unknown effects: lipids, cognitive function, other biologic systems Cost

40. Adjuvant trials. SWOG 9921: adjuvant androgen deprivation versus mitoxantrone plus prednisone plus androgen deprivation in selected high-risk prostate cancer patients following radical prostatectomy, phase III. Prior neoadjuvant therapy is permitted if the duration is 4 months or less and if clinical criteria (PSA  15 ng/mL or biopsy GS  7 or PSA  10 ng/mL and GS  6) are satisfied prior to surgery.

41. Adjuvant trials. RTOG 99-02: phase III protocol of androgen suppression (AS) and radiation therapy (RT) versus AS and RT followed by chemotherapy with paclitaxel, estramustine, and etoposide for localized high-risk prostate cancer.

42. Adjuvant hormonal therapy. Survival improvements were noted only in one trial conducted by the European Organization for Research and Treatment of Cancer with the use of adjuvant hormonal therapy. (Adapted from Bolla et al.)

43. Adjuvant hormones. Adjuvant hormones after radical prostatectomy have demonstrated survival enhancement in patients with pathologically positive lymph nodes. (Adapted from Messing et al.

44. SWOG Intergroup 0162 trial of continuous versus intermittent androgen deprivation

45. Hormone-independent prostate cancer. The development of hormonal escape is depicted. Despite a high initial response rate to androgen deprivation, essentially all men will fail and progress to androgen independence and ultimately hormone refractory status. Treatment for patients with hormone-refractory prostate cancer must be tailored individually, and take into account the need to maintain quality of life in this terminal stage of the disease. Antiandrogen withdrawal, second-line hormonal therapy, palliative supportive care measures including radiation therapy (external or systemic) and pain control, and chemotherapy are all valid options.

46. Mitoxantrone + Steroids Versus Steroids Alone Chemotherapy Patients, nRRMS Tannock et al. [33] Pred81P 12%P 18 wk Mitox + pred80P 29%P 43 wk Kantoff et al. [34] HC121PSA 14%12.3 mo HC+mitox121PSA 19%12.6 mo Table of randomized chemotherapy trials in metastatic disease. Although chemotherapy has not demonstrated an impact on survival yet, the use of mitoxantrone and steroids has, however, demonstrated a significant palliative effect in randomized trials

47. SWOG trial of chemotherapy in metastatic disease. SWOG Intergroup 9916 randomized phase III study of docetaxel + estramustine versus mitoxantrone + prednisone in patients with hormone-refractory prostate cancer; 620 patients must be entered to detect a 33% survival difference. Future directions include exploring biologic therapies such as epithelial growth factor receptor inhibitors and antiangiogenesis strategies.

48. Combined Androgen Deprivation Compared with Monotherapy in Advanced Prostate Cancer Author TreatmentPatients, nmPFSMSP value Crawford et al.Leup+plac30013.928.30.03 (PFS) Leup+flut30316.535.60.03 (OS) Keuppens et al. Orch163diff (s) 35 wksdiff (ms) 7 m0.009 (PFS) Gos+flut161diff (o) 48 wksdiff (c) 15 m0.05 (OS) Goserelin+flut arm superior in subjective and objective PFS, OS, and rate of cancer deaths. Tyrrell et al.Gos282NR37.70.08 (PFS) Gos+flut287NR42.40.14 (OS) Hucher et al.Orch+Anan545NR 0.05 (PFS) Orch+Plac498NR NS (OS) Iversen et al.Orch13316.827.60.69 (RFS) Gos+flut12916.522.70.49 (OS) Eisenberger et al. Orch+plac68718.629.90.26 (RFS) Orch+flut70020.433.50.16 (OS

49. Docetaxel in HRPC Multiple phase II studies Responses in 45-82% (similar 95% CI duration) Estramustine based RR higher but more toxic Single agent data (weekly and every 3 wks) consistently safe and effective Superior to mitoxantrone + prednisone?

50. TAX327 Study Design Stratification Pain level PPI ≥ 2 or AS ≥ 10 vs. PPI < 2 or AS < 10 KPS ≤ 70 vs. ≥ 80 Docetaxel 75 mg/m 2 q3 wks + Prednisone 5 mg bid Mitoxantrone 12 mg/m 2 q3 wks + Prednisone 5 mg bid RANDOMIZERANDOMIZE Docetaxel 30 mg/m 2 wkly 5 of 6 wks + Prednisone 5 mg bid Treatment duration in all 3 arms = 30 wks

51. Overall Survival Median survival Hazard (mos) ratio P-value Combined:18.20.830.03 D 3 wkly: 18.90.760.009 D wkly: 17.30.910.3 Mitoxantrone16.4 –– Months 0612182430 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Probability of Surviving

52. TAX 327 Docetaxel 3 Weekly Safe Significantly improves: – Survival (18.9 vs 16.5 months) 24% reduction in the risk of death (95% CI 0.62-0.94, p=.009) – PSA decline - 45% vs. 32%, p<.0005 – Pain response - 35% vs. 22%, p=.01 – Quality of life

53. Prostate Cancer Treatment Paradigms Clinically Localized Hormone Refractory Local treatment Docetaxel + P q3 wks Improves survival Endocrine Relapsed and Newly diagnosed M+

54. Prostate Cancer Treatment Paradigms Clinically Localized Hormone Refractory Local treatmentEndocrine Docetaxel Relapsed and Newly diagnosed M+ ? ?

55. Prostate Cancer Treatment Paradigms Clinically Localized Hormone Refractory Local treatmentEndocrine Mitoxantrone+P for symptoms Relapsed and Newly diagnosed M+ No Survival Benefit