CARCINOMA DELLA PROSTATA

PROSTATE CANCER Prostate Anatomy

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

PROSTATE CANCER DEATHS BY AGE

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

Risk for Developing Prostate Cancer

Genetic alterations associated with progression of prostate cancer

Hypothalamus pituitary testicular axis

Detailed schematic: Lateral section of a normal prostate

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

The Gleason scoring system for prostate cancer. 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.

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

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

Screening for Prostate Cancer

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

Screening … For & Against

•

Organ confined prostate cancer is curable

•

More men die with Prostate cancer than of it

•

Advanced prostate cancer is incurable

•

PSA test not accurate enough

•

Screening offers earlier diagnosis

•

Biopsy and treatment may cause morbidity

•

Early detection is our only hope for mortality reduction

•

No trial to show mortality reduction

Factors Increasing PSA

• • • • • • •

Cycling Prostate massage Cystoscopy Ejaculation Prostate biopsy Transrectal Ultrasound Prostate disease

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

Screening - Improving the PSA

•

PSA Velocity > 0.75 ng/ml/yr

•

PSA Density

•

Age adjusted PSA

•

Molecular forms- free / total PSA

PSA Isoforms

•

Free and complexed PSA ACT

•

FREE / TOTAL ratio < 10% suggestive

•

Complex now measurable

Digital Rectal Exam for Prostate Tumors

Transrectal ultrasound-guided biopsy of the prostate

Management Alternatives

•

Expectant -- Watchful Waiting

•

Radical Prostatectomy

• •

Radiation Therapy -- EBRT, 3D - CRT, Brachytherapy: HDR, Seed Hormonal -- Mono Rx, MAB

•

Combination

Trans-urethral Resection

Prostate Cancer

Treatment Paradigms Clinically Localized Relapsed and Newly diagnosed M+ Hormone Refractory Local treatment Endocrine Chemotherapy

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

Endocrine control of prostate cancer

Strategies for Androgen Deprivation

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

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

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

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.

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.

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.

)

Adjuvant hormones. Adjuvant hormones after radical prostatectomy have demonstrated survival enhancement in patients with pathologically positive lymph nodes. (

Adapted from

Messing

et al.

SWOG Intergroup 0162 trial of continuous versus intermittent androgen deprivation

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.

Mitoxantrone + Steroids Versus Steroids Alone Patients, n RR MS Chemotherapy

Tannock

et al.

[33] Pred Mitox + pred Kantoff

et al.

[34] HC HC+mitox 81 80 121 121 P P 12% 29% PSA PSA 14% 19% P P 18 wk 43 wk 12.3 mo 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

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.

Author Combined Androgen Deprivation Compared with Monotherapy in Advanced Prostate Cancer Treatment Patients, n mPFS MS P value

Crawford

et al.

Leup+plac Keuppens

al.

et

Leup+flut Orch Iversen

et al.

Orch Gos+flut Eisenberger

et al.

Orch+plac Orch+flut 300 303 163 133 129 687 700 13.9

16.5

diff (s) 35 wks Gos+flut 161 diff (o) 48 wks diff (c) 15 m 0.05 (OS) Goserelin+flut arm superior in subjective and objective PFS, OS, and rate of cancer deaths.

Tyrrell

et al.

Gos 282 NR 37.7

0.08 (PFS) Hucher

et al.

Gos+flut Orch+Anan Orch+Plac 287 545 498 NR NR NR 42.4

NR NR 0.14 (OS) 0.05 (PFS) NS (OS) 16.8

16.5

18.6

20.4

28.3

35.6

diff (ms) 7 m 27.6

22.7

29.9

33.5

0.03 (PFS) 0.03 (OS) 0.009 (PFS) 0.69 (RFS) 0.49 (OS) 0.26 (RFS) 0.16 (OS

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?

TAX327 Study Design

Stratification Pain level PPI ≥ 2 or AS ≥ 10 vs.

PPI < 2 or AS < 10 KPS ≤ 70 vs. ≥ 80 R A N D O M I Z E Docetaxel 75 mg/m 2 Prednisone 5 mg bid Docetaxel 30 mg/m 5 of 6 wks + Prednisone 5 mg bid Mitoxantrone 12 mg/m 2 q3 wks + Prednisone 5 mg bid Treatment duration in all 3 arms = 30 wks q3 wks + 2 wkly

Overall Survival

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 Combined: D 3 wkly: D wkly: Mitoxantrone Median survival (mos) 18.2

18.9

17.3

16.4

6 12 Hazard ratio 0.83

0.76

0.91

– Months P-value 0.03

0.009

0.3

– 18 24 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone 30

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

Prostate Cancer Treatment Paradigms

Clinically Localized Relapsed and Newly diagnosed M+ Hormone Refractory Local treatment Endocrine Docetaxel + P q3 wks Improves survival

Prostate Cancer Treatment Paradigms

Clinically Localized Local treatment ?

Relapsed and Newly diagnosed M+ ?

Hormone Refractory Endocrine Docetaxel

Prostate Cancer Treatment Paradigms

Clinically Localized Relapsed and Newly diagnosed M+ Hormone Refractory Local treatment Endocrine Mitoxantrone+P for symptoms No Survival Benefit