CARCINOMA DELLA PROSTATA

PROSTATE CANCERPROSTATE 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 AGEPROSTATE CANCER DEATHS BY AGE

Risk Factors for Prostate CancerRisk 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 DevelopingRisk for Developing Prostate Cancer Prostate Cancer

Genetic alterations associated with progression of prostate cancer

Hypothalamus pituitary testicular axis

Detailed schematic: Lateral sectionof a normal prostate

PROSTATE CANCERPROSTATE 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 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.

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 CancerSymptoms 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 CancerScreening 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

Screening … For & AgainstScreening … 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

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

Percentage risk of CaP

PSA < 4 (%)

4-10 (%)

>10 (%)

DRE neg 9 20 31

DRE pos 17 45 77

Screening - Improving the PSAScreening - Improving the PSA

• PSA Velocity > 0.75 ng/ml/yr

• PSA Density

• Age adjusted PSA

• Molecular forms- free / total PSA

PSA IsoformsPSA 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 AlternativesManagement Alternatives• Expectant -- Watchful Waiting

• Radical Prostatectomy

• Radiation Therapy -- EBRT, 3D - CRT,Brachytherapy: HDR,

Seed• Hormonal -- Mono Rx, MAB

• Combination

Trans-urethral Resection

http://caonline.amcancersoc.org/content/vol52/issue3/images/large/F015401.jpeg

Prostate CancerProstate CancerTreatment ParadigmsTreatment Paradigms

ClinicallyLocalized

HormoneRefractory

Local treatment Endocrine Chemotherapy

Relapsedand

Newly diagnosed M+

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

5  R = 5-alpha reductase.

LH = Luteinizing hormone

AR = Androgen receptor

T = Testosterone

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        NilutamidePrimary gonadal suppression + antiandrogen

Side Effects of Androgen Deprivation

Impotence:    75%-100%Hot flashes:     60%Accelerated osteoporosis, muscle massGI upset, weight gain, leg edema, gynecomastiaUnknown effects: lipids, cognitive function, other biologic systemsCost

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

ChemotherapyPatients, n RR MS

Tannock et al. [33]

Pred 81 P         12% P         18 wk

Mitox + pred 80 P         29% P         43 wk

Kantoff et al. [34]

HC 121 PSA         14% 12.3 mo

HC+mitox 121 PSA         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

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.

Combined Androgen Deprivation Compared with Monotherapy in Advanced Prostate Cancer

AuthorTreatment Patients, n mPFS MS P value

Crawford et al. Leup+plac 300 13.9 28.3 0.03 (PFS)

Leup+flut 303 16.5 35.6 0.03 (OS)

Keuppens et al.

Orch 163 diff (s) 35 wks diff (ms) 7 m 0.009 (PFS)

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)

Gos+flut 287 NR 42.4 0.14 (OS)

Hucher et al. Orch+Anan 545 NR NR 0.05 (PFS)

Orch+Plac 498 NR NR NS (OS)

Iversen et al. Orch 133 16.8 27.6 0.69 (RFS)

Gos+flut 129 16.5 22.7 0.49 (OS)

Eisenberger et al.

Orch+plac 687 18.6 29.9 0.26 (RFS)

Orch+flut 700 20.4 33.5 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?

TAX327TAX327Study DesignStudy Design

Stratification

Pain levelPPI ≥ 2 or AS ≥ 10

vs.PPI < 2 or AS < 10

KPS≤ 70 vs. ≥ 80

Docetaxel 75 mg/m2 q3 wks + Prednisone 5 mg bid

Mitoxantrone 12 mg/m2 q3 wks +

Prednisone 5 mg bid

RANDOMIZE

Docetaxel 30 mg/m2 wkly 5 of 6 wks +

Prednisone 5 mg bid

Treatment duration in all 3 arms = 30 wks

Overall Survival

Mediansurvival Hazard

(mos) ratio P-value Combined: 18.2 0.83 0.03D 3 wkly: 18.9 0.76 0.009D wkly: 17.3 0.91 0.3Mitoxantrone 16.4 – –

Months0 6 12 18 24 30

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Docetaxel 3 wklyDocetaxel wklyMitoxantrone

Prob

abili

ty o

f Sur

vivi

ng

TAX 327Docetaxel 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 CancerProstate CancerTreatment ParadigmsTreatment Paradigms

ClinicallyLocalized

HormoneRefractory

Local treatmentDocetaxel + P

q3 wks

Improves survival

Endocrine

Relapsedand

Newly diagnosed M+

Prostate CancerProstate CancerTreatment ParadigmsTreatment Paradigms

ClinicallyLocalized

HormoneRefractory

Local treatment Endocrine Docetaxel

Relapsedand

Newly diagnosed M+

?

?

Prostate CancerProstate CancerTreatment ParadigmsTreatment Paradigms

ClinicallyLocalized

HormoneRefractory

Local treatment EndocrineMitoxantrone+Pfor symptoms

Relapsedand

Newly diagnosed M+

No SurvivalBenefit