SRO Tutorial: Prostate Cancer May 7th, 2010

Daniel M. Aebersold

Klinik und Poliklinik für Radio-Onkologie Universität Bern, Inselspital

Overview I

  Basics 13:00 - 14:00   Epidemiology   Genetics   Work up / Staging / Follow up   Androgen dependence

  Treatment Options 14:00 - 15:00   Wait and see   Androgen ablation   Surgery (D. Nguyen)   Radiotherapy

Overview II

  Radiotherapy: Techniques 15:00 - 15:30   Planning issues, Toxicities   EBRT (3DCRT, IMRT)   Brachytherapy (LDR, HDR)   IGRT, Organ tracking

  Radiotherapy: Clinics 15:30 - 16:00   Dose escalation   Combined androgen ablation   Pelvic Irradiation

SRO Tutorial: Prostate Cancer

Basics May 7th, 2010

Daniel M. Aebersold

Klinik und Poliklinik für Radio-Onkologie Universität Bern, Inselspital

Epidemiology

Cancer Incidence Rates* for Men, 1975-2002

*Age-adjusted to the 2000 US standard population.Source: Surveillance, Epidemiology, and End Results Program, 1975-2002, Division of Cancer Control andPopulation Sciences, National Cancer Institute, 2005.

0

50

100

150

200

250

1975 1978 1981 1984 1987 1990 1993 1996 1999 2002

Prostate

Lung

Colon and rectum

Urinary bladder

Non-Hodgkin lymphoma

Rate Per 100,000

Melanoma of the skin

2006 Estimated US Cancer Cases*

*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.Source: American Cancer Society, 2006.

Men720,280

Women679,510

31% Breast

12% Lung & bronchus

11% Colon & rectum

6% Uterine corpus

4% Non-Hodgkinlymphoma

4% Melanoma of skin

3% Thyroid

3% Ovary

2% Urinary bladder

2% Pancreas

22% All Other Sites

Prostate 33%

Lung & bronchus 13%

Colon & rectum 10%

Urinary bladder 6%

Melanoma of skin 5%

Non-Hodgkin 4% lymphoma

Kidney 3%

Oral cavity 3%

Leukemia 3%

Pancreas 2%

All Other Sites 18%

Cancer Death Rates*, for Men, US,1930-2002

*Age-adjusted to the 2000 US standard population.Source: US Mortality Public Use Data Tapes 1960-2002, US Mortality Volumes 1930-1959,National Center for Health Statistics, Centers for Disease Control and Prevention, 2005.

0

20

40

60

80

10019

30

1935

1940

1945

1950

1955

1960

1965

1970

1975

1980

1985

1990

1995

2000

Lung

Colon & rectum

Stomach

Rate Per 100,000

Prostate

Pancreas

LiverLeukemia

2006 Estimated US Cancer Deaths*

ONS=Other nervous system.Source: American Cancer Society, 2006.

Men291,270

Women273,560

26% Lung & bronchus

15% Breast

10% Colon & rectum

6% Pancreas

6% Ovary

4% Leukemia

3% Non-Hodgkinlymphoma

3% Uterine corpus

2% Multiple myeloma

2% Brain/ONS

23% All other sites

Lung & bronchus 31%

Colon & rectum 10%

Prostate 9%

Pancreas 6%

Leukemia 4%

Liver & intrahepatic 4%bile duct

Esophagus 4%

Non-Hodgkin 3% lymphoma

Urinary bladder 3%

Kidney 3%

All other sites 23%

Risk Factors/Genetics

Age and Prostate Cancer

•  Approximately 75% of new prostate cancer patients are older than 65 years of age.

•  However, the incidence of diagnosis in men age 50-59 has increased significantly since the 1970s.

•  Attributed to PSA and is considered a screening effect.

histologic prostate cancer

localized prostate cancer

tumor suppressor gene inactivation / mutation?

oncogene activation?

androgen independent cancer

metastatic prostate cancer

curable incurable

normal prostate epithelium

histologic prostate cancer

localized prostate cancer

Loss of 8p NKX3.1?

beta catenin,

AR mutation

androgen independent cancer

metastatic prostate cancer

curable incurable

normal prostatic epithelium

GSTP1 hypermethylation

Loss of 13q, 5q,16q, 6q Gain of 8q, Xq

Mutation of PTEN, p53

Loss of p27 expression

Risk Factors for Prostate Cancer

•  Age

•  Ethnicity

•  Environmental

•  Genetic

–  Rare high penetrance alleles

–  Common low penetrance alleles

Family History

Risk Factors (I)

•  First degree relative: 2.0 increased relative risk

•  Second degree relative: 1.7 increased relative risk

•  First and second degree relative: 8.8 increased relative risk

•  African-American race 30-50% increased risk of developing prostate cancer

Risk Factors (II)

•  Diet? •  Low incidence in Asians •  Risk increases when transplanted to Western

countries suggesting an environmental factor. – Vitamins/Minerals: Vit E, selenium? – Dietary Fat? – Westerm Diet? – Sunlight?

Microbes Identified in Prostate Tissue

•  Viruses –  HPV (16 and 18) –  HSV (1, 2, 8, EBV) –  Polyoma (JC, BK)

•  Bacteria –  Chlamydia, E. coli, Staph., Strep., Corynebact.,

Entero., Peptostrep., Aeromonas, etc. –  High frequency of 16s rDNA positive samples

•  Others –  Mycoplasmas (Ureaplasma) –  Protozoa (T. vaginalis)

Prostate Cancer Risk and STDs

•  After many studies, clear relationship not firmly established

•  Largest case control study reported to date indicates cases more likely to report a history of gonorrhea or syphilis (OR = 1.6 (CI 1.2-2.1)) (981 cases AA and Cauc., 1351 controls) (Hayes 2000)

•  Risk increased with increasing number of episodes of gonorrhea (OR = 3.3 (CI 1.4-7.8) Ptrend = 0.0005)

Inflammation, infection and prostate cancer?

Areas of chronic inflammation and potential regenerative

lesions (PIA) are commonly found in biopsy and prostatectomy specimens

•  Hypothesize that inflammation as a response to –  Infection –  Hypoxia –  Autoimmunity –  Hormonal changes with age

creates a pro-carcinogenic environment and may increase risk of prostate cancer development or progression.

Androgens and Prostate Cancer

•  Clearly, androgens are important for the growth and survival of prostate cells.

•  It is thought that abnormally elevated androgen levels result in accelerated proliferation of prostate cells and prostatic tumorigenesis.

•  Factors that affect androgen levels: high fat consumption, obesity, heavy alcohol usage.

•  Several studies have shown that men with very high levels of testosterone have a relative risk of ~2.3-2.6 of developing prostate cancer.

Sexual Activity and Vasectomy

•  Sexual Activity: No consistent association with prostate cancer risk.

•  Vasectomy: No significant association with prostate cancer risk (Debated Relative risk = 1.1 – 1.2)

Prevention: Conclusion

•  Prevention of Prostate Cancer most likely feasible – Anti-inflammatory, anti-oxidants, antibiotics

PSA Screening

Incidence of Prostate Cancer

•  ~ 40 to 50% % of men over age 50 have histological evidence of prostate cancer

•  ~ 1/4 of these will be clinically detected

•  ~ 1/5 clinically detected will lead to death

•  Defining and identifying clinically relevant prostate cancer is critical!

Prostate Specific Antigen (PSA)

•  Prostate specific, not cancer specific •  Lacks sensitivity and specificity •  Elevated in BPH, infection •  25% of men with prostate cancer

have PSA < 4.0

Prostate Specific Antigen (PSA)

•  Excellent for monitoring treatment response

•  Frequently used as a surrogate marker of survival endpoints

Prostate Cancer Screening

•  Serial PSA measurements •  Serial DRE

•  Not enough to do one without the other

⇑ PSA: Karzinom, BPH, nach Manipulationen (Palpation, Biopsie)

Quotient freies/totales PSA

normal: 55-99% PSA an Antiproteasen gebunden 5-45% als freies PSA

Indikation: totales PSA < 10

>15% geringes Maliginitätsrisiko 11-15% Voraussagewert unklar

Overdiagnosis, Tumor Heterogeneity, and Life Expectancy

Death from Other Causes Death from Other Causes

Prog

ress

ion

of D

isea

se

Disease Not Detectable

Patient 1

Detectable Presymptomatic Phase

Symptomatic Phase

Remaining Expected Lifetime

Patient 2

Patient 4

Dea

th F

rom

Oth

er C

ause

s Patient 3

= Detection = PSA Screening

Death From Prostate Cancer

Screening Recommendations (I) (American Cancer Society)

•  Screen any man > 50 years old with a 10 year life expectancy

•  Screen any man > 45 years old if: - African-American - Positive family history

•  Stop screening when life expectancy is

•  For men at average risk and high risk, information should be provided about what is known and what is uncertain about the benefits and limitations of early detection and treatment of prostate cancer so that they can make an informed decision about testing

Screening Recommendations (II) (American Cancer Society)

•  PSA screening detects cancers earlier.

•  Treating PSA-detected cancers may be effective but we are uncertain.

•  PSA may contribute to the declining death rate but we are uncertain.

•  False positives are common.

•  Overdiagnosis is a problem but we are uncertain about the magnitude.

•  Treatment-related side effects are fairly common.

Potential Benefits

Summary Screening Potential Harms

Bottom line: Uncertainty about benefits and magnitude of harms

Work up/Staging

Digital Rectal Exam

•  Poorly reproducible •  Lacks sensitivity and specificity

•  25% of men with an abnormal DRE and a PSA < 4.0 have prostate cancer

•  50% of DRE-detected prostate cancer is non-organ confined

Prostate Biospy

•  Recommended for abnormal PSA and/or abnormal DRE

•  Office procedure, local anesthesia •  Ultrasonic guidance •  Uncomfortable, not painful

Gleason Grade

The Sum of the most common pattern plus the second most common pattern yields the gleason score. – < 6: well differentiated – 7: moderately differentiated – > 8: poorly differentiated

prostate cancer

radical prostatectomy

specimen

urethra

Definition: T1-T2a and PSA ≤ 10 and Gleason 2-6

Definition: T2b –T2c or Gleason 7 or PSA 10-20

Definition: T3a or

Gleason 8-10 or

PSA > 20

Definition: T3b – T4

any T, N1

any T, any N, M1

Molecular Staging

•  Proteomonic Profile •  Genetic Profile

– Tissue/DNA Arrays •  Immunohistochemical

Assesment

H&E Tissue architecture

Section 1

Ki-67 Proliferation

Section 2

Chromogranin A Neuroendocrine cells

Section 3

Tissues from many different individuals are represented in a tissue micro-array

Many different patterns of expression can be checked on sequential sections of the same tissue from a single patient

Hormon Therapy

Regulation of Testosterone

Hypothalamus

Pituitary

GnRH (Gonadotropin Releasing Hormone)

Testes

LH & FSH

Testosterone

Prostate Growth and

Function

(Gonadotropins) Some agents interfere

Hormone Therapy   Prostate cells and prostate cancer cells are dependant

upon androgens (male sex hormones) for survival and growth.

  Removal of androgens kills a majority of prostate cancer cells.

Testes Prostate

Growth and Function

Testosterone

95%

Adrenal Androgen

5%

Removing Androgens

  Orchiectomy (castration): surgical removal of the testicles

  Drugs which have the same effect as castration: Block testosterone production. Include LHRH agonists and antagonists and oral estrogens

  Anti-androgens which block the effects of testosterone

  Combination therapies

Follow up

1.  PSA 6 monthly for 5y after 1x per y

2.  DRE (digital rectal examination) 1x/y

3.  Bones scan: In case of symptoms or rapid PSA increase

Failure pattern according to level of PSA Nadir, Time to Nadir, and PSA

Doubling Time

Pattern PSA Nadir (ng/mL) Time to Nadir

(months) PSA Doubling Time (months)

NED Local failure Distant failure

0.4-0.5 2-3 5-10

22-33 10-12 17-20

NA 11-13 3-6

NED, no evidence of disease; PSA, prostate-specific antigen

A. Biochemical failure

B. Clinical failure

C. Overall survival

D. Disease specific survival

ASTRO 1997: 3 consecutive increases in PSA value with the date of failure being backdated midway between the date of postirradiation nadir PSA value and the first of the 3 consecutive increases

Any locoregional failure Any distant metastasis PSA > 25 later than 6 months after RT

Int J Radiation Oncology Biol Phys 2001;50:1212-1219 Int J Radiation Oncology Biol Phys 2002; 53:304-315