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
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%
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
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 <11% erhöhtes Malignitätsrisiko
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 <10 years
• 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
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
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
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
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
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