PROSTATE%20CANCER%20FOR%20THE%20INTERNIST

1
PROSTATE CANCER FOR THE INTERNIST
2

• The dream of all oncologists (and many
  physicians) is to cure cancer
• But has prostate cancer become
• The Cancer with too many cures?

3
Prostate Cancer has come to Challenge 2
fundamental concepts in Oncology

1. Early Dx of Ca will lead to more cures.
2. A simple and sensitive screening test for early
   cancer (such as the PSA tests) will result in
   early detection and more cures of that cancer.

4
Questions for the INTERNIST in 2009

• Who should have a PSA?
• Who should have a DRE?
• Who should have a Prostate Bx?
• Who should have prostate surgery, prostate RT
  hormonal Rx, chemo Rx?

5

• Your father, who is 55 yrs old calls. He has
  just seen his internist for a check up. The
  latter included a DRE which revealed BPH, no
  nodule. The PSA was 3.5. The internist
  recommended seeing a urologist for a prostate bx.
  Do you tell your father
• See the urologist and take the Bx?
• See the urologist but dont take a Bx?
• Wait 3 6 months and repeat everything?
• Get a new internist?
• Youll do a prostate risk calculation and get
  back to him?

6
Risk of Bx-detectable Prostate Ca

• Thompson et al. (JNCI 2006 98 529-34) studied
  5,519 men over age 55 who had early DRE PSAs
  and took placebo for 7 years. All had a at least
  one prostate bx by the end of 7 years . Thompson
  et al. set up a risk calculator available to all
  online.

7
Risk of Bx-detectable Prostate Ca

• Webpage http//deb.uthscsa.edu/URORiskCalc/Pages/
  calcs.jsp
• Enter 7 variables age, race, PSA DRE results,
  family history, prior bx, Finasteride use.

8
Risk of Biopsy-Detectable Prostate Cancer
Result
Based on the data provided, the person's estimated risk of biopsy-detectable prostate cancer is 38.6. The 95 Confidence Interval for this prediction is 35.2 to 43.More information about the confidence interval The person's estimated risk of biopsy-detectable high grade prostate cancer is 5. The 95 Confidence Interval for this prediction is 3.2 to 6.9.More information about the confidence interval
Your Information
Race Caucasian
Age 55
PSA Level 3.5 ng/ml
Family History of Prostate Cancer Yes
Digital Rectal Examination Normal
Prior Prostate Biopsy Never Had A Biopsy
Is the patient taking finasteride? No

Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information
Race Caucasian
Age 55
PSA Level 3.5 ng/ml
Family History of Prostate Cancer Yes
Digital Rectal Examination Normal
Prior Prostate Biopsy Never Had A Biopsy
Is the patient taking finasteride? No

Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information Your Information
Race Caucasian
Age 55
PSA Level 3.5 ng/ml
Family History of Prostate Cancer Yes
Digital Rectal Examination Abnormal
Prior Prostate Biopsy Never Had A Biopsy
Is the patient taking finasteride? No
9
Prostate CA Background
Most common cancer among American men and
2nd leading cause of cancer deaths after lung
cancer American Cancer Society 218, 090 new
cases of prostate cancer in the US in 2007
and 27,050 estimated deaths Risk will
increase substantially since males gt65 y/o will
more than double in the next 25 years
Presence of microscopic foci of prostate cancer
?Men gt50 y/o 10 incidence ?Men gt80 y/o
70 incidence Prostate CA -confined to
prostate gland Median survival gt 5 years
-locally advanced usually not curable but MS lt5
years -metastatic incurable and Median
survival 1-3 years
10
Risk Factors in Prostate Cancer

• Age
• Race/Ethnicity
• Genetic/Familial Factors
• Diet
• Obesity
• Others Vasectomy, Prostatitis, BPH, Hormone
  levels

11
Prostate Cancer Stage Distribution() in US
SEER 1995-2000
12
Prostate Cancer Diagnosis and Pathology

• Diagnosis TRUS, FNA, Bone biopsy
• Staging and Scoring TNM Gleason Grade
• Histologic subtypes
• Adenocarcinoma (95)
• Transitional Cell
• Basal Cell
• Carcinosarcoma
• Lymphoma
• Neuroendocrine/Small Cell

13
(No Transcript)
14
Gleason 2
15
Gleason 4
16
Molecular Basis of Prostate Cancer

• Despite the increasing incidence of Prostate
  Cancer, our knowledge of the molecular and
  cellular biology of Prostate Adenocarcinoma
  remains significantly less than other neoplasms.
• Although mutations in a wide variety of tumor
  suppressor genes and oncogenes in prostate cancer
  have been reported, no single gene has been
  identified as a major "gatekeeper. p53, PTEN,
  k-ras etc.
• Candidate genes in linkage studies HPC2/ELAC2,
• RNASEL, MSR1 ? effect limited to small
  subset of hereditary prostate cancer families
• Role of KLF-6 tumor suppressor gene (Narla 2005)

17
American Cancer Society Prostate Cancer Screening
Guidelines

• Men, age 50
• Digital rectal exam(DRE) and PSA
• DRE and PSA should be offered annually starting
  age 50, for men who have a life expectancy of 10
  years

18
Controversies on PSA Screening and Treatment of
Localized Prostate Cancer

• 1. PSA lacks specificity and ability to
  differentiate between less aggressive, non-lethal
  PC and aggressive PC that needs treatment.
• In 2007 we expect
• 35 million PSA test
• 1.6 million prostate biopsies performed.
• 25 million men with elevated PSA and negative
  biopsy

19
(No Transcript)
20
Prostate Cancer Incidence in the USA
21
Annual Age-adjusted Cancer Death Rates
22
J. Natl. Cancer Inst 2003 95868-78
Conclusion Regular screening for PC advances
the diagnosis by approx 10 years About 50 of the
screen detected cancer would not have been
diagnosed without screening The introduction of
screening would lead to 60-90 overdetection of PC
23

Conclusion
There is no cutpoint of PSA with simultaneous
high sensitivity and high specificity for
monitoring healthy men for prostate cancer, but
rather a continuum of prostate cancer risk at all
values of PSA. The risk of finding cancer on
biopsy is directly related to PSA levels.
Biopsy-detected prostate cancer, including
high-grade cancers, is not rare among men with
PSA levels of 4.0 ng/mL. There is No PSA value
below which a man can be assured that he has no
risk of prostate cancer.
Thompson I et al. N Engl J Med 20043502239-2246
24
(No Transcript)
25
Prevalence screen cohort with the observed
pCA-specific mortality of Dutch males diagnosed
at the age of 6074 yr during four different time
periods
PC Diagnosis 1014 /4,117 Median follow 55 mo
Mean Overdiagnosis 48 Mean Lead Time 9.1
years Death 126 (12.4) PC death 20 (2.0)
Predictive of PC death in Multivariate analysis
Gleason 8 (p 0.025)
T3-4 (p0.026)
5-yr Disease-Specific Survival Observed 97.7
Expected 82,
de Vries, SH. et al. Eur Urol 2007 51366-74
26
(No Transcript)
27
ERSPC Rotterdam Section Results

• 50 of detected PCs would not have become
  symptomatic even if not detected.
• Forwarding the diagnosis resulted in 2 death
  from PC compared to 6 when diagnosis was made at
  time of clinical symptoms in a recent trial.
• It is not necessary to diagnose all PC initially
  presenting with low PSA value. More than 95 can
  still be curable if diagnosed 4 and 8 years
  later.
• High Risk patients appear to do better with local
  therapy than endocrine therapy.

28
Treatment of Prostate Cancer

• Localized Radical Prostatectomy
• Radiation Therapy
• Metastatic No curative systemic therapy
• ? 80-90 of patients will involve or be
  limited to the bone (TxBisphosphonates)
• ? Hormone Sensitive Prostate Cancer
• ? Hormone Refractory Prostate Cancer
• (HRPC)

29

• Hormone Refractory prostate cancer refers to
  pts refractory to androgen deprivation
  (orchiectomy, LHRH agonists, anti-androgens) Now
  referred to as Castrate Resistant prostate Ca

30

• Known for years LHRH agonists reduce serum
  testosterome markedly but do not ablate androgen
  in the prostate itself. P. Ca on LHRH Rx devps
  changes in androgen receptors that make the Ca
  cells exquisitely sensitive to the minute amts of
  androgen present in the prostate itself.

31
Early Prostate Cancer

• Since PSA screening was introduced for the
  detection of prostate cancer the number of men
  with newly diagnosed disease has increased
• gt90 of cases have localized disease.
• The number of definitive local procedures
  increased in parallel with detection.
• The hope was that early eradication of localized
  prostate cancer would avert suffering from
  metastasis and death from the disease.
• The rate of prostate cancer deaths has not
  substantially decreased.
• The benefit of PSA screening asymptomatic men for
  prostate cancer is unknown. The results of two
  ongoing studies will take many years to mature.
• What have we learned from this experience? Should
  we be more Cautious about treatment
  recommendations of localized prostate cancer?

32
Estimated risk of needing secondary treatment
among 1158 men undergoing watchful waiting in the
research database of the DODCPD
33
Death from Prostate Cancer and Other Causes Among
2333 Men Conservatively Treated for Localized
Prostate Cancer According to Age 70y at
Diagnosis, Baseline PSA and Gleason Score
(1990-1996)
Cause of Death Dark grey PC Light Grey other
causes
Cuzik, J et al. Br. J Cancer 2006, 951186-94
34
(No Transcript)
35
(No Transcript)
36
(No Transcript)
37
(No Transcript)
38
Urinary Function and Bother in 1,213 Prostate
Cancer Survivors who Underwent Radical
Prostatectomy
Penson, DF. et al. J Urol 2005 1731701-5
39
Sexual Function and Bother in 1,213 Prostate
Cancer Survivors who Underwent Radical
Prostatectomy
Penson, DF. et al. J Urol 2005 1731701-5
40
(No Transcript)
41

• Does definitive treatment affect outcome of men
  with newly diagnosed prostate cancer?

42
Survival and Cumulative Mortality From Prostate
Cancer and Other Causes Up to 20 Years After
Diagnosis. Retrospective Study of 767 men, 55-75
years, who Chose Observation or Delayed Androgen
Deprivation (1971-1984)

• Conclusion 
• The annual mortality rate from prostate cancer
  remains stable after 15 years from diagnosis.
• Aggressive treatment for localized low-grade
  prostate cancer does not appear justified.
• Younger men with high Gleason grade are at high
  risk of PC cancer death up to 15 years form Dx

Albertsen, P. C. et al. JAMA 20052932095-2101.
.
43
The Scandinavian Prostate Cancer Study Group
Randomized 695 Men with Early Prostate Cancer
to Radical Prostatectomy vs Watchful Waiting
Overall Death
P0.04
Death according to Age
Bill-Axelson, A. et al. N Engl J Med 2005
3521977-84
44
Cumulative Incidence of Mortality and Progression
with Corresponding Relative Risks
Conclusion The absolute reduction in the risk of
death after 10 years of radical prostatectomy is
small, but the reductions in the risks of
metastasis and local tumor progression are
substantial. The benefit in decreased mortality
is primarily for men lt65 years of age
Bill-Axelson, A. et al. N Engl J Med 2005
3521977-84
45
Who Should and Should Not be Treated for
Localized Prostate Cancer?
High grade PC (Gleason 8-10) have a high risk of
death from PC and appear to benefit from local
therapy. Low-grade PC (Gleason 6) will rarely
require treatment. Intermediate-grade PC
(Gleason 7) have an intermediate cumulative risk
of progression after 20 years of follow-up. A
majority of these men will die from competing
medical conditions during a period of 15 to 20
years. Gleason score combined with PSA levels
refines the prognostic categories Men who have
PSA recurrence following surgery have a high
probability of disease progression during a
period of 10 to 15 years.
46
Radiotherapy following radical prostatectomy
Adjuvant SalvageHormonal
Therapy Benefits, Adverse Effects
Timing
BIOCHEMICAL RELAPSE
47
(No Transcript)
48

• How to prolong remission and survival after local
  therapy (protatectomy or RT) in high risk pts?
• Trials of adjuvant androgen deprivation (Lupron,
  Zoladex) begun in 1990s

49
What are the benefits?What are the side
effects?Who should be treated?
Early versus Late Androgen Deprivation
50
Impact of PSA Doubling Time After Radical
Prostatectomy on Prostate Cancer Specific
Survival and Overall Survival
PSADT months Actual PC deaths (7y median f/u) Actual PC deaths (15 y actuarial f/u) Percent of all 15-y actuarial deaths attributed to PC
lt3.0 15 (20) 23 (13) 100
3.0-8.9 39 (51) 85 (50) 92
9.0-14.9 12 (16) 37 (22) 89
gt15 10 (13) 26 (15) 36
Total 76 (100) 171 (100) 75
Freedland et al, ASCO Proceedings 4568, 2006
51
Androgen Deprivation Syndrome
Impotence Anemia Osteoporosis Mood
changes Androgen independence
Hot flushes Muscle atrophy Gynecomastia Depression
52
Androgen-Deprivation Related Diabetes and
Cardiovascular Diseases
Smith, M.R. Treatment-related diabetes and
cardiovascular disease ASCO 2007 Prostate
Cancer Symposium
53

• Bolla et al (NEJM 2009 360 2516) treated 1,112
  men with locally advanced prostate Ca with EB RT
  anti androgen Rx for 6 mo. Pts were then
  randomized to receive no further Rx or an
  additional 30 mos. of anti androgen Rx.

54
Significant reduction in overall and prostate
Ca-specific mortality with 30 mo. androgen
deprivation vs 6 mo.

• Cardiac mortality rates same in both groups
• Bolla M et al. N Engl J Med 20093602516-2527

55
Side effects (insomnia, hot flashes, sexual
activity and interest) same in both 30 mo 6 mo
anti-androgen Rx groups
Bolla M et al. N Engl J Med 20093602516-2527
56
Androgen Deprivation ConclusionsAdjuvant
androgen deprivation improves Survival of men
with high risk localized disease treated with
definitive radiation and D1 disease treated with
radical prostatectomy.Immediate androgen
deprivation for men not suitable for local
definitive therapy results in modest increase in
overall survival but does not affect prostate
cancer mortality or symptoms from hormone
refractory disease.The adverse effects of
androgen deprivation may not be justified in all
men with recurrent prostate cancer after
definitive therapy
57
Treatment Metastatic Hormone Sensitive Prostate
Cancer

• Bilateral Orchiectomy
• DES(Diethylstilbestrol)
• LHRH agonist /- anti-androgen
• ?PSA decline in 80-85 of patients
• ?Median PFS 12-18 months
• ?Median OS 24-30 months
• ?Virtually all patients will progress

58
Treatment Metastatic Hormone Refractory
Prostate Cancer

• Chemotherapy Taxotere Prednisone
• ?Previous various single agent or combination
  chemotherapy RR15-30, PSA RR50-60 but no
  improvement in survival
• Anti-androgen withdrawal
• ?RR15-20, PSA RRgt50 median response lasting
  3-12 months

59
History of the Role of Chemotherapy in Metastatic
HRPC

• 1990s No role for cytotoxic chemotherapy
• 1996 Mitoxantrone Prednisone palliates bone
  pain but no impact on overall survival led to FDA
  approval 1996
• Taxotere Prednisone vs Mitoxantrone
  Prednisone (NEJM Tannock, 2004) TAX327 Study
• ?Median Survival 18.9 mos vs 16.5 mos led to
  FDA approval 2004

60
Probability of Overall Survival with Taxotere in
Metastatic HRPC
NEJM 2004
61
Conclusions

• A 30 or greater PSA decline within 3-months of
  therapy initiation represents the optimal
  surrogate in TAX327 for overall survival,
  confirming the SWOG 9916 analysis1
• Other measures of PSA change or pain response had
  independent prognostic significance, but did not
  achieve a higher degree of surrogacy
• PSA declines represent a continuum of prognosis
  however, any cut-off is not biologically based or
  fully predictive of the survival benefits with
  chemotherapy
• Overall survival should remain the primary
  endpoint for phase III HRPC trials at this time

Andrew J. Armstrong et al. Prostate Symposium,
February, 2007
62
2009

• Dear Grandpa,
• Regarding your PSA and prostate cancer, we
  havent made much progress since 1990 when Willet
  Whitemore the chief of Urology at Sloan Kettering
  asked
• Is cure possible in those for whom it is
  necessary, and is cure necessary in those for
  whom it is possible?
• 
  Regretfully,
• 
  Your Grandson