Transcript Document

PROSTATE
CANCER FOR
THE INTERNIST
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The dream of all oncologists (and many
physicians) is to cure cancer
But has prostate cancer become:
The Cancer with too many cures?
Prostate Cancer has come to
Challenge 2 fundamental concepts in
Oncology:
1)
2)
Early Dx of Ca will lead to more cures.
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.
Questions for the INTERNIST in
2009
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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?
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:
1)
See the urologist and take the Bx?
2)
See the urologist but don’t take a Bx?
3)
Wait 3 – 6 months and repeat everything?
4)
Get a new internist?
5)
You’ll do a prostate risk calculation and get back to
him?
Risk of Bx-detectable Prostate Ca
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Thompson et al. (JNCI 2006; 98: 529-34)
studied 5,519 men over age 55 who had early
DRE & PSA’s 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.
Risk of Bx-detectable Prostate Ca
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Webpage:
http://deb.uthscsa.edu/URORiskCalc/Pages/cal
cs.jsp
Enter 7 variables; age, race, PSA & DRE
results, family history, prior bx, Finasteride
use.
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
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 >65 y/o will
more than double in the next 25 years
• Presence of microscopic foci of prostate cancer
→Men >50 y/o 10% incidence
→Men >80 y/o 70% incidence
• Prostate CA
-confined to prostate gland: Median survival > = 5 years
-locally advanced: usually not curable but MS <=5 years
-metastatic: incurable and Median survival 1-3 years
Risk Factors in Prostate Cancer
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Age
Race/Ethnicity
Genetic/Familial Factors
Diet
Obesity
Others: Vasectomy, Prostatitis, BPH,
Hormone levels
Prostate Cancer: Stage Distribution(%)
in US SEER 1995-2000
100
90
80
70
60
50
40
30
20
10
0
All Races
White
Black
Localized
Distant
Prostate Cancer: Diagnosis and
Pathology
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Diagnosis: TRUS, FNA, Bone biopsy
Staging and Scoring: TNM & Gleason Grade
Histologic subtypes:
Adenocarcinoma (95%)
Transitional Cell
Basal Cell
Carcinosarcoma
Lymphoma
Neuroendocrine/Small Cell
Gleason 2
Gleason 4
Molecular Basis of Prostate
Cancer
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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)
American Cancer Society Prostate
Cancer Screening Guidelines
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Men, age 50+
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Digital rectal exam(DRE) and PSA
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DRE and PSA should be offered annually
starting age 50, for men who have a life
expectancy of 10 years
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
Prostate Cancer Incidence in the USA
Annual Age-adjusted
Cancer Death Rates
J. Natl. Cancer Inst 2003; 95:868-78
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
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 2004;350:2239-2246
Prevalence screen cohort with the observed pCA-specific mortality of Dutch
males diagnosed at the age of 60–74 yr during four different time periods
5-yr Disease-Specific Survival
PC Diagnosis
Median follow
1014 /4,117
55 mo
Observed: 97.7%
Mean Overdiagnosis:
48%
Expected: 82%,
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 (p=0.026)
de Vries, SH. et al. Eur Urol 2007; 51:366-74
ERSPC Rotterdam Section
Results
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50% of detected PC’s would not have become symptomatic
even if not detected.
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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.
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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.
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High Risk patients appear to do better with local therapy than
endocrine therapy.
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 (Tx:Bisphosphonates)
→ Hormone Sensitive Prostate Cancer
→ Hormone Refractory Prostate Cancer
(HRPC)
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“ Hormone Refractory” prostate cancer refers
to pts refractory to androgen deprivation
(orchiectomy, LHRH agonists, anti-androgens)
Now referred to as “ Castrate Resistant”
prostate Ca
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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.
Early Prostate Cancer
•Since PSA screening was introduced for the detection of prostate cancer the
number of men with newly diagnosed disease has increased
•>90% 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?
Estimated risk of needing secondary
treatment among 1158 men undergoing
watchful waiting in the research database of
the DODCPD
Risk group *
No
patient
s
No with secondary treatment
(percent)
Second treatment-free survival
rates (percent)
2 - year
5-year
7-year
Low
251
62 (25)
86
73
65
Intermediate
332
142 (43)
72
48
47
High
331
194 (59)
63
34
24
Death from Prostate Cancer and Other Causes Among 2333 Men Conservatively Treated for Localized
Prostate Cancer According to Age ± 70y at Diagnosis,
Cause of Death
Dark grey= PC
Light Grey= other causes
Baseline PSA and Gleason Score (1990-1996)
Cuzik, J et al. Br. J Cancer 2006, 95:1186-94
Urinary Function and Bother in 1,213 Prostate Cancer Survivors
who Underwent Radical Prostatectomy
Penson, DF. et al. J Urol 2005; 173:1701-5
Sexual Function and Bother in 1,213 Prostate Cancer Survivors
who Underwent Radical Prostatectomy
Penson, DF. et al. J Urol 2005; 173:1701-5
Does definitive treatment affect
outcome of men with newly
diagnosed prostate cancer?
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
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The annual mortality rate from prostate cancer remains stable after 15 years from diagnosis.
2.
Aggressive treatment for localized low-grade prostate cancer does not appear justified.
3.
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 2005;293:2095-2101.
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The Scandinavian Prostate Cancer Study Group Randomized 695 Men
with Early Prostate Cancer to Radical Prostatectomy vs Watchful Waiting
Overall Death
P=0.04
Death according
to Age
Bill-Axelson, A. et al. N Engl J Med 2005; 352:1977-84
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 <65 years of age
Bill-Axelson, A. et al. N Engl J Med 2005; 352:1977-84
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.
BIOCHEMICAL RELAPSE
Radiotherapy following radical prostatectomy:
Adjuvant
Salvage
Hormonal Therapy:
Benefits,
Adverse Effects
Timing
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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 1990’s
Early versus Late
Androgen Deprivation
What are the benefits?
What are the side effects?
Who should be treated?
Impact of PSA Doubling Time After Radical
Prostatectomy on Prostate Cancer Specific
Survival and Overall Survival
PSADT
months
Actual PC deaths Actual PC deaths Percent of all 15y actuarial
(7y median f/u)
(15 y actuarial
deaths
f/u)
attributed to PC
<3.0
15 (20%)
23 (13%)
100%
3.0-8.9
39 (51%)
85 (50%)
92%
9.0-14.9
12 (16%)
37 (22%)
89%
>15
10 (13%)
26 (15%)
36%
Total
76 (100%)
171 (100%)
75%
Freedland et al, ASCO Proceedings #4568, 2006
Androgen Deprivation Syndrome
Impotence
Anemia
Osteoporosis
Mood changes
Androgen
independence
Hot flushes
Muscle atrophy
Gynecomastia
Depression
Androgen-Deprivation Related Diabetes and
Cardiovascular Diseases
Adjusted
P Value
Hazard Ratio
Incidence Diabetes
1.44
>0.001
Incident CVD
1.16
>0.001
Myocardial infarction
1.16
0.03
0
1.0
Better
2.0
Worse
Smith, M.R. Treatment-related diabetes and cardiovascular disease: ASCO 2007 Prostate Cancer Symposium;
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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.
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 2009;360:2516-2527
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 2009;360:2516-2527
Androgen Deprivation Conclusions
Adjuvant 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
Treatment: Metastatic Hormone
Sensitive Prostate Cancer
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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
Treatment: Metastatic Hormone
Refractory Prostate Cancer
Chemotherapy: Taxotere + Prednisone
→Previous various single agent or combination
chemotherapy: RR=15-30%, PSA RR=50-60%
but no improvement in survival
• Anti-androgen withdrawal
→RR=15-20%, PSA RR>50% median response
lasting 3-12 months
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History of the Role of Chemotherapy
in Metastatic HRPC
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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
Probability of Overall Survival with
Taxotere in Metastatic HRPC
NEJM 2004
Conclusions
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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
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Other measures of PSA change or pain response had
independent prognostic significance, but did not achieve
a higher degree of surrogacy
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PSA declines represent a continuum of prognosis;
however, any cut-off is not biologically based or fully
predictive of the survival benefits with chemotherapy
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Overall survival should remain the primary endpoint
for phase III HRPC trials at this time
Andrew J. Armstrong et al. Prostate Symposium, February, 2007
2009
Dear Grandpa,
Regarding your PSA and prostate cancer, we
haven’t 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