PROSTATE PROSTATE CANCER FOR CANCER FOR

THE INTERNISTTHE INTERNIST

The dream of all oncologists (and many The dream of all oncologists (and many physicians) is to cure cancerphysicians) is to cure cancer

But has prostate cancer become: But has prostate cancer become: The Cancer with too many cures?The Cancer with too many cures?

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

Oncology:Oncology:1)1) Early Dx of Ca will lead to more cures.Early Dx of Ca will lead to more cures.

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

Questions for the INTERNIST in Questions for the INTERNIST in 20092009

Who should have a PSA?Who should have a PSA? Who should have a DRE?Who should have a DRE? Who should have a Prostate Bx?Who should have a Prostate Bx? Who should have prostate surgery, prostate RT Who should have prostate surgery, prostate RT

hormonal Rx, chemo Rx?hormonal Rx, chemo Rx?

Your father, who is 55 yrs old calls. He has just seen Your father, who is 55 yrs old calls. He has just seen his internist for a check up. The latter included a his internist for a check up. The latter included a DRE which revealed BPH, no nodule. The PSA was DRE which revealed BPH, no nodule. The PSA was 3.5. The internist recommended seeing a urologist 3.5. The internist recommended seeing a urologist for a prostate bx. Do you tell your father:for a prostate bx. Do you tell your father:

1)1) See the urologist and take the Bx?See the urologist and take the Bx?

2)2) See the urologist but don’t take a Bx?See the urologist but don’t take a Bx?

3)3) Wait 3 – 6 months and repeat everything?Wait 3 – 6 months and repeat everything?

4)4) Get a new internist?Get a new internist?

5)5) You’ll do a prostate risk calculation and get back to You’ll do a prostate risk calculation and get back to him?him?

Risk of Bx-detectable Prostate Risk of Bx-detectable Prostate CaCa

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

Risk of Bx-detectable Prostate Risk of Bx-detectable Prostate CaCa

Webpage: Webpage: http://deb.uthscsa.edu/URORiskCalc/Pages/calhttp://deb.uthscsa.edu/URORiskCalc/Pages/calcs.jspcs.jsp

Enter 7 variables; age, race, PSA & DRE Enter 7 variables; age, race, PSA & DRE results, family history, prior bx, Finasteride results, family history, prior bx, Finasteride use.use.

ResultResult

Based on the data provided, the person's estimated risk of biopsy-detectable prostate cancer is Based on the data provided, the person's estimated risk of biopsy-detectable prostate cancer is 38.6%38.6%..

The The 95%95% Confidence Interval for this prediction is Confidence Interval for this prediction is 35.2%35.2% to to 43%43%..More information about the confidence intervalMore information about the confidence interval

The person's estimated risk of biopsy-detectable The person's estimated risk of biopsy-detectable high gradehigh grade prostate cancer is prostate cancer is 5%5%..

The The 95%95% Confidence Interval for this prediction is Confidence Interval for this prediction is 3.2%3.2% to to 6.9%6.9%..More information about the confidence intervalMore information about the confidence interval

Your InformationYour Information

RaceRace Caucasian Caucasian

AgeAge 5555

PSA LevelPSA Level 3.5 ng/ml 3.5 ng/ml

Family History of Prostate Cancer Family History of Prostate Cancer Yes Yes

Digital Rectal Examination Digital Rectal Examination Normal Normal

Prior Prostate Biopsy Prior Prostate Biopsy Never Had A Biopsy Never Had A Biopsy

Is the patient taking finasteride? Is the patient taking finasteride? No No

Prostate CA: BackgroundProstate 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 CancerRisk Factors in Prostate Cancer

AgeAge Race/EthnicityRace/Ethnicity Genetic/Familial FactorsGenetic/Familial Factors DietDiet ObesityObesity Others: Vasectomy, Prostatitis, BPH, Others: Vasectomy, Prostatitis, BPH,

Hormone levelsHormone levels

Prostate Cancer: Stage Distribution(%) Prostate Cancer: Stage Distribution(%) in US SEER 1995-2000in US SEER 1995-2000

0102030405060708090

100

Localized Distant

All RacesWhiteBlack

Prostate Cancer: Diagnosis and Prostate Cancer: Diagnosis and PathologyPathology

Diagnosis: TRUS, FNA, Bone biopsyDiagnosis: TRUS, FNA, Bone biopsy Staging and Scoring: TNM & Gleason GradeStaging and Scoring: TNM & Gleason Grade Histologic subtypes:Histologic subtypes: Adenocarcinoma (95%)Adenocarcinoma (95%) Transitional CellTransitional Cell Basal CellBasal Cell CarcinosarcomaCarcinosarcoma LymphomaLymphoma Neuroendocrine/Small CellNeuroendocrine/Small Cell

Gleason 2Gleason 2

Gleason 4Gleason 4

Molecular Basis of Prostate Molecular Basis of Prostate CancerCancer

Despite the increasing incidence of Prostate Cancer, Despite the increasing incidence of Prostate Cancer, our knowledge of the molecular and cellular biology of our knowledge of the molecular and cellular biology of Prostate Adenocarcinoma remains significantly less Prostate Adenocarcinoma remains significantly less than other neoplasms.than other neoplasms.

Although mutations in a wide variety of tumor Although mutations in a wide variety of tumor suppressor genes and oncogenes in prostate cancer suppressor genes and oncogenes in prostate cancer have been reported, no single gene has been identified have been reported, no single gene has been identified as a major "gatekeeper.” p53, PTEN, k-ras etc.as a major "gatekeeper.” p53, PTEN, k-ras etc.

Candidate genes in linkage studies: HPC2/ELAC2,Candidate genes in linkage studies: HPC2/ELAC2,

RNASEL, MSR1: RNASEL, MSR1: effect limited to small subset of effect limited to small subset of hereditary prostate cancer familieshereditary prostate cancer families

Role of KLF-6 tumor suppressor gene (Narla 2005)Role of KLF-6 tumor suppressor gene (Narla 2005)

American Cancer Society Prostate American Cancer Society Prostate Cancer Screening Guidelines Cancer Screening Guidelines

Men, age 50+Men, age 50+

Digital rectal exam(DRE) and PSADigital rectal exam(DRE) and PSA

DRE and PSA should be offered annually DRE and PSA should be offered annually starting age 50, for men who have a life starting age 50, for men who have a life expectancy of 10 yearsexpectancy of 10 years

Controversies on PSA Screening and Controversies on PSA Screening and Treatment of Localized Prostate Treatment of Localized Prostate

CancerCancer

1. PSA lacks specificity and ability to differentiate 1. PSA lacks specificity and ability to differentiate between less aggressive, non-lethal PC and between less aggressive, non-lethal PC and aggressive PC that needs treatment.aggressive PC that needs treatment.

In 2007 we expect In 2007 we expect

~35 million PSA test ~35 million PSA test

1.6 million prostate biopsies performed. 1.6 million prostate biopsies performed.

25 million men with elevated 25 million men with elevated PSA and negative PSA and negative biopsybiopsy

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 yearsAbout 50% of the screen detected cancer would not have been diagnosed without screeningThe introduction of screening would lead to 60-90% overdetection of PC

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

Conclusion

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

de Vries, SH. et al. Eur Urol 2007; 51:366-74

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 (p=0.026)

5-yr Disease-Specific Survival

Observed: 97.7%

Expected: 82%,

ERSPC Rotterdam Section Results

• 50% of detected PC’s would not have become symptomatic even 50% of detected PC’s would not have become symptomatic even

if not detected.if not detected.

• Forwarding the diagnosis resulted in 2% death from PC compared Forwarding the diagnosis resulted in 2% death from PC compared

to 6% when diagnosis was made at time of clinical symptoms in a to 6% when diagnosis was made at time of clinical symptoms in a

recent trial.recent trial.

• It is not necessary to diagnose all PC initially presenting with low 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 PSA value. More than 95% can still be curable if diagnosed 4 and

8 years later. 8 years later.

• High Risk patients appear to do better with local therapy than High Risk patients appear to do better with local therapy than

endocrine therapy.endocrine therapy.

Treatment of Prostate CancerTreatment of Prostate Cancer

Localized: Radical Prostatectomy Localized: Radical Prostatectomy Radiation TherapyRadiation Therapy• • Metastatic: No curative systemic therapyMetastatic: No curative systemic therapy → → 80-90% of patients will involve or be 80-90% of patients will involve or be

limited to the bone (Tx:limited to the bone (Tx:BisphosphonatesBisphosphonates)) → → Hormone Sensitive Prostate CancerHormone Sensitive Prostate Cancer → → Hormone Refractory Prostate CancerHormone Refractory Prostate Cancer (HRPC)(HRPC)

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

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

Early Prostate Cancer 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 Estimated risk of needing secondary treatment among 1158 men undergoing treatment among 1158 men undergoing watchful waiting in the research database of watchful waiting in the research database of the DODCPDthe DODCPD

Risk group * No patien

ts

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

Cuzik, J et al. Br. J Cancer 2006, 95:1186-94

Death from Prostate Cancer and Other Causes Among 2333 Men Conservatively Treated for Localized Death from Prostate Cancer and Other Causes Among 2333 Men Conservatively Treated for Localized

Prostate Cancer According to Age ± 70y at Diagnosis,Prostate Cancer According to Age ± 70y at Diagnosis,

Baseline PSA and Gleason Score (1990-1996)Baseline PSA and Gleason Score (1990-1996)Cause of DeathDark grey= PCLight Grey= other causes

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 Does definitive treatment affect

outcome of men with newly outcome of men with newly

diagnosed prostate cancer?diagnosed prostate cancer?

.Albertsen, P. C. et al. JAMA 2005;293:2095-2101.

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  1. 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

The Scandinavian Prostate Cancer Study Group Randomized 695 Men

with Early Prostate Cancer to Radical Prostatectomy vs Watchful Waiting

Bill-Axelson, A. et al. N Engl J Med 2005; 352:1977-84

Overall Death

Death according to Age

P=0.04

Cumulative Incidence of Mortality and Progression with Corresponding Relative Risks

Bill-Axelson, A. et al. N Engl J Med 2005; 352:1977-84

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

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.

Who Should and Should Not be Treated Who Should and Should Not be Treated for Localized Prostate Cancer?for Localized Prostate Cancer?

Radiotherapy following radical prostatectomy:Radiotherapy following radical prostatectomy:AdjuvantAdjuvantSalvageSalvage

Hormonal Therapy:Hormonal Therapy:Benefits, Benefits,

Adverse Effects Adverse Effects

TimingTiming

BIOCHEMICAL RELAPSE

How to prolong remission and survival after How to prolong remission and survival after local therapy (protatectomy or RT) in high risk local therapy (protatectomy or RT) in high risk pts?pts?

Trials of Trials of adjuvantadjuvant androgen deprivation androgen deprivation (Lupron, Zoladex) begun in 1990’s(Lupron, Zoladex) begun in 1990’s

What are the benefits?What are the benefits?

What are the side effects?What are the side effects?

Who should be treated?Who should be treated?

Early versus Late Early versus Late

Androgen DeprivationAndrogen Deprivation

Impact of PSA Doubling Time After Radical Impact of PSA Doubling Time After Radical Prostatectomy on Prostate Cancer Specific Prostatectomy on Prostate Cancer Specific

Survival and Overall SurvivalSurvival and Overall Survival

PSADTPSADT

monthsmonths

Actual PC deathsActual PC deaths

(7y median f/u)(7y median f/u)

Actual PC deathsActual PC deaths

(15 y actuarial (15 y actuarial f/u)f/u)

Percent of all 15-Percent of all 15-y actuarial y actuarial deaths deaths attributed to PCattributed to PC

<3.0<3.0 15 (20%)15 (20%) 23 (13%)23 (13%) 100%100%

3.0-8.93.0-8.9 39 (51%)39 (51%) 85 (50%)85 (50%) 92%92%

9.0-14.99.0-14.9 12 (16%)12 (16%) 37 (22%)37 (22%) 89%89%

>15>15 10 (13%)10 (13%) 26 (15%)26 (15%) 36%36%

TotalTotal 76 (100%)76 (100%) 171 (100%)171 (100%) 75%75%

Freedland et al, ASCO Proceedings #4568, 2006

Androgen Deprivation Syndrome

ImpotenceAnemiaOsteoporosisMood changesAndrogen independence

Hot flushesMuscle atrophyGynecomastiaDepression

Androgen-Deprivation Related Diabetes and Cardiovascular Diseases

Adjusted Hazard Ratio

P Value

1.44 >0.001

1.16 >0.001

1.16 0.03

Incidence Diabetes

Incident CVD

Myocardial infarction

0 1.0 2.0

Better Worse

Smith, M.R. Treatment-related diabetes and cardiovascular disease: ASCO 2007 Prostate Cancer Symposium;

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

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

Cardiac mortality rates same in both groupsBolla M et al. N Engl J Med 2009;360:2516-2527

Side effects (insomnia, hot flashes, sexual Side effects (insomnia, hot flashes, sexual activity and interest) activity and interest) samesame in both 30 mo & 6 in both 30 mo & 6

mo anti-androgen Rx groupsmo anti-androgen Rx groups

Bolla M et al. N Engl J Med 2009;360:2516-2527

Androgen Deprivation ConclusionsAndrogen Deprivation Conclusions

Adjuvant androgen deprivation improves Survival of men with Adjuvant androgen deprivation improves Survival of men with high risk localized disease treated with definitive radiation and high risk localized disease treated with definitive radiation and D1 disease treated with radical prostatectomy.D1 disease treated with radical prostatectomy.

Immediate androgen deprivation for men not suitable for local Immediate androgen deprivation for men not suitable for local definitive therapy results in modest increase in overall survival definitive therapy results in modest increase in overall survival but does not affect prostate cancer mortality or symptoms from but does not affect prostate cancer mortality or symptoms from hormone refractory disease.hormone refractory disease.

The adverse effects of androgen deprivation may not be The adverse effects of androgen deprivation may not be justified in all men with recurrent prostate cancer after justified in all men with recurrent prostate cancer after definitive therapydefinitive therapy

Treatment: Metastatic Hormone Treatment: Metastatic Hormone Sensitive Prostate CancerSensitive Prostate Cancer

Bilateral OrchiectomyBilateral Orchiectomy DES(Diethylstilbestrol)DES(Diethylstilbestrol) LHRH agonist +/- anti-androgenLHRH agonist +/- anti-androgen

→ →PSA decline in 80-85% of patientsPSA decline in 80-85% of patients

→ →Median PFS: 12-18 monthsMedian PFS: 12-18 months

→→Median OS: 24-30 monthsMedian OS: 24-30 months

→ →Virtually all patients will progressVirtually all patients will progress

Treatment: Metastatic Hormone Treatment: Metastatic Hormone Refractory Prostate CancerRefractory Prostate Cancer

Chemotherapy: Taxotere + PrednisoneChemotherapy: Taxotere + Prednisone

→→Previous vPrevious various single agent or combination arious single agent or combination chemotherapy: RR=15-30%, PSA RR=50-60% chemotherapy: RR=15-30%, PSA RR=50-60% but no improvement in survival but no improvement in survival

• • Anti-androgen withdrawalAnti-androgen withdrawal

→ →RR=15-20%, PSA RR>50% median response RR=15-20%, PSA RR>50% median response lasting 3-12 months lasting 3-12 months

History of the Role of Chemotherapy History of the Role of Chemotherapy in Metastatic HRPCin Metastatic HRPC

1990s: No role for cytotoxic chemotherapy1990s: No role for cytotoxic chemotherapy 1996: 1996: Mitoxantrone + PrednisoneMitoxantrone + Prednisone palliates palliates

bone pain but no impact on overall survival bone pain but no impact on overall survival led to FDA approval 1996led to FDA approval 1996

Taxotere + PrednisoneTaxotere + Prednisone vs vs Mitoxantrone + Mitoxantrone + PrednisonePrednisone (NEJM Tannock, 2004) (NEJM Tannock, 2004) TAX327 StudyTAX327 Study

→→Median Survival 18.9 mos vs 16.5 mos Median Survival 18.9 mos vs 16.5 mos led to FDA approval 2004led to FDA approval 2004

Probability of Overall Survival with Probability of Overall Survival with Taxotere in Metastatic HRPCTaxotere in Metastatic HRPC

NEJM 2004

ConclusionsConclusions A 30% or greater PSA decline within 3-months A 30% or greater PSA decline within 3-months ofof therapy therapy

initiation represents the optimal surrogate in TAX327 for initiation represents the optimal surrogate in TAX327 for overall survival, confirming the SWOG 9916 analysisoverall survival, confirming the SWOG 9916 analysis11

Other measures of PSA change or pain response had Other measures of PSA change or pain response had independent prognostic significance, but did not achieve a independent prognostic significance, but did not achieve a higher degree of surrogacyhigher degree of surrogacy

PSA declines represent a continuum of prognosis; however, PSA declines represent a continuum of prognosis; however, any cut-off is not biologically based or fully predictive of the any cut-off is not biologically based or fully predictive of the survival benefits with chemotherapysurvival benefits with chemotherapy

Overall survivalOverall survival should remain the primary endpoint for should remain the primary endpoint for phase III HRPC trials at this timephase III HRPC trials at this time

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

20092009

Dear Grandpa,Dear Grandpa, Regarding your PSA and prostate cancer, we Regarding your PSA and prostate cancer, we

haven’t made much progress since 1990 when haven’t made much progress since 1990 when Willet Whitemore the chief of Urology at Sloan Willet Whitemore the chief of Urology at Sloan Kettering asked:Kettering asked:

“ “ Is cure Is cure possiblepossible in those for whom it is in those for whom it is necessarynecessary, and is cure , and is cure necessarynecessary in those for in those for whom it is whom it is possiblepossible??

Regretfully,Regretfully, Your GrandsonYour Grandson