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PROSTATE CANCER FOR THE INTERNIST

PROSTATE CANCER FOR THE INTERNIST. 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:. Early Dx of Ca will lead to more cures.

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PROSTATE CANCER FOR THE INTERNIST

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  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: • 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.

  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 don’t take a Bx? • Wait 3 – 6 months and repeat everything? • Get a new internist? • You’ll 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 & 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.

  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

  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 >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

  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. Gleason 2

  14. Gleason 4

  15. 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)

  16. 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

  17. 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

  18. Prostate Cancer Incidence in the USA

  19. Annual Age-adjusted Cancer Death Rates

  20. 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

  21. 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

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

  23. ERSPC Rotterdam Section Results • 50% of detected PC’s 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.

  24. 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)

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

  26. 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.

  27. 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? Early Prostate Cancer

  28. Risk group * No patients 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 Estimated risk of needing secondary treatment among 1158 men undergoing watchful waiting in the research database of the DODCPD

  29. 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, 95:1186-94

  30. Urinary Function and Bother in 1,213 Prostate Cancer Survivors who Underwent Radical Prostatectomy Penson, DF. et al. J Urol 2005; 173:1701-5

  31. Sexual Function and Bother in 1,213 Prostate Cancer Survivors who Underwent Radical Prostatectomy Penson, DF. et al. J Urol 2005; 173:1701-5

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

  33. 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 2005;293:2095-2101. .

  34. 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

  35. 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

  36. 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.

  37. BIOCHEMICAL RELAPSE Radiotherapy following radical prostatectomy: Adjuvant SalvageHormonal Therapy: Benefits, Adverse Effects Timing

  38. 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

  39. What are the benefits?What are the side effects?Who should be treated? Early versus Late Androgen Deprivation

  40. Impact of PSA Doubling Time After Radical Prostatectomy on Prostate Cancer Specific Survival and Overall Survival Freedland et al, ASCO Proceedings #4568, 2006

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