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Clinical Division of Oncology Department of Medicine I






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  • Prostate Cancer: Incidence Rates The incidence of prostate cancer varies widely by world region. Representing 9.2% of male cancers worldwide, this cancer is more common in developed countries (14.3% of male cancers) than in developing countries (4.3% of male cancers). Routine screening has led to a tremendous increase in the diagnosis of prostate cancer in the US, with recorded incidence doubling between 1984 and 1992, largely due to the introduction of prostate specific antigen (PSA) as a screening method.
  • Prostate Cancer: 5-Year Survival Rates Worldwide, prostate cancer is the sixth most common cause of cancer death in men, representing 5.6% of male cancer deaths. Five-year survival is poorer in developing countries (41%) than in developed countries (64%), where common use of screening procedures probably leads to earlier diagnosis. Worldwide, 5-year survival for prostate cancer is 58%.
  • Prostate Cancer: 5-Year Survival by Stage As with all cancers, prostate cancer has a better prognosis if it is detected in the early stages of the disease. In the US, the majority of prostate cancers are diagnosed when the tumor is localized or regionally advanced. African American men experience poorer survival at all stages of the disease than do white Americans.
  • Prostate Cancer: Genetic Events in Prostate Carcinogenesis A number of genes have been identified that regulate the division, growth, motility, and hormone dependence of prostate cells. Mutations in individual genes have been identified, and these genetic events have been implicated in the development and progression of prostate cancer. Among the genes that are altered are the retinoblastoma and p53 genes, which regulate cell division and growth. Mutations in these genes result in the uncontrolled cell proliferation that is characteristic of malignancies. In addition, overexpression of the bcl-2 gene inhibits cell death induced by androgen ablation, allowing prostate cells to become androgen independent.
  • Prostate Cancer: Risk Factors Age is the most important risk factor for prostate cancer, with 82% of cases in developed countries occurring in men over 65 years of age. Men who have diets that are high in saturated fat are believed to be at increased risk, as are men with relatives who have had the disease. African American males have a higher incidence of prostate cancer than Caucasian males, possibly due to their increased levels of serum testosterone. Finally, exposure to certain industrial chemicals may increase the risk of developing prostate cancer.
  • Prostate Cancer: Screening The role of routine prostate cancer screening is controversial. Because early prostate cancer is generally curable, the American Cancer Society (ACS) recommends that all men over the age of 50 and a life expectancy of at least 10 years have an annual digital rectal examination (DRE) and serum PSA determination. Patients who are African American or have a family history of prostate cancer should initiate screening at age 45 .
  • Prostate Cancer: Screening Tools DRE, PSA, and TRUS are three tools that are used to screen for prostate cancer. All three have limitations in that they can often yield false positive and false negative results. Because TRUS cannot visualize a large percentage of tumors, it should be used principally to guide biopsy and estimate prostate volume during diagnostic procedures. One study found that the combination of these three screening techniques resulted in a 90% cancer detection rate but was costly. An ACS study concluded that DRE and PSA combined offer the best balance of sensitivity, specificity, and cost, and may decrease prostate-cancer–related mortality. However, according to the most recent NCCN prostate cancer treatment guidelines, in the absence of symptoms, survival may be enhanced and morbidity decreased by not pursuing any treatment.
  • Prostate Cancer: Prostate Specific Antigen (PSA) PSA is a protein made by cells in the acini and ducts of the prostate and is secreted into the lumen. In men with prostate disease, PSA enters the capillaries in the prostate and becomes detectable in the circulation. PSA testing is very useful in the detection of prostate cancer, but its specificity is compromised by the fact that PSA levels may be elevated by BPH, prostatitis, or other factors. However, PSA is also valuable in staging of the cancer, predicting prognosis, and monitoring patients for disease progression after treatment.
  • Prostate Cancer: Improving Accuracy of PSA Several variations on the PSA test have been investigated to improve its predictive value. The benefit of PSA density has not yet been proven. PSA velocity may be informative but measures should be taken at a minimum of 1-year intervals for at least 3 years. The use of age-adjusted PSA levels improves the positive predictive value of the test but significantly reduces the detection rate. PSMA is a protein that is expressed more frequently in aggressive cancers, so it may be useful in diagnosis and staging. Free-to-total PSA ratio has proven to be an important new variation on the PSA test, however a number of issues remain with respect to the calculation of the ratio. None of these tests has a role in routine management.
  • Prostate Cancer: Free-to-Total PSA This new test is based on the fact that PSA can circulate in a free form or complexed to other proteins. It has been determined that free PSA is present in a higher proportion in men without prostate cancer. The ratio of free-to-total PSA is calculated, giving a measure of the risk of prostate cancer. Men with the disease have a higher total PSA value, but a lower free-to-total PSA ratio. This test is especially useful in assigning risk for men with borderline PSA values (4 ng/mL-10 ng/mL).
  • Prostate Cancer: Screening and Diagnosis An abnormal DRE, elevated serum PSA, and/or symptoms should prompt further investigation to detect prostate cancer. However, because this disease may be slow growing, men with a life expectancy of less than 10 years should not be tested for early disease, and it is not yet clear that routine PSA screening is appropriate. A diagnosis of prostate cancer is ultimately established through a TRUS-guided transrectal needle biopsy. In addition to sampling the tumor, three cores should be taken from each lobe of the prostate to detect cancer in other areas of the gland.
  • Prostate Cancer: Stage at Diagnosis Widespread use of the PSA test has led to earlier diagnosis of prostate cancer in the US, with approximately 60% of cases detected at the localized stage. Fewer than 5% of prostate malignancies are diagnosed after they have become metastatic.
  • Prostate Cancer: Signs and Symptoms The signs and symptoms of prostate cancer depend on the location and extent of the tumor. Peripheral zone tumors usually do not cause symptoms in the early stages. Transition zone tumors and those that encroach on the urethra produce urinary symptoms. In progressive disease, symptoms are a function of which structures are invaded by the tumor. Bone pain is the most common complaint of patients with metastatic disease.
  • Prostate Cancer: Pathological Classification Over 99% of prostate cancers are epithelial cell adenocarcinomas. Germ cell and mesenchymal tumors are rare. Small cell tumors, transitional cell carcinomas, and carcinosarcomas have poor prognoses because of their propensity to metastasize early. Lymphoma is rarely a primary prostatic neoplasm, but is one of the most common cancers to metastasize to the prostate.
  • Prostate Cancer: Tumor Distribution The prostate is composed of three glandular zones: the transition, central, and peripheral zones. For the transition and central zones, malignancies appear at frequencies that are not proportional to the amount of prostate tissue represented by these zones. The transition zone is much more likely to be the site of benign prostatic hypertrophy (BPH) than of cancer. The peripheral zone represents about 65% of the prostate and 70% of prostate cancers arise there.
  • Prostate Cancer: Local Extension Left untreated, prostate cancer will progress and become more malignant over time. Local extension of prostate tumors into and through the prostatic capsule tends to occur at sites where the capsule is weak. This is common in areas where the prostate and adjoining organs meet, or where structures such as the ejaculatory ducts or urethra enter or exit the prostate.
  • Prostate Cancer: Lymphatic Spread The primary sites for lymphatic metastases of prostate cancer are the obturator nodes followed by the presacral, presciatic, and internal and external iliac nodes.
  • Prostate Cancer: Distant Metastatic Spread Bone is the most common site of metastatic prostate cancer, with bone metastases appearing in 80% of patients who die from the disease. The spine is the bone most frequently involved, followed by the femur, pelvis, rib cage, skull, and humerus.
  • Prostate Cancer: Stage Grouping TNM stands for primary Tumor, lymph Node involvement, and distant Metastases, and designates the extent of the disease. “G” stands for the histologic grade of the tumor, as defined by the Gleason system. This system assigns a score of 1-5 to the cancer cells, where 1 is the most differentiated with glandular formation present, and 5 is the most undifferentiated, with loss of glandular structure. The two Gleason scores that are assigned to the primary and secondary growth patterns of the tumor are added to reach a number that predicts the aggressiveness of the tumor. In the stage grouping, Stage I is the earliest stage of disease and stage IV, metastatic disease, is the most advanced.
  • Prostate Cancer: Stage I Stage I prostate cancer refers to T1 tumors, with histopathological grade 1 (well differentiated, slight anaplasia), and no regional or distant metastases. T1 tumors are not palpable or visible by imaging.
  • Prostate Cancer: Stage II Stage II prostate cancer includes T1a N0 M0 G2, 3-4 or Any T1 N0 M0 Any G. T1a and T1b tumors are found incidentally during transurethral resection of the prostate (TURP) and T1c tumors are found through needle biopsy performed because of an elevated PSA value.
  • Prostate Cancer: Stage II Stage II prostate cancer also includes Any T2 N0 M0 Any G. T2 tumors are confined within the prostate and are subclassified depending on how much of the gland is involved.
  • Prostate Cancer: Stage III Stage III prostate cancer is Any T3 N0 M0 Any G. T3 tumors are termed “locally advanced” because they extend through the prostatic capsule without evidence of metastasis.
  • Prostate Cancer: Stage IV Stage IV prostate cancer is T4 N0 M0 Any G, Any T N1 M0 Any G, or Any T Any N M1 Any G. T4 tumors are fixed or invade adjacent structures other than the seminal vesicles. Stage IV tumors that are N1 or M1 are metastatic to the lymph nodes or to distant sites, respectively.
  • Prostate Cancer: Prognostic Factors for Advanced Disease Prognostic variables in men undergoing hormonal therapy for advanced prostate cancer include presence of symptoms, patient performance status, disease extent (visceral versus no visceral metastases) and location (axial skeleton versus axial plus appendicular skeletal involvement), and the number of bone metastases. Serum testosterone and alkaline phosphatase levels appear to have prognostic value. Pretreatment PSA value has not been shown to be a reliable predictor of the duration of response or survival, likely stemming from the variability in PSA production among prostate tumors.
  • Prostate Cancer: Commonly Used Therapies Patients with newly diagnosed stage I/II prostate cancer typically undergo radical prostatectomy or radiation therapy, with consideration of patient age and health status. Watchful waiting often is employed in patients with a poor prognosis, based on estimated life expectancy, the presence of comorbidities, or unfavorable tumor characteristics. Most patients with stage III disease receive radiation therapy plus adjuvant hormonal therapy, although a small proportion of patients will undergo surgery. Pharmacologic castration is the most common first-line management of stage IV disease, and a second hormonal therapy may be used when failure to the first option becomes evident. Additional therapeutic alternatives for hormone-refractory prostate cancer include antiandrogen withdrawal or continued testicular deprivation (which are associated with a short response duration), chemotherapy, or radiation therapy.
  • Prostate Cancer: Response to Surgery Prostate cancer is eradicated in approximately 85% of patients who initially undergo prostatectomy for newly diagnosed stage I/II disease. The majority of patients who do not achieve a postsurgical disease-free status will develop advanced disease within the same year, immediately becoming eligible for hormonal therapy.
  • Prostate Cancer: Risk Factors for Biochemical Recurrence In patients with prostate cancer, biochemical recurrence is defined as rising prostate-specific antigen levels following definitive local therapy for localized or locally advanced disease. It is widely accepted that patients with pretreatment clinical stage T3 or T4 disease, a serum PSA level >20 ng/mL, and/or poorly differentiated tumor histology are at high risk for disease recurrence. The Gleason scoring system, the most widely used method of grading prostate cancer, assigns a score of 1 to 5 to the two most predominant histologic patterns in a given biopsy sample. A Gleason score of 8 to 10 (which is the sum of the individual scores) reflects a poorly differentiated tumor histology.
  • Prostate Cancer: Response to Hormonal Therapy Patients with advanced prostate cancer at diagnosis typically receive hormonal therapy, response to which is often defined as at least a 50% reduction in prostate-specific antigen levels from baseline. Approximately 85% of patients with newly diagnosed stage III/IV prostate cancer will respond to hormonal therapy. Twenty percent of these responding patients will achieve a disease-free status and terminate therapy, whereas 80% will exhibit a response but not complete disease eradication. The mean duration of response to hormonal therapy is 3 years, after which patients progress to hormone-refractory disease. Prognosis for patients with hormone-refractory prostate cancer is poor, with a median survival duration of 6 to 12 months.

Clinical Division of Oncology Department of Medicine I Clinical Division of Oncology Department of Medicine I Presentation Transcript

  • Prostate Cancer
  • PROSTATE CANCER Incidence *Incidence per 100,000 population. Parkin DM, et al. CA Cancer J Clin. 1999;49:53. 39.55 16.75 8.51 49.70 1.08 5.13 31.03 92.39 Eastern Europe Japan Australia New Zealand China North Africa South Africa North America Western Europe
  • PROSTATE CANCER 5-year survival rates Parkin DM, et al. CA Cancer J Clin. 1999;49:37. Estimated 5-Year Survival (%). 49% 22% 52% 63% 40% 40% 41% 79% South Europe Japan Australia New Zealand China North Africa Sub-Saharan Africa North America Northwestern Europe
  • PROSTATE CANCER 5-year survival by stage Greenlee RT, et al. CA Cancer J Clin . 2001;51:15-36.
  • PROSTATE CANCER Genetic events in prostate carcinogenesis Abeloff M, et al. Clinical Oncology. 1995;1439. Normal prostate Histologic prostate cancer Localized prostate cancer Metastatic prostate cancer Androgen-independent prostate cancer Tumor suppressor gene inactivation p53 gene inactivation H- ras oncogene overexpression bcl-2 oncogene overexpression Metastasis gene suppressor inactivation Decreased adhesion molecule expression Retinoblastoma gene loss
  • PROSTATE CANCER Risk factors
    • Age
    • Diet
    • Family history
    • Race
    • Environmental factors
    Parkin DM, et al. CA Cancer J Clin . 1999;49:33-64. Carroll PR, et al. Cancer: Principles & Practice of Oncology . 6th ed. 2001;1418-1479.
    • Advantages
    • Early disease highly curable; advanced disease generally incurable
    • Screening relatively simple
      • Routine PSA and DRE
    • Disadvantages
    • Value of screening not proven
    • Suboptimal sensitivity, specificity, predictive value of tests (DRE, PSA, TRUS)
    • Not all prostate cancers clinically significant:
      • Psychological and economic burden of diagnosis
      • Morbidity of potentially unnecessary treatment
    Oesterling J, et al. Cancer: Principles & Practice of Oncology . 5th ed. 1997;1322-1386. Carroll PR, et al. Cancer: Principles & Practice of Oncology . 6th ed. 2001;1418-1479. Rimer BK, et al. Cancer: Principles & Practice of Oncology . 6th ed. 2001;.627-640.
  • PROSTATE CANCER Screening tools Rimer BK, et al. Cancer: Principles & Practice of Oncology . 6th ed. 2001;627-640. Method Sensitivity (%) Specificity (%) Positive Predictive Value (%) DRE 45-84 45-97 21-43 PSA 67-82 48-82 32-48 TRUS 77-92 27-94 15-54
  • PROSTATE CANCER Prostate specific antigen (PSA)
    • Single-chain glycoprotein
    • Produced by prostate epithelial cells; secreted into prostatic lumen
    • Blood level of <4 ng/mL considered normal
    • PSA 4-10 ng/mL associated with 22% positive biopsy rate
    • PSA >10 ng/mL associated with 66% positive biopsy rate
    • Elevated by any prostate disease, prostate manipulation, medication
    • Used for staging, monitoring, prognosis
    Oesterling J, et al. Cancer: Principles & Practice of Oncology . 5th ed. 1997;1322-1386. Kelly WK, Dodd PM. The American Cancer Society Textbook of Clinical Oncology . 3rd ed. 2001;427-435. Brawer MK. CA Cancer J Clin . 1999;49:264-281.
  • PROSTATE CANCER Improving accuracy of PSA
    • PSA density
      • Serum PSA level/prostate volume
    • PSA velocity
      • Change in serum PSA over time
    • Age-adjusted PSA
      • Different cutoff levels for different age groups
    • Prostate-specific–membrane antigen (PSMA)
    • Free-to-total PSA
      • Measurement of free and complexed circulating PSA
    • None of these tests has a role in routine management
    Brawer MK. CA Cancer J Clin . 1999;49:264-281.
  • PROSTATE CANCER Free-to-total PSA*
    • PSA Probability of Cancer
    • 2 ng/mL 1%
    • 2-4 ng/mL 15%
    • 4-10 ng/mL 25%
    • >10 ng/mL >50%
    Brawer MK. Prostate-specific antigen: Current status. CA Cancer J Clin . 1999;49(5):264-281. *Men with non-suspicious DRE results, regardless of patient age. % FPSA Probability of Cancer 0-10% 56% 10-15% 28% 15-20% 20% 20-25% 16% >25% 8%
  • PROSTATE CANCER Screening and Diagnosis Carroll PR, et al. Cancer: Principles & Practice of Oncology . 6th ed. 2001;1418-1479. Initial Evaluation Screening Results Follow-up DRE + total PSA DRE negative and Annual DRE/PSA PSA normal Counseling for DRE negative with: prostate cancer - PSA >10 ng/mL - TRUS biopsy screening - PSA 4-10 mg/mL - TRUS biopsy or % free PSA - Abnormal age- - Consider TRUS biopsy referenced PSA Family history DRE positive and TRUS biopsy History of prostate PSA normal or positive disease Medication/supplements Prior PSA/DRE
  • PROSTATE CANCER Stage at diagnosis 5% 35% 60% 0 10 20 30 40 50 60 70 Localized Regional Distant Stage % of Cases Kassabian VS, et al. The American Cancer Society Textbook of Clinical Oncology . 2nd ed. 1995;311-318. Zinner NR, et al. Everyone’s Guide to Cancer Therapy . 1997;634-649.
  • PROSTATE CANCER Signs and symptoms
    • Early Disease
    • Peripheral zone: none
    • Transition zone:
      • Urinary hesitancy, frequency, urgency
      • Decreased force of urine stream
      • Nocturia
    • Progressive Disease
    • Hematospermia
    • Decreased ejaculate volume
    • Impotence
    • Advanced Disease
    • Bone pain
    Oesterling J, et al. Cancer: Principles & Practice of Oncology . 5th ed. 1997;1322-1386.
  • PROSTATE CANCER Pathological classification
    • Epithelial Neoplasms
    • Adenocarcinomas
      • Pure ductal
      • Mucinous
    • Small cell tumors
    • Transitional cell carcinomas
    • Carcinoma in situ (intraepithelial neoplasia) and precursors of neoplasia
    • Carcinosarcomas
    • Nonepithelial Neoplasms
    • Mesenchymal—benign and malignant
    • Lymphoma
    • Germ Cell Tumors
    Oesterling J, et al. Cancer: Principles & Practice of Oncology . 5th ed. 1997;1322-1386.
  • PROSTATE CANCER Tumor distribution Oesterling J, et al. Cancer: Principles & Practice of Oncology . 5th ed. 1997;1322-1386.
  • PROSTATE CANCER Local extension
  • PROSTATE CANCER Lymphatic spread
  • PROSTATE CANCER Distant metastatic spread
  • PROSTATE CANCER Stages AJCC ® Cancer Staging Manual, 5th edition (1997) published by Lippincott-Raven Publishers, Philadelphia, Pennsylvania. Stage I T1a N0 M0 G1 Stage II T1a N0 M0 G2,3-4 T1b N0 M0 Any G T1c N0 M0 Any G T1 N0 M0 Any G T2 N0 M0 Any G Stage III T3 N0 M0 Any G Stage IV T4 N0 M0 Any G Any T N1 M0 Any G Any T N2 M0 Any G Any T N3 M0 Any G Any T Any N M1 Any G
  • PROSTATE CANCER Stage I AJCC ® Cancer Staging Manual, 5th edition (1997) published by Lippincott-Raven Publishers, Philadelphia, Pennsylvania.
  • PROSTATE CANCER Stage II AJCC ® Cancer Staging Manual, 5th edition (1997) published by Lippincott-Raven Publishers, Philadelphia, Pennsylvania.
  • PROSTATE CANCER Stage II (cont’d) AJCC ® Cancer Staging Manual, 5th edition (1997) published by Lippincott-Raven Publishers, Philadelphia, Pennsylvania. *Note: Tumor found in one or both lobes by needle biopsy, but not palpable or reliably visible by imaging, classified as T1c.
  • PROSTATE CANCER Stage III AJCC ® Cancer Staging Manual, 5th edition (1997) published by Lippincott-Raven Publishers, Philadelphia, Pennsylvania. *Note: Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is not classified as T3, but as T2.
  • PROSTATE CANCER Stage IV AJCC ® Cancer Staging Manual, 5th edition (1997) published by Lippincott-Raven Publishers, Philadelphia, Pennsylvania.
  • PROSTATE CANCER Prognostic factors for advanced disease
    • Presence of symptoms
    • Performance status
    • Location and extent of disease
    • Number of lesions on bone scan
    • Serum testosterone and alkaline phosphatase levels
    Carroll PR, et al. Cancer: Principles & Practice of Oncology . 6th ed. 2001;1418-1479.
  • PROSTATE CANCER Commonly used therapies
    • Disease Stage Treatment
    • Stage I/II Radical prostatectomy (if <70 years old and healthy);
    • Radiation (if >70 years old and healthy); or
    • Watchful waiting (if < 10 year life expectancy,
    • significant comorbidity, or unfavorable tumor characteristics)
    • Stage III Radiation therapy or surgery (in rare cases) plus adjuvant hormonal therapy
    • Stage IV Pharmacologic castration (LHRH analogues, antiandrogens)
    • HRPC Antiandrogen withdrawal or continued testicular androgen deprivation;
    • Second-line hormonal therapy;
    • Chemotherapy; or
    • Radiation therapy
  • PROSTATE CANCER Response to surgery Diagnosis of Stage I/II disease (45% to 55% of new prostate cancer diagnoses) SURGERY 85% Respond Without Further Intervention and Achieve a Disease-Free Status 15% Fail to Respond , Developing Stage III/IV Disease Within 1 Year
  • PROSTATE CANCER Risk factors for biochemical failure
    • Rising serum PSA levels after definitive local therapy are indicative of recurrence
    • Pretreatment disease characteristics predictive of poor outcome following curative-intent prostatectomy:
      • Clinical stage T3 or T4 disease
      • Serum PSA levels >20 ng/mL
      • Poorly differentiated histology (ie, biopsy Gleason score  8)
    D’Amico AV, et al. JAMA . 1998;280:969-974.
  • PROSTATE CANCER Response to hormonal therapy Enter Hormone- Refractory Status (Median Survival = 6 to 12 months from time of diagnosis) 20% Achieve a Disease-Free Status and Terminate Therapy Diagnosis of Stage III/IV disease (45% to 55% of new prostate cancer diagnoses) HORMONAL THERAPY 85% Respond (ie, PSA decline  50%) 15% Fail to Respond 80% Respond While Continuing Therapy (Mean Response Duration = 3 Years)