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Prostate cancer progression OBJECTIVES BY CLINICAL STATE INITIAL LOCALIZED EVALUATION: DISEASE NO CANCER DIAGNOSIS PREVENTION RISING PSA CLINICAL CLINICAL METASTASES: METASTASES: NON-CASTRATE CASTRATE MINIMIZE PREVENT MORBIDITY/ METASTASES MAXIMIZE CURE ELIMINATE / PREVENT SYMPTOMS DEATH OF DISEASE 2006 Estimated US Cancer Cases* Men 720,280 Women 679,510 Prostate 33% 31% Breast Lung & bronchus 13% 12% Lung & bronchus Colon & rectum 10% 11% Colon & rectum Urinary bladder 6% 6% Uterine corpus Melanoma of skin 5% 4% Non-Hodgkin lymphoma 4% Non-Hodgkin lymphoma 4% Melanoma of skin Kidney 3% 3% Thyroid Oral cavity 3% 3% Ovary Leukemia 3% 2% Urinary bladder Pancreas 2% 2% Pancreas 18% 22% All Other Sites All Other Sites *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2006. Cancer Incidence Rates* for Men, 1975-2002 Rate Per 100,000 250 Prostate 200 150 Lung 100 Colon and rectum 50 Urinary bladder Non-Hodgkin lymphoma Melanoma of the skin 0 1975 1978 1981 1984 1987 1990 1993 1996 1999 2002 *Age-adjusted to the 2000 US standard population. Source: Surveillance, Epidemiology, and End Results Program, 1975-2002, Division of Cancer Control and Population Sciences, National Cancer Institute, 2005. 2006 Estimated US Cancer Deaths* Lung & bronchus 31% Colon & rectum 10% Men 291,270 Women 273,560 26% Lung & bronchus 15% Breast Colon & rectum Prostate 9% 10% Pancreas 6% 6% Pancreas Leukemia 4% 6% Ovary Liver & intrahepatic bile duct 4% 4% Leukemia 3% Esophagus 4% Non-Hodgkin lymphoma Non-Hodgkin lymphoma 3% 3% Uterine corpus 2% Multiple myeloma Urinary bladder 3% 2% Brain/ONS Kidney 3% All other sites 23% ONS=Other nervous system. Source: American Cancer Society, 2006. 23% All other sites Cancer Death Rates*, for Men, US,1930-2002 100 Rate Per 100,000 Lung 80 60 Stomach Prostate 40 Colon & rectum 20 Pancreas Leukemia Liver *Age-adjusted to the 2000 US standard population. Source: US Mortality Public Use Data Tapes 1960-2002, US Mortality Volumes 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2005. 2000 1995 1990 1985 1980 1975 1970 1965 1960 1955 1950 1945 1940 1935 1930 0 Probability of developing invasive prostate cancer increases with age Age (Male) Birth39 yr 4059 yr 6079 yr Lifetime risk All Sites 1 in 73 1 in 12 1 in 3 1 in 2 American Cancer Society, Inc. Available at: http://www.cancer.org/downloads/STT/CAFF_finalPWSecured.pdf Prostate 1 in 12,833 1 in 44 1 in 7 1 in 6 Factors that may increase risk for developing prostate cancer • • • • • • • Obesity Dietary fat Smoking High testosterone levels Diabetes Infectious agents Occupational exposures Giovannucci E et al. J Natl Cancer Inst. 2003;95:1240 Giovannucci E et al. J Natl Cancer Inst. 1993;85:1571 Sharpe CR et al. Epidemiology. 2001;12:546 Hoffman RM et al. J Natl Cancer Inst. 2001;93:388 Siddiqui MK et al. Biomed Environ Sci. 2002;15:298 Family History • Men with a first-degree affected are twice as likely to develop prostate cancer • Men with two or three first degree relatives have a 5 and 11-fold increased risk of developing prostate cancer Hereditary aspects • Hereditary (> 3 relatives or > 2 with early-onset disease – Associated with early onset and a Mendelian autosomal dominant inheritance with incomplete penetrance – Less than 10% of all cases – More than 40% of cases in men younger than 55 years Epidemiology-Nutrition • Increased risk – High content of animal fat in the diet – Low intakes selenium, ligands and isoflavenoids – Inversely related to sun exposure (Vitamin D) – Deficient in vitamin E • Decreased risk – Diets rich with carotenoids (Vitamin A) Hippocrates • It is more important to know what sort of person has a disease, than to know what sort of disease a person has. Willet F. Whitmore • Is cure possible in those for whom it is necessary? • Is cure necessary in those for whom it is possible American Cancer Society Guidelines for Screening Annual Digital Rectal Exam/PSA Screening • Age 50 • Age 45: family history or African American • PSA <2.0 at yr 1 of screening, screen q 2 yr American Cancer Society, Inc. Available at: http://www.cancer.org/downloads/STT/CAFF_finalPWSecured.pdf Han M et al. Med Clin North Am. 2004;88:245 The Gleason scoring system for prostate cancer • Cells are assigned a no. between 1 and 5 • The scores of the 2 most common cell patterns are added together Gleason Grade • The Sum of the most common pattern plus the second most common pattern yields the gleason score – < 6: well differentiated – 7: moderately differentiated – > 8: poorly differentiated Prostatic Intraepithelial Neoplasia • 85% carcinomas have associated PIN • High grade PIN has 3050% risk of CA on subsequent biopsies • PIN does not cause elevated PSA • Atypical foci in 3-5% of biopsies, 50% risk of cancer on repeat biopsy Diagnosis • The need to pursue the diagnosis is based on: – symptom – an abnormal DRE – an abnormal PSA level • The diagnosis is established by a TRUS-guided transrectal needle biopsy. • Any palpable abnormality should be pursued, – only 25% to 50% of men with an abnormal DRE prove to have prostate cancer – a normal DRE does not exclude presence of cancer Symptoms of Prostate Cancer • • • • • • • • Frequent urination Inability to urinate Trouble starting and stopping urination Painful or burning urination Blood in the urine or semen Painful ejaculation Impotence Today, men rarely present with symptoms of metastatic disease Digital Rectal Exam • Poorly reproducible • Lacks sensitivity and specificity • 25% of men with an abnormal DRE and a PSA < 4.0 have prostate cancer • 50% of DRE-detected prostate cancer is non-organ confined DRE examination T1 T3 T2 T4 PSA • PSA is a 28-kD protein of the kallikrein family, a group of serine proteases whose genes are found on chromosome 19q13 • PSA induces liquefaction of seminal fluid and the release of mobile spermatozoa • PSA is synthesized in the ductal and acinar epithelium and is secreted into the lumina • PSA is organ specific and not cancer specific Factors Increasing PSA • • • • • • Cycling Prostate massage Cystoscopy Ejaculation Prostate biopsy Transrectal Ultrasound Serum PSA • Normal PSA: <4.0 ng/mL – Age- and race-based reference ranges • Sensitivity: 67.5%80% • Improve sensitivity: use lower PSA cut-off level of 2.5 ng/mL (higher false positive, decreased specificity) • Improve specificity: measure % free PSA, complexed PSA (c-PSA) American Urological Association. Oncology. 2000;14:267 Tanguay S. Urology. 2002;59:261 Okihara K. J Urol. 2002;167:2017 PSA Derivatives • PSA velocity: rise in PSA over time (>0.75 ng/ml/yr associated with cancer; useful for men with PSA <4) • PSA density: PSA/prostate volume (>0.15 is associated with cancer; useful in men with large glands) • Free PSA: measures “unbound” PSA (<25% is associated with cancer; useful in men with PSA between 4-10 ng/ml) Circulating PSA is complexed covalently (irreversibly) to the protease inhibitor 1-antichymotrypsin, which covers a specific epitope on the kallikrein loop, allowing immunoassays for the "free" form representing 10% to 35% of the total PSA PSA levels and cancer Transrectal Ultrasound - TRUS • Classic picture of a hypoechoic area • Many cancers are isoechoic and only detectable through systemic biopsies. • TRUS has two potential roles in the diagnosis of CaP: – To identify lesions suspected of malignancy – To improve the accuracy of prostate biopsy. • TRUS detects 50% more patients with CaP than physical examination Screening recommendations Screen any man > 50 years old with a 10 year life expectancy. • Screen any man > 45 years old if: African-American Positive family history. • Stop screening when life expectancy is <10 years. • Radiographic staging • CT – Rarely useful for staging • Bone scan – more sensitive than plain films – Lacks specificity – If the patient has no symptoms referable to bone, the PSA is less than 8 ng/mL, and the tumor is not extensive (T3) or poorly differentiated, true positive results are rare – Abnormal bone scans are often followed by other technology MRI • Endorectal MRI more accurately identifies the presence of ECE and seminal vesicle invasion (SVI), helps to identify invasion in the area of the neurovascular bundles (NVBs), and improves staging accuracy compared to DRE and all other available staging studies Early Diagnosis and Outcomes • Majority (86%) of cases diagnosed in local and regional stages • Usually no symptoms • 5-yr survival with early detection: 100% • Survival rates for all stages combined: 5 yr = 98%, 10 yr = 84%, 15 yr = 56% • Sites of metastases: lymph nodes, bone American Cancer Society, Inc. Available at: http://www.cancer.org/downloads/STT/CAFF_finalPWSecured.pd f CaPSURE: Risk Category at Diagnosis 100 Patients (%) 80 High risk 36.6% 30.2% 25.1% 16.0% 37.2% 60 Intermediate risk 37.3% 38.5% 33.8% 40 20 46.8% Low risk 29.5% 32.5% 36.4% 0 1989 1990 1991 1992 1993 1994 1995 1996 1997 1999 2000 2001 2002 Reprinted with permission from Cooperberg MR et al. J Urol. 2003;170:S21 Preventing Prostate Cancer • Prostate Cancer Prevention Trial (PCPT) – Evaluated the potential of finasteride to decrease the incidence of PRCA – Result: decrease in PCA by about 25% but increase in higher Gleason grade tumors • Selenium and Vitamin E Chemoprevention Trial (SELECT) – Evaluating the role of selenium and vitamin E in preventing PRCA • Dietary modification(?): soy, lycopene Localized prostate cancer What to do? Dealing with localized prostate cancer Requires a balancing act Prognostic models • Partin tables • Kattan nomograms • D’amicco prognostic groups Risk Classification for PSA Failure After RP or RT Classification Low Risk Intermediate Risk High Risk Criteria PSA <10 ng/mL and Gleason <7 and AJCC ≤T2a PSA 10–20 ng/mL or Gleason 7 or AJCC T2b PSA 20 ng/mL or Gleason >7 or AJCC ≥T2c 5-yr Outcome <25% PSA Failure 25%50% PSA Failure >50% PSA Failure The most clinically relevant prognostic factors are: Gleason, PSA and stage Adapted with permission from D'Amico AV et al. JAMA. 1998;280:969 Risk Stratification: Localized Prostate Cancer Low Risk High Risk 100 100 90 80 90 70 70 60 60 50 50 40 40 30 30 20 10 0 80 164 109 10 6 147 77 8 4 117 42 5 3 83 17 2 3 55 4 1 2 36 2 0 1 20 10 0 0 1 2 3 4 5 239 309 23 19 158 218 14 13 0 1 Time (yr) 102 99 3 4 2 47 38 0 0 26 12 0 0 11 0 0 0 3 4 5 Time (yr) RP Implant and Neoadjuvant Hormonal Therapy External Beam RT Implant Reprinted with permission from D’Amico AV et al. JAMA. 1998;280:969 Localized prostate cancer Medical decision making • Life expectancy (age, comorbidity) of the patient • Probability of metastases and death from prostate cancer over time for the untreated (or conservatively managed) patient • Particular characteristics of the primary tumor (prognostic features) • Effectiveness of the treatment being considered • Complication rates and side effects from the treatment • Patient uses (values) for each health state affected by the cancer and its treatment Primary treatments for localized prostate cancer • • • • • • • Watchful waiting Active surveillance Interstitial brachytherapy External beam radiotherapy Radical prostatectomy Primary hormonal therapy Others (e.g., cryotherapy, HIFU) Radical prostatectomy Multiple approaches • Transperineal (uncommon) • Retropubic (most common) • Laparoscopic (pure, robot assisted) Randomized Trial Comparing Surgery and Watchful Waiting • 695 men with early stage prostate cancer randomized to radical prostatectomy or watchful waiting • Median of 8.2 years of follow-up 83 deaths in surgery group and 106 in watchful waiting group (P=0.04). • 30 of the 347 men assigned to surgery and 50 of the 348 men assigned to watchful waiting, death was due to prostate cancer Radical Prostatectomy: Outcomes Long-Term Survival Following Anatomic Radical Retropubic Prostatectomy Likelihood of Undetectable PSA 1.00 T1a T1c 0.75 T1b T2a T2c 0.50 T2b T3a 0.25 0 0 5 10 15 Years Post-operative Reprinted with permission from Han M et al. Urol Clin North Am. 2001;28:555 20 Long-term biochemical disease-free Survival following Radical Retropubic Prostatectomy PSA Progression-Free vs Gleason Score Han,Partin,Pound,Epstein,Walsh Urol Clin N Am 28(3):555, 2001 Pathological findings • Approximately 8% to 15% of cancers confined to the prostate pathologically do recur. • Extracapsular invasion • Seminal Vesicles involvement • Positive surgical margins COMPLICATIONS • Up to 80% will be impotent • 57% of patients will be temporarily incontinent • 10% urethral scarring • 10% mild incontinence • 7% rectal injury • 3% severe incontinence • 2% will be permanently incontinent Erectile disfunction • Recovery – Extent of preservation – Age – Quality of erections before the operation – Experience of the operating surgeon • With preservation of both nerves – First erection- 4 months – Continue to improve for 2 to 3 years Radiation Therapy • • • • 3D IMRT Brachytherapy External irradiation offers the same longterm survival results as surgery • External irradiation provides a quality of life at least as good as that provided by surgery Radiation therapy dose effect • Multiple studies support the notion that local tumor control is directly related to dose and indicate that more than 70 Gy is needed to control prostate cancer After the local therapy Natural history of progression after PSA elevation following radical prostatectomy 1997 men, 15 years after surgery • Cancer-specific survival = 91 % • Biochemical disease-free survival = 85 % • PSA elevation = 15 % • Of these, developed metastases = 34 % • Median actuarial time to metastases = 8 years from time of PSA elevation • Median actuarial time to death = 5 years from developing metastases Pound, Partin, Walsh, et al JAMA 281:1591, 1999 EORTC Trial • Bolla et al NEJM 1997 – 415 patients with locally advanced prostate cancer were randomized to radiotherapy alone or radiotherapy plus immediate hormone therapy – Therapy continued for 3 years – Median follow-up 45 months – Local control, metastases free and overall survival advantage to the adjuvant hormonal group Post Radical Prostatectomy Rising PSA Clinical variable Local Distant recurrence recurrence • Onset of PSA rise > 2 years < 2 years • PSA doubling time > 1 year < 6 months < 0.75 > 0.75 • PSA velocity (ng/mL/year) Active surveillance • Definition: selected men are managed expectantly with the intention to apply curative treatment if signs of progression occur Active surveillance: eligibility criteria • • • • • • PSA-level at diagnosis <= 10 ng/mL PSA density (PSA D) less than 0.2 ng/ml/cc Clinical stage T1C or T2 Appropriate biopsy sampling Gleason score 3+3=6 (or less) One or 2 biopsy cores invaded with prostate cancer • Participants must be willing to attend the follow-up visits Active Surveillance Criteria • Epstein criteria for insignificant disease – Gleason score of 6 or less – < 1/3 of positive cores – An involvement of 50% or less of individual cores • The criteria for tumor volume can be relaxed for patients over the age of 65 years • Patients over 75 years might be candidates if they have a Gleason score of 7 (3 + 4) • PSA DT > 3 years • PSA velocity < 2.0 ng/ml per year Active surveillance: monitoring disease and continuation criteria • PSA test (every 3 months) / PSA (kinetics) • DRE (every 6 months) • Biopsy (every 1,4,7, and 10 years, according to biopsy scheme) • Patient content to continue active surveillance New approaches • Cryotherapy – Patients with low-risk or intermediate-risk represent potential candidates for CSAP. – Prostate size should be < 40 mL – Long-term results are lacking and 5-year biochemical progression-free rates are inferior to those achieved by radical prostatectomy in low-risk patients – Patients have to be informed according • HYPO • Radiofrequency interstitial tumour ablation (RITA) PSA progression after local therapy • After prostatectomy – PSA is expected to be undetectable within 3 weeks after a successful radical prostatectomy – Two consecutive values of 0.2 ng/mL or greater • After radiotherapy – ASTRO defines failure after radiation therapy as three consecutive rises in PSA level, > 2 ng/ml, irrespective of the nadir value Evaluation of PSA progression • PSA DT • DRE is not useful – 5% had an abnormal DRE • Endorectal coiled MRI – local recurrence was correctly identified in 81%, with the mean PSA at time of diagnosis being 2 ng/mL • TRUS and biopsy – In the presence of a palpable lesion or a hypoechoic lesion on transrectal ultrasound yield 80% • Bone scintigraphy and CT scans • Of no additional diagnostic value unless the PSA > 20 ng/mL or unless the PSA velocity > 20 ng/mL/year • CT-PET Management of biochemical progression after local therapy • After radical prostatectomy – Salvage radiation therapy at a PSA serum level ≤ 1.5 ng/mL – Expectant management is an option – Early hormonal therapy reduces frequency of clinical metastases therapy (grade A recommendation • After radiation therapy – Salvage radical prostatectomy in carefully selected patients – Cryotherapy and interstitial brachytherapy are alternative experimental procedures in patients not suitable for surgery – Hormonal therapy Metastatic prostate cancer CHARLES HUGGINS Evolution of Hormone Blockade Orchiectomy <1940 DES 1940 LHRH Agonist 1985 LHRH Agonist + Antiandrogen (CAB) 1989 GnRH Antagonists 2002–03 Hormonal therapy Hypothalamus LHRH Agonists/ Antagonists LHRH Pituitary Ketoconazole FHS, LH Orchiectomy Testicles Testosterone Direct antagonists DES Prostate cancer cell Adrenals Hormonal Therapy LHRH Agonists •LHRH agonists initially act at the level of the pituitary to stimulate LH release , resulting in a temporary surge in serum testosterone levels • Subsequent LHRH downregulation to castrate levels of testosterone •Onset 2-4 weeks Hormonal therapy • Bilateral orchiectomy – Rapid effect 2-6 hrs. – Eliminates 95% of sex steroids – Emotional effect • Estrogens – down-regulation of LHRH secretion, androgen inactivation, direct suppression of Leydig cell function and direct cytotoxicity to the prostate epithelium – Cardiotoxic (parental, topical application) Hormonal therapy • LHRH Antagonist – Binds immediately and competitively to LHRH receptors in the pituitary gland – Effect is a rapid decrease in LH, FSH and testosterone levels without any flare Hormonal therapy • Antiandrogens – Steroidal • synthetic derivatives of hydroxyprogesterone. In addition to peripherally blocking androgen receptors, they have progestational properties and inhibit gonadotrophin (LH and FSH) release and suppress adrenal activity – Non-steroidal • Adds to LHRH therapy • High dose monotherapy emerged as an alternative to castration for patients with locally advanced (M0) and in highly selected, well-informed cases of M1 Combination hormonal therapy • Complete androgen-blockage • Minimal androgen blockage – Finasteride + antiandrogen • Peripheral androgen blockage – High dose Casodex • Intermittent therapy • Immediate vs differed – Adjuvant for microscopic nodal disease – MRC trial The patient-based meta-analysis showed no significant benefit of MAB after 8000+ pts and 27 trials MAB is expensive, has increased toxicity and should not be used 5/23/2017 2nd and 3rd line hormonal therapy • About 90% of men respond to initial therapy with orchidectomy or LHRH agonist • At progression about one third respond to addition of a peripheral antiandrogen (e.g. flutamide, bicalutamide) • Of those who respond and then progress about 20% respond to withdrawal of the peripheral antiandrogen • Men may respond to further hormonal treatments such as dexamethasone, estrogen, or ketoconazole and hydrocortisone דיכוי יצירת Testosterone ממקור יותרת-הכליה Abiraterone in Androgenindependent prostate cancer אחרי טיפול הורמונאלי • PSA response 27/44 (61%) • RECIST response 12/21 (57%) Taxotere אחרי • PSA response 14/28 (50%) • RECIST response 4/18 (22%) Side Effects of Androgensupression • • • • • • • • Hot flashes Loss of libido Impotence Gynecomastia and breast tenderness Increased appetite Weight redistribution Muscle wasting Bone loss Metabolic Syndrome and Prostate Ca >73,000 men age>65 treated for localized Ca prostate 1992-1999, observed through 2001 >1 in 3 received ADT Events per 1000 person-years Diabetes CHF MI Sudden death No treatment 20.9 61.3 10.9 9.0 LHRH agonist 29.0 72.3 13.6 12.9 Orchiectomy 24.5 63.3 13.2 12.5 Androgen-independent prostate cancer Hormone Refractory Prostate Cancer Characteristics • • • • Median survival of 9-12 months Only 20-30% have measurable disease Bone only disease in 90-95% Considerable decrease of life quality: Intense bone pain, Pathological fractures, Spinal Cord Compression, Myelosuppression Bone hunger syndrome, Hyper/hypocalcemia Oncogenic Hypophosphatemia,Osteomalacia, Anemia, cachexia, sepsis, death Brief History of FDA Approval of Agents for Prostate Cancer AGENT • • • • Docetaxel Zomera Mitoxantrone Estramustine YEAR ENDPT. 2004 2003 1996 1981 survival QOL QOL old rules Phase III Docetaxel Studies in HRPC Demonstrating Survival Benefit Mitoxantrone 12 mg/m2 Prednisone 10 mg q day Q 21 days up to 10 cycles N=1006 Randomize TAX 327 N=770 *Warfarin and aspirin Randomize SWOG 9916 Docetaxel 30 mg/m2/wk Prednisone 10 mg q day 5 on; 1 off x 6 cycles Docetaxel 75 mg/m2 Prednisone 10 mg q day Q 21 days up to 10 cycles Mitoxantrone 12 mg/m2 Prednisone 5 mg bid Q 21 days Docetaxel 60 mg/m2 d 2 Estramustine 280 mg d1-5* Dexamethasone 20 mg, tid d 1 & 2 Tannock et al. N Engl J Med 2004:351;1502-1512; Petrylak et al. N Engl J Med 2004;351:1513-1520. Chemotherapy for HRPC SWOG 9916 TAX 327 Docetaxel PSA response rate 50% 45.4% Mitoxantrone PSA response rate 27% 32% Docetaxel overall survival (months) 18 18.9 Improvement in survival (months) 2 2.5 0.01 0.009 p-value HRPC potential new compounds in Phase III Advanced disease Taxotere combo Monotherapy Secondline GVAX M1 First-line chemo M1 DN101 Atrasentan Avastin Taxotere Denosumab Provenge window GVAX Denosumab M0 Early disease2004 Aflibercept 2005 2006 2007 2008 2009 2010 89 Strontium 2011