In autopsy, 70% of men >80yr have occult prostate ca

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1 Prostate Cancer UpToDate: Introduction: Risk Factors: Biology: Symptoms: Diagnosis: Two randomized trials showed survival benefit of adding docetaxol to ADT in fit man with very high localized disease or high tumor burden metastatic prostate cancer. In autopsy, 70% of men >80yr have occult prostate ca - Age (most important) - Ethnic: Black > White > Asia. - Genetic factors: BRCA2 (4.8-fold ), BRCA1 (1.8 fold for <65yrs). - Family history: 2-fold (esp. dx <40yrs or > two relatives have PC ) - Diet: fats, fatty acid α-linoleic acid (2-3 fold risk) 1). Anatomy: - Peripheral zone: PC (70%) - Transitional zone: PC (20%), BPH(most common). 2). Androgen Signaling Activation: prostate cancer growth - TMPRSS2-ERG fusion gene: present in 50% PC and regulated by androgen pathway. Asymptomatic in early stage, bone pain in later stage A. Screening: Annual PSA and DRE, * indicated for men >50 yr or men >45 yr with positive family history or black man B. Diagnosis: prostate biopsy with minimum of cores. * indicated for PSA >4ng/ml or abnormal DRE. C. Risk-stratification: Very Low Risk Low Risk Intermediate High Risk Very High T: T1c T1-T2a T2b-T2c T3a T3b-T4 GS: < 6 < 6 or 7 or > 8 PSA: <10 <10 or or >20 * > 4 core positive with GS >8 is an indication for very high risk Pathology: A. Histopathology: - Adenocarcinoma (99%) - Others (<1%): Pure ductal and micinous variants, small cell tumors, sarcoma, transitional cell cancers B. Gleason grading system: describe the morphology of adenocarcinoma of the porstate. - Gleason < 6 well differentiated - Gleason = 7 moderately differentiated Page 1 of 5

2 - Gleason > 8 pooly differentiated A higher gleason score is associated with more aggressive disease, greater risk of extrcapsular extesnion, nodule involvement and subsequent metastasis. C. Staging: T1: NOT Palpable - T1a: found on TURP, <5% cancerous tissue - T1b: found on TURP, >5% cancerous tissue - T1c: diagnosed by needle biopsy due to elevated PSA T2: Palpable (within prostate) - T2a: < 50% one lobe. - T2b: > 50% one lobe. - T2c: both lobes T3: extend through prostate capsule - T3a: extracapsular extension - T3b: seminal vesicles involvement T4: Tumor invades adjacent structures pn1: mets to regional LN M1 - M1a: mets to none-regional LN (supraclavicular) - M1b: Bony mets - M1c: mets to sites other than bone or LN. Staging: - I: T1aN0M0, G1 (well differentiated) - II: T1-2N0M0, for T1a (G2, 3-4) - III: T3N0M0 - IV: T4N0M0 or any TN1N0; or anytanynm1 Prognosis: Tx Principle: - High gleason score (> 8 risk for recurrence after primary treatment). - PAS nadir >1.0 after radiation - Short interval between definitive local tx and biochemical recurrence -Rapid PSA increase A. Active Surveillance: - Indicated for low risk patients. * Very Low Risk (T1c, GS < 6, PSA < 10), life span < 20 yrs. * Low-risk (T1 - T2a, GS < 6, PSA < 10), life span < 10 ys. - PSA, q3 months DRE or prostate biopsy q 12 months calculate PSA doubling time if doubleing time <3 yrs start treatment (surgery, or radiation). B. Therapy for loocalized prostate cancer: 1) Surgery: radical prostatectomy Page 2 of 5

3 - Indication: low risk patient with life span > 10 yrs, or intermediate and higher risk patients - Neoadj androgen deprivation therapy (ADT): not well established in surgery setting. - Adj ADT +/- Docetaxol considered however for high risk patients: start ADT immediately after surgery if positive lymph node metastasis or high risk features prolong survival. - Adj RT indicated for patient with high risk features (positive margins, seminal vesicle invasion, extracapsular extension) after prostatectomy, nodal metastasis or failure of PSA to below undetable post surgery. - Note: PSA should be undetectable after surgery. 3) Radiation therapy: - Indication: not a candidate for surgery or patient does not want surgery. - Neoadj and adj ADT: well established and concurrently administered with radiation. * ADT for 4-6 month for intermediate risk patient. * ADTfor 2-3 years for high risk patient. - Note: PSA should be <1.0 after radiation. - Indication for Brachytherapy: * Low-risk prostate cancer: T1-T2a, PSA<10, and Gleason < 6, * Can be used in combination with EBRT for high-risk PC. * Do not use brachytherapy for large prostate, pre-implant obstructive urinary symptoms, prior TURP, and perineural prostate cancer invasion on biopsy. C. Castration-sensitive metastatic prostate cancer (mpc): 1) Asymptomatic mpc or biochemical recurrence: - Work-up: bone scan, CT/MRI, prostate bed biopsy - Early intervention, rather then delayed, favored for younger men with high-grade disease (eg GS 8-10, PSA-DT <10-12 months or high-risk features on the initial prostatectomy specimen (grossly positive margins, seminal vesical invasion, high tumor volume) DFS, not OS. 2) Symptomatic mpc: - ADT +/- Decetaxel 75mg/m2 x 6 cycles: * GnRH agonist (lupron) +/- antiandrogen for 2-4 wks to prevent testosterone flare continue GnRH monotherapy after initial induction, rather than combined GnRH and anti-androgen (reduced side effects). * Orchiectomy: obsolete, but can be considered for elderly not candidate for ADT. - Common Agents: * GnRH agnosit: Leuprolide (Lupron), Goserelin (Zoladex) * Antiandrogen: Flutamide (Eulexin), Bicalutamide (Casodex), Nilutamide. - Do not use ADT if severe pain, urinary symptoms, spinal cord compromise D. Castration-resistant metastatic prostate cancer (CRPC); 1) Definition: Rising PSA on ADT? Castration-resistant Page 3 of 5

4 2) First step: - Keep LHRH agonist - Maintain testosterone level at castrated level <50ng/ml - Stop antiandrogen Continue GnRH agonist PSA after a few weeks 2) Immunotherapy with Sipuleucel-T (Provenge) indicated for asymptomatic patients or minimal symptom, no hepatic mets, life expectancy > 6 months. i3) Further treatments: 3) Systemic therapy for CRPC: - Chemotherapy: * Docetaxel if not used before * Mitoxantrone: for docetaxel-resistent tumor but inferior to carbazitaxel * Cabazitaxel if prior therapy with docetaxel. - 2nd generation antiandrogen: Enzalutamide (Xtandi) - Androgen biosynthesis inhibitor: Arbiraterone (Zytiga) * indicated for ketoconazole-naïve patients and docetaxel-resistant - Ketoconazole plus hydrocortisone or corticosteroid alone. E. Bone metastases in advanced prostate cancer 1) Bisphophonate: - Pamidronate (Aredia): prevents or treat osteoporosis associated with androgen deprivation - Zoledronic acid/zometa: FDA approved to treat bony metastasis in CRPC (reduces SRE. 2) Xgeva: more effective than Zoledronic acid in preventing skeletal related events in men with CRPC (FDA approved). 3) Xofigo: bone metastasis in CRPC without visceral mets. Follow-Up: A. Surveillance after initial definitive therapy: - PSA q 6-12 months for 5 yrs, then yearly - DRE every year, but may be omitted if PSA undetectable - N1 or M1 Physical exam (including DRE) + PSA q3-6 months B. Chemoprevention: - RCT data showed that 5-α-reductase (5-AR) inhibitor incidence of prostate cancer, does NOT mortality. - Finasteride and dutasteride rate of high-grade prostate cancers - SE of 5-AR: gynecomastia, decreased libido, erectile dysfunction, decreased ejaculate volume - FDA has not approved 5-AR as a chemoprevention agent Pharmacology: A. Sipuleucel-T (Provenge): dendritic cell vaccine - Vaccine: autologous CD54+ cells activated by GM-CSF - Dosing: infusion, q 2 wks, x 3 doses - Indicated for asymptomatic or minimally symptomatic CRPC B. Abiraterone (Zytiga): potent inhibitor of CYP17 Page 4 of 5

5 - Indicated for metastatic castrate-resistant prostate cancer in pts previously treated with docetaxel. - Dosing: 1000mg bid, plus 10mg prednisone - SE: fluid retension, hypokalemia C. Pivotal trials: - TROPIC: Cabazitaxel Plus Prednisone OS (+2.4 mos) vs Mitoxantrone/Prednisone in docetaxel-refractory mcrpc. - ASCENT2: Weekly Docetaxel a/w shorter survival vs standard Docetaxel regimen (q3weeks) in pts with CRPC. Page 5 of 5