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Updates in the Management of Localized Prostate Cancer Abdul Naser Shunaigat, MD. FACS Cancer Incidence and Mortality Rates age-adjusted, standardized over time http://www.cancer.org/Research/CancerFactsFigures/CancerFactsFigures/cancer-facts-figures-2012 PROSTATE CANCER PREVALENCE AND MORTALITY • Newborn American male has 16% lifetime risk of being diagnosed with prostate cancer – 1 new case every 3 minutes • 1/3 of men over age 60 and 1/2 of men over age 70 have prostate cancer • But lifetime risk of death from prostate cancer is only 3% Prostate Cancer • Risk Factors – Age-median age of diagnosis is 72 years. • Incidence of prostate cancer increases with age so that up to 70-80% of men in their 80-90’s have autopsy evidence of prostate cancer – Smoking – High Fat/ Western diet – Family History-8-9% of all cancers due to inherited gene higher for younger men Prostate Cancer • Prostate Cancer Development – Develops from the epithelium • Possibly from the basal cell layer – Requires androgens to develop • Patients castrated before puberty do not develop BPH or Prostate cancer – Increased cell proliferation and decreased apoptosis – BPH is not a risk factor Prostate Cancer • Premalignant Lesions • PIN-prostatic intraepithelial neoplasia – May be a precursor lesion to prostate cancer • Characterized by cytologically atypical cells with architecturally benign glands • Approximately 20% of patients with PIN will go on to have a subsequently positive biopsy • ASAP-atypical small acinar proliferation – Atypical glands and cells but can’t quite call it cancer • Up to 50% will have a future positive biopsy Prostate Cancer • Screening?? • Is PSA Screening for Prostate Cancer Dead? • Is there anything better? Prostate Cancer Screening Trials American Trial: • 76,693 men between 55 and 74 randomized to either annual screening or usual care • After 7-10 years of follow-up, death rate from prostate cancer was very low and did not differ significantly between the two study groups European Trial: • 162,243 men between 55 and 69 randomized to either annual screening or no screening • For first 10 years of follow-up, risk of death from prostate cancer was the same between the two groups, but, after 10 years, there was a 20% decrease in risk of death in the screened group Why the recommendation against screening for prostate cancer? Screening and consequent treatment, as currently practiced, are often harmful: – Too much screening of elderly men with a short life expectancy – Too liberal criteria for biopsy – Too aggressive treatment of low risk cancers – Inadequate treatment of high risk cancers – Treatment largely administered by low volume providers (higher risks of side effects and lower risks of cure) Vickers AJ, Lilja H. Time for another rethink on prostate cancer screening. Nat Rev Clin Oncol. 2011; 9:7-8. • 5 treated tp prevent one death Screening Smarter: How to Increase the Benefits and Reduce the Risks of Screening for Prostate Cancer • Risk-adjust screening by age and PSA (reduce false positives) • Reduce false positive PSA results by repeating (verifying) positives and by adding additional markers (reduce indications for biopsy) • Active surveillance for low-risk cancers (reduce harms of unnecessary therapy) • Refer patients who need treatment to high-volume physicians or centers (reduce harm of necessary therapy) Vickers A, Roobol M, Lilja H. Annu. Rev. Med. 2012. 63:161–70. Memorial Sloan-Kettering Cancer Center 2010 Guidelines Risk-adjusted Screening for Prostate Cancer • Begin PSA testing at age 45 • For men age 45 - 59 • PSA ≥ 3 ng/ml : consider biopsy • PSA > 1 but < 3 ng/ml : return for PSA every 2-4 years • PSA <1 ng/ml : return for PSA in 5 years or at age 50 or 60, whichever comes first •For men age 60 – 70 • PSA ≥ 3 ng/ml : consider biopsy • PSA > 1 but < 3 ng/ml : return for PSA every two years • PSA < 1 ng/ml : no further screening • For men age 71 or higher • No further screening Prostate Cancer • Who should I treat? • How to treat? • When to treat? Prostate Cancer • Current guidelines from the AUA, recommend that initial evaluation of, and treatment discussion with a patient with PC focus on the following two factors: – Patient’s overall life expectancy – The biologic characteristics of the tumor, together with its predicted aggressiveness and behavior Prostate Cancer • Whether one of the several different modalities used for treating localized prostate cancer offers survival benefits over others remain controversial. • The choice of definitive therapy has been suggested to make a significant difference in long term survival in less than 10% of patients. Risk Stratifications Organizational pre-treatment Prostate Cancer risk stratification Organization Low Risk Intermediate High Risk Harvard,AUA, EAU T1-T2a and GS ≤6 and PSA≤10 T2b and/or GS=7 and/or PSA˃10-20 Not low risk ≥T2c or PSA˃20 or GS 8-10 GUROC, NICE T1-T2a and GS ≤6 and PSA≤10 T1-T2 and/or GS≤7 and/or PSA≤20 NOT low risk ≥T3a or PSA˃20 or GS 8-10 CAPSURE T1-T2a and GS ≤6 and PSA≤10 T2b and/or GS=7 and/or PSA˃10-20 not low risk T3-4 or PSA˃20 or GS 8-10 NCCN T1-T2a and GS ≤6 and PSA≤10 Not very low risk AND very low risk category T1c and GS≤6 and PSA˂10 and fewer than 3 biopsy cores positive T2b or T2c and/or GS=7 and/or PSA˃10-20 not low risk T3a or PSA˃20 or GS 8-10 ESMO T1-T2a and GS ≤6 and PSA˂10 Not high and Not low risk (the remainder) T3-4 or PSA˃20 or GS 8-10 AUA: American Urological Association; EAU: European Association of Urology; GUROC: GenitoUrinary Radiation Oncologists of Canada; NICE: National Institute for Health and Clinical Excellence; CAPSURE: Cancer of the Prostate Strategic Urologic Research Endeavour; NCCN: National Comprehensive Cancer Network; ESMO: European Society of Medical Oncology Localized Prostate Cancer • Standard treatments for clinically localized Pca includes the following: (Low risk) – – – – – – Active Surveillance Watchful Waiting Radical Prostatectomy Radiation Therapy Hormonal Therapy Cryotherapy. - Proton Beam Radiation. - HIFU Deferred treatment (active surveillance/watchful waiting) • Active Surveillance. – Active surveillance aims to achieve correct timing for curative treatment, rather than delayed application of palliative treatment – Patients remain under close surveillance, and treatment is prompted by predefined thresholds indicative of potentially life-threatening disease, while considering individual life expectancy. Watchful Waiting • Watchful Waiting: – (deferred or symptom-guided treatment). It refers to conservative management, until the development of local or systemic progression. • TURP or other procedures for urinary tract obstruction, • Hormonal therapy or radiotherapy for palliation of metastatic lesions. • No standardized follow-up is recommended. Bill-Axelson; NEJM, 2005 Iverson P; Scand J Urol Nephrol Suppl, 1995 Wilt, T. J, J Urol, 1994 Active surveillance • Increasingly being recommended for men with low-risk disease • Evolving option, although no randomized studies have yet been conducted • Current NCCN recommendations for active surveillance include the following: – PSA no more often than every 6 mo unless clinically indicated – DRE no more often than every 12 mo unless clinically indicated – Repeat prostate biopsy no more often than every 12 mo unless clinically indicated Klotz L et al. J Clin Onc 2010; 28:126 All-cause mortality for men with conservatively managed prostate cancer Charlson Comorbidity index 0 J Rider et al. Long-term outcomes according to risk category of prostate cancer. Nation-wide, population-based cohort. Eur Urol 2012. Radical Prostatectomy • Currently, RP is the only treatment for localized PCa to show a benefit for OS and cancer-specific survival (CSS), compared with conservative management, as shown in one prospective randomized trial.* • RALP is displacing RRP as the gold standard surgical approach for clinically localized PCa in the USA and is being increasingly used in Europe and other parts of the world. *Bill-Axelson A. N Engl J Med 2014 Mar;370(10):932-42. Intermediate and High Risk Pathologic Organ Confined Biopsy Gleason 6 1000 800 600 Low Risk 400 200 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 0.80 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0.00 Number of new patients enrolled in active surveillance by year PIVOT: RP v. Observation Overall results: all-cause and prostate cancer-specific mortality N=731 Wilt et al. N Engl J Med 2012; 367:203 PIVOT: RP v. Observation Patients with high risk cancers PSA > 10 All cause mortality in patients (n=251) with PSA > 10 ng/mL (HR 0.36, p<0.02). AUA High risk Prostate cancer mortality in patients (n=157) with high-risk cancer (HR 0.40, p=0.05) Wilt et al. N Engl J Med 2012; 367:203213 PIVOT • The Prostate Intervention Versus Observation Trial (PIVOT), showed no statistically significant difference between radical prostatectomy and watchful waiting with respect to either: – all-cause mortality (47% versus 49.9%, respectively), or – prostate cancer–specific mortality (5.8% versus 8.4%, respectively) after a median follow-up of 10 years. RANDOMIZED TRIAL OF WATCHFUL WAITING VERSUS RADICAL PROSTATECTOMY • Scandinavian randomized trial of 695 men found absolute risk reduction of 6.1% in prostate cancer deaths at 15 years in men undergoing radical prostatectomy vs watchful waiting – Number needed to treat to prevent 1 prostate cancer death – 15 • Benefit more pronounced in men < 65 years of age – Number needed to treat – 7 • Men in “low risk” group also derived benefit – 4.2% reduction Bill-Axelson, A, et al, Radical prostatectomy versus watchful waiting in early prostate cancer: NEJM 364:18 (1708-1717), 2011. Indications for nerve-sparing surgery • Nerve-sparing RP can be performed safely in most men with localized PCa undergoing RP. In the past decade, a dramatic shift towards lower-stage tumors has become evident. More importantly, men are younger at the time of diagnosis and more interested in preserving sexual function. Nevertheless, clear contraindications are patients in whom there is a high risk of extra-capsular disease, such as any cT2c or cT3 PCa, any GS > 7 on biopsy, or more than one biopsy > 6 at the ipsilateral side. External Beam Radiation therapy • Offers potential for curative treatment of local disease. – 3-D conformal Radiation Therapy (3-D CRT) – Intensity Modulated Radiation Therapy. (IMRT) • QoL after 2 years: IMRT is equal to RP * • Early salvage RT is comparable to adjuvant RT with regard to biochem. recurrence. ** •Geinitz H; Int J Radiat Oncol Biol Phys. 2011 ** Briganti A; Eur Urol. 2012 Radiation vs Surgery • No solid evidence to determine whether any type of RT results in fewer deaths or cancer recurrence than RP in low risk patients. Agency for Healthcare Research and Quality. October 2012 Treatment: definitive radiotherapy • Intensity-modulated radiotherapy (IMRT), with or without image-guided radiotherapy (IGRT), is the gold standard for EBRT. All centers that do not yet offer IMRT should plan to introduce it as a routine method for the definitive treatment of PCa. Hormonal Therapy • ADT alone, has not been considered a "standard" treatment option for localized disease • Increased risk of cardiovascular disease and diabetes • In some cases only. Neoadjuvant and adjuvant hormonal therapy and radical prostatectomy • Since PCa is an androgen-dependent tumor, NHT is an appealing concept. A recent review and meta-analysis studied the role of NHT and prostatectomy. NHT significantly reduced positive margin rates, extra-prostatic extension, and lymph node invasion. • However, this was not associated with improved OS or disease-free survival (DFS). Locally Advanced PCa • • • • Radiation Therapy Hormonal Therapy Radical Prostatectomy Brachytherapy Intermediate risk • • • • • Active surveillance Brachytherapy Radiotherapy Radical prostatectomy Cryotherapy * * Bahn D, et al. Eur Urol. 2012 High-risk and locally advanced prostate cancer • At an increased risk of: – PSA failure – Need for secondary therapy – Mets progression – Death. • Radical Prostatectomy & Extended PLND Metastatic PCa • Rarely curable • Directed toward symptomatic relief Prostate Cancer • Categorize your patient – Complete work up – General health • Complete and Comprehensive patient counseling.