Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
·:{iC0Fp'16 ACOFP 53rd Annual Convention & Scientific Seminars Prostate Cancer Update 2016 Ronnie Martin, DO, FACOFP dist. ACOFP FULL DISCLOSURE FOR CME ACTIVITIES Please check where applicable and sign below. Provide additional pages as necessary. Name of CME Activity: ACOFP 53rd Annual Convention and Scientific Seminars Dates and Location of CME Activity: April 6-9, 2016, The San Juan Puerto Rico Convention Center Your presentation: Friday, Apri 2016 7:00am-8:00am; Men's Health: Prostate DISCLOSURE OF FINANCIAL RELATIONSHIPS WITHIN 12 MONTHS OF DATE OF THIS FORM \/ --J:-- A. Neither I nor any member of my immediate family has a financial relationship or interest with any proprietary entity producing health care goods or services. 8. I have, or an immediate family member has, a financial relationship or interest with a proprietary entity producing health care goods or services. Please check the relationship(s) that applies. Research Grants Stock/Bond Holdings (excluding mutual funds) Employment Speakers' Bureaus• Ownership Partnership Others, please list: Consultant for Fee Please indicate the name(s) of the organization(s) with which you have a financial relationship or interest, and the specific clinical area(s) that correspond to the relationship(s). If more than four relationships, please list on separate piece of paper: Organization With Which Relationship Exists Clinical Area Involved 1. 1. 2. 2. 3. 3. 4. 4. *If you checked "Speakers' Bureaus� in item 8, please continue: Did you participate in company-provided speaker training related to your proposed Topic? Did you travel to participate in this training? Did the company provide you with slides of the presentation in which you were trained as a speaker? Did the company pay the travel/lodging/other expenses? Did you receive an honorarium or consulting fee for participating in this training? Have you received any other type of compensation from the company? Please specify: When serving as faculty for ACOFP, will you use slides provided by a proprietary entity for your presentation and/or lecture handout materials? Will your Topic1 involve information or data obtained from commercial speaker training? Yes: Yes: Yes: Yes: Yes: Yes: No: No: No: No: No: No: Yes: No: No: Yes: DISCLOSURE OF UNLABELED/INVESTIGATIONAL USES OF PRODUCTS __){_A. The content of my material(s)/presentation(s) in this CME activity will not include discussion of unapproved or investigational uses of products or devices. ___B. The content of my material(s)lpresentation in this CME activity will include discussion of unapproved or investigational uses of products or devices as indicated below: I have read the ACOFP policy on full disclosure. If I have indicated a financial relationship or interest, I understand that this information will be reviewed to determine whether a conflict of interest may exist, and I may be asked to provide additional information. I understand t failure or refusal to disclose, false disclosure, or inability to resolve conflicts will require the ACOFP to identify acement. Signature: Ronnie Martin, DO, FACOFP, dist. Please email this form to [email protected] as soon as possible Deadline: Friday, January 15. 2016 3/17/2016 Prostate Cancer Update 2016 Ronnie B. Martin, DO, FACOFP Dean Liberty University College of Osteopathic Medicine Prostate cancer 33% of the none cutaneous malignancy’s in men in USA. 2nd most common cause of cancer deaths in men. In 2015 expected >220,000 newly diagnosed cases in the U.S. 27,500 will die of P-Ca 2015, less than 2005 in spite of increased diagnosis of disease. Prostate cancer Ethnic and genealogical propendency: – African Americans having highest incidence in world (224 cases per 100,000 vs. White Americans at 150/100,00, Japanese at 8.5/100,000 and Chinese at 1.1. – Genetic link with familial pattern demonstrated – Environmental link less clearly established 1 3/17/2016 Prostate cancer diagnosis peaked in 1993 at > 350,000 with advent of PSA testing. Lifetime odds of developing P-Ca is 1:8 to 1:14. Mortality from prostate cancer declined 2.6% each year 1990 to 1998 but has plateaued since then. Prostate cancer Identified risk factors include: – Advancing Age While q.s. 20% Men < 40 demonstrate histological evidence of CA, clinical disease rare 20-30% of men > 50 have histological evidence of disease > 50% of men > than 80 years of age have histological disease Prostate cancer Identified risk factors include: – Family History Men with first degree relatives with P-CA have 2 to 3 fold increase risk, men with two or more first degree relatives have 5 fold increased risk. Familial prostate cancer estimated 5 to 10% of total cases and q.s. 50% of cases in men less than 55 years old. – Genetic Factors Androgen receptor gene CAG sequence repeats (AA have fewer repeats) 2 3/17/2016 General Information Rarely found in men younger than 40 Vasectomy - recent studies have not found increased risk No correlation with BPH Prostate cancer Identified risk factors include: – Diet Red meat, animal fat and higher total fat, and high calcium intake all increase risk. Lycopene, selenium, fatty fish, Vitamin E, soy and Vit. D may help decrease risk – Hormone Levels Androgen level elevation, especially free testosterone, increases risk Screening for Prostate Cancer Goal is to detect organ confined prostate cancer (potentially curable stage). Digital Rectal Examination is foundation of diagnosis but inadequate alone: – Interpretation variable among physicians – majority of cancers not palatable before metastatic. 3 3/17/2016 Screening for Prostate Cancer Prostate Specific Antigen: – Produced by both normal and malignant prostate epithelial cells (rate of release into serum in P-CA is 30x higher) – Also produced by seminal vesicles, breasts, adrenals, parotid, etc. – Elevated by inflammation, infection, ejaculation, instrumentation, trauma, and increased gland mass such as found with BPH BPH is most common cause of elevated serum PSA. PSA Normal range 0 - 4 ng/ml ( Complexed measurement) “gray zone” 4 - 10 ng/ml – Chances of finding CA in this “gray zone” ranges from 25 to 30% – Recommended that you perform free PSA when levels in gray zone if no other findings. Predictable CA (> 60%) when PSA > 10 ng/ml Can obtain these levels from BPH, prostatitis, orchitis, etc. Can make more specific with calculations such as: Free PSA – PSA velocity – PSA density Screening for Prostate Cancer Screening for prostate cancer combines use of PSA and DRE – Today, more cancers detected are organ confided with use of combined diagnosis techniques and more screening. – PSA will detect CA an average of 5.5 years before clinical detection alone. 4 3/17/2016 Screening for Prostate Cancer American Urological Society recommends shared decision between Doctor and patient about annual DRE and PSA for men older than 55 who otherwise have a life expectancy of >10 years. – Epidemiological studies do not support implementation of routine PSA screening of low risk asymptomatic men under 40-54. – Screening is not indicated for men >69 or those with less than 10 year life expectancy, recognizing that some men > 70 with projected life expectancy > 10 years may benefit. If PSA is < 2.5 then screening if elected should be done no more often then every two years. Screening for Prostate Cancer High Risk Patients: especially African American Males and those with family history, screening may begin as early as age 40 or < 54 years of age – Annual screening being challenged, some recent megaanalysis show that screening at 40 and if normal again at 45 and then only every 2 years produce less morbidity and similar mortality outcomes. Problems with PSA and DRE Combined Screenings Lack of specificity between 4 and 10 leads to mix results: – Unnecessary treatment for insignificant cancers with increased morbidity and cost. – Most levels in this range are BPH on biopsy morbidity and cost of biopsies is significant. PSA > 10 generally CA but also most often organ confined cancer. 10-15% of P-CA will have PSA level of < 4 and will not be palpated by DRE. – These malignancy’s tend to higher grade as well. 5 3/17/2016 Compensations for PSA Age specific PSA: – Especially important in younger men where threshold of 2.6 ng/ml has been advocated for men < 50. – Less sensitivity in older men if raise level and may miss non organ confined disease if > 4 ng/ml. Race Specific PSA: – AA males have base line levels higher than white males. Compensations for PSA PSA Velocity: – Measure rate of increase in PSA. – Doubling time is correlated with mortality and morbidity as well as response to therapy. Especially useful in younger men with normal or “grey area” PSA readings. PSA increase of > 2.0 ng/ml in year prior to surgery was significantly associated with lymph node metastases and high grade disease and higher mortality, reoccurrence. PSA doubling time found to be independent predictor of time to development of metastatic disease. < 3 month doubling time was significantly associated with death from prostrate cancer ( 20x the risk of other patients). Compensations for PSA PSA Density: – Higher PSA/volume of gland with CA is supposed to reflect more accurately elevations. Problem is measurement of gland volume via TRUS and few studies have documented value. Free PSA: – Percentage of PSA not bound to serum proteins. – Normally 30-40% of total. – Men with P-CA have less free PSA and higher levels of complexed PSA. – The lower the % of free PSA, the more likely malignancy. – With threshold of 20-25% of Complexed PSA, accurate 90% of time in predicting cancer. 6 3/17/2016 Partin Tables, Kattan Nomogram, D’Amico’s Model Prognostic models that combine 3 or more independent variables, useful in predicting outcomes and may direct management. – Partin utilizes PSA, clinical stage and Gleason score to predict organ confined disease vs. cancer spread to seminal vesicles or lymph nodes. Accurate in independent studies to stage tumor 70-80% of the time. – D”Amico uses preoperative PSA, Gleason, AJCC tumor stage to predict 10 year PSA failure free survival post radical prostatectomy. 10 year PSA free rate in those classified as low risk was 83%, 46% in those in intermediate risk and 29% in those in high risk categories. Patients may live years after reappearance of PSA. Disease Markers Under Investigation: IGF-1--Insulin like growth factor, increase associated with P-CA Prostate specific membrane antigen – PSMA—Detected with ProstaScint, may discriminate BPH, CA and no disease. Telomerase activity—present in majority of CA patient but not in benign prostate tissues. Prevention of Prostate CA Study using finasteride, a 5-alpha reductase inhibitor that lower testosterone conversion to DHEA demonstrate ~25% reduction in prostate CA after 7 year follow up. – Those cancers that did develop were much higher grade and aggressive – Side effects were significant and often precluded completion of study. 7 3/17/2016 Diagnosis of Prostate Cancer Prostate Biopsy is cornerstone: – Generally do a min. of 6 biopsies to cover all areas of gland – Indicated with elevated PSA, abnormal DRE or both. Biopsies are guided by Trans-Rectal U.S. – TRUS by itself is not reliable screen or diagnostic of P-CA. – TRUS helpful in determining volume of gland and calculating volume adjusted PSA. Pathology Overwhelming adenocarcinoma, occasional small cell or sarcoma 70% of prostate cancers arise in the peripheral zone 15 - 20% arise in the central zone 10 - 15% arise in the transition zone Pathology - Gleason Grading System Based on glandular disorganization in architecture on examination of biopsy. Tumors are graded 1 to 5 and total of the two most common added together to get Gleason Score. 2 - 4 well-differentiated 5 - 7 moderately differentiated 8 - 10 poorly differentiated Utilization limited by rarity to get score of less than 6. Clinically differentiation is: – Low grade< 6. – Intermediate grades 6 to 8 – High grade > 8 For staging and prognosis charts. 8 3/17/2016 Staging of Prostate Cancer Purpose is to determined if organ confined (thus potentially curable) or not organ confined. – Local spread to capsule, seminal vesicles and local lymph nodes – Disease’s tendency is to metastasis to bone, lymph nodes Rare today to make diagnosis through evidence of boney mets. – Rarer to have metastasis to visceral organs such as lung or liver Staging of Prostate Cancer Clinical Staging: Localized tumors are T1 and T2. – Potentially curable with surgery or radiation. Local advanced tumors are T3 and T4. Today, with aggressive utilization of PSA, most commonly cancers detected are non palatable T1c cancers. – Rarely curable by surgery or radiation alone Multifactorial Staging of Prostate Cancer Combines use of clinical staging, Gleason score and serum PSA level. – Useful to determine if low, moderate or high risk of relapse after therapy. Prognosis worse if PSA increased by more than 2 ng/ml in year preceding diagnosis of P-CA 9 3/17/2016 Multifactorial Staging of Prostate Cancer Bone Scan, and MRI or CT useful in patients with prostate CA and serum PSA level > 10 ng/ml, Gleason score 7 to 10 or who have T3 or T4 tumors to find regional lymph node and boney spread. Symptoms of Prostate CA P-CA rarely causes local symptoms until very large or advanced. – S/S are more common with BPH. urinary hesitancy post void dribbling urinary retention hematuria incontinence Metastatic Prostate CA Symptoms Bone pain Neurological symptoms secondary to cord compression Pathologic fractures 10 3/17/2016 Treatment for Prostate CA: Observation Indications & Natural Progression In cases with high grade tumors (Gleason score >/= 7) and patient < 74, the patient should be treated. All tumors with Gleason score of >/= 7 should be considered high grade tumors and should be treated. Patient’s age at diagnosis appears to have little impact on 15 year mortality regardless of low grade or high grade tumor. Treatment for Prostate CA: Natural Progression and Observation Age at diagnosis can lead to determination of treatment if locally confined. 10 year prognosis same with treatment or without treatment is essentially the same in the Connecticut Tumor Registry Study and the SEER date bases (Surveillance, Epidemiology, and End Results database): – 70 year old man has 13.6 years of life expectancy. – 75 year old man has 10.8 years of life remaining – 80 year old man has 8.1 years of life remaining Treatment for Localized Prostate Cancer (T1 &T2) Treatment decisions generally made by patient based on physicians bias since there is an absence of randomized studies showing a therapeutic superiority for surgery or radiation therapy present in compatible populations. 11 3/17/2016 Treatment for Localized Prostate Cancer (T1 &T2) Radical Prostatectomy – Most common treatment in US for localized disease – Retropubic approach most common since allows possibility of lymph node dissection [extended pelvic lymphadenectomy], preservation of nerves and wide resection margins. – Side effects and complications of urinary incontinence ( 535% of patients), sexual dysfunction (50-75% of men) largely based on skill of surgeon – Use of nerve sparing techniques, robotics et al have improved co-morbidities, blood loss, side effect static's but only a little. Treatment for Localized Prostate Cancer (T1 &T2) Radiation Therapy – Computer aided 3-D conformal treatment available today allows higher doses than traditional 7000 rads, fewer side effects and better chance of cure today. – Side effects and efficiency both considerations – Rectal injury’s seen more commonly than with surgery with tenesmus, proctitis, colitis, bleeding et al. – Urinary incontinence (including urgency, frequency, hematuria) and erectile dysfunction less common than produced by surgery but still present in majority of patients. Treatment for Localized Prostate Cancer (T1 &T2) Observation: Low risk patients, localized tumor, low combined Gleason and PSA scores. – Outcome at 10 years same with NO treatment as with radiation or surgery in meta analysis of studies. 12 3/17/2016 Treatment for Localized Prostate Cancer (T1 &T2) Brachytherapy: – Implantation of I-125 (slower growing) or Palladium 103 (higher grade tumors) seeds into tumor. – Advantage: Ease of treatment (one step), favorable toxicity profile – Concerns: May leave “cold spots” that allow cancer persist or grow. – Better static's in intermediate and high risk patients if combined with external radiation and hormone manipulation. Treatment for Localized Prostate Cancer (T1 &T2) Cryotherapy – Becoming utilized again with better probes and less localized damage due to technique. Works by local destruction and possibly activation of immunological system Hormonal therapy – More commonly adjunctive therapy in early stages because of anticipated loss of response and chance of cure with other therapy. – More common as palliative therapy in advanced cases in USA. Management of Intermediate Risk Patients Higher cancer volume, occult metastatic risk higher or spread already apparent. Surgery is still curative in locally spread cases about 50% of the time. – Little benefit demonstrated by using androgen ablation before surgery to reduce tumor size. Combined external beam radiation and brachytherapy used in some cases with mixed results. Combined external bean radiation and androgen ablation has been shown to provide survival benefit in intermittent risk patients. 13 3/17/2016 Adjunctive Therapy and Relapse Therapy: Radiation after surgery is beneficial for: – Adverse pathological finding such as not clean margins, capsular penetration, seminal vesicle involvement. Rising PSA post operatively is indication for radiation adjunctive therapy &/or hormonal manipulation: – Prognosis is predicted by several factors: time to rise in PSA (> 2 years better) Serum PSA < 1 ng/ml at time of salvage radiation therapy Adjunctive Therapy and Relapse Therapy: Androgen ablation has been useful after surgery or radiation. – Three years of androgen deprivation therapy demonstrated statically significant improvement in outcome in men treated with radiation in recent European study. Management of Patients with Advanced or Metastatic Cancer (T3 or T4) Local therapy alone rarely curative, therefore the morbidity of surgery rarely justified. Most treated with combined androgen ablation followed by external beam radiation therapy. 14 3/17/2016 ANDROGEN ABLATION THERAPY Prostate cells require androgen for growth and survival Two mechanism of therapy: – Lower the production of testosterone – Blockage of the binding to androgen receptor ANDROGEN ABLATION THERAPY PSA drops rapidly Symptoms from metastases lessen or disappear rapidly Androgen ablation is palliative rather than curative. – Duration of response, dependent on androgen sensitivity of the tumor, before first rise in PSA being noted is generally 12 to 18 months if patients had metastasis at initiation of treatment, much longer if no metastasis present. ANDROGEN ABLATION THERAPY Castration: Surgical or chemical. Orchiectomy – Often not well received by many patients due to emotional trauma, side effects, sexual deficits, hot flashes, loss of muscle tone, weight gain etc. LH-RH Agonists – block production at pituitary of releasing hormones and thus decrease production of testosterone at end organ. – Leuprolide (Lupron) , Goserelin (Zoladex) – Administered every 1 to 4 months 15 3/17/2016 Side Effects of LH - RH Agents Hot flashes Night Sweats Testicular atrophy Sexual dysfunction; decreased libido and impotency Nausea Gynecomastia Weight Gain (adipose fat leads to risk of diabetes) Loss of bone and muscle mass with resultant osteoporosis, fractures, etc. ANDROGEN ABLATION THERAPY Antiandrogens – Flutamide (Eulexin), Bicalutamide (Casodex) and Nilutamide (Nilandron) Inhibits androgen uptake and binding to androgen receptors. Timing of Ablation Therapy Early androgen suppression has been shown to reduce disease progression and related complications and slightly improve 10 year survival rate in patient who had either surgery or radiation for locally advanced or metastatic prostate cancer. 16 3/17/2016 Optimal Androgen Deprivation Therapy Antiandrogen monotherapy appears to be inferior to LHRH agonist, orchiectomy or estrogens alone in patients with know advanced disease. Recent study analysis have concluded that if combined androgen blockade [use of leuprolide plus flutamide] (CAB) does benefit patients with established mets, the benefit is “extremely modest”. Adjunctive Prostate CA Therapy Estrogen: Diethylstilbestrol lowers LH levels and may have direct effect on cancer cells. – Increased thromboembolic risk and cardiovascular effects have caused loss of use in US. Gn-RH – antagonist – Abarelix (Plenaxis) limited availability in US Zoledronic Acid (Zomeda) interferes with Ca metabolism and interferes with boney reabsorption due to orthoclastic activity. Chemotherapy Established role in hormone refractory prostate cancer. Mitoxantrone (Novantrone) approved by FDA for treatment of hormone refractory prostate cancer. [Use in conjunction with corticosteroids] Taxanes: Docetaxel (Taxotene) and Paclitaxel (Taxol) – Inhibit mitosis in prostate epithelial cells. – Docetaxel plus prednisone in accepted as standard chemotherapy for men with metastatic prostate cancer. 17 3/17/2016 Chemotherapy Cyclophosphamide methrotrexate 5 - fluorouricil Newer Therapies for Prostate Cancer Tyrosine kinase inhibitors and proteasome inhibitors used in combination with chemotherapy. Endothelin-1 inhibitor (Atrasentan) Angiogenesis inhibitors. Therapeutic vaccines and monoclonal antibodies. Palliative Therapy Localized radiation for bone pain at specific sites of mets. Radiopharmaceuticals such as Strontium 89 or Samatium-153 concentrate in osseous tissue and are used to treat multiple sites of pain. Analgesics-NSAID or Opioids TURP-for obstruction problems 18