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MACRA June 2016 EXCLUSIVE COVERAGE Our columnists explain what you need to know Coding 20 The Bottom Line 23 Washington and You 43 *Source: Kantar Media Expert clinical analysis. Practice advice. Policy perspectives. UrologyTimes.com VOL. 44, NO. 7 with Readers* Since 2001 ‘Apology’ dilemma evolves Urologist-led study supports value of apology laws, but others say they raise liability risk Randy Dotinga | UT CORRESPONDENT APOLOGY LAWS BY STATE DO THEY MAKE A DIFFERENCE? National Report—To Victor Cotton, MD, JD, an attorney and former practicing physician, practicing medicine means never having to say you’re sorry. “In simple terms, a doctor who gives his or her best effort does not owe the patient an apology for anything,” he said. For decades, however, apologies have been on the minds of researchers and lawmakers, if not necessarily on the lips of physicians themselves. First, a slew of new state laws attempted to make it easier for medical professionals to apologize without having to worry about making themselves vulnerable in malpractice lawsuits. The wave of legislation has waned. But now there’s a new trend: communication-and-resolution programs that encourage physicians and medical facilities Thirty-eight states currently have apology laws. A University of Wisconsin study found: Full apology law No apology law NH WA BEFORE AND AFTER Litigation length was 4.4±3.3 years before the laws were enacted and 3.3±2.0 years afterwards (p<.001). Partial apology law MT OR ND ID WY NV VT WI SD CA CO MI IL KS AZ OK NM IN OH WV TN VA NC SC AR MS AL TX PA KY MO LAW TYPE Litigation length was shorter (2.6±1.4 years) in states with full apology laws than those with partial laws (3.3±2.0, p<.001). NY IA NE UT ME MA MN RI CT NJ DE MD GA LA FL AK Source: Graphic reprinted with permission of Patrick McKenna, MD, and Christina Sauder, MS HI Please see APOLOGY, on page 36 Inside HANDS ON 18 How to manage recurrent UTIs in postmenopausal women MALPRACTICE 44 Could necrotizing fasciitis have been diagnosed sooner? HIFU-treated patients see drop in positive Bx cores Randy Dotinga | UT CORRESPONDENT San Diego—As the controversy over the use of high-intensity focused ultrasound (HIFU) continues, efficacy research from a device manufacturer offers new insight into how low-risk, low-grade prostate cancer patients fare under the treatment. The researchers reported that transrectal HIFU produced a statistically significant increase— from 70.8% to 92.3%—in per-core negative biopsy rates. But lead study author Cary Robertson, MD, cautioned that the findings, from 2007 to 2010, shouldn’t necessarily encourage urologists to embrace HIFU treatment for low-risk patients. “The landscape is changed, and the patient with intermediate cancer is probably the ideal patient,” said Dr. Robertson, associate professor of surgery (urology) at Duke University Medical Center and Duke Cancer Institute, Durham, NC. He spoke with Urology Times about his study, which was presented at the AUA annual meeting in San Diego. Last fall, the FDA cleared SonaCare Medical to market its Sonablate 450 device for ablation of prostate tissue. It later approved the marketing of EDAP TMS SA’s Ablatherm for the same indication. Please see HIFU, on page 39 NO GLASS NO BREAKAGE smooth sailing Prefilled. Preassembled. Preferred by 80%1 of polled U.S. urologists and urology nurses. CHOOSE THE GLYDO® PREFILLED SYRINGE FOR RELIABILITY, CONVENIENCE AND SAVINGS. SAGENT Pharmaceuticals® is proud to offer GLYDO (lidocaine HCl jelly, 2%), a sterile urethral anesthetic lubricant provided in prefilled plastic syringes. The GLYDO prefilled syringe is the nonbreakable, cost-saving 2 alternative to competitive glass vial-based syringes that can inadvertently break. The plastic GLYDO syringe is shatter-proof. If you’re tired of experiencing broken glass prior to use, try GLYDO. The novel GLYDO syringe is prefilled, preassembled and ready to use, providing efficiency and convenience from use through disposal. It has been used in 40 countries, with more than 500 million applications and 40 years of experience.3 GLYDO is available in 11 mL and 6 mL easily disposable syringes in sterile individual packs. 1 A description of GLYDO was preferred by 159/193 clinicians in a June 2014 survey. 2 Data on file, Sagent Pharmaceuticals, Inc., 2015. 3 Data on file, Sagent Pharmaceuticals, Inc., 2014. Visit www.glydo.com for more details, as well as information on how to receive GLYDO samples and how to order GLYDO. Please see a brief summary of prescribing information for GLYDO (lidocaine HCl jelly USP, 2%) on the next page. FEATURING PreventIV Measures Packaging and Labeling SM SAGENT Pharmaceuticals is a registered trademark of Sagent Pharmaceuticals, Inc. SAGENT Urology is a trademark of Sagent Pharmaceuticals, Inc. PreventIV Measures is a service mark of Sagent Pharmaceuticals, Inc. GLYDO is a registered trademark of FARCO-PHARMA GmbH. ©2016 Sagent Pharmaceuticals, Inc. Printed in USA 2131 GLYDO (lidocaine HCl jelly USP, 2%) Brief Summary of Prescribing Information INDICATIONS AND USAGE GLYDO (lidocaine HCl jelly USP, 2%) is indicated for prevention and control of pain in procedures involving the male and female urethra, for topical treatment of painful urethritis, and as an anesthetic lubricant for endotracheal intubation (oral and nasal). CONTRAINDICATIONS Lidocaine is contraindicated in patients with a known history of hypersensitivity to local anesthetics of the amide type or to other components of GLYDO. WARNINGS EXCESSIVE DOSAGE, OR SHORT INTERVALS BETWEEN DOSES, CAN RESULT IN HIGH PLASMA LEVELS AND SERIOUS ADVERSE EFFECTS. PATIENTS SHOULD BE INSTRUCTED TO STRICTLY ADHERE TO THE RECOMMENDED DOSAGE AND ADMINISTRATION GUIDELINES AS SET FORTH IN THIS PACKAGE INSERT. THE MANAGEMENT OF SERIOUS ADVERSE REACTIONS MAY REQUIRE THE USE OF RESUSCITATIVE EQUIPMENT, OXYGEN, AND OTHER RESUSCITATIVE DRUGS. GLYDO should be used with extreme caution in the presence of sepsis or severely traumatized mucosa in the area of application, since under such conditions there is the potential for rapid systemic absorption. When used for endotracheal tube lubrication care should be taken to avoid introducing the product into the lumen of the tube. Do not use the jelly to lubricate the endotracheal stylettes. If allowed into the inner lumen, the jelly may dry on the inner surface leaving a residue which tends to clump with flexion, narrowing the lumen. There have been rare reports in which this residue has caused the lumen to occlude. (See also ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION.) PRECAUTIONS General The safety and effectiveness of lidocaine depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. (See WARNINGS and ADVERSE REACTIONS.) The lowest dosage that results in effective anesthesia should be used to avoid high plasma levels and serious adverse effects. Repeated doses of lidocaine may cause significant increases in blood levels with each repeated dose because of slow accumulation of the drug or its metabolites. Tolerance to elevated blood levels varies with the status of the patient. Debilitated, elderly patients, acutely ill patients, and children should be given reduced doses commensurate with their age and physical status. Lidocaine should also be used with caution in patients with severe shock or heart block. GLYDO should be used with caution in patients with known drug sensitivities. Patients allergic to para-aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross sensitivity to lidocaine. Many drugs used during the conduct of anesthesia are considered potential triggering agents for familial malignant hyperthermia. Since it is not known whether amide-type local anesthetics may trigger this reaction and since the need for supplemental general anesthesia cannot be predicted in advance, it is suggested that a standard protocol for management should be available. Early unexplained signs of tachycardia, tachypnea, labile blood pressure, and metabolic acidosis may precede temperature elevation. Successful outcome is dependent on early diagnosis, prompt discontinuance of the suspect triggering agent(s) and institution of treatment, including oxygen therapy, indicated supportive measures and dantrolene (consult dantrolene sodium intravenous package insert before using). Information for Patients When topical anesthetics are used in the mouth, the patient should be aware that the production of topical anesthesia may impair swallowing and thus enhance the danger of aspiration. For this reason, food should not be ingested for 60 minutes following use of local anesthetic preparations in the mouth or throat area. This is particularly important in children because of their frequency of eating. Numbness of the tongue or buccal mucosa may enhance the danger of unintentional biting trauma. Food and chewing gum should not be taken while the mouth or throat area is anesthetized. Carcinogenesis—Long-term studies in animals have not been performed to evaluate the carcinogenic potential of lidocaine. Mutagenesis—The mutagenic potential of lidocaine has been tested in the Ames Salmonella reverse mutation assay, an in vitro chromosome aberrations assay in human lymphocytes and in an in vivo mouse micronucleus assay. There was no indication of any mutagenic effect in these studies. Impairment of Fertility: The effect of lidocaine on fertility was examined in the rat model. Administration of 30 mg/kg, s.c. (180 mg/m2) to the mating pair did not produce alterations in fertility or general reproductive performance of rats. There are no studies that examine the effect of lidocaine on sperm parameters. There was no evidence of altered fertility. Use in Pregnancy Teratogenic Effects: Pregnancy Category B Reproduction studies for lidocaine have been performed in both rats and rabbits. There was no evidence of harm to the fetus at subcutaneous doses of up to 50 mg/kg lidocaine (300 mg/m2 on a body surface area basis) in the rat model. In the rabbit model, there was no evidence of harm to the fetus at a dose of 5 mg/kg, s.c. (60 mg/m2 on a body surface area basis). Treatment of rabbits with 25 mg/kg (300 mg/m2) produced evidence of maternal toxicity and evidence of delayed fetal development, including a non-significant decrease in fetal weight (7%) and an increase in minor skeletal anomalies (skull and sternebral defect, reduced ossification of the phalanges). The effect of lidocaine on post-natal development was examined in rats by treating pregnant female rats daily subcutaneously at doses of 2, 10, and 50 mg/kg (12, 60, and 300 mg/m2) from day 15 of pregnancy and up to 20 days post partum. No signs of adverse effects were seen either in dams or in the pups up to and including the dose of 10 mg/ kg (60 mg/m2); however, the number of surviving pups was reduced at 50 mg/kg (300 mg/m2), both at birth and the duration of lactation period, the effect most likely being secondary to maternal toxicity. No other effects on litter size, litter weight, abnormalities in the pups and physical developments of the pups were seen in this study. A second study examined the effects of lidocaine on post-natal development in the rat that included assessment of the pups from weaning to sexual maturity. Rats were treated for 8 months with 10 or 30 mg/kg, s.c. lidocaine (60 mg/m2 and 180 mg/m2 on a body surface area basis, respectively). This time period encompassed 3 mating periods. There was no evidence of altered post-natal development in any offspring; however, both doses of lidocaine significantly reduced the average number of pups per litter surviving until weaning of offspring from the first 2 mating periods. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Labor and Delivery Lidocaine is not contraindicated in labor and delivery. Should GLYDO be used concomitantly with other products containing lidocaine, the total dose contributed by all formulations must be kept in mind. Nursing Mothers Lidocaine is secreted in human milk. The clinical significance of this observation is unknown. Caution should be exercised when lidocaine is administered to a nursing woman. Pediatric Use Although, the safety and effectiveness of GLYDO in pediatric patients have not been established, a study of 19 premature neonates (gestational age <33 weeks) found no correlation between the plasma concentration of lidocaine or monoethylglycinexylidide and infant body weight when moderate amounts of lidocaine (i.e. 0.3 mL/kg of lidocaine gel 20 mg/mL) were used for lubricating both intranasal and endotracheal tubes. No neonate had plasma levels of lidocaine above 750 mcg/L. Dosages in children should be reduced, commensurate with age, body weight, and physical condition. (See DOSAGE AND ADMINISTRATION.) ADVERSE REACTIONS Adverse experiences following the administration of lidocaine are similar in nature to those observed with other amide local anesthetic agents. These adverse experiences are, in general, dose-related and may result from high plasma levels caused by excessive dosage or rapid absorption, or may result from a hypersensitivity, idiosyncrasy, or diminished tolerance on the part of the patient. Serious adverse experiences are generally systemic in nature. The following types are those most commonly reported: There have been rare reports of endotracheal tube occlusion associated with the presence of dried jelly residue in the inner lumen of the tube. (See also WARNINGS and DOSAGE AND ADMINISTRATION.) Central Nervous System CNS manifestations are excitatory and/or depressant and may be characterized by lightheadedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensations of heat, cold or numbness, twitching, tremors, convulsions, unconsciousness, respiratory depression, and arrest. The excitatory manifestations may be very brief or may not occur at all, in which case the first manifestation of toxicity may be drowsiness merging into unconsciousness and respiratory arrest. Drowsiness following the administration of lidocaine is usually an early sign of a high blood level of the drug and may occur as a consequence of rapid absorption. Cardiovascular System Cardiovascular manifestations are usually depressant and are characterized by bradycardia, hypotension, and cardiovascular collapse, which may lead to cardiac arrest. Allergic Allergic reactions are characterized by cutaneous lesions, urticaria, edema, or anaphylactoid reactions. Allergic reactions may occur as a result of sensitivity either to the local anesthetic agent or to other components in the formulation. Allergic reactions as a result of sensitivity to lidocaine are extremely rare and, if they occur, should be managed by conventional means. The detection of sensitivity by skin testing is of doubtful value. OVERDOSAGE Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use of local anesthetics. (See ADVERSE REACTIONS, WARNINGS, and PRECAUTIONS.) Management of Local Anesthetic Emergencies The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the patient’s state of consciousness after each local anesthetic administration. At the first sign of change, oxygen should be administered. The first step in the management of convulsions consists of immediate attention to the maintenance of a patent airway and assisted or controlled ventilation with oxygen and a delivery system capable of permitting immediate positive airway pressure by mask. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated, keeping in mind that drugs used to treat convulsions sometimes depress the circulation when administered intravenously. Should convulsions persist despite adequate respiratory support, and if the status of the circulation permits, small increments of an ultra-short acting barbiturate (such as thiopental or thiamylal) or a benzodiazepine (such as diazepam) may be administered intravenously. The clinician should be familiar, prior to use of local anesthetics, with these anticonvulsant drugs. Supportive treatment of circulatory depression may require administration of intravenous fluids and, when appropriate, a vasopressor as directed by the clinical situation (e.g., ephedrine). If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia, acidosis, bradycardia, arrhythmias, and cardiac arrest. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted. Dialysis is of negligible value in the treatment of acute overdosage with lidocaine. The oral LD50 of lidocaine HCl in non-fasted female rats is 459 (346 to 773) mg/kg (as the salt) and 214 (159 to 324) mg/kg (as the salt) in fasted female rats. Mfd. for SAGENT Pharmaceuticals Schaumburg, IL 60195 (USA) Mfd. by Klosterfrau Berlin GmbH Made in Germany ©2014 Sagent Pharmaceuticals, Inc. March 2014 You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088. Please see full prescribing information for GLYDO (lidocaine HCl jelly USP, 2%). FEATURING PreventIV Measures Packaging and Labeling SM SAGENT Pharmaceuticals is a registered trademark of Sagent Pharmaceuticals, Inc. SAGENT Urology is a trademark of Sagent Pharmaceuticals, Inc. PreventIV Measures is a service mark of Sagent Pharmaceuticals, Inc. GLYDO is a registered trademark of FARCO-PHARMA GmbH. ©2016 Sagent Pharmaceuticals, Inc. Printed in USA 2131 www.SagentPharma.com | www.glydo.com 4 ❳Perspective❲ JUNE 2016 ∣ UrologyTimes.com Prostate HIFU lands in the U.S. Now what? T he first prostate high-intensity focused ultrasound (HIFU) units were approved in Europe in 2000 and in Canada in 2003. HIFU is now available to men who live in the United States to be treated in the U.S. The two devices approved in 2015 by the FDA are the Sonablate 450 HIFU system (SonaCare Medical) and the Ablatherm Robotic HIFU (EDAP Technomed). Recently, EDAP filed for FDA approval for its Focal One HIFU, which combines MRI-ultrasound fusion to target specific prostate lesions. This unit is approved in several countries outside the U.S. (See related article on page 1.) This FDA approval did not specify “prostate cancer” but rather “prostate tissue ablation,” a source of some confusion. FDA determined that HIFU was a safe and effective tool for the destruction of prostate tissue but was unconvinced that the data supported a prostate cancerspecific approval. While the short-term PSA and biopsy data (1-2 years) were encouraging for Leonard G. Gomella, MD Dr. Gomella, a member of the Urology Times Editorial Council, is chairman of the department of urology and senior director for clinical affairs, Jefferson Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia. prostate cancer treatment, it would take many years and many patients to demonstrate HIFU’s superiority for localized disease. The HIFU side effect profile appears similar to that of other localized prostate cancer treatments. As noted by several authorities, this HIFU approval is analogous to a scalpel— a tool that can effectively cut tissue but not approved to treat a specific disease. HIFU involves the use of ultrasound to induce tissue damage by thermal and mechanical effects and cavitation. With this broad approval, it is now up to the urologic community to further define JUNE 2016 VOL. 44, NO. 7 ❳Mission❲ Urologists and allied health professionals rely on Urology Times for analysis, perspective, and practical advice about current health policy, clinical, and business challenges. As the #1 read publication in the field and a leading online resource, our goal is to keep practitioners up to date while helping them practice more efficiently. ❳Editorial Consultants❲ Leading urologic surgeons, with broad experience, who help ensure the quality of our editorial how to best use HIFU. With over 20 years of international experience, we must objectively study the world literature to optimize patient outcomes. For prostate cancer, should HIFU be complete, hemi-gland ablation, or focal therapy? What are the optimum patient and tumor characteristics? With our expanding understanding of immunotherapy, is there a role for prostate ablation as an immune primer for treating metastatic disease? With all this uncertainty, the good news is that men will no longer need to travel to Canada or elsewhere for prostate HIFU therapy. Leonard G. Gomella, MD ❳Clinical Practice Board❲ Feedback Send your comments to Dr. Gomella c/o Urology Times, at [email protected] Urologists who inform the editors of issues facing physicians “in the trenches” Sheila K. Gemar, MD Willmar, MN Daniel M. Kaplon, MD Sarasota, FL Sivaprasad D. Madduri, MD Poplar Bluff, MO Henry M. Rosevear, MD Colorado Springs, CO ❳Content❲ Barry R. Rossman, MD Princeton, NJ Neal D. Shore, MD Myrtle Beach, SC Steven M. Wahle, MD Cedar Rapids, IA 24950 Country Club Blvd., Suite 200, North Olmsted, OH 44070 800-225-4569 | E-mail: [email protected] Sara Michael VP, Content & Strategy Ray Painter, MD/Mark Painter Coding/Reimbursement Columnists J. Brantley Thrasher, MD Professor and Chair of Urology | University of Kansas Medical Center, Kansas City Teresa A. McNulty Group Content Director Bob Gatty UT Washington Correspondent Philip M. Hanno, MD, MPH Emeritus Professor of Urology | University of Pennsylvania, Philadelphia Richard R. Kerr Content Channel Director Nancy Bitteker Director, Design and Digital Production Stephen Y. Nakada, MD Professor and Chairman | Department of Urology | University of Wisconsin, Madison 440-891-2758 | [email protected] ❳Editorial Council❲ Experts in 12 key subspecialties of urology who direct in-depth coverage of their field MEN’S HEALTH/BPH Steven A. Kaplan, MD Professor of Urology | Icahn School of Medicine at Mount Sinai, New York MEN’S HEALTH/PROSTATE CANCER Stacy Loeb, MD, MSc Assistant Professor of Urology | New York University School of Medicine, New York CLINICAL EPIDEMIOLOGY Peter C. Albertsen, MD Chief of Urology | University of Connecticut Health Center, Farmington Robert McGarr Art Director Benjamin P. Saylor Content Managing Editor 440-891-2780 | [email protected] ❳Advertising❲ 485 Route 1, Building F, Suite 210, Iselin, NJ 08830 Georgiann DeCenzo EVP, Managing Director Aviva Belsky Group Publisher Renée Schuster List Account Executive 440-891-2613 | [email protected] SEXUAL DYSFUNCTION Arthur L. Burnett, II, MD, MBA Professor of Urology | Johns Hopkins University School of Medicine, Baltimore 732-346-3044 | [email protected] FEMALE UROLOGY Shlomo Raz, MD Professor of Surgery/Urology | University of California School of Medicine, Los Angeles Bill Markowitz Associate Publisher MEN’S HEALTH/INFERTILITY James M. Hotaling, MD, MS Assistant Professor of Surgery (Urology) | University of Utah, Salt Lake City 732-346-3083 | [email protected] Reprints services: Wright’s Media 877-652-5295 ext. 121 PEDIATRIC UROLOGY Barry A. Kogan, MD Chief of Urology | Albany Medical College, Albany, NY Joanna Shippoli Account Manager, Recruitment [email protected] | Outside US, UK, direct dial: 281-419-5725. Ext. 121 HEALTH POLICY/SOCIOECONOMICS Jeffrey E. Kaufman, MD | Private Practice, Santa Ana, CA STONES/ENDOUROLOGY Dean G. Assimos, MD Professor and Chair of Urology | University of Alabama, Birmingham TRAUMA/RECONSTRUCTION Allen F. Morey, MD Professor of Urology | UT Southwestern Medical Center, Dallas UROLOGIC CANCER Leonard G. Gomella, MD Professor and Chairman of Urology | Thomas Jefferson University, Philadelphia UROLOGIC LAPAROSCOPY J. Stuart Wolf, Jr, MD Professor of Urology | University of Michigan, Ann Arbor 440-891-2615 | [email protected] ❳Production ▪ Circulation ❲ Maureen Cannon Permissions 440-891-2742 | [email protected] 131 West First Street, Duluth, MN 55802-2065 Customer Service: 888-527-7008 Karen Lenzen Production Director Subscriber Customer Service: 218-740-6477 | FAX: 218-740-6371 | [email protected] 218-740-6437 Urology Times strives to avoid placing advertising near articles that discuss a product or service related to the advertisement. This policy may not always be enforceable because of space restrictions. UROLOGY TIMES (ISSN 0093-9722 PRINT), (ISSN 2150-7384 DIGITAL) is published 13 times a year: monthly with 2 issues in April by UBM Medica 131 W First St., Duluth MN 55802-2065. Subscription rates: $99 for 1 year in the United States and Possessions; $147 for 1 year in Canada and Mexico; all other countries $195 for 1 year. Price includes air-expedited service. 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UROLIFT IS CHANGING THE GAME ® RAPID BPH SYMPTOM RELIEF BACKED BY STRONG CLINICAL DATA • 16 peer-reviewed publications • 4 years of clinical data1 • Excellent safety profile • Typically no catheter required after treatment2,4 • Preservation of sexual function3 • Rapid and significant relief in AUASI, Qmax and QoL2,4 Most common adverse events reported include hematuria, dysuria, micturition urgency, pelvic pain, and urge incontinence. Most symptoms were mild to moderate in severity and resolved within two to four weeks after the procedure. Pre-procedure Post-procedure IMPROVE YOUR BPH GAME TODAY. Check out the data and learn more at UroLift.com Follow us on @UroLift 1. Roehrborn. AUA 2016. 4 year LIFT study results. Data on file. 2. Shore, 2014 Can J Urology 3. McVary, 2014 J Sexual Medicine 4. Roehrborn, 2013 J Urol. ©2016 NeoTract, Inc. All rights reserved. MAC00197-02 Rev D 6 ❳Inter ctive❲ Your guide to what’s happening online at UrologyTimes.com tube JUNE 2016 ∣ Urology Times ‘Y’tube is a video resource for urologists and other physicians who focus on men’s health. Videos cover surgical aspects of a variety of men’s health issues, with the goal of providing clinicians a current reference. UROLOGYTIMES.COM/YTUBE James M. Hotaling, MD, MS, | Section Editor THIS MONTH’S INSTALLMENT Techniques help transition this procedure from the OR to an office setting Neil Baum, MD Steven N. Gange, MD Lance P. Walsh, MD, PhD compares UroLift with TURP and discusses his experience with the use of nitrous oxide as an effective sedative. demonstrates UroLift placement under topical anesthesia and includes comments from several patients. provides an overview of the UroLift procedure, highlighting the entire cycle of patient care. JUNE’S QUESTION OF THE MONTH AACU LEGISLATIVE UPDATE Feds flex muscle on health care mergers With increasing frequency, the Federal Trade Commission exerts its influence on issues that impact the practice of medicine, including health system mergers, facility regulation, and non-physician provider scope of practice. This all falls under the agency’s goal to maintain competition by preventing anticompetitive mergers and exploitative business practices. Does fear of being sued often affect how you practice? Not Sure 6% No 21% urologytimes.com/health-mergers 73% Yes UT FOLLOWER OF THE MONTH @BEkidneystone Brian Eisner, MD, Massachusetts General Hospital endourologist, is the Urology Times Twitter TWITTER.COM/UROLOGYTIMES follower of the month! To be featured in this section, engage with us. Our followers tweet about the AUA annual meeting Stacy Loeb, MD @LoebStacy My 2 questions to consider before tweeting: 1-ok if on NY Times front page? 2-does someone in Australia care? #AUA16 Manoj monga @endourologyccf Working on the night shift - not so good for sexual function. (Baylor Houston MP47-01)Take home messages #AUA16 #lastdaymatters Abhinav Sidana @AbhinavSidana #AUA16 too many presentations with complex nomograms! Dont need nomograms for every clinical decision! Jorg Oddens @Joddens Perioperative blood transfusion impairs oncological outcome in renal cell carcinoma surgery. #AUA16 #highlights Urology Times App *HWDFFHVVWRDOOWKHEHQHÀWV Urology TimesRIIHUVDW\RXUÀQJHUWLSV The Urology TimesDSSIRUL3DGDQG L3KRQHLVQRZIUHHLQWKHL7XQHVVWRUH QUESTION FOR JUNE What’s your take on using HIFU in men with prostate cancer? Answer the survey online at urologytimes.com/survey-HIFU LIKE US on Facebook and participate in the discussion. FACEBOOK.COM/UROLOGYTIMES Medical Economics App Contemporary Pediatrics App 7KHOHDGLQJEXVLQHVV UHVRXUFHIRUSK\VLFLDQV LVQRZDYDLODEOHLQDIUHH DSS'RZQORDGWRGD\ IURPWKHL7XQHVVWRUH 7KHEHVWLQWHUDFWLYH PDJD]LQHH[SHULHQFH LQSHGLDWULFVLVIUHHWR GRZQORDGIRUL3DGDQG L3KRQHLQWKHL7XQHVVWRUH UrologyTimes.com ∣ ❳ Clinical Updates ❲ JUNE 2016 7 Stone Disease Reintervention rate comparable for two approaches Renal calculi: Dusting, basketing both have roles Randy Dotinga UT CORRESPONDENT San Diego—The rise of laser lithotripsy has rev- olutionized the treatment of larger kidney stones, but there’s been a big mystery: Is it better to pulverize the stone into bits and leave them in the kidney (“dusting”) or pull the fragments out via ureteroscope (“basketing”)? Dusting is quicker and possibly less damaging, while basketing gets rid of remnants that could cause trouble later. Now, a new study, presented at the AUA annual meeting in San Diego, offers insight into the outcomes of both procedures after 4 to 6 weeks. The verdict: “At first blush, there’s not a difference between patients who were dusted or basketed,” said study co-author Mitchell Humphreys, MD, professor of urology at Mayo Clinic, Phoenix. “I can’t say one is clearly better than the other. This shows that both techniques have a role in stone disease.” According to Dr. Humphreys, dusting has become a feasible option thanks to the advent of high-powered lasers that offer flexibility in terms of increasing frequency rather than hertz. “Some people dusted before, but it wasn’t as efficient because you could only take your hertz up so much,” he said. Now, basketing is feasible too, and the question is: Which one is better? “People who do basketing feel that the patient has a better chance of not having any subsequent stone episodes: ‘If I leave something behind, that will turn into another stone,’ ” Dr. Humphreys said. “Plus, patients like hearing Clinical Updates Prostate Cancer page 10 Female Urology page 14 Sexual Dysfunction page 16 Pediatric Urology page 17 For up-to-date news, visit urologytimes.com/InBrief that all the stone is out.” But proponents of dusting Table Dusting vs. basketing are skeptical that the fragments in laser lithotripsy will become problematic, he said, and they like the potential Dusting Basketing for savings due to not needing 56.1% 80.7% Fragment-free rate accessory devices such as a ureNumber of patients requiring teroscopic access sheath or bas2 3 reintervention ket. And, he said, they like not Patients with fragments who having to make “trips” in and out 4/20 3/9 suffered from symptoms of the kidney with the extra risk Source: Mitchell Humphreys, MD of damage to the ureter, although Dr. Humphreys said that might be alleviated by the ureteroscopic access sheath. basketing patients. The readmission rate to In the study, Dr. Humphreys, representing hospital or emergency room was 14% to 15% the Endourology Disease Group for Excellence in both groups; postoperative creatinine and research consortium, prospectively enrolled stone analyses were the same in both groups. 152 patients at high-volume stone centers with Three of nine patients who were basketed well-established standardized protocols—three and had leftover fragments suffered from sympdusting sites and five basketing sites. toms, Dr. Humphreys said, and four out of 20 who were dusted and had leftover fragments suffered from symptoms. “All in all, if you have fragments left, you’ve “If you have fragments left, you’ve got a good chance of having symptoms,” he said, “but it made no difference whether you got got a good chance of having dusted or basketed, at least in the short term.” symptoms, but it made no difference Dr. Humphreys acknowledged that the study doesn’t include a cost analysis because it would whether you got dusted or basketed, be too complex to complete due to the number of different price structures involved. But the at least in the short term.” authors hope to analyze expenses in the future. Also, he said, long-term analyses still need to MITCHELL HUMPHREYS, MD be completed. “Most people do one technique,” Dr. HumWhat should urologists take from the phreys said, “and maybe the other in special research? circumstances.” “For patients who are dusted, it’s quicker, Of the subjects, 48% were male and 52% you can attack bigger stones, and you have no female; all had renal stones measuring between increased risk of complications,” he said. “But 5 and 20 mm. All received laser lithotripsy, you’re leaving fragments behind, and we don’t were stented postoperatively, and received an know about the long-term consequences.” alpha-blocker for 30 days. All underwent KUB In comparison, basketing doesn’t appear and ultrasound imaging within 3 months. to translate to extra benefits in the immediate The authors found that the dusting patients weeks after procedures, he said. had slightly larger stones, and significantly more Dr. Humphreys cautioned that each techlaser energy was needed to perform dusting ver- nique might have value in certain situations. sus basketing. Not surprisingly, the basketing Patients with narrow ureters and big stones procedures took longer, Dr. Humphreys said. may do better with dusting because it doesn’t pose the risk of repeated trauma from basketing Little difference in fragment impact seen or the need for a ureteroscopic access sheath, Of the basketing patients, 80.7% were fragment- he said. And basketing may be best for patients free compared to 56.1% of the dusting patients who have a stone that’s easy to get to, very hard, at first follow-up. and likely to break into discrete fragments. A In terms of these outcomes, the authors patient with a solitary kidney may be another found little clinical difference in the impact of good option for basketing, he said, because it’s the residual fragments. Two dusting patients especially important to remove fragments and required reintervention compared with three avoid future problems. UT ❳ UT ❲ 8 ❳ Clinical Updates ❲ JUNE 2016 ∣ Urology Times Urinary proteome may guide stone prevention strategy Research reveals significant differences in COM-binding proteins in adults, children Cheryl Guttman Krader UT CONTRIBUTING EDITOR San Diego—Analyses of urine samples col- lected from children and adults provide the first comprehensive catalog of urinary calcium oxalate monohydrate (COM) binding proteins and reveal significant differences in the level and make-up of these proteins between the two populations, urologists from Washington University School of Medicine, St. Louis, reported at the AUA annual meeting in San Diego. The study, which included subjects with no history of urinary stone disease (USD), is part of a larger ongoing project aiming to characterize the urinary proteome in children and adults for insights on USD pathogenesis as well as age-related clinical differences, and eventually to guide development of better prognostic approaches and therapeutic strategies. “In previous work, we demonstrated there UTSTAT The total concentration of COM-binding proteins was significantly higher in the adults than in the children, and the proportion of high affinity COMbinding proteins was 39% greater in adults. are populations of proteins within human urine that have very high affinity for COM. In addition, we showed that some of these proteins inhibit crystal adhesion and crystal growth and aggregation in solution,” said first author Joel Koenig, MD, pediatric fellow at Washington University. “So far, in this phase of our research, we have found there are age-related differences in the urinary proteome and specifically with regard to COM-binding proteins. Moving ahead, we are conducting additional analyses to better characterize the differences,” added Dr. Koenig, who worked on the study with Paul Austin, MD, and colleagues. Findings from basic chemistry studies done to measure the concentration of various proteins in the urine samples along with affinity chromatography performed using control and COM crystal-loaded columns showed that in both the pediatric and adult subjects, proteins with a high selective affinity for COM comprised a minor proportion of the total protein content of the urine. Consistent with some previous research, the proportion of proteins with a high selective affinity for COM accounted for only about 10% to 20% of total protein in the urine, Dr. Koenig reported. Higher protein concentration in adults However, the total concentration of COMbinding proteins was significantly higher in the adults than in the children, and the propor- tion of high affinity COM-binding proteins was 39% greater in adults. Currently, the investigators are performing HPLC-mass spectrometry for high throughput identification of the urinary proteins and immunoblotting and ELISA for protein-specific analyses. In terms of clinical application of their research, they hypothesize that urinary proteins found to have a strong effect for preventing COM crystal adherence and/or aggregation could be used as biomarkers to predict risk of stone recurrence and also provide therapeutic targets. “Hopefully, with the identification of such proteins, a quick spot test of a urine specimen could reduce the need for a cumbersome 24-hour collection,” Dr. Koenig explained. “And our ultimate goal is to use the findings from our studies to design a therapeutic intervention that might increase the secretion of the protective proteins as an approach for preventing kidney stone formation.” As next steps, they will expand their research by comparing the urinary proteome of populations of patients with and without a history of USD and also study patients with a history of recurrent USD. “The finding of differences in these initial groups of children and adults with no history of stone formation encourages us to keep our project going,” Dr. Koenig told Urology Times. UT InBrief❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯❯ FOR UP-TO-DATE NEWS, VISIT urologytimes.com/InBrief FDA approves advanced bladder cancer treatment Atezolizumab targets the PD-1/PD-L1 pathway and in doing so may help the The FDA has granted accelerated immune system fight cancer cells, accordapproval to atezolizumab (TECENing to an FDA press release. In all patients in TRIQ) for the treatment of patients with a clinical trial, 14.8% experienced at least a locally advanced or metastatic urothelial car- partial shrinkage of their tumors. In patients cinoma who have disease progression during who were positive for PD-L1 expression, 26% or following platinum-based chemotherapy, showed a tumor response (vs. 9.5% of those or whose disease has worsened within 12 who were negative for PD-L1 expression). months of receiving platinum-based neoadjuvant or adjuvant chemotherapy. Urology Times brings home Atezolizumab is the first FDA-approved gold for best blog treatment for people with this type of bladder cancer in more than 30 years, developer Urology Times is pleased to announce Genentech said. that it is the recipient of a Gold award ❯❯ ❯❯ from the American Society of Healthcare Publication Editors in the category of “Best Blog.” The award recognizes blog posts written by Henry Rosevear, MD, a member of the Urology Times Clinical Dr. Rosevear Practice Board. “This award is well deserved,” said Richard R. Kerr, editor-inchief. “Dr. Rosevear has a keen insight into the issues facing practicing urologists. He writes with wit, wisdom, and a firm stance.” To read Dr. Rosevear’s blog posts, go to www.urologytimes.com/Rosevear. 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Decipher accurately identifies which patients may benefit from early or adjuvant radiation and which may be safely managed by observation of PSA levels or delayed radiotherapy, allowing more time for recovery after surgery.1 Also, for patients with PSA rise or BCR after surgery, Decipher helps you identify patients who will likely do well with salvage radiation alone from those who may require systemic or intensified therapy beyond radiation.2 1 There are many management and treatment options available to patients after a radical prostatectomy. Decipher is the only test that accurately tells you which ones are best suited for each patient, no doubt about it. (1) Den, R.B., et al., A Genomic Classifier Identifies Men with Adverse Pathology after Radical Prostatectomy who Benefit from Adjuvant Radiation Therapy. Journal of Clinical Oncology, 2015 Mar; 33(8): 944-951. (2) Freedland, S.J., et al., Utilization of a Genomic Classifier for Prediction of Metastasis Following Salvage Radiation Therapy after Radical Prostatectomy European Urology. 2016. DOI:10.1016/j.eururo.2016.01.008. (3) Karnes, R.J., et al. Validation of a Genomic Classifier that Predicts Metastasis Following Radical Prostatectomy in an At Risk Patient Population. J Urol, 2013 Dec, 190(6), 2047-2053. Post-op For more information visit us at www.deciphertest.com or call Customer Support today at 888.792.1601 E-mail: [email protected] 1 10 ❳ Clinical Updates ❲ JUNE 2016 ∣ Urology Times Prostate Cancer Findings suggest not all Gleason 6 cancers are indolent Prostate cancer clones trackable by fusion biopsy Cheryl Guttman Krader UT CONTRIBUTING EDITOR San Diego—Researchers using cutting-edge diagnostic techniques demonstrated that repeat sampling of the same clonal focus of prostate cancer can be achieved over time using magnetic resonance imaging/ultrasound fusion biopsy (“fusion biopsy”). In addition, their findings strongly suggest that high-grade prostate cancer may arise clonally from a low-grade cancer. “Our study provides the first definitive evidence that serial biopsies can be obtained from the same prostate cancer clonal focus through fusion biopsy, and so it supports use of this technique for following men during active surveillance,” said Ganesh S. Palapattu, MD, associate professor of urology and chief of urologic oncology at the University of Michigan, Ann Arbor. “It also raises the provocative idea that not all Gleason 6 prostate cancers may be indolent. Our findings point to the need for further research focusing on better characterizing these ‘high-risk low-grade’ cancers. Ultimately, these are the ones we need to follow.” Conducted as a collaboration between urologists at the University of Michigan and the University of California, Los Angeles, the study included 31 men (mean age, 65 years, mean PSA at diagnosis, 4.6 ng/mL) with low-volume, Gleason 6 prostate cancer who were enrolled in an active surveillance program. All men underwent an initial diagnostic MR/fusion biopsy with individual needle core tracking and had a follow-up fusion biopsy of the same region. The median time between biopsies was 12 months. Clonality of the initial and follow-up biopsies was assessed using immunohistochemistry to assay ERG status. In addition, targeted RNA/ DNA next-generation sequencing (NGS) was performed to identify common oncogenic mutations in routine formalin-fixed paraffinembedded biopsy tissues. “Active surveillance for men with low-grade cancer is based on the notions that we are able to sample the same clonal focus of cancer over time and that low-grade disease can progress to high-grade disease,” said Dr. Palapattu. “Ours is a first-in-kind study providing evidence to support these ideas through the use of sophisticated molecular techniques.” Twenty-six of the 31 men had tissue that was evaluable for molecular studies at both the diagnostic and follow-up biopsies, and 10 men had progression to Gleason 7 or higher cancer on targeted surveillance biopsy. 96% ERG expression concordance seen Immunohistochemical analysis demonstrated ERG expression concordance between serially obtained samples in 25 (96%) of the 26 men with evaluable tissues and in all 10 men whose cancer progressed. “The 96% ERG expression concordance between the initial and surveillance targeted biopsy is a much higher rate than could be attributable to chance, strongly suggesting that the same clonal focus was sampled over time,” Dr. Palapattu said. “Furthermore, the concordance of ERG status between the samples from the men whose cancer progressed strongly suggests that the higher grade cancer originated from the Gleason 6 cancer.” While approximately 50% of paired samples displayed oncogenic mutations, no consistent mutational event that predicted grade progression was observed. “Our research is also noteworthy for establishing the feasibility of identifying somatic genetic alterations with high confidence using very minute tissue samples obtained through prostate biopsy as well as for showing that deleterious genetic alterations can be present in low-volume low-grade prostate cancer,” Dr. Palapattu said. He acknowledged the study has two main limitations. One is its small cohort size, and the other relates to sampling bias; ie, the possibility that tissue assayed in the follow-up biopsy was in fact present at the initial biopsy but simply not sampled. UT Post-TRUS Bx infection linked to higher transfusion risk Oncologic, functional outcomes similar between study groups, data indicate Mac Overmyer UT CONTRIBUTING EDITOR San Diego—Infections that follow transrectal ultrasound (TRUS)-guided prostate biopsies are associated with an increased risk of blood transfusions and increased readmission following radical prostatectomy, even though the infections may have been clinically resolved well before the procedure was conducted, according to a study from the Institute for Clinical Evaluative Sciences and the University of Western Ontario, London, Ontario, Canada. Paradoxically, the authors did not find a negative effect in the functional outcomes they analyzed. Results also showed that the risk of additional oncologic therapies was similar despite the presence of an infectious compli- functional outcomes were similar. Physicians cation after prostate biopsy. should inform patients who experience infec“It may be that infectious complications tious complications following a prostate biopsy affect the complexity of the case to increase Please see TRUS, page 11 blood transfusion rates following radical prostatectomy. But at the end, the proportion of the evaluTable Biopsy-related infection: ated surgical complications was Effect on outcomes similar,” said first author Daniel Patients with Patients with no Olvera-Posada, MD, an endoubiopsy-associated biopsy-associated rology fellow from the Univerinfection infection sity of Western Ontario. 19.6% 13.1% Transfusion rate “Using administrative data 30-day post-RP from the province of Ontario, 6.6% 3.3% readmission we found that infectious complirate cations significantly increased Source: Daniel Olvera-Posada, MD along the years of the study even though oncological and ❳ UT ❲ UrologyTimes.com ∣ ❳ Clinical Updates ❲ JUNE 2016 TRUS: ‘Real-world data’ from multiple centers continued from page 10 that although prostatectomy outcomes are similar, there is a slightly increased risk of the need for blood transfusion,” Dr. Olvera-Posada told Urology Times. No effect on 30-day post-op mortality The study, which was presented at the AUA annual meeting in San Diego, noted that no differences were found in the proportion of patients requiring adjuvant radiation, hormonal therapy, or surgical procedures to treat incontinence or erectile dysfunction. The 30-day post-op mortality was not affected. Outcomes were assessed in the first 12 to 24 months after radical prostatectomy. The study was extensive. Using data from the Institute for Clinical Evaluation Services (ICES), the authors identified a populationbased cohort of 27,637 patients from Ontario who had undergone a radical prostatectomy between April 2002 and March 2013. Infectious complications were defined as hospitalization with evidence of a urinary tract infection or sepsis within 30 days of a TRUS-guided prostate biopsy. A total of 530 patients (1.9%) had an infectious event following biopsy. The primary endpoint was a composite of surgical complications that included the need for postoperative treatment of urinary fistula, intestinal diversion, upper urinary tract obstruction, or ureteral repair. Patients with a biopsy-associated infection showed a 19.6% rate of transfusion, compared to 13.1% of the non-infectious complication group. The 30-day post-prostatectomy hospital readmission rate for those with infections following biopsy was twice that of those with no recorded infections (6.6% vs. 3.3%; OR: 2.06, 95% CI: 1.46-2.93, p<.0001). The statistical difference in the length of hospital stay was not clinically meaningful. “The analyzed data come from many centers with dozens of surgeons using different approaches. It is real-world data that includes outcomes from community and teaching hospitals. Unfortunately, the information did not contain patient-level data; however, populationbased information represents the real world,” said Dr. Olvera-Posada, working with Stephen E. Pautler, MD, and colleagues. “We were using administrative information and were unable to see important variables such as the pathological stage, prostate volume, or baseline urinary function. Those and other variables should be taken into consideration to get a better answer to the clinical questions the study raised,” Dr. Olvera-Posada said. Dr. Olvera-Posada said the research was con- ducted to add more information regarding the deleterious impact of infectious complications following prostate biopsy. The initial research that raised this issue, published by Nam et al in the Journal of Urology (2010; 183:963-8), found that hospital readmission rates for men undergo- Flexor Parallel ® ing TRUS biopsies in Ontario had quadrupled from 1.0% to 4.1% between 1996 and 2005 (p for trend <.0001) The vast majority (72%) of the readmission rates were related to infections. “We knew that there is an increased rate of infectious complications following a prostate biopsy. We wanted to find out what effects those complications might have on surgical outcomes following radical prostatectomies,” said Dr. Olvera-Posada. UT ™ R A P I D R E L E A S E ™ U R E T E R A L A C C E S S S H E AT H MEDICAL 11 12 ❳ Clinical Updates ❲ JUNE 2016 ∣ Urology Times Assay predicts outcomes in men taking mCRPC agent AR-V7 detection associated with 0% PSA response, significantly inferior survival Wayne Kuznar UT CORRESPONDENT San Francisco—Expression of androgen recep- tor splice variant 7 (AR-V7) in whole blood predicts worse cancer-related outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) who are treated with abiraterone acetate (ZYTIGA). Using a real-time polymerase chain reaction (RT-PCR) assay, detection of AR-V7 transcripts in whole blood was associated with a 0% PSA response rate and significantly inferior progression-free survival and overall survival in patients treated with abiraterone, Australian researchers reported at the Genitourinary Cancers Symposium in San Francisco. AR-V7, a truncated form of the androgen receptor that lacks the ligand-binding domain, is relatively common among men with mCRPC. The missing C-terminal of AR-V7 is important because it’s the part of the androgen receptor that androgen receptor inhibitors bind. Previous work at Johns Hopkins University, Baltimore has shown that AR-V7 expression in circulating tumor cells was associated with resistance to abiraterone and enzalutamide (XTANDI) (N Engl J Med 2014; 371:1028-38). In this study, PSA response rates were also 0% in AR-V7positive patients who were treated with either abiraterone or enzalutamide. “Ours is a small cohort at only 37 patients, but in our patients who have AR-V7-positive disease, we’re seeing similar results in terms of no PSA response rate and poorer survival,” said coauthor Arun Azad, MD, a medical oncologist at Monash University, Melbourne, Australia. “You might ask what’s the benefit of our study on top of what we already know from the Johns Hopkins study,” he said. “The difference here is the assay. This is a whole blood RNA assay using PAXgene tubes, which are not time sensitive, unlike the AdnaGen test that was used in the Johns Hopkins study, which also requires collection of circulating tumor cells.” PAXgene RNA tubes are collected using 2.5 mL of whole blood. The tube is inverted eight to 10 times and then placed into a –70ºC freezer, after which it can be analyzed at any time up to 7 years later. ‘A very user-friendly assay’ “It’s a very user-friendly assay, unlike the AdnaGen, which needs to be done within 4 hours and has a lot of other steps in terms of processing,” said Dr. Azad. Using this assay, while at the British Colum- bia Cancer Agency in Vancouver, BC, he and Table AR-V7 expression and colleagues including outcomes in men with mCRPC Tilman Todenhöfer, AR-V7-posi- AR-V7-negaMD (who led develtive patients tive patients p-value opment of the assay), 0% 41.9% .04 sought to correlate PSA50 response rate AR-V7 expression with 0% 52% .051 PSA30 response rate outcomes in 37 patients Median progression0.7 4 <.001 with mCRPC treated free survival (months) with abiraterone aceMedian overall survival 6.6 22.1 .0004 tate. RT-PCR was per(months) formed for the following Source: Arun Azad, MD genes: AR-V7, FOXA1, GR H L2, HOX B13, K LK2, K LK3, and TMPRSS2:ERG. For each gene, the highest com- cial or other relationship with Astellas Pharma, puted tomography value among 20 normal con- Janssen Pharmaceuticals, Janssen Oncology, trols was set as the threshold for a positive test. and/or other pharmaceutical companies. UT Median patient age was 70 years and 59% had received prior docetaxel (Taxotere). None had received abiraterone or enzalutamide previously. Four patients (11%) were AR-V7-positive. AR-V7-positive patients were more likely to have high levels of alkaline phosphatase (p=.04) By Lisette Hilton and lactate dehydrogenase (p=.07) and more often had Eastern Cooperative Oncology Group In a study of 8,820 men with metastatic castrationPerformance Status ≥2 (p=.052) than those who resistant prostate cancer, researchers found the were AR-V7-negative. prognosis differs substantially based on where the The PSA50 response rate, defined as PSA cancer has spread. decline ≥50% confirmed ≥3 weeks later, was Spread to the liver is associated with shorter sur0% in AR-V7-positive patients compared with vival than lung and bone spread, and patients with 41.9% in AR-V7-negative patients (p=.04). lymph node metastases only have the best overall PSA30 response rates were 0% and 52% survival, according to co-author Andrew Armstrong (p=.051) in the AR-V7-positive and AR-V7MD, ScM, of Duke Cancer Institute, Durham, NC. negative patients, respectively. The study, which was published in the Journal Median progression-free survival was of Clinical Oncology (2016; 34:1652-9), is based on a 0.7 months in AR-V7-positive patients and 4 substantial sample of men who received docetaxel months in AR-V7-negative patients (p<.001). (Taxotere) chemotherapy in nine phase III trials, Median overall survival was 6.6 months in the according to the study’s abstract. AR-V7-positive patients and 22.1 months in the The authors categorized the sites of metastases AR-V7-negative patients (p=.0004). as lymph node only, bone with or without lymph Significant predictors of worse overall surnode (with no visceral metastases), any lung metasvival were AR-V7-positive status (p=.007), an tases (but no liver), and any liver metastases. increased level of ALP (p=.02), ≤36 months on They found that more than 72% of those studied primary hormone therapy (p=.03), >2 markhad bone with or without lymph node metastases, ers that were positive (p=0.03), and HOXB13 9.1% had lung metastases, 8.6% had liver metastasis, positivity (p=.02). and 6.4% had lymph node-only disease. “It’s reassuring that the PAXgene tubes assay The highest median survival of about 32 months is showing similar results to what has been seen occurred in the lymph node-only group. Overall with the AdnaGen assay, but it’s potentially median survival for the majority who had bone more user friendly and therefore more useful metastases was just over 21 months. Men with lung as a companion diagnostic down the line,” said metastases had a median survival of 19 months. And Dr. Azad. men with liver metastasis fared the worst with a Dr. Azad has received honoraria from Jansmedian survival of nearly 14 months. sen-Cilag and is a consultant/adviser for Astellas Pharma. Several of his co-authors have a finan- ❳ UT ❲ PCa: Site of metastases impacts prognosis NOW APPROVED Learn more at TECENTRIQ.com/info © 2016 Genentech USA, Inc. All rights reserved. PDL/111215/0102 14 ❳ Clinical Updates ❲ JUNE 2016 ∣ Urology Times AS successful among very low-, low-risk PCa patients Surveillance also found viable in select men with intermediate-/high-risk disease Wayne Kuznar UT CORRESPONDENT San Diego—Active surveillance (AS) as a man- agement paradigm is associated with low rates of mortality and metastases among patients with very low- or low-risk prostate cancer, and also among selected men with intermediate- and high-risk disease, according to a chart review of patients managed with AS at Cleveland Clinic. The investigators also cited the high success of patients with deferred therapy, supporting the safety of AS in appropriate prostate cancer patients. “What you can gather from our experience, with regards to the safety of AS, is that rarely do men chosen for surveillance have mortality as a result of their cancer,” said lead investigator Yaw Nyame, MD, who presented the findings at the AUA annual meeting. “It happens, but it’s just not common.” Follow-up data from 635 men managed with AS for localized prostate cancer from 2002 to 2015 were reported. Patients selected for AS are managed with interval PSA measurement and prostate biopsy at the discretion of 11 different urologists. Curative treatment was recommended with an increase in disease grade or volume (>50% of total cores). Of the 635 men, 514 were classified as very low risk/low risk (median age at diagnosis, 65.1 years) and 117 as intermediate risk/high risk (median age at diagnosis, 68.6 years). Data were insufficient to classify four of the men. “When we first were offering active surveillance in our institution, we used criteria that had been established by clinicians at Johns Hopkins, and a lot of the patients that we were surveilling were not only low risk but they were very low risk because that’s where the data was most supportive of less intervention,” said Dr. Nyame, a urology resident at the Glickman Urological and Kidney Institute at Cleveland Clinic working with Eric A. Klein, MD, and colleagues. “So if you look at our experience, we have a higher percentage of low-risk and very low-risk patients in our early experience that are being offered surveillance. At the same time, there were these rare patients that were a little older and a little sicker that were intermediate risk that we were offering surveillance to because we felt that the morbidity of surgery and risk of surgery outweighed the risk of prostate cancer mortality.” About one-third of men in the intermediate-/ high-risk category had a serum PSA of 10.1 to 20.0 ng/mL and an additional 6.8% had serum PSA >20.0 ng/mL. Some 57.3% of this group had Gleason 3+4 disease and 9.4% had a Gleason 4+3 pattern. More than 90% (92.3%) of the intermediate-/high-risk group were considered intermediate risk by National Comprehensive Cancer Network (NCCN) criteria and 7.7% were NCCN high risk. The median follow-up was 50.5 months (51.2 months in the very low-risk/low-risk cohort; 44.2 months in the intermediate-/high-risk cohort). The primary outcome was mortality and the development of metastasis. No PCa-specific deaths reported All-cause mortality while on AS was 2.5% (16 deaths), with no prostate cancer-specific deaths, and 0.8% (4/533) developed metastatic disease. By risk category, the cumulative incidence of mortality at 5 years was 0.37% in the very lowrisk/low-risk patients and 1.38% in the intermediate-/high-risk patients. The 5-year incidence of local or distant metastases was 0.15% and 0.24% in the two risk groups, respectively. About one-third of men (35.2%) received treatment with curative intent, with a median time to treatment of 16 months. The most common primary therapy was radical prostatectomy (46.1%) followed by brachytherapy (37.1%), external beam radiation (7.8 %), and cryoablation (6.4%). “Roughly sixty percent of the 635 men at 5 years didn’t require an operation or radiation, and that’s significant,” said Dr. Nyame. “Our data are very similar to what has been reported previously even though we had a more heterogeneous risk group, but longer follow-up is needed with our intermediate-/high-risk patients to ensure they have similar outcomes reported from the Toronto and Hopkins cohorts.” UT Female Urology Benefit seen in patients with UI, UF, or both Neuromodulation: QoL improvement seen at 3 years Randy Dotinga UT CORRESPONDENT San Diego—A new industry-funded study has found that sacral neuromodulation patients with urgency incontinence, urgency frequency, or both—almost all of whom were women— report improvement in quality of life measures after 3 years of treatment. The patients had failed an average of two medications, said lead author Karen Noblett, MD, professor of clinical obstetrics and gynecology and chair of obstetrics and gynecology at the University of California Riverside School of Medicine, Riverside. According to Dr. Noblett, the findings “suggest we probably should move to third-line therapies more quickly and not prescribe medication after medication if they’ve failed a couple.” T he I nterSt i m system (Medtronic, Minneapolis) is FDA-approved for urinary incontinence, urgency-frequency, urinary retention, and fecal incontinence. “It’s a third-line therapy Dr. Noblett after behavioral therapy and medications,” Dr. Noblett told Urology Times, and unique because patients can test the therapy over a trial period to see if it helps them. If the treatment works, then the device is implanted permanently in the body. “It’s a very minimally invasive outpatient procedure, done with just local anesthesia and IV sedation,” she said. The new study, presented at the AUA annual meeting in San Diego, is a retrospective subanalysis of a 5-year prospective study into the use of tined leads to hold the device in tissue. This research satisfies the FDA’s request for post-approval analysis, she noted. “We saw significant improvement,” Dr. Noblett said, “and we wanted to see if that would differ in patients with just urgency frequency versus those with urgency incontinence.” The study examined 272 subjects, 91% of whom were female, with an average age of Please see NEUROMODULATION, page 15 UrologyTimes.com ∣ ❳ Clinical Updates ❲ JUNE 2016 15 Renal mass biopsy: How it impacts management Strong positive predictive value when paired with size-based management algorithm Robert M. Turner, II, MD SPECIAL TO UROLOGY TIMES Ann Arbor, MI—At the 2015 Society of Urologic Oncology annual meeting in Washington, J. Stuart Wolf, Jr., MD, addressed concerns about the diagnostic inaccuracies of core renal biopsy in the diagnosis of small renal masses. In his presentation, Dr. Wolf argued, “Biopsy does not need to perfectly identify histologic type and grade when it is paired with a riskstratified, size-based management algorithm.” In a study conducted at the University of Michigan, Ann Arbor, where Dr. Wolf is professor of urology, investigators considered an approach that combined core biopsy risk stratification with an algorithm based on size (J Urol 2013; 189:441-6). To test reliability of the approach, the authors compared the treatment assignment (surveillance vs. excision) in 151 patients based on size and biopsy histology with the appropriateness of that assignment as which incorporates both size and biopsy histoldetermined by final pathology after surgical ogy, been applied preoperatively. “The greatest liability [of incorporation of excision. Dr. Wolf demonstrated that use of renal mass biopsy, combined with a size-based renal mass biopsy in treatment decisions] is management algorithm, has an excellent posiPlease see RENAL MASS BX, page 16 tive predictive value (100% in that study) but an imperfect negative predictive value (86%). The combination of renal mass biopsy with a size-based management algorithm was also applied to a multi-institutional database compiled by active robotic partial nephrectomy surgeons (J Urol 2014; 192:1337-42). In that study, the authors concluded that Crafted for Perfection. about half the patients theoretically could have avoided Created for Performance. surgery had the algorithm, Lipshultz Epididymovasostomy Microdissection Scissors are like Diamonds... Cut with Precision... the way you do. NEUROMODUL AT ION continued from page 14 57 years. Of the subjects, 104 (51%) had both incontinence and frequency symptoms, while 54 (27%) had incontinence only, and 44 (22%) had frequency symptoms only. All groups showed significant improvement over baseline at 36 months in Health Related Quality of Life and ICIQ-OABqol subscales of Concern, Coping, Sleep, Social, and Interference (all p<.0001). “Not only are their diaries showing that they have fewer bladder symptoms, but these improvements are having a significant effect on their quality of life,” Dr. Noblett said. However, incontinence-only patients showed less improvement than the other groups in the Sleep subscale (p<.02), and they scored lower on the Coping subscale than those with both conditions. Nearly 80% improvement in Interference On the Interference measure, which refers to interference with daily activities, about 80% of the subjects in all three groups reported they improved or greatly improved. This is an intriguing finding because some observers might assume that patients with incontinence would experience the greatest benefit due to the effects of leaking urine, Dr. Noblett said. While patients often don’t have full relief from urinary symptoms, she said, patients are often still pleased. “They’ve gone from wearing a diaper to a panty liner. If you’re an adult woman, and you don’t have a diaper anymore, that will have a significant impact on quality of life.” Overall, she said, “We were very happy to see the response was so robust and well-maintained over the 48 months we’ve collected the data,” she said. “We’ll continue to compile outcome data at 48 months and at 60 months of the 5-year period. We want to identify the ideal candidates for this therapy and predict who may respond more than others.” The study was funded by Medtronic. Dr. Noblett serves on the advisory board for the company and was a participant in the InSite trial of the InterStim system. Several of Dr. Noblett’s coauthors were consultants/ advisers and/or investigators for or employees of Medtronic. UT Larry I. Lipshultz, M.D., Professor of Urology, Baylor College of Medicine Gentle curve at the tip assures perfect elliptical cut. SDC-15R VL Micropoint tip. Enables the careful dissection of the tunica of the epididymis for epididymal tubular exposure. Decreases the chance of inadvertently opening an epididymal tube during dissection. Well-balanced, resting easily in the hand. Unusually smooth ventrally. ® ACCURATE SURGICAL & SCIENTIFIC INSTRUMENTS® For diamond perfect performance® accurate surgical & scientific instruments corporation 800.645.3569 516.333.2570 fax: 516.997.4948 west coast: 800.255.9378 www.accuratesurgical.com © 2015 ASSI® 16 ❳ Clinical Updates ❲ JUNE 2016 ∣ Urology Times Sexual Dysfunction Curvature reduced most dramatically after first cycle Peyronie’s treatment cycles evaluated in study UT CONTRIBUTING EDITOR San Diego—Findings of a retrospective review of men receiving intralesional collagenase clostridium histolyticum (CCH; Xiaflex) for Peyronie’s disease may help inform therapeutic decisions on number of cycles. Conducted by researchers at Tulane University School of Medicine in New Orleans, the study analyzed serial and total changes in penile curvature in 77 men, of whom 41 (53%) completed four cycles of CCH treatment (eight total injections). The findings were presented at the AUA annual meeting in San Diego. Overall, mean curvature decreased significantly from 58.2° at baseline to 41.0° after the last cycle of injections. Comparing men who achieved a ≥20° change from baseline to those with less curvature reduction based on a number of variables showed the two groups differed significantly only in the amount of curvature reduction achieved after the first treatment cycle (–16.2° vs. –5.9°, respectively; p<.001). Analysis of change in penile curvature after each injection cycle was done using a repeated measures model. It showed mean curvature was reduced most dramatically after the first cycle (–12.0°), and there was continued improvement between the second and third and third and fourth sets of injections (mean reduction of –4.6° and –4.8°, respectively). However, there was essentially no significant change in penile curvature as a result of the fourth cycle, said first author James Anaissie, a fourth-year medi- RE N A L M A S S B X continued from page 15 false negatives,” Dr. Wolf conceded. He noted that, in his updated series, 17% of patients would have been incorrectly assigned to surveillance, and in fact harbored worse pathology than suggested by biopsy. He was reassured, however, that those patients who underwent delayed intervention had similar rates of partial nephrectomy and adverse pathology when compared with those patients who underwent early intervention. Furthermore, in patients undergoing surveillance, increasing growth rate was associated with adverse pathology. In data from the University of Michigan, there was a 10% increase in odds of adverse pathology for each 1 mm/ year change in growth rate. cal student at Tulane University. “CCH can be an effective treatment for Peyronie’s disease, but the response is variable, it is expensive, and the injections are painful,” he said. of CCH on mean ❳ UT Figure ❲ Effect curvature in Peyronie’s 80 How to counsel patients 58.2° 60 “Our study indicates that urologists may counsel patients who have a strong response to the first cycle that they are likely to have 41.0° a better final outcome, so they may feel 40 more confident about continuing. On the other hand, men who had a more modest change in curvature could be told they may 20 still achieve significant benefit with further cycles, but that they are less likely to have a bigger response at the end.” Senior author Wayne J.G. Hellstrom, 0 Baseline After last cycle of MD, noted that four CCH cycles has treatment become standard of care for treating PeySource: James Anaissie and Wayne J.G. Hellstrom, MD ronie’s disease because it was the regimen used in the large Investigation for Maximal Peyronie’s Reduction Efficacy and Safety Studies (IMPRESS). The findings tors of final curvature reduction ≥20° included of this retrospective study, however, call the patient age, duration of Peyronie’s disease, pretreatment curvature, curvature direction, degree four-cycle protocol into question. “What constitutes the optimal number of of fibrosis, vascular findings from duplex DopCCH cycles has not been systematically inves- pler examination, and number of treatment cycles. tigated. Our study does not provide conclusive Aside from response to the first cycle, none of the data to state definitively that a fourth cycle is factors was found to differ significantly comparnot effective,” said Dr. Hellstrom, professor of ing men with a final curvature reduction ≥20° urology and chief of andrology at Tulane Uni- with those having a lesser response. versity School of Medicine. Dr. Hellstrom was lead investigator for the In addition to change in curvature after the first IMPRESS trials and is a speaker for Endo Pharcycle, the variables analyzed as possible predic- maceuticals. UT Mean curvature Cheryl Guttman Krader Based on these findings, Dr. Wolf concluded that patients incorrectly assigned to surveillance can be adequately salvaged, mitigating much of the concern about false negative renal biopsy. Renal mass biopsy also informed type of treatment in those patients who were ultimately treated, said Dr. Wolf. Using a subset of the University of Michigan small renal mass Dr. Wolf database, he demonstrated that worse pathology on biopsy was associated with increased rate of radical nephrectomy in patients aged 55-75 years. Referring to this and other work, Dr. Wolf concluded, “The clinical utility of biopsy is greatest in patients 55 to 75 years of age with tumors 2-4 cm in size.” Lastly, Dr. Wolf made a case that renal mass biopsy has not been useful to identify those patients who are likely to be maintained on active surveillance. He pointed to data from his institution that demonstrated that size and growth rate, but not biopsy pathology, was associated with delayed intervention in those patients on surveillance. Dr. Wolf left the audience with an air of optimism about the future of renal mass biopsy. He previewed yet-to-be presented data introducing a multi-gene signature with a highly discriminative association with renal cancer recurrence and cancer specific mortality. “We may finally be at the doorstep of the holy grail of renal mass biopsy, which is to get molecular markers to really help us determine the risk for [an individual] patient,” he said. UT For men with mCRPC who have progressed on ADT Z Y T I G A® & P R E D N I S O N E LET’S STRONG DO THIS TOGETHER INDICATION ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). IMPORTANT SAFETY INFORMATION Contraindications—ZYTIGA® is not indicated for use in women. ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant. Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) because these patients were excluded from these randomized clinical trials. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly. Adrenocortical Insufficiency (AI)—AI was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations. mCRPC = metastatic castration-resistant prostate cancer; ADT = androgen-deprivation therapy. Please see additional Important Safety Information on the next pages. Please see brief summary of full Prescribing Information on subsequent pages. For men with mCRPC who have progressed on ADT ZYTIGA® & PREDNISONE: (abiraterone acetate) In the final analysis of the pivotal phase 3 trial*… ZYTIGA® + prednisone achieved a median OS of almost 3 years (34.7 months) after a median 4 years (49 months) of follow-up† 4.4 months improvement in median overall survival—34.7 months with ZYTIGA® + prednisone vs 30.3 months with placebo + prednisone (active compound)‡ — Co-primary end point—median OS: hazard ratio (HR)=0.81; 95% CI: 0.70, 0.93; P=0.0033 Co-primary end point—at the prespecified rPFS analysis, median not reached for ZYTIGA® + prednisone vs a median of 8.28 months for placebo + prednisone; HR=0.425; 95% CI: 0.347, 0.522; P<0.0001§II IMPORTANT SAFETY INFORMATION Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. Adverse Reactions—The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. Drug Interactions—Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. In a drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA® treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA® dosing frequency only during the co-administration period [see Dosage and Administration (2.3)]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone. continued on next page Janssen Biotech, Inc. © Janssen Biotech, Inc. 2016 02/16 044350-151207 Please see brief summary of full Prescribing Information on subsequent pages. Let’s do this Prespecified secondary end point¶ ZYTIGA® + prednisone significantly delayed median time to initiation of cytotoxic chemotherapy ZYTIGA® + prednisone vs placebo + prednisone: 25.2 vs 16.8 MONTHS Secondary end point—HR=0.580; 95% CI: 0.487, 0.691; P<0.0001 IMPORTANT SAFETY INFORMATION—continued Use in Specific Populations—Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C). 034441-150514 Drug Interactions—continued ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate drug. In a CYP2C8 drug interaction trial in healthy subjects, the AUC of pioglitazone, a CYP2C8 substrate, was increased by 46% when administered with a single dose of ZYTIGA®. Patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA®. OS = overall survival; rPFS = radiographic progression-free survival. *Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, doubleblind, placebo-controlled, multicenter trial in patients with mCRPC who had not received prior chemotherapy (N=1,088). Patients were using a luteinizing hormone-releasing hormone (LHRH) agonist or were previously treated with orchiectomy. In the ZYTIGA® arm, patients received ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily. In the placebo arm, patients received placebo orally once daily + prednisone 5 mg orally twice daily. In this study, the co-primary efficacy end points were OS and rPFS. Select exclusion criteria included aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≥2.5X ULN, liver metastases, moderate or severe pain, opiate use for cancer pain, prior ketoconazole treatment for prostate cancer, a history of adrenal gland or pituitary disorders, and visceral organ metastases. Concurrent use of spironolactone was not allowed during the study period. † At a prespecified final analysis for OS, 65% (354/546) of patients treated with ZYTIGA® + prednisone compared with 71% (387/542) of patients treated with placebo + prednisone had died. ‡ Prednisone, as a single agent, is not approved for the treatment of prostate cancer. § rPFS was assessed with the use of sequential imaging studies and was defined by bone scan identification of 2 or more new bone lesions with confirmation (Prostate Cancer Working Group 2 [PCWG2] criteria) and/or modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria for progression of soft tissue lesions. Analysis of rPFS utilized centrally reviewed radiographic assessment of progression. II At the prespecified rPFS analysis, 150 (28%) of patients treated with ZYTIGA® + prednisone and 251 (46%) of patients treated with placebo + prednisone had radiographic progression. ¶ The secondary efficacy analysis presented here is as of the December 20, 2011, cutoff date.1 Reference: 1. Data on file. Janssen Biotech, Inc. Learn more today at www.zytigahcp.com STRONG T O G E T H E R ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information. ZYTIGA® (abiraterone acetate) Tablets INDICATIONS AND USAGE ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer. CONTRAINDICATIONS Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations]. Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients. The most common adverse reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5X ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months. WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information]. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions]. Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information]. The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown. ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and Precautions]. • Adrenocortical Insufficiency [see Warnings and Precautions]. • Hepatotoxicity [see Warnings and Precautions]. Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Table 1: Adverse Reactions due to ZYTIGA in Study 1 ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/discomfort2 29.5 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3 General disorders Edema4 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract infection 11.5 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0 Injury, poisoning and procedural complications Fractures5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest discomfort7 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.3 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness 4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture 6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively). 8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased ZYTIGA® (abiraterone acetate) Tablets ZYTIGA® (abiraterone acetate) Tablets Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm. Table 4: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of Study 2 Abiraterone (N=542) Placebo (N=540) Laboratory Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Abnormality % % % % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry 56.6 6.5 50.9 5.2 Hyperglycemia1 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 1Based on non-fasting blood draws Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) Placebo (N=394) Laboratory All Grades Grade 3-4 All Grades Grade 3-4 Abnormality (%) (%) (%) (%) Hypertriglyceridemia 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Hypokalemia 28.3 5.3 19.8 1.0 Hypophosphatemia 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 Study 2: Metastatic CRPC Prior to Chemotherapy: Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases. Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months. Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 25.1 0.4 20.7 1.1 Edema2 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders 30.3 2.0 25.2 2.0 Joint swelling/discomfort3 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2 Vascular disorders Hot flush 22.3 0.2 18.1 0.0 Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 13.5 0.2 Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders Insomnia 13.5 0.2 11.3 0.0 Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0 Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm. Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group. In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms. Post Marketing Experience The following additional adverse reactions have been identified during post approval use of ZYTIGA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis. Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis. DRUG INTERACTIONS Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3) in full Prescribing Information]. Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information]. In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone (CYP2C8 substrate) was increased by 46% when pioglitazone was given together with a single dose of 1,000 mg abiraterone acetate. Therefore, patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA [see Clinical Pharmacology (12.3) in full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could ZYTIGA® (abiraterone acetate) Tablets ZYTIGA® (abiraterone acetate) Tablets affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients. Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of ZYTIGA in pediatric patients have not been established. Geriatric Use: Of the total number of patients receiving ZYTIGA in Phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (N=8) or moderate (N=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function. In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (N=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold and the fraction of free drug increased 2-fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function. No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (ChildPugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C). If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3)] in full Prescribing Information. Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations]. OVERDOSAGE Human experience of overdose with ZYTIGA is limited. There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function. Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted in the range from 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician. • Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone. • Patients should be informed that ZYTIGA should not be taken with food and that no food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions. • Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to their physician’s instructions. • Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician. • Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests. • Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA. Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 ©Janssen Biotech, Inc. 2012 Revised: Dec 2015 044724-151215 UrologyTimes.com ∣ ❳ Clinical Updates ❲ JUNE 2016 17 Pediatric Urology Prevention of future UTI is parents’ most important consideration VUR decision tool incorporates parent preference Cheryl Guttman Krader UT CONTRIBUTING EDITOR San Diego—Researchers developing a stan- dardized shared decision-making tool for use by urologists and parents of children with vesicoureteral reflux (VUR) expect that it will be helpful for improving the quality of the provider-family discussion on VUR management options and ultimately parental satisfaction with care. The purpose of the tool is to enable parents and physicians to identify issues that are most important to the family when deciding on treatment. It would thereby allow a more robust and thoughtful conversation regarding treatment options that is framed around a particular family’s prioritization of risks and benefits. At the AUA annual meeting in San Diego, the authors presented the findings from completion of the first phase of the project that entailed detailed content analysis of semi-structured parental qualitative interviews to identify core themes describing parental preferences. “Management options for children with VUR include watchful waiting, antibiotic prophylaxis, and surgery. However, these choices may offer a similar risk-benefit balance, and so there is often no one right answer for a given child, but there may be a best answer that accounts for the family’s values and preferences. To date, however, there are no clinical tools that can assist parents in formulating an evidence-based decision while simultaneously taking their preferences into account,” said senior author Hillary L. Copp, MD, MS, “Our hypothesis is that using the tool to allow more informed decisionmaking will lead to improvement in overall decision quality and also parental satisfaction with care.” HILLARY L. COPP, MD, MS associate professor of urology at the University of California, San Francisco. “Such a decision-making tool is only as good as the foundation on which it is built. We are confident that we have now identified the different attributes of decision-making that are important to parents of children with VUR and have a solid base for creating the decisionmaking tool.” To identify core themes describing issues important to parents of children with VUR, Dr. Copp conducted semi-structured, qualitative interviews with parents of children who had been managed with the various treatment options. She continued to conduct interviews until no new ideas or concepts emerged. Then, transcripts of the interviews were reviewed and statements specifically differentiating between treatment options were extracted and grouped into themes by two independent researchers. 13 major themes identified Through that process, 13 major themes were identified, Dr. Copp said. The most frequently cited related to the ability of the option to prevent future urinary tract infections (85%). Other dominant themes related to each treatment option’s unique efficacy rate (85%), compliance burdens (77%), risk of antibiotic resistance (69%), risk of chronic kidney damage (62%), providing the feeling of taking action (62%), invasiveness (58%), and anesthesia requirement (50%). After building the decision tool, the authors will evaluate it in the clinic to determine when and how it is best used. In addition, they are planning to conduct clinical trials in which parents might be randomly assigned to receive standard information about VUR management options alone or with use of the decision-making tool in order to assess if the tool affects issues such as decisional quality, conflict, and regret. “Our hypothesis is that using the tool to allow more informed decision-making will lead to improvement in overall decision quality and also parental satisfaction with care,” Dr. Copp told Urology Times. Dr. Copp’s collaborators in this project include Christopher Saigal, MD, MPH, of the University of California Los Angeles, who developed a shared decision-making tool for men with prostate cancer; Anand Bodapati, PhD, MS, of Anderson School of Management, University of California Los Angeles, who has expertise in conjoint analysis for marketing science; Jonathan C. Routh, MD, MPH, of Duke University; and Geraldine Tran, of the University of California, San Francisco. UT Guidelines needed for pediatric counseling on fertility, sexual function In a commentary published online ahead of print in Pediatrics (May 19, 2016), researchers call for the creation of a panel of experts to develop communication guidelines for providers to use when counseling young patients on fertility and sexual function. The authors cite a growing body of literature on the long-term impact of various pediatric conditions and treatments on fertility and sexual function. Thus far, the main focus of research has been on fertility preservation prior to cancer therapy, according to a press release from Moffitt Cancer Center, Tampa, FL, which was one of the institutions involved with the commentary. There is minimal guidance for providers with regard to discuss- ing issues related to fertility and sexual function with pediatric patients after cancer treatment has ended, and on an ongoing basis in other pediatric populations. Although awareness about reproductive and sexual health is gradually increasing in the care of patients with rheumatic diseases, hematologic conditions, disorders of sex development, transgender health, and many genetic conditions, consistent practices regarding counseling are still lacking, the authors say. In some cases, the initial discussions about fertility may take place in infancy or early childhood, resulting in a situation where the patient could remain unaware of these implications until much later in life. The authors suggest that an interdisciplinary task force should be formed to develop specific guidelines for fertility and sexual function counseling in at-risk pediatric populations. They urge that these guidelines specify key points to cover at different developmental stages, discuss which health care provider holds responsibility for these communications, and provide direction on how to balance the goals of parents and patients. “Acknowledging the impact of reproductive and sexual function on patients’ long-term quality of life and incorporating routine counseling on these issues into treatment plans is essential to achieving optimal outcomes,” the authors concluded. 18 ❳Hands On❲ TH E L ATEST I N U RO LO G I C SU RG I C AL TECH N I Q U E S AN D O FFICE - BA S E D PRO CE D U R E S JUNE 2016 ∣ Urology Times How to manage recurrent UTIs in postmenopausal women Successful strategies incorporate treatment of contributing factors, preventive regimens Wade Bushman, MD, PhD ▪ Brian V. Le, MD, MA R Dr. Bushman Dr. Le Dr. Bushman is professor of urology and Dr. Le is assistant professor of urology at the University of Wisconsin, Madison. ecurrent urinary tract infections (UTIs) in postmenopausal women can be a particularly challenging problem. We acknowledge there is no clear-cut solution to this vexing problem, but various strategies can be employed that have found success. Asymptomatic bacteriuria is common in postmenopausal women, and the incidence increases with age, diabetes, and sexual activity. There is a correlation of bacteriuria with risk for symptomatic UTI; however, it is not recommended to treat asymptomatic bacteriuria, as it may paradoxically increase the risk of symptomatic UTI. The goal, then, is to treat as necessary but to avoid overtreatment. UTIs in postmenopausal women may occur with typical symptoms (urgency, frequency, dysuria, incontinence, and foul odor) or fever. In some patients, such as those with impaired mentation, the diagnosis can be less obvious and is often implicated as a causative factor in temporary decreased cognition. In patients with a history of lower urinary tract symptoms (LUTS), symptoms may be exacerbated by UTI, but in the absence of typical UTI symptoms it is often difficult to determine whether an up-tick in LUTS is really due to UTI or is simply symptomatic fluctuation superimposed on asymptomatic bacteriuria. Detailed history Section Editor Christopher M. Gonzalez, MD, MBA, is professor and chairman of urology at University Hospitals Case Medical Center and Case Western Reserve University School of Medicine, Cleveland. The appropriate management of a patient presenting with “recurrent UTIs” starts with an appropriate evaluation. First, a detailed history must be taken to elicit symptoms, severity (fevers, hospitalizations, ER visits), frequency (weekly, monthly), microbiology (organisms and resistance patterns), comorbidities, prior evaluations, treatments, and responses to date. Contributing conditions may be identified on physical examination, bimanual and vaginal exam, and post-void residual measurement. A key step is to elicit the symptoms associated with reported UTI episodes and match them with laboratory findings. Many times, the patient’s urinary symptoms are not due to bacterial infection. This distinction is critical to make, since prevalence of both asymptom- atic bacteriuria and LUTS is high in elderly women and bacteriuria may be inappropriately implicated as the cause of the patient’s troubles. In fact, patients may have primary voiding dysfunction and the diagnosis of “recurrent UTIs” may result from the follow-up cultures obtained by a diligent primary care physician after antibiotic treatment that really only shows re-colonization with asymptomatic bacteriuria. A key step in taking a patient’s history is to elicit the symptoms associated with reported UTI episodes and match them with laboratory findings. If a history is obtained that is consistent with recurrent bacterial UTIs with associated symptoms and prompt response to culture-directed antimicrobial therapy, then the next step is to rule out recurrent UTIs due to a hidden nidus of infection such as a stone, tumor, or foreign body. The tip-off is quickly relapsing infection with the same organism. If this is found, then a complete urologic evaluation with upper tract imaging and cystoscopy is indicated. In patients with recurrent UTIs with a variety of organisms and no history of febrile infection, neither cystoscopy nor upper tract imaging is necessary and the focus moves to management: treatment of contributing factors, prevention, and antibiotic treatment. Treatment of contributing factors Vaginal atrophy is common in postmenopausal women and can be identified on pelvic examination by the appearance of dry, friable, and thin mucous membranes. The pathogenesis of recurrent UTIs is believed to be due to alterations in bacterial flora, changes in vaginal pH, and breakdown of natural mucosal barriers pre- UrologyTimes.com ∣ ❳Hands On❲ JUNE 2016 venting ascending infection. The mechanism of local estrogen replacement stimulates blood flow, increases pH, and aims to restore mucosal barriers. A Cochrane review from 2008 cited two randomized clinical trials (RCTs) showing that vaginal estrogens reduced the recurrence of UTIs compared to placebo with RR of 0.25 and 0.64 in each study (Cochrane Database Syst Rev 2008:CD005131). No such benefit was found with oral estrogens. In our practice, if there is evidence of vaginal atrophy on pelvic examination, we strongly consider such an approach. The risks for local therapy are very low, with the most common side effect being local irritation. Preventive strategies The use of probiotics is controversial. Some RCTs show benefit while others do not. A major confounder is that the term “probiotics” is not specific. It includes oral and vaginal administration and may utilize either specific or multi-strain regimens. Thus, meta-analysis interpretation is limited. Furthermore, few studies looked specifically at UTIs in postmenopausal women. The purported mechanism of action of probiotics is to establish vaginal colonization that acts as a barrier to ascending infection, prevent re-colonization of the vagina by potential uropathogens, and modulate host defenses. The most compelling evidence is for use of intravaginal suppositories of Lactobacillus crispatus. In a recent RCT, use of such an approach had a relative risk of 0.50 in young women (Clin Infect Dis 2011; 52:1212-7). Given the low risk-benefit profile of intravaginal suppositories taken on a weekly basis after treatment of the acute UTI, this tends to be an attractive option for patients interested in non-antibiotic-based approaches. If intravaginal Lactobacillus suppositories are not available at a retail pharmacy, patients may be directed to online retailers such as Amazon. Cranberry extracts or cocktails taken on a daily basis are believed to reduce the risk of recurrent UTIs. The magnitude of their effect is somewhat under question as highlighted by a recent Cochrane analysis, but several RCTs and meta-analyses have demonstrated benefit compared to placebo (Cochrane Database Syst Rev 2012; 10:CD001321). Some of this variation may be due to lack of standardization of treatment. Nevertheless, cranberry extracts are an inexpensive, well-tolerated dietary supplement that has evidence supporting its use. Antibiotic strategies Antibiotic prophylaxis is a highly effective way to reduce the incidence of recurrent UTI. 19 ❳ UT Table ❲ Antibiotic prophylaxis for recurrent UTI Agent Brand name(s) Dosage Precautions Side effects Severe allergic reaction, fever, rash, GI symptoms GI symptoms, dizziness, seizure, arthralgia, tendon rupture Trimethoprimsulfamethoxazole Bactrim, Sulfatrim 400/80 mg Sulfa-allergy, liver or kidney dysfunction Ciprofloxacin Cipro, Proquin 250 mg Cephalexin Keflex 250 mg Interactions with medications affecting absorption, renal dysfunction (None) Nitrofurantoin Macrobid, Furadantin, Macrodantin 100 mg Kidney dysfunction GI symptoms, severe allergic reaction, rash Pulmonary fibrosis (rare), interstitial pneumonitis, abnormal urine color Source: Wade Bushman, MD, PhD, Brian V. Le, MD, MA The agents most commonly used are trimethoprim-sulfamethoxazole or trimethoprim (Bactrim, Sulfatrim), ciprofloxacin (Cipro, Proquin), cephalexin (Keflex), and nitrofurantoin (Macrobid, Furadantin, Macrodantin) (table). Standard dosing regimens use low-dose nightly administration to produce effective antibiotic concentrations in the urine without inducing resistance in the gut flora. This is critical since the gut is the source of potential uropathogens and higher doses will compromise the effectiveness of the prophylactic regimen. The recommended doses are trimethoprimsulfamethoxazole, 400/80 mg; ciprofloxacin, 250 mg; and cephalexin, 250 mg. Trimethoprim, 80 mg can be used in patients with sulfa allergy. Nitrofurantoin is a very useful prophylactic agent, especially because it is effective against many extended spectrum beta lactamase-producing Escherichia coli and is less likely to breed resistance, but use in the elderly is generally discouraged because of a relatively higher risk of serious side effects, including pulmonary fibrosis. Its use should therefore be based on a careful consideration of benefit versus risk. In postmenopausal women whose UTIs are clearly related to sexual activity, post-coital prophylaxis can be prescribed. Several studies have demonstrated that women, when appropriately counseled, can reliably recognize the symptoms of UTI and initiate empiric treatment. The concept of self-start therapy is to provide the patient with a treatment for early intervention for UTIs that occur with modest frequency (3-6 times per year). They are prescribed a single agent, and at the earliest signs of infection start therapy for a full treatment course—typically 3 days for an uncomplicated UTI. If symptoms do not respond quickly or are associated with fever, then they must seek prompt medical attention. Self-start therapy often alleviates patient anxiety, reduces the time-to-treat, and provides the patient with a sense of control. However, it must be emphasized that this strategy is recommended only for a highly reliable patient who has been thoroughly evaluated and appropriately counseled. Conclusions Recurrent UTI in the postmenopausal woman is a common problem that can be effectively addressed by a step-wise approach that produces historical and laboratory evidence for recurrent symptomatic UTIs, rules out bacterial persistence and relapsing infections that merit further diagnostic evaluation, identifies and addresses contributing conditions, and offers the patient an effective regimen of prophylaxis or self-start therapy. This entity should be distinguished from asymptomatic bacteriuria, which should be managed conservatively without antibiotics. UT 20 ❳Business of Urology❲ JUNE 2016 ∣ Urology Times MIPS: A first look at how it will affect your practice ‘Four-legged stool’ replaces PQRS, meaningful use, value-based payment modifier T he Centers for Medicare & Medicaid Services (CMS) has released a proposed rule regarding the implementation of the Medicare Access and CHIP Reauthorization Act (MACRA) of 2015. This article will summarize some of the details of the proposed rule, including an outline of the Merit-Based Incentive Payment System (MIPS), one of the key components of MACRA. It is important to remember the MACRA legislation was focused solely on Medicare and replacing the sustainable growth rate. In short, MACRA is not up for repeal, nor is this a piece of legislation tied to the Affordable Care Act directly; therefore, it is not expected to change even if there is a change following the presidential election. The proposed rule, released on April 27, 2016, is in fact the first step in introducing the rules for MIPS. As with any proposed rule from the Medicare system, there is a 90-day comment period allowing any interested party to criticize the rule, point out any inconsistencies, suggest changes, and propose modifications. The AUA, American Medical Association, American College of Surgeons, and other specialty organizations will be submitting comments by the deadline of June 27, 2016. As a participating provider, you have the opportunity to provide comments directly to CMS or to any one of the organizations that you feel may represent you. CMS expects a number of comments will be received and that modifications to this initial proposal will follow. CMS also indicated that it expects this program Ray Painter, MD, Mark Painter Urologist Ray Painter, MD, is president of Physician Reimbursement Systems, Inc., in Denver and is also publisher of Urology Coding and Reimbursement Sourcebook. Mark Painter is CEO of PRS Urology SC in Denver. will be modified as it is implemented over a period of several years. MIPS: The four-legged stool One of the key provisions of MACRA was the replacement of the current Physician Quality Reimbursement System, meaningful use, and value-based payment mod- ❳ ❯❯ THE BOT TOM LINE ❯❯ MONE Y MAT TERS 29 Health savings account provides triple benefit Please see MIPS, page 22 Proposed data submission ❲ clinicians reporting individually UT Table 1 mechanisms for MIPS-eligible Performance category/submission Combinations accepted Quality Data submission mechanisms Claims Qualified Clinical Data Registry (QCDR) Qualified registry EHR Administrative claims (no submission required) Resource Use Administrative claims (no submission required) Advancing Care Information Attestation QCDR Qualified registry EHR Clinical Practice Improvement Activities Attestation QCDR Qualified registry EHR Administrative claims (if technically feasible, no submission required) Business of Urology 23 MACRA pay models: What you can expect ifier—the three-legged “quality” stool— with MIPS, a four-legged stool comprising Quality, Resource Use, Clinical Practice Improvement Activities, and Advancing Care Information. For reporting under MIPS, CMS has indicated that it will continue to accept virtually all MIPS-required reporting via multiple formats. Similar to the reporting for the value-based payment modifier (VBM) today, some reporting will be considered automatic or administrative, meaning CMS will use information submitted to CMS via claims to calculate a portion of the composite program score (CPS). The CPS is a single scoring system that will be used for eligible clinicians. One of the stated goals of the new system is to eliminate overlap and decrease the workload of providers. (The jury is definitely still out on this projection.) Bonuses and penalties have been consolidated in the new system with a stair step approach to an eventual potential 9% bonus or a 9% penalty for all Medicare payments. Bonuses/penalties will be Coding and Reimbursement Source: Centers for Medicare & Medicaid Services Simply see more. NBI Narrow Band Imaging (NBI) visualized more bladder cancer than WLI* Now, there is an even more powerful way to visualize bladder cancer than traditional WLI. NBI is a patented Olympus visualization technology clinically proven to help physicians see up to 28% more Carcinoma In Situ (CIS). Just push the NBI button — it’s that simple. Call 1-800-848-9024 or visit SimplySeeMore.com to learn more about NBI. +17% White Light Imaging (WLI) Narrow Band Imaging (NBI) Patients +24% Tumors +28% Carcinoma 0U:P[\*0: *Based on a weighted average, studies have shown that using NBI allows physicians to visualize lesion boundaries. NBI is not intended to replace histopathological sampling as a means of diagnosis. 6S`TW\Z(TLYPJH0UJ;YHKLTHYRVYYLNPZ[LYLK;YHKLTHYRVM6S`TW\ZHUKP[ZH SPH[LKLU[P[PLZPU[OL<:HUKVYV[OLYJV\U[YPLZVM[OL^VYSK(SSWH[LU[ZHWWS`6(0<96(+ ❳Business of Urology❲ 22 JUNE 2016 Quality, EHR use among CPS components continued from page 20 awarded based on a sliding scale and are budget neutral, which means you will be in competition with your colleagues. Tables 1 and 2 demonstrate the group and individual reporting methods proposed for MIPS. The four elements of the CPS The proposed rule outlines the components of the MIPS CPS (table 3). Initially, the CPS will consist of the following elements: Quality Performance. CMS has touted that MIPS lowers the administrative burden. The Quality Performance area does provide a small amount of relief because although measures are still required (similar to and including exist- ❳ ❲ ing PQRS measures), there will “only” be six measures required, down from nine under the current PQRS. Additionally, the Quality Performance component allows for more flexibility as the restriction of three cross-cutting measures has been removed. Now, the six measures must include only one cross-cutting measure and one outcome measure, if available. If an outcome measure is not available, the eligible clinician may select a “high-priority” measure. As you can see from the tables, practices will be allowed to report in multiple ways. However, Medicare proposes to provide bonus points in the CPS for quality if you report through a qualified clinical data registry Proposed data submission mechanisms UT Table 2 for groups Performance category/submission Combinations accepted Quality Data submission mechanisms QCDR Qualified registry EHR CMS web interface (groups of 25 or more) CMS-approved survey vendor for CAHPS for MIPS (must be reported in conjunction with another data submission mechanism) Administrative claims (no submission required) Resource Use Administrative claims (no submission required) Advancing Care Information Attestation QCDR Qualified registry EHR CMS web interface (groups of 25 or more) Clinical Practice Improvement Activities Attestation QCDR Qualified registry EHR CMS web interface (groups of 25 or more) Administrative claims (if technically feasible, no submission required) Source: Centers for Medicare & Medicaid Services ❳ UT Table 3 ❲ Components of MIPS MIPS component Quality Performance Resource Use Clinical Practice Improvement Activities Advancing Care Information Comments Percentage of total CPS Replaces PQRS and part of the VBM 50% Replaces part of the VBM 10% No current measures in this area 15% Replaces MU program 25% Source: Centers for Medicare & Medicaid Services ∣ Urology Times (QCDR), certified EHR, qualified registry, or web interface. Resource Use. This component as proposed currently continues to employ similar formulas and methods currently in use in the VBM. CMS has acknowledged the system is flawed and is vowing to make some changes, but in the form of additional measures for episodes of care. This component is measured on the claims submitted to Medicare for each beneficiary and includes not only those services submitted by urologists but also services submitted by others. No additional reporting is required. Clinical Practice Improvement Activities (CPIA). CPIA is a new measure under MACRA. The proposed rule allows for points for participating in any CPIA selected from a list to add points to increase your score in this component. Individuals and groups will be essentially graded on a curve compared to others. Medical home participants and those in alternative payment models will be required/encouraged to participate by including CPIAs in the requirement for those programs. The Quality Performance component of MIPS allows for more flexibility as the restriction of three cross-cutting measures has been removed. CPIAs include tasks like using telehealth for treatment, developing patient surveys and improvement protocols based on results, participation in population health review and study, improved coordination of care, active engagement of Medicare beneficiaries, patient safety protocols and practice assessment, and participation in a QCDR. In all, there are 90 proposed CPIAs with varying values that can be implemented for a period of 90 days. Medicare has encouraged more input in this area, and more clarification and education undoubtedly will be required once the final rule is published. Advancing Care Information (ACI). Primarily, this portion of the CPS is to continue to encourage (insist/implore/require) the use of electronic health records based on the objectives of the HITECH Act, which provided incentives to adopt an EHR. As such, the proposed rule modifies the existing requirements for meanPlease see MIPS, page 23 The information in this column is designed to be authoritative, and every effort has been made to ensure its accuracy at the time it was written. However, readers are encouraged to check with their individual carrier or private payers for updates and to confirm that this information conforms to their specific rules. UrologyTimes.com ∣ 23 JUNE 2016 MACRA pay models: What you can expect CMS estimates >8,000 urologists will be subject to merit-based incentive payment system M ore than 1 year ago, President Obama signed into law the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA). This legislation was the product of overwhelmingly bipartisan support and was lauded by many health care stakeholders because it repealed the unpopular sustainable growth rate (SGR) method for updating the Medicare physician fee schedule. As physicians well know, the SGR led to uncertainty, threats of major pay cuts, and annual corrections known as the “doc fix.” MACRA is most notable for its sweeping changes to the way health care will be reimbursed in the future, and many have awaited details of its implementation. Those details began to emerge on April 27, 2016, when the Centers for Medicare & Medicaid Services (CMS) released its proposed rule for implementing MACRA. In a series of articles this year, I will examine what you need to know about the law, what the CMS proposed rule for implementation implies for the near and long-term future, and—when it is issued later this year—what the final rule means to your urology practice. (For more on the MACRA rollout, see “MIPS: A first look at how it will affect your practice, page 20, and “MACRA proposed rule brings new decisions,” page 43.) What MACRA does Here are the basics of the law: MACRA repealed the SGR updates to the Medicare Physician Fee Schedule and replaced it with a flat 0.5% annual fee increase until 2019; no further increases will occur until 2026. In 2019 and beyond, physician reimbursement will be tied to quality through participation in either the Merit-Based Incentive Payment System (MIPS) or an Advanced Alternative Payment Model (APM). Finally, in 2026, the Physician Fee Schedule will begin to increase again, but slightly faster for physicians in Advanced APMs than those in MIPS. Who is in MIPS versus an Advanced APM? According to the law, all eligible professionals will be subject to MIPS unless they meet one of three exceptions: They are in their first year of participation in Medicare; they do not exceed a low volume threshold of Medicare payments or patients; or they are a qualifying participant in an Advanced APM. In the proposed rule, CMS has suggested that the low volume threshold be less than or equal to $10,000 in Medicare payments or 100 Medicare patients. It is important to understand that MIPS is the default pathway, and it is only by qualifying for an exception that a professional can be excluded from MIPS. Most urologists are not in their first year of Medicare participation, and most urologists would exceed the low volume thresholds being proposed by CMS. The proposed criteria for being a qualifying participant in an Advanced APM are constraining for many specialists, including urologists. Therefore, it is widely believed (including AMA identifies several problematic issues continued from page 22 ingful use. The reporting period under MIPS is for a full calendar year. Clinical quality measures, computerized physician order entry, and clinical decision support have been removed as specific reporting measures. The CPS for this element is a combination of requirements including patient access and interoperability. Bonus points will be awarded to reporting to multiple sources and increasing patient access. Summary Stay tuned for the final rule, and be prepared to participate in or consider an alternative to par- ticipating in Medicare. There is a lot of money at stake. A few issues that were identified by the AMA as problematic include limited measures for some specialties, including urology; retention of current flawed methods for VBM; costs to providers for certified EHR technology; lack of ability of providers to perform true security risk assessments; reliance on hospital-based programs for clinical services; continuation of policies that physicians already fail; and a complexity that makes MIPS difficult to understand and implement, among other issues. MIPS, as noted by many, is going to impact The Bottom Line Robert A. Dowling, MD Dr. Dowling is vice president of medical affairs and policy for IntrinsiQ Specialty Solutions (an AmerisourceBergen Specialty Group company), a board-certified clinical informaticist, and the former medical director of a large metropolitan urology practice. He resides in Ft. Worth, TX. by CMS) that most physicians will be starting in MIPS in 2019. CMS will make this determination each year based upon the law and the criteria for “qualifying participant in an APM” when those criteria are finalized. Changes in reimbursement How will Medicare professionals be reimbursed under MIPS? Physicians will continue to be paid according to the Physician Fee Schedule with the adjustments outlined above. In addition, MACRA retires and replaces three federal programs and their associated payment adjustments at the end of 2018: the Physician Quality Reporting System, the Value-Based Payment Modifier, and the EHR Incentive Program (meaningful use). MIPS will instead adjust Medicare payments to professionals based on a composite score (on a scale of 0-100) of weighted performance in four areas: Quality, Cost, Advancing Care Information, and Clinical Practice Improvement Activities. (The proposed details for scoring performance, measurement periods, data submission, exceptions, and more are outlined in the CMS proposed rule and will be the subject of a future article.) A threshold of median or mean performance will be determined for the collective provider population in MIPS, and MIPS providers will Please see MACRA MODELS, page 28 the smaller practice more harshly than the larger group. Clearly, CMS has much work to do. Equally as obvious, physician groups have their work cut out for them. This rule is not final, but history tells us that a proposed rule is the foundation for any final rule set. MACRA requires change, and the changes outlined in the proposed rule comply. We encourage you to watch for your AMA, AUA, and state publications, read the summaries, and react to them or in concert with them as you see fit. This change is not going to be easy, but change never is. For our part, we will continue to watch for updates and attempt to develop recommendations and actions to meet the requirements of the “new Medicare” regardless of their final form. UT Actor portrayals. INDICATION XIAFLEX® is indicated for the treatment of adult men with Peyronie’s disease with a palpable plaque and curvature deformity of at least 30 degrees at the start of therapy. IMPORTANT SAFETY INFORMATION FOR XIAFLEX® WARNING: CORPORAL RUPTURE (PENILE FRACTURE) OR OTHER SERIOUS PENILE INJURY IN THE TREATMENT OF PEYRONIE’S DISEASE Corporal rupture (penile fracture) was reported as an adverse reaction in 5 of 1044 (0.5%) XIAFLEX®-treated patients in clinical studies. In other XIAFLEX®-treated patients (9 of 1044; 0.9%), a combination of penile ecchymoses or hematoma, sudden penile detumescence, and/or a penile “popping” sound or sensation was reported, and in these cases, a diagnosis of corporal rupture cannot be excluded. Severe penile hematoma was also reported as an adverse reaction in 39 of 1044 (3.7%) XIAFLEX®-treated patients. Signs or symptoms that may reflect serious penile injury should be promptly evaluated to assess for corporal rupture or severe penile hematoma which may require surgical intervention. Because of the risks of corporal rupture or other serious penile injury, XIAFLEX® is available for the treatment of Peyronie’s disease only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the XIAFLEX® REMS Program. • XIAFLEX® is contraindicated in the treatment of Peyronie’s plaques that involve the penile urethra due to potential risk to this structure and in patients with a history of hypersensitivity to XIAFLEX® or to collagenase used in any other therapeutic application or application method • Injection of XIAFLEX® into collagen-containing structures such as the corpora cavernosa of the penis may result in damage to those structures and possible injury such as corporal rupture (penile fracture). Therefore, XIAFLEX® should be injected only into the Peyronie’s plaque and care should be taken to avoid injecting into the urethra, nerves, blood vessels, corpora cavernosa or other collagen-containing structures of the penis • In the double-blind, placebo-controlled portions of the clinical trials in Peyronie’s disease, a greater proportion of XIAFLEX®-treated patients (4%) compared to placebo-treated patients (1%) had localized pruritus after up to 4 treatment cycles (involving up to 8 XIAFLEX® injection procedures). The incidence of XIAFLEX®-associated pruritus was similar after each injection regardless of the number of injections administered When Peyronie’s disease is on his mind THINK XIAFLEX ® FOR YOUR APPROPRIATE PATIENTS The only FDA-approved nonsurgical treatment option for adult men with Peyronie’s disease with a palpable plaque and curvature deformity of at least 30 degrees at the start of therapy XIAFLEX® should be administered by a healthcare provider experienced in the treatment of male urological diseases. Your patients may find it difficult to start a discussion about their erectile curvature, which could be Peyronie’s disease.1 You play an integral role in making sure they get help. Upon assessment, be sure to clarify with your patients, “Do you have a curved erection?” Get started Become a trained injector or refer your patients to trained injectors nearest them. Visit XIAFLEX.com /urot to find trained injectors. • Because XIAFLEX® contains foreign proteins, severe allergic reactions to XIAFLEX® can occur. Anaphylaxis was reported in a post-marketing clinical trial in one patient who had previous exposure to XIAFLEX® for the treatment of Dupuytren’s contracture. Healthcare providers should be prepared to address severe allergic reactions following XIAFLEX® injections. The safety of more than one treatment course of XIAFLEX® is not known • In the XIAFLEX® controlled trials in Peyronie’s disease, 65.5% of XIAFLEX®-treated patients developed penile hematoma, and 14.5% developed penile ecchymosis. Patients with abnormal coagulation (except for patients taking low-dose aspirin, eg, up to 150 mg per day) were excluded from participating in these studies. Therefore, the efficacy and safety of XIAFLEX® in patients receiving anticoagulant medications (other than low-dose aspirin, e.g., up to 150 mg per day) within 7 days prior to XIAFLEX® administration is not known. In addition, it is recommended to avoid use of XIAFLEX® in patients with coagulation disorders, including patients receiving concomitant anticoagulants (except for low-dose aspirin) • In the XIAFLEX® clinical trials for Peyronie’s disease, the most frequently reported adverse drug reactions (≥25%) and at an incidence greater than placebo included: penile hematoma, penile swelling, and penile pain Please see Brief Summary of full Prescribing Information, including Boxed Warning, on following pages. Reference: 1. Nehra A, Alterowitz R, Culkin DJ, et al. Peyronie’s disease: AUA guideline. J Urol. 2015;194(3):745-753. Rx Only XIAFLEX® is a registered trademark of Endo International plc or one of its affiliates. © 2016 Endo Pharmaceuticals Inc. All rights reserved. Malvern, PA 19355 XP-04473b/April 2016 www.xiaflex.com 1-800-462-ENDO (3636) XIAFLEX® (collagenase clostridium histolyticum) for injection, for intralesional use Brief Summary of Prescribing Information For complete information, see the full prescribing information for XIAFLEX. WARNING: CORPORAL RUPTURE (PENILE FRACTURE) OR OTHER SERIOUS PENILE INJURY IN THE TREATMENT OF PEYRONIE’S DISEASE Corporal rupture (penile fracture) was reported as an adverse reaction in 5 of 1044 (0.5%) XIAFLEX-treated patients in clinical studies. In other XIAFLEX-treated patients (9 of 1044; 0.9%), a combination of penile ecchymoses or hematoma, sudden penile detumescence, and/or a penile “popping” sound or sensation was reported, and in these cases, a diagnosis of corporal rupture cannot be excluded. Severe penile hematoma was also reported as an adverse reaction in 39 of 1044 (3.7%) XIAFLEX-treated patients [see Warnings and Precautions]. Signs or symptoms that may reflect serious penile injury should be promptly evaluated to assess for corporal rupture or severe penile hematoma which may require surgical intervention [see Warnings and Precautions]. Because of the risks of corporal rupture or other serious penile injury, XIAFLEX is available for the treatment of Peyronie’s disease only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the XIAFLEX REMS Program [see Warnings and Precautions]. INDICATIONS AND USAGE XIAFLEX is indicated for the treatment of adult men with Peyronie’s disease with a palpable plaque and curvature deformity of at least 30 degrees at the start of therapy. DOSAGE AND ADMINISTRATION Dosing Overview for Peyronie’s Disease XIAFLEX should be administered by a healthcare provider experienced in the treatment of male urological diseases, who has completed required training for use of XIAFLEX in the treatment of Peyronie’s disease. XIAFLEX, supplied as lyophilized powder, must be reconstituted with the provided diluent prior to use [see Dosage and Administration (2.2)]. The dose of XIAFLEX is 0.58 mg per injection administered into a Peyronie’s plaque. If more than one plaque is present, inject into the plaque causing the curvature deformity. A treatment course consists of a maximum of 4 treatment cycles. Each treatment cycle consists of two XIAFLEX injection procedures [see Dosage and Administration (2.2)] and one penile modeling procedure [see Dosage and Administration (2.2)]. The second XIAFLEX injection procedure is performed 1 to 3 days after the first. The penile modeling procedure is performed 1 to 3 days after the second injection of the treatment cycle. The interval between treatment cycles is approximately six weeks. The treatment course therefore, consists of a maximum of 8 injection procedures and 4 modeling procedures. If the curvature deformity is less than 15 degrees after the first, second or third treatment cycle, or if the healthcare provider determines that further treatment is not clinically indicated, then the subsequent treatment cycles should not be administered. The safety of more than one treatment course of XIAFLEX is not known. The table below displays an overview of the volume of sterile diluent for reconstitution and the reconstituted XIAFLEX solution to be used in the intralesional injection [see Dosage and Administration (2.2)]. Volumes Needed for Reconstitution and Administration Sterile Diluent for Reconstitution Volume 0.39 mL Reconstituted XIAFLEX Solution to be Injected1 Volume 1 0.25 mL The reconstituted XIAFLEX solution to be used in the intralesional injection contains 0.58 mg of XIAFLEX. Note: The entire reconstituted XIAFLEX solution contains 0.9 mg of XIAFLEX. Reconstituted XIAFLEX solution remaining in the vial after the injection should be discarded. Reconstitution of the Lyophilized Powder for Peyronie’s Disease a) Before use, remove the vial containing the lyophilized powder of XIAFLEX and the vial containing the diluent for reconstitution from the refrigerator and allow the two vials to stand at room temperature for at least 15 minutes and no longer than 60 minutes. Visually inspect the vial containing XIAFLEX. The cake of lyophilized powder should be intact and white in color. b) After removal of the flip-off cap from each vial, using aseptic technique swab the rubber stopper and surrounding surface of the vial containing XIAFLEX and the vial containing the diluent for reconstitution with sterile alcohol (no other antiseptics should be used). c) Use only the supplied diluent for reconstitution. The diluent contains calcium which is required for the activity of XIAFLEX. d) Using a 1 mL syringe with 0.01 mL graduations with a 27-gauge ½-inch needle (not supplied), withdraw a volume of 0.39 mL of the diluent supplied. e) Inject the diluent slowly into the sides of the vial containing the lyophilized powder of XIAFLEX. Do not invert the vial or shake the solution. Slowly swirl the solution to ensure that all of the lyophilized powder has gone into solution. f) The reconstituted XIAFLEX solution can be kept at room temperature (20º to 25ºC/68º to 77ºF) for up to one hour or refrigerated at 2º to 8°C (36º to 46°F) for up to 4 hours prior to administration. If the reconstituted XIAFLEX solution is refrigerated, allow this solution to return to room temperature for approximately 15 minutes before use. g) Discard the syringe and needle used for reconstitution and the diluent vial. Identification of Treatment Area for Peyronie’s Disease a) Prior to each treatment cycle, identify the treatment area as follows: • Induce a penile erection. A single intracavernosal injection of 10 or 20 micrograms of alprostadil may be used for this purpose. Apply antiseptic at the site of the injection and allow the skin to dry prior to the intracavernosal injection. • Locate the plaque at the point of maximum concavity (or focal point) in the bend of the penis. • Mark the point with a surgical marker. This indicates the target area in the plaque for XIAFLEX deposition. Injection Procedure for Peyronie’s Disease a) The reconstituted XIAFLEX solution should be clear. Inspect the solution visually for particulate matter and discoloration prior to administration. If the solution contains particulates, is cloudy, or is discolored, do not inject the reconstituted solution. b) Apply antiseptic at the site of the injection and allow the skin to dry. c) Administer suitable local anesthetic, if desired. d) Using a new hubless syringe containing 0.01 mL graduations with a permanently fixed 27-gauge ½-inch needle (not supplied), withdraw a volume of 0.25 mL of reconstituted solution (containing 0.58 mg of XIAFLEX). e) The penis should be in a flaccid state before XIAFLEX is injected. Place the needle tip on the side of the target plaque in alignment with the point of maximal concavity. Orient the needle so that it enters the edge of the plaque and advance the needle into the plaque itself from the side. Do not advance the needle beneath the plaque nor perpendicularly towards the corpora cavernosum. f) Insert and advance the needle transversely through the width of the plaque, towards the opposite side of the plaque without passing completely through it. Proper needle position is tested and confirmed by carefully noting resistance to minimal depression of the syringe plunger. g) With the tip of the needle placed within the plaque, initiate injection, maintaining steady pressure to slowly inject XIAFLEX into the plaque. Withdraw the needle slowly so as to deposit the full dose along the needle track within the plaque. For plaques that are only a few millimeters in width, the distance of withdrawal of the syringe may be very minimal. The goal is always to deposit the full dose entirely within the plaque. h) Upon complete withdrawal of the needle, apply gentle pressure at the injection site. Apply a dressing as necessary. i) Discard the unused portion of the reconstituted solution and diluent after each injection. Do not store, pool, or use any vials containing unused reconstituted solution or diluent. j) The second injection of each treatment cycle should be made approximately 2 to 3 mm apart from the first injection. Penile Modeling Procedure for Peyronie’s Disease Penile modeling helps relieve curvature deformity and straighten the penile shaft. At a follow-up visit 1 to 3 days after the second injection of each treatment cycle, perform a penile modeling procedure (as described below) on the flaccid penis to stretch and elongate the treated plaque: • Administer suitable local anesthetic, if desired. • Wearing gloves, grasp the plaque or indurated portion of the flaccid penis about 1 cm proximal and distal to the injection site. Avoid direct pressure on the injection site. • Using the target plaque as a fulcrum point, use both hands to apply firm, steady pressure to elongate and stretch the plaque. The goal is to gradually create bending opposite to the patient’s penile curvature, with stretching to the point of moderate resistance. Hold pressure for 30 seconds then release. • After a 30 second rest period, repeat the penile modeling technique for a total of 3 modeling attempts at 30 seconds for each attempt. In addition to the in-office penile modeling procedure, patients should be instructed to self-perform penile modeling activities at home each day for the 6-week period following the investigator penile plaque modeling visit of each treatment cycle as follows: • During spontaneous erections, gently attempt to straighten the penis without producing pain and hold the penis in a straightened position for 30 seconds. • The flaccid penis should be gently stretched three times daily. Slow, gentle force should be used without producing pain. CONTRAINDICATIONS XIAFLEX is contraindicated in: • the treatment of Peyronie’s plaques that involve the penile urethra due to potential risk to this structure. • patients with a history of hypersensitivity to XIAFLEX or to collagenase used in any other therapeutic application or application method [see Warnings and Precautions]. WARNINGS AND PRECAUTIONS Corporal Rupture (Penile Fracture) or Other Serious Injury to the Penis in the Treatment of Peyronie’s Disease Corporal rupture was reported as an adverse reaction after XIAFLEX injections in 5 of 1044 (0.5%) XIAFLEX treated patients in the controlled and uncontrolled clinical trials in Peyronie’s disease. In other XIAFLEX-treated patients (9 of 1044; 0.9%), a combination of penile ecchymoses or hematoma, sudden penile detumescence, and/or a penile “popping” sound or sensation was reported, and in these cases, a diagnosis of corporal rupture can not be excluded. These patients were managed without surgical intervention, but the long-term consequences are unknown. Severe penile hematoma was also reported as an adverse reaction in 39 of 1044 patients (3.7%) in the controlled and uncontrolled clinical trials in Peyronie’s disease [see Adverse Reactions]. Signs or symptoms that may reflect serious injury to the penis should be promptly evaluated in order to assess for corporal rupture or severe penile hematoma, which may require surgical intervention. Injection of XIAFLEX into collagen-containing structures such as the corpora cavernosa of the penis may result in damage to those structures and possible injury such as corporal rupture (penile fracture). Therefore, XIAFLEX should be injected only into the Peyronie’s plaque and care should be taken to avoid injecting into the urethra, nerves, blood vessels, corpora cavernosa or other collagen-containing structures of the penis. XIAFLEX REMS Program Because of the risks of corporal rupture (penile fracture) or other serious penile injury in the treatment of Peyronie’s disease, XIAFLEX is available only through the XIAFLEX REMS Program [see Warnings and Precautions]. Required components of the XIAFLEX REMS Program include the following: • Prescribers must be certified with the program by enrolling and completing training in the administration of XIAFLEX treatment for Peyronie’s disease. • Healthcare sites must be certified with the program and ensure that XIAFLEX is only dispensed for use by certified prescribers. Further information is available at www.XIAFLEXREMS.com or 1-877-313-1235. Hypersensitivity Reactions, including Anaphylaxis In the double-blind, placebo-controlled portions of the clinical trials in Peyronie’s disease (Studies 1 and 2), a greater proportion of XIAFLEX-treated patients (4%) compared to placebo-treated patients (1%) had localized pruritus after up to 4 treatment cycles (involving up to 8 XIAFLEX injection procedures). The incidence of XIAFLEX-associated pruritus was similar after each injection regardless of the number of injections administered. Because XIAFLEX contains foreign proteins, severe allergic reactions to XIAFLEX can occur. Anaphylaxis was reported in a post-marketing clinical trial (Study 3) in one patient who had previous exposure to XIAFLEX for the treatment of Dupuytren’s contracture. Some patients with Dupuytren’s contracture developed IgE-anti-drug antibodies in greater proportions and higher titers with successive XIAFLEX injections. Healthcare providers should be prepared to address severe allergic reactions following XIAFLEX injections. Risk of Bleeding in Patients with Abnormal Coagulation In the XIAFLEX controlled trials in Peyronie’s disease (Studies 1 and 2), 65.5% of XIAFLEX-treated patients developed penile hematoma, and 14.5% developed penile ecchymosis (see Adverse Reaction Table). Patients with abnormal coagulation (except for patients taking low-dose aspirin, e.g., up to 150 mg per day) were excluded from participating in these studies. Therefore, the efficacy and safety of XIAFLEX in patients receiving anticoagulant medications (other than low-dose aspirin, e.g., up to 150 mg per day) within 7 days prior to XIAFLEX administration is not known. In addition, it is recommended to avoid use of XIAFLEX in patients with coagulation disorders, including patients receiving concomitant anticoagulants (except for low-dose aspirin). ADVERSE REACTIONS The following serious adverse reactions in patients with Peyronie’s disease are discussed in greater detail elsewhere in the labeling: Corporal rupture (penile fracture) and severe penile hematoma [see Warnings and Precautions]. In other XIAFLEX-treated patients, a combination of penile ecchymoses or hematoma, sudden penile detumescence, and/or a penile “popping” sound or sensation was reported, and in these cases, a diagnosis of corporal rupture cannot be excluded [see Warnings and Precautions]. Clinical Studies Experience in Patients with Peyronie’s Disease Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In the controlled and uncontrolled clinical studies of XIAFLEX in Peyronie’s disease, 1044 patients received a total of 7466 XIAFLEX injections. Corporal Rupture and Other Serious Penile Injury Corporal rupture was reported as an adverse reaction after XIAFLEX injections in 5 of 1044 (0.5%) XIAFLEX treated patients. In other XIAFLEX-treated patients (9 of 1044; 0.9%), a combination of penile ecchymoses or hematoma, sudden penile detumescence, and/or a penile “popping” sound or sensation was reported, and in these cases, a diagnosis of corporal rupture cannot be excluded. These patients were managed without surgical intervention, but the long-term consequences are unknown. Severe penile hematoma was also reported as an adverse reaction in 39 of 1044 patients (3.7%) in the controlled and uncontrolled clinical trials in Peyronie’s disease [see Adverse Reactions]. The data described below are based on two identical, pooled, randomized, double-blind, placebo-controlled, multi-center trials through Day 365 in patients with Peyronie’s disease (Studies 1 and 2). These trials included 832 patients of whom 551 and 281 received XIAFLEX and placebo, respectively. In these trials, patients were given up to 4 treatment cycles of XIAFLEX or placebo. In each cycle, two injections of XIAFLEX or two injections of placebo were administered 1 to 3 days apart. A penile modeling procedure was performed at the study site on patients 1 to 3 days after the second injection of the cycle. The treatment cycle was repeated at approximately 6-week intervals up to three additional times, for a maximum of 8 total injection procedures and 4 total modeling procedures [see Clinical Studies in the full Prescribing Information]. The majority of Peyronie’s patients experienced at least one adverse reaction (92% XIAFLEX-treated patients, 61% placebo-treated). Most adverse reactions were local events of the penis and groin and the majority of these events were of mild or moderate severity, and most (79%) resolved within 14 days of the injection. The adverse reaction profile was similar after each injection, regardless of the number of injections administered. The most frequently reported adverse drug reactions (≥ 25%) in the XIAFLEX clinical trials in patients with Peyronie’s disease were penile hematoma, penile swelling, and penile pain. The table below shows the incidence of adverse reactions that were reported in greater than or equal to 1% of XIAFLEX-treated patients and at a frequency greater than placebo-treated patients after up to 8 injections in the pooled placebo-controlled trials through Day 365. Adverse Reactions Occurring in ≥ 1% of XIAFLEX-Treated Patients with Peyronie’s disease and at a Greater Incidence than Placebo After Up to Four Treatment Cycles in Studies 1 and 2 Combined Adverse Reaction XIAFLEX N=551 Placebo N=281 84.2% 36.3% 65.5% 19.2% Penile swelling 55.0% 3.2% Penile painc 45.4% 9.3% Penile ecchymoses 14.5% 6.8% Blood blister 4.5% 0 Penile blister 3.3% 0 Pruritus genital 3.1% 0 Painful erection 2.9% 0 Erectile dysfunction 1.8% 0.4% Skin discoloration 1.8% 0 Procedural pain 1.6% 0.7% All Adverse Reactions a Penile hematoma b d Injection site vesicles 1.3% 0 Localized edema 1.3% 0 Dyspareunia 1.1% 0 Injection site pruritus 1.1% 0 Nodule 1.1% 0 Suprapubic pain 1.1% 0 a Includes: injection site hematoma and penile hematoma were reported with the verbatim term of penile bruising or injection site bruising in 87% of subjects. Includes: injection site swelling, penile edema, penile swelling, local swelling, scrotal swelling, and injection site edema. c Includes: injection site pain, penile pain, and injection site discomfort. d Includes: contusion, ecchymoses, penile hemorrhage, and injection site hemorrhage. Severe penile hematoma or severe injection site hematoma were reported in 33/551 (6.0%) of XIAFLEXtreated patients and 0/281 (0%) of placebo-treated patients, in Studies 1 and 2 combined. Reports of penile “popping” sounds or sensations A popping noise or popping sensation in the penis, sometimes described as “snapping” or “cracking”, and sometimes accompanied by detumescence, hematoma and/or pain, were reported in 73/551 (13.2%) XIAFLEX-treated patients and 1/281 (0.3%) placebo-treated patients. There were no clinically meaningful differences in the incidence of adverse events following treatment with XIAFLEX based on the severity of baseline erectile dysfunction or concomitant phosphodiesterase type 5 (PDE5) inhibitor use. XIAFLEX was not associated with shortening of penile length in clinical trials in the treatment of Peyronie’s disease. Immunogenicity During clinical studies in Dupuytren’s contracture and Peyronie’s disease, patients were tested at multiple time points for antibodies to the protein components of XIAFLEX (AUX-I and AUX-II). In the Peyronie’s disease clinical studies, at 6 weeks after the first treatment cycle of XIAFLEX 0.58 mg, approximately 75% of patients had antibodies against AUX-I and approximately 55% of patients had antibodies against AUX-II. Six weeks after the eighth injection (fourth treatment cycle) of XIAFLEX, >99% of XIAFLEX-treated patients developed high titers of antibodies to both AUX-I and AUX-II. Neutralizing antibodies were assayed for a subset of 70 samples selected to be representative of high and low titer binding antibody responses at week 12 of treatment. For each subject in whom a Week 12 sample was selected, the corresponding Week 6, 18, 24, and 52 samples were assayed if they were also binding antibody positive. Neutralizing antibodies to AUX-I or AUX-II, were detected in 60% and 51.8%, respectively, of patients tested. In patients treated for these two indications, there was no apparent correlation of antibody frequency, antibody titers, or neutralizing status to clinical response or adverse reactions. Since the protein components in XIAFLEX (AUX-I and AUX-II) have some sequence homology with human matrix metalloproteinases (MMPs), anti-product antibodies could theoretically interfere with human MMPs. In vitro studies showed no evidence of cross-reactivity between anti-drug-antibody positive patient sera and a series of relevant MMPs. In addition, no clinical safety concerns related to the inhibition of endogenous MMPs have been observed. Immunogenicity assay results are highly dependent on the sensitivity and specificity of the assay used in detection and may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to collagenase clostridium histolyticum with the incidence of antibodies to other products may be misleading. DRUG INTERACTIONS Anticoagulant drugs: XIAFLEX should be used with caution in patients receiving concomitant anticoagulants (except for low-dose aspirin) [see Warnings and Precautions]. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B There are no adequate and well-controlled studies of XIAFLEX in pregnant women. Because animal reproduction studies are not always predictive of human response, XIAFLEX should be used during pregnancy only if clearly needed. Risk Summary Based on animal data, XIAFLEX is not predicted to increase the risk for major developmental abnormalities in humans. Human Data Human pharmacokinetic studies showed that XIAFLEX levels were not quantifiable in the systemic circulation following injection into a Dupuytren’s cord. Low levels of XIAFLEX were quantifiable in the plasma of evaluable male subjects for up to 30 minutes following administration of XIAFLEX into the penile plaque of subjects with Peyronie’s disease [see Clinical Pharmacology in the full Prescribing Information]. Almost all patients develop anti-product antibodies (anti-AUX-I and anti-AUX-II) after treatment with XIAFLEX, and the clinical significance of anti-product antibody formation on a developing fetus is not known [see Adverse Reactions]. Animal Data Reproduction studies have been performed in rats with intravenous exposures up to approximately 11 times the maximum recommended human dose (MRHD) of XIAFLEX on a mg/m2 basis, and have revealed no evidence of impaired fertility or harm to the fetus due to collagenase clostridium histolyticum. Nursing Mothers It is not known whether collagenase clostridium histolyticum is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when XIAFLEX is administered to a nursing woman. Pediatric Use The safety and effectiveness of XIAFLEX in pediatric patients less than 18 years old have not been established. Geriatric Use Of the 551 XIAFLEX-treated patients in the double-blind, placebo-controlled, clinical trials in Peyronie’s disease (Studies 1 and 2), 100 (18%) were 65 years of age or older and 5 (0.9 %) were 75 years of age or older. No overall differences in safety or effectiveness of XIAFLEX were observed between these patients and younger patients. OVERDOSAGE The effects of overdose of XIAFLEX are unknown. It is possible that multiple simultaneous or excessive doses of XIAFLEX may cause more severe local effects than the recommended doses including serious adverse reactions in the injected area (e.g., tendon ruptures or corporal ruptures dependent on the injection site). Supportive care and symptomatic treatment are recommended in these circumstances. Manufactured and Distributed by: Auxilium Pharmaceuticals, Inc. Malvern, PA 19355 This Brief Summary is based on PL-0108-001.g Revised 05/2015 b XP-03921 28 ❳Business of Urology❲ JUNE 2016 ∣ Urology Times How physicians can prepare now before CMS removes the ICD-10 safety net By Mark Rowh On October 1, the Centers for Medicare & Medicaid Services’ (CMS) grace period for denials of claims under ICD-10 will end. Physicians will do well to recognize that while the updated and expanded standards for coding specificity offer a new level of accuracy, they may also affect the bottom line. Prior to the ICD-10 rollout out last year, CMS announced that Medicare claims would neither be denied nor audited based on their coding as long as practices submitted an ICD-10 code from the appropriate family of codes. But that doesn’t mean a permanent free pass. “Physicians need to ensure they are up-to-date with the added specificity in ICD-10,” said David McCann, of Berkeley Research Group in Hunt Valley, MD, and a trained coder. Especially with high-volume diagnoses, he says, close review of coding options should become the norm. The months leading up to the October deadline will be vital for staff training and reinforcing correct ICD10 coding, says Mary Jean Sage, CMA-AC, of The Sage Associates, a consulting firm in Pismo Beach, CA. “It’s important that when the grace period is lifted, practices are thoroughly prepared and not just preparing.” Every practice needs to plan for decreased staff productivity and prepare for the possibilities of other financial challenges during the remainder of the ICD-10 grace period. “The last thing a practice wants to do is begin training when the claims are finally being denied,” Sage said. Lisa Thomsen, MD, a family practitioner in Glendora, CA, says her practice has not experienced any denials or claims adjustment post-ICD-10 because payers are only requiring a three-digit placeholder with each code. Come October 1, however, that will expand to five to seven digits, “which will impact the coding accuracy, thus the financial consequences” for incorrectly coded claims. Dr. Thomsen says even seasoned physicians with years of ICD-9 experience routinely have a small percentage of denied claims. “In addition, the clearinghouses for these claims have their electronic glitches and server capacity issues,” she said. “You can always count on the unexpected to occur, so all practices should brace themselves.” MIPS: More winners than losers in urology continued from page 23 be compared to that threshold. Providers with a lower MIPS composite score during the measurement period will receive negative adjustments for a payment year, and those with higher scores will receive positive adjustments to their fee schedule payments. The maximum negative adjustment starts at –4% in 2019 and increases each year until it reaches –9% in 2026. There ❳t Practice Pointers ❲ The Medicare Access and CHIP Reauthorization Act of 2015 replaced the sustainable growth rate formula with a flat 0.5% annual fee increase until 2019; no further increases will occur until 2026. t According to MACRA, all eligible professionals will be subject to the Merit-Based Incentive Payment System unless they meet one of three exceptions: They are in their first year of participation in Medicare; do not exceed a low volume threshold of Medicare payments or patients; or participate in an Advanced Alternative Payment Model. t CMS estimates that in 2019, 8,814 urologists will be subject to MIPS. are allowances for superior performance and additional payments, but in aggregate the law requires that total negative adjustments equal total positive adjustments. That is, MIPS will redistribute payments in a budget-neutral fashion. Beginning in 2026, MIPS physicians will see an annual fee schedule increase of 0.25% in addition to any payment adjustments described above. How will Medicare professionals be reimbursed if they are excluded from MIPS by successfully participating in Advanced APMS? APMs and Advanced APMs are strictly defined in the proposed rule (the subject of a future article), and qualifying participation includes a minimum threshold of Medicare payments or patients passing through the Advanced APM. APMs will have quality metrics also. If professionals become “qualifying participants” in this manner, they will receive a 5% Medicare bonus payment on their Part B professional services in the respective payment year. They will receive no other payment adjustments until 2026, when qualifying participants will see an annual 0.75% annual fee schedule increase (larger than MIPS). Finally, these bonus payments and fee schedules are Even without mistakes, navigating the new standards is likely to slow down processing. “The biggest complaint I hear from practices is that it now takes more time to select an appropriate code,” Sage said. “Finding the correct code comes with practice.” The key is adopting a new mindset. “Start using the ICD-10 lingo,” Dr. Thomsen said. “This means changing your old thinking.” Use nomenclature that aids in triggering the necessary codes. This might mean with a diagnosis of chronic kidney disease, for example, specifying stage 1-5, also noting that it is due to diabetes or hypertension. “This mindset forces you to think more specifically,” Dr. Thomsen said. “Your biller and coder now know the complete diagnosis. They don’t have to waste time reading through your notes.” Ongoing education is critical, McCann says. Review publications and sources of guidance continually. He advises doing an audit to identify documentation gaps and provide ongoing monitoring of high-volume diagnoses and those that can be further specified. in addition to any other financial benefits or risks incurred by participating in the advanced payment model (such as receiving a portion of shared savings) itself. In the proposed rule, CMS estimates that in 2019, 8,814 urologists will be subject to MIPS. Based on existing data and a midpoint sensitivity analysis, 40.5% of those will receive negative payment adjustments totaling $13 million, and 59.2% will receive positive payment adjustments totaling $31 million. Note that there are more winners than losers in MIPS by this estimate in urology and most specialties; notable exceptions include chiropractic, dentistry, plastic surgery, podiatry, and psychiatry. Finally, CMS estimates that in 2019, 1,754 urologists will be excluded from MIPS for one of the reasons mentioned above—including qualifying participation in an APM. Bottom line: Medicare fee for service is not dead, but instead now virtually all physician fees in Medicare will be directly tied to participation in a quality-based reimbursement model through the popular law called MACRA. In the beginning, most physicians will probably be measured and their fees adjusted downward or upward in MIPS; as time goes on, CMS expects more participation in APMs and exclusion from MIPS. In subsequent articles, I will discuss the details of MIPS and APMs that you will need to understand to traverse the landscape of reimbursement reform. UT UrologyTimes.com ∣ 29 JUNE 2016 Health savings account provides triple tax benefit Tax-free withdrawals for eligible medical expenses among HSA’s advantages Q What are the benefits of a health savings account? A One of the greatest benefits of being covered under a high-deductible health plan (HDHP) is generally the ability to open a health savings account (HSA) and receive taxpreferred treatment on money saved for medical expenses. Specifically, HSAs provide a triple tax benefit: tax-deductible contributions, tax-free earnings, and tax-free withdrawals. Being aware of the tax-saving opportunities of an HSA will give you a better understanding of how to take full advantage. An HSA is used to save money to cover outof-pocket medical expenses not covered by your health insurance plan. Many banks and brokerage firms offer HSA plans with various interest- and dividend-earning options. One benefit of having an HSA is that your contributions are tax deductible. Although there are annual limits to the amount that can be contributed, your HSA contributions can be claimed as a deduction on your tax return even if you do not itemize your deductions. For 2016, if you have individual health coverage, the maximum tax-deductible contribution remains the same as last year at $3,350, and for family coverage the contribution limit increased to $6,750. For those 55 and older, the additional contribution limit remains at $1,000. ❳t Financial Tips ❲ A health savings account is used to save money to cover out-of-pocket medical expenses not covered by your health insurance plan. t HSAs provide a triple tax benefit: tax-deductible contributions, tax-free earnings, and tax-free withdrawals. t If you make a withdrawal from an HSA for noneligible medical expenses before age 65, you will have to pay tax on the amount withdrawn plus a 20% penalty. t Money in an individual retirement account can be used to purchase a home without incurring a tax penalty, but only if it’s a withdrawal for a first-time home purchase. Many employers offset a portion of your health care costs by making contributions to your HSA. Although you may not deduct any contributions made by your employer, those amounts are generally excluded from your gross income, meaning they are tax free. In addition, the contribution limits remain the same whether the contributions are made by you or your employer. Although there are annual limits to the amount that can be contributed, HSA contributions can be claimed as a deduction on your tax return even if you do not itemize. For example, if you had individual coverage the entire year and are under the age of 55, your contribution limit is $3,350. If your employer contributed $1,000 to your HSA, the amount you may contribute, and deduct, is limited to $2,350. Contributions to your HSA can be made throughout the year or in one lump sum. To encourage you to maximize your HSA contribution benefit, if the annual contribution limit is not reached by year-end, you may continue to make contributions to your HSA through the tax return filing deadline the following year (without extensions) until the limit is reached. A second tax advantage of owning an HSA is that withdrawals for eligible medical expenses are tax free. Eligible medical expenses are those that would generally qualify as an itemized medical expense deduction. A third great tax benefit of HSAs is that any interest or dividends earned on them are tax free. Since HSAs do not have a mandatory distribution requirement, the contributions made to your HSA can stay there and continue to grow tax free until you need to make a withdrawal. If you make a withdrawal for non-eligible medical expenses before age 65, you will have to pay tax on the amount withdrawn plus a 20% penalty. If you are 65 or older, there is no penalty, but you will still have to pay tax. Finally, another benefit of owning an HSA is that you may keep your HSA open and continue to enjoy tax-free growth and tax-free withdrawals even if you are no longer eligible to make Money Matters Joel M. Blau, CFP, Ronald J. Paprocki, JD, CFP, CHBC Joel M. Blau, CFP, (top) is president and Ronald J. Paprocki, JD, CFP, CHBC, is chief executive officer of MEDIQUS Asset Advisors, Inc. in Chicago. They can be reached at 800-883-8555 or [email protected] or [email protected]. tax-deductible contributions. This means that when you are no longer enrolled in an HDHP, or if you change employers or leave the work force, your HSA can remain open. With a better understanding of how HSAs work and their benefits, it is easier to appreciate their value. As the owner of an HSA, you will get not only the triple tax benefit of taxdeductible contributions, tax-free earnings, and tax-free withdrawals, but also the opportunity to build a healthy medical nest egg to cover current and future health care expenses. Q Can you use money in an individual retirement account to purchase a home without incurring a tax penalty? A Yes, but only if it’s a withdrawal for a firsttime home purchase. This exception allows penalty-free IRA withdrawals to the extent the money is spent by the IRA owner within 120 days to pay for qualified acquisition costs for a principal residence. However, there’s a lifetime $10,000 limit on this exception. The principal residence can be acquired by: the IRA owner or the IRA owner’s spouse the IRA owner’s child, grandchild, or grandparent, or the spouse’s child, grandchild, or grandparent. The buyer of the principal residence (and the spouse if the buyer is married) must not have owned a present interest in a principal residence within the 2-year period that ends on the acquisition date. r r r Send us your questions Send your questions about estate planning, retirement, and investing to Joel M. Blau, CFP, c/o Urology Times, at [email protected]. Questions of general interest will be chosen for publication. The information in this column is designed to be authoritative. The publisher is not engaged in rendering legal, investment, or tax advice. 30 ❳Business of Urology❲ JUNE 2016 Tips to improve cyber security, protect finances Small practices often have the weakest security, leaving physicians vulnerable to threats A fter more than $27,000 goes missing from his business account, a Texas physician learns that cyber criminals initiated a wire transfer using a fake domain name and an email almost identical to his own. Another physician returns from an international trip to find that criminals hacked his email and used it to transfer more than $30,000 from his medical group’s account to an unknown bank in Hong Kong. In both cases—taken from the files of a cyber liability insurance underwriter associated with Austin, TX-based Texas Medical Liability Trust (TMLT)—the victims’ banks were not liable for the losses because an authorized account holder approved the transfers, says John Southrey, CIC, CRM, manager of consulting services at TMLT, which provides medical professional liability insurance to Texas Medical Association members. “Cyber fraud is the most underestimated and underappreciated risk faced by small businesses, particularly in health care,” said Southrey. “Most physicians are not budgeting enough for computer data security because they think their practices are too small to attract the attention of cyber criminals. However, losses incurred as a result of a data breach can be worse than a direct tangible property loss such as from a fire or tornado. Many cybercriminals consider physician practices to be low-hanging fruit because they have not kept up with technology.” Sara Hempfling, vice president of treasury management at St. Peters, MO-based Enterprise Bank and Trust, recommends that all of her clients purchase cyber liability insurance. Large companies may pay about $2,500 per month for $1 million in coverage, but smaller business often pay much less and some coverage is often included in standard professional liability policies, says Hempfling, who works with the bank’s medical clients. TMLT added cyber liability coverage in 2011. Since then it has handled more than 250 incidents, with more coming in nearly every week, Southrey says. The majority of cases involve data breaches of personal health information (PHI), which can take a financial toll CYBER SECURITY CHECKLIST The Texas Medical Liability Trust created the following checklist to help medical practice administrators assess their readiness to combat cyber crime: Is there a cyber risk management plan in force? procedures that address the HIPAA privacy, security, and breach notification rules? Are all mobile devices that contain electronic personal health information (ePHI) encrypted? And is your network monitored for intrusion attempts? Are new employees receiving privacy and security awareness training to comply with federal and state medical privacy and security laws? Are risk assessments conducted annually, including HIPAA privacy, security, and breach notification assessments? Have you vetted the cyber security of your third-party vendors/business associates who have access to your PHI? Have all previously identified vulnerabilities been addressed? Have you purchased suitable cyber liability insurance to cover potential first party and third party data breach claims? Do you have up-to-date written policies and ∣ Urology Times Health Law & Policy Janet Colwell Ms. Colwell is a contributing author for Medical Economics, where this article was first published. on a practice, exceeding the base cyber liability coverage limit. Lax security leaves practices vulnerable Criminal attacks are the leading cause of health care data breaches, ahead of employee negligence and lost or stolen devices, according to the Ponemon Institute, a nonprofit research group based in Traverse City, MI. Criminal attacks “Many cyber-criminals consider physician practices to be lowhanging fruit because they have not kept up with technology.” JOHN SOUTHREY, CIC, CRM Texas Medical Liability Trust have risen by 125% over the past 5 years as cyber criminals increasingly recognize the vulnerability of medical organizations that store a trove of potentially lucrative personal data, according to the institute’s 2015 Fifth Annual Benchmark Study on Privacy and Security of Healthcare Data. More than 90% of the health care organizations included in the study reported experiencing a data breach, with 40% reporting more than five over the past 2 years, the report says. At the same time, only half of survey respondents reported feeling confident that they had the resources or processes and technology in place to detect loss or theft of patient data. Theft of electronic PHI (ePHI) has substantial financial implications, because victims are responsible for the costs of investigating the breach, notifying customers, paying any government fines, and other crisis-management activities. It can take months or years to recover from the financial damage of a data breach, Southrey says. Under the Health Insurance Portability and Accountability Act (HIPAA), for example, practices can be fined for failing to conduct a comprehensive risk analysis of their policies and procedures and not having appropriate safeguards in place to protect ePHI. As a case in point, Phoenix Cardiac Surgery in Phoenix agreed to pay the U.S. DepartPlease see CYBER SECURITY, page 32 ™ FemTouch Laser Legacy, Versatility, Performance Improve Vaginal Health and Much More … 3\TLUPZPZWYV\K[VPU[YVK\JL-LT;V\JO;OPZLHZ`WHPUMYLL Ä]LTPU\[LPUVJLWYVJLK\YLYLTVKLSZ[OL]HNPUHSJHUHSHUK PTWYV]LZV]LYHSS]HNPUHSOLHS[O;OPZPUKLTHUKWYVJLK\YL HKKYLZZLZH[Y\S`\UTL[ULLKPU^VTLU»ZOLHS[OHUKOHZOLSWLK \YVSVNPZ[ZQ\Z[SPRL`V\L_WHUKPU[VJHZOWH`VJLWYVJLK\YLZ The FemTouch Laser also treats: ₔ*VUK`SVTHZ ₔ<UL]LU ₔ5\TLYV\ZV[OLY WPNTLU[H[PVU ₔ:`TW[VTZHZZVJPH[LK OLHS[OJVUKP[PVUZ ₔ- PULSPULZHUKZJHYZ ^P[O]HNPUHSH[YVWO` ;VÄUKV\[TVYL]PZP[VYJHSS! FEMTOUCH.COM FemTouch Handpiece ©2016. All Rights Reserved. The Lumenis Group of Companies. PB-2005117 rev A 1.877.LUMENIS 32 ❳Business of Urology❲ C Y BE R SECURI T Y continued from page 30 ment of Health and Human Services (HHS) $100,000 and implement new security measures in 2012 after an Office of Civil Rights (OCR) investigation found that it had violated HIPAA rules, according to HHS. In the OCR investigation, which lasted more than 3 years, “In smaller offices, one office manager might have full control over online banking and there is no system set up to have a second person authorize big transactions. That’s a risk.” SARA HEMPFLING Enterprise Bank and Trust investigators found that the practice had been posting surgical appointments on a publicly accessible web-based calendar and had not taken appropriate measures to protect the information. In addition to potential fines under federal and state privacy laws, practices must take steps to mitigate the effects of the breach, Southrey says. These can include notifying patients, providing credit-monitoring services, hiring a public relations firm, working with an attorney, and contracting with a forensics specialist to trace the source of the breach and recover unduplicated data. “That’s not to mention the potential lost revenue due to an interruption in business or staff overtime to reconstruct files and recover data,” he said. “And you may lose patients if they come to view your practice as a security risk.” Many of those costs are covered by cyber insurance up to certain limits (see “What cyber insurance covers,” below), he says. For example, one physician insured with TMLT filed a cyber extortion claim involving more than 6,000 patient records after a hacker demanded several thousand dollars to decrypt his files. After reporting the breach to HHS, the physician received notice of an OCR investigation and a request to provide extensive documentation on his security practices. “He blew through his $50,000 limit in cyber liability coverage in less than 2 months,” Southrey said, noting that TMLT now offers up to $1 million or higher in coverage limits. “And he had to continue to pay other out-of-pocket costs, such as installing a new server.” Staff training is key In many cases, small practices are particularly vulnerable to fraud because they do not implement procedures that might prevent errors, says Hempfling. In addition, they lack the resources to dedicate one computer exclusively to banking. “In smaller offices, one office manHealth care providers can transfer some of their cyberager might have full control over online related risks by purchasing cyber liability insurance, banking and there is no system set up according to John Southrey, CIC, CRM, manager of to have a second person authorize big consulting services at Austin, TX-based Texas Medical transactions,” she said. “From a bankLiability Trust (TMLT). TMLT includes cyber liability coving standpoint, that’s a risk.” erage limits of $100,000 per claim subject to a $500,000 While your employees might be fully aggregate if the entity is also insured per policy period, deserving of that trust, mistakes can hapwith the option to purchase increased limits up $1 milpen, she adds. For example, many cyber lion or higher on a stand-alone basis. crimes involve tricking someone into disclosing financial information. The coverage also includes: One of her manufacturing clients fell privacy regulatory defense and penalty coverage victim to a fraudulent wire transfer. The security and privacy liability coverage client received a phone call from somemultimedia liability coverage one they believed to be an employee of network asset protection coverage (including a vendor notifying the client that the business interruption) vendor’s bank account had changed. privacy breach response costs, patient notification Hempfling’s client requested a bank veriexpenses, and patient support and credit monification letter, which was immediately toring expenses coverage provided and looked legitimate. Trusting cyber extortion coverage that the contact was who they said they cyber terrorism coverage (including business were, the finance manager then changed interruption). the vendor’s bank account information on the company’s computer system. WHAT CYBER INSURANCE COVERS r r r r r r r JUNE 2016 ∣ Urology Times “Our bank called the owner and warned him to double check the transaction before verifying it because it might be fraud,” Hempfling said. “But he was in a hurry and OK’d it anyway, trusting that his staff had already done their due diligence.” Employee training is a critical part of protecting your practice from cyber fraud, says Rebecca Busch, RN, president and CEO of Westmont, IL-based Medical Business Associates and a faculty member of the Association of Certified Fraud Examiners. Employees should learn how to recognize spam emails that appear to be from a payroll company, for example, and not to open or download programs from unknown sources that could be malicious software giving criminals access to the practice’s records. Cyber criminals might also install “ransomware” on your computer, which prevents you from accessing your data unless you pay a fee to unlock it. Such incidents led TMLT to add cyber extortion coverage to its medical malpractice policies. “Your inventory should include any data that has a connection to your banking accounts.” REBECCA BUSCH, RN Medical Business Associates “Cyber extortion can be devastating from a revenue perspective,” Southrey said. “If you can’t access your data, how do you do your billing or conduct your patient exams?” Notifications about changes to your bank account should be verified “100% of the time,” Hempfling said. Remember, as soon as the business owner verifies a wire transaction, the money is sent and it is very difficult to reverse the process. “Consumers always get reimbursed but banks have discretion over whether or not to cover business losses,” she said. Banks are governed by very specific rules relating to check fraud, she adds. For example, the bank is exempt from liability if the business uses a signature stamp to sign a check instead of the account holder’s actual signature. Mitigation and awareness are critical to protecting your practice from fraud, Busch says. Physicians should inventory where their financial information is stored and have constant access to their financial accounts. “Your inventory should include any data that has a connection to your banking accounts,” she said. “You need to know when those accounts are accessed and how, and constantly monitor those channels.” For accurate risk assessment from biopsy, Decipher tells you which way to go. ® The accuracy of localized prostate cancer prognosis has just reached a new level: the extensively validated and clinically adopted Decipher test is now available for biopsy samples. No other measure comes close to Decipher’s performance in predicting risk: Decipher delivers a game-changing accuracy measured by Area Under the Curve (AUC) of 0.87 in predicting metastasis within 5 years and 0.71 in predicting high-grade disease. Decipher achieves that accuracy without relying on other clinical risk factors. Note, too, that these are meaningful endpoints – they’re not just data, they’re specific predictions your patients care about and you can use to help determine treatment. What’s more, Decipher reclassifies the NCCN risk category in 46% of patients, which means more appropriate treatment recommendations. Higher accuracy in predicting metastasis means better classification by risk and more appropriate levels of treatment. What makes Decipher a unique breakthrough is that it was developed using the whole genomic signature, identifying the best-performing markers from over 46,000 genes and 1.4 million biomarkers. The result is unmatched prognostic accuracy. And, that accuracy has been extensively validated in multiple studies, in multiple countries, with thousands of patients. Decipher is appropriate for all patients with localized prostate cancer at the time of biopsy. So don’t hide from the facts. Look into Decipher, and reach a new level of accuracy. Reference: Klein, E.A., et al., Decipher Genomic Classifier Measured on Prostate Biopsy Predicts Metastasis Risk. Urology, 2016; In Press. Biopsy For more information visit us at www.deciphertest.com or call Customer Support today at 888.792.1601 E-mail: [email protected] 34 ❳Voices in Urology❲ Commentary from residents, non-physician providers, and other voices in the field JUNE 2016 ∣ Urology Times Does this protocol represent the future of post-cystectomy care? Enhanced Recovery After Surgery can improve patient care and reduce morbidity R ecently my partner and I were performing a cystectomy, and as is common during most long cases, our discussion became a bit philosophical. Both of us were trained in the era of open cystectomy, but as this case was being done robotically, the conversation turned toward the future of surgical treatment of muscle-invasive bladder cancer. Surgical treatment of bladder cancer has a long and storied history dating back to 1852. Detubularization to create a low-pressure reservoir was a milestone by Kock in the mid1960s, and Mitrofanoff described the transappendicular continent cystostomy in 1980. In 1992, the first pure laparoscopic simple cystectomy was reported, and by 2003, case series of robot-assisted cystectomy and diversion were reported. (For a more detailed account, see “Bladder cancer and diversion: A historical perspective” below.) Now, completely intracorporeal robotic procedures have been reported and are common. Henry Rosevear, MD Dr. Rosevear, a member of the Urology Times Clinical Practice Board, is in private practice in Colorado Springs, CO. So where do we go from here? Unless someone is able to grow a new bladder using the patient’s own tissue, the surgical technique we have maintains good oncologic principles while providing an outcome that mimics the patient’s original bladder and can be done in a minimally invasive manner. Are we done advancing the field? Absolutely not. While the technique works, radical cystectomy still carries an unacceptably high complication rate likely secondary to a combination of patient-specific issues (patients tend to be older and sicker) and disease- and procedure- specific issues (the operation still exposes patients to major abdominal surgery combined with the metabolic changes that go along with exposing urine to the bowel). Bladder cancer and diversion: A historical perspective Even though the Ebers’ Papyrus (a collection of ancient Egyptian manuscripts dating from 2600-1200 BC found in a tomb at Thebes in 1862) describe in great detail hematuria and the presence of parasites in the bladder (schistosomiasis anyone?), the earliest cystoprostatectomy and urinary diversion didn’t happen until 1852 when J. Simon performed a ureteroproctostomy for exstrophy. The patients didn’t do very well, and it wasn’t until 1911 when Coffey modified the technique of ureteral implantation that ureterosigmoidostomy became standard. That same year, Zaayer introduced the ileal conduit and by 1950 with modifications by Bricker, ileal conduits were now standard due in no small part to the more manageable metabolic changes associated with them. The concept of a true continent diversion was the subject of work by Tizzoni and Foggi as far back as 1888. By the turn of the century, others such as Verhoogen (1908), Makkas (1910), and Laengemann (1912) had explored the idea of using an ileocecal segment with the appendix as the continent mechanism. By the 1950s, Gilchrist and Merricks modified the procedure to use the terminal aperistaltic segment of ileum as the continent mechanism. The concept of detubularization to create a lowpressure reservoir was introduced by Kock in the mid1960s and led to significant improvement in results. Using these principles, new techniques combining different bowel segments with various continence mechanisms were proposed (the Kock pouch using ileum and a nipple valve for continence, the Indiana pouch using an ileocecal segment with a tapered ileal segment for continence, and finally the Mainz pouch using ileum and an intussucepted ileal nipple). Mitrofanoff described the trans-appendicular continent cystostomy in 1980 that finally allowed for an easily reproducible continence mechanism. In the late 1980s, Studer and Hautmann described the orthotopic neobladder and after almost 150 years of work, we finally had a continent diversion that closely duplicated the original bladder. In 1992, with the advent of the laparoscopic era, the first pure laparoscopic simple cystectomy was reported and by 2003, case series of robot-assisted cystectomy and diversion were being reported. (Drs. Hautmann [Eur Urol 2006; 50:1139–50] and Studer [Probl Urol 1991; 5:197–202] provide excellent historical reviews for those interested in more details.) What is the future? The future is Enhanced Recovery After Surgery, or ERAS. The beauty of ERAS is that is allows those of us in the trenches of urology who don’t work at a major academic center to provide the same excellent perioperative care, just without residents. Quoting Dr. Urbach, “The immediate challenge to improving the quality of surgical care is not discovering new knowledge, but rather how to integrate what we already know into practice.” Fast-track recovery protocols were introduced in the 1990s, and I’m sure most of us had some in-house developed protocol for patients after cystectomy. The ERAS society is dedicated to standardizing perioperative care by maintaining a constantly updated, peerreviewed, evidence based protocol which is free to access and has been shown in numerous papers to decrease the post operative morbidity of the procedure. ERAS in the peer-reviewed literature European Urology recently published a review of this protocol that concludes, “ERAS pathways clearly improve patient care, reduce morbidity, and shorten LOS. All studies evaluating elements of the ERAS care pathways in radical cystectomy have found benefits in postoperative morbidity, return to bowel function, or LOS.” (Eur Urol 2014; 65:263-66). In addition, Clinical Nutrition published the current ERAS protocol for perioperative care after radical cystectomy (Clin Nutr 2013; 32:87987). The beauty of this protocol is that is allows those of us in the trenches of urology who don’t work at a major academic center to provide the same excellent perioperative care, just without residents. And that is not necessarily a disadvantage! If anyone else is transitioning their hospital to an ERAS protocol and has had either good or bad experiences with such a protocol, please write and let me know. UT UrologyTimes.com ∣ JUNE 2016 Phase III trial to evaluate magnetic resonance imaging for prostate Ca The Movember Foundation, the Ontario Institute for Cancer Research, and Prostate Cancer Canada recently announced $3 million in funding for a new phase III clinical trial to evaluate whether magnetic resonance imaging (MRI) can replace the current standard of care to diagnose prostate cancer. The primary objective of the multicenter trial, called PRECISE, is to determine whether MRI can spare some men from undergoing a biopsy and avoid the possible associated side effects. The trial will be led by Laurence Klotz, MD, of the Sunnybrook Research Institute in Toronto, according to a press release from the Ontario Institute for Cancer Research. Collaboration, license agreement reached for prostate Ca compound Janssen Biotech, Inc. has entered a worldwide collaboration and license agreement with TESARO, Inc., for exclusive rights to the investigational compound niraparib in prostate cancer. Niraparib is an orally administered poly polymerase inhibitor currently in late-stage development for patients with metastatic breast cancer and ovarian cancer. According to terms of the license agreement and collaboration arrangement, Janssen will have global rights and be responsible for all development and commercialization activities for niraparib for use in prostate cancer, except in Japan. TESARO will maintain global development, manufacturing, and commercial rights for all other indications. In addition to an upfront payment, TESARO will be eligible to receive milestone payments, based upon the achievement of specified development, regulatory, and commercial milestones, as well as royalties on future worldwide sales. Nocturia nasal spray shows efficacy in phase III clinical study At the AUA annual meeting in San Diego, researchers reported results from a phase III clinical study of SER120, a nasal spray with a novel formulation of low-dose desmopressin, in patients with nocturia. As part of the study, researchers from multiple institutions across the United States sought to determine whether two doses of SER120 is an effective and safe option for treating adults age 50 years and older with nocturia. Results showed that individuals taking SER120 urinated at night significantly less compared to those taking the placebo and that individuals taking SER120 reported a statistically significant improvement in quality of life versus those DRUGS AND DEVICES IN DEVELOPMENT taking the placebo, according to a press release from the AUA. Positive results announced for urothelial carcinoma test Pacific Edge Ltd. recently announced the presentation of positive results from a prospective multicenter, blinded study of Cxbladder Monitor, the company’s new urine-based gene expression test for the investigation of urothelial carcinoma in patients presenting for monitoring of recurrent disease. Results presented at the AUA annual meeting in San Diego demonstrated that Cxbladder Monitor is an effective rule out test with a sensitivity of 93% and a negative predictive value of 97%, significantly outperforming all other existing urine-based tests evaluated across all stages and grades of tumor, according to Pacific Edge. The test is currently available in New Zealand, and Pacific Edge says it plans to begin marketing it in the United States later this year. Novel prostate cancer vaccine will proceed to phase II trials OncBioMune Pharmaceuticals, Inc. recently provided an update on the clinical advancement of ProscaVax, the company’s novel cancer vaccine in development for prostate cancer. In the United States, a phase Ia/Ib trial of ProscaVax is ongoing at the Veterans’ Administration Medical Center and the University of California, San Diego Medical School, both in La Jolla, CA. Data to date show ProscaVax to have a meaningful impact in reducing the rise in PSA levels in 60% of patients (six out of 10) receiving six vaccinations and an increased immune response in 89% (eight out of nine) patients at 31 weeks after administration of the vaccine, according to OncBioMune Pharmaceuticals. The company says the data are compelling enough that it has elected to forego the phase Ib component and advance ProscaVax into two separate phase II studies. First patient dosed in phase II study of androgen receptor modulator Transition Therapeutics Inc. announced the dosing of the first patient of a phase II study of selective androgen receptor modulator drug candidate TT701. The phase II study will evaluate the efficacy and safety of TT701 in improving the symptoms of androgen deficiency (sexual symptoms, fatigue/low vitality, and physical dysfunction) in men with prostate cancer who have undergone radical prostatectomy for organ-localized prostate cancer. Brigham and Women’s Hospital in Boston is conducting the Uro Pipeline 35 investigator-led phase II clinical study, which is expected to enroll up to 125 subjects at selected specialized clinical sites. Patents granted for implantable neuromodulation technology Axonics Modulation Technologies, Inc., developer of a rechargeable implantable sacral neuromodulation system for the treatment of urinary and fecal dysfunction, said the U.S. Patent and Trademark Office has granted Axonics six U.S. patents relating to implantable neuromodulation technology and recharging systems. The company’s neuromodulation platform includes a miniaturized rechargeable implantable neuromodulation stimulator (IPG) that is approximately one-fourth the size of the smallest currently marketed rechargeable IPGs and can be directed toward numerous clinical applications, according to Axonics. Pre-clinical studies show feasibility of stent system Three recently completed pre-clinical model studies of the ConvertX Nephroureteral Stent System were presented at the Society of Interventional Radiology annual scientific meeting in Vancouver, BC. The studies demonstrated the feasibility of the ConvertX System in converting from an internal-external nephroureteral (NU) catheter into an internal NU stent without an invasive procedure, according to developer BrightWater Medical, Inc. The company says it will submit applications for the ConvertX System in the near future to the FDA for 510(k) clearance as a Class II device. Lab services agreement reached for trial of immunosuppressive agents Transplant Genomics reported that it has signed a laboratory services agreement with Astellas Pharma Global Development, Inc. Under terms of the agreement, Astellas will provide Transplant Genomics with funding and blood samples from renal transplant patients collected as part of a 2-year, prospective, randomized, multicenter clinical trial examining surrogate markers for long-term kidney transplant outcomes while comparing two immunosuppressive agents. The primary outcome measure is a composite endpoint combining the incidence of de novo donorspecific antibodies and molecular phenotyping using Transplant Genomics’ TruGraf test. Transplant Genomics will provide real-time molecular analysis of blood samples collected during the trial using TruGraf, which will measure molecular signatures of immune activation in renal transplant patients. 36 ❳ Cover Feature ❲ JUNE 2016 ∣ Urology Times ‘APOLOGY’ DILEMMA Apology legislation: 38 states have laws continued from page 1 to do much more than just say they’re sorry when mistakes happen. Meanwhile, two new studies—including one presented at the 2016 AUA annual meeting—offer conflicting perspectives on whether the laws are working, at least in terms of reducing litigation. All this makes for a complex apology landscape, one that continues to divide attorneys, doctors, and patient advocates. Are apology laws really “traps for the unwary physician,” as Dr. Cotton describes them? Should they be replaced by communication-and-resolution programs, seen by some as a kind of apology law-plus? Or perhaps the laws are serving a purpose by promoting openness, honesty, and accountability. Whatever the case, “Few physicians are familiar with apology law and even fewer understand the significance,” said Patrick McKenna, MD, chief of the division of pediatric urology at American Family Children’s Hospital and professor of urology at the University of Wisconsin, Madison. Judging by Dr. McKenna’s new research supporting the value of apologies, what physicians don’t know could hurt them after they hurt patients. “A doctor who gives his or her best effort does not owe the patient an apology for anything.” “Apologies decrease patients’ anger toward their doctor and increase patients’ trust.” PATRICK MCKENNA, MD VICTOR COTTON, MD, JD “The profession was embarrassed to be open about the aspects of care that weren’t going well.” History lesson: No apologies here Apologies and medicine are not bosom buddies. Throughout much of history, physicians simply didn’t say they were sorry, says Thomas H. Gallagher, MD, professor and associate chair of the department of medicine and professor in the department of bioethics and humanities at the University of Washington in Seattle. “There was a sense that we can talk with our peers about things that have gone wrong, but it’s not good to air our dirty laundry outside of the profession,” he said. “Some of this was couched in terms of trying to promote trust. Sharing information about an error might diminish that trust.” Self-protection played a role too. “The profession was embarrassed to be open about the aspects of care that weren’t going well,” Dr. Gallagher said. And then there’s the matter of money. Malpractice law has its roots in the middle of the 19th century, not the 20th, Dr. Gallagher says. So there’s long been a real threat that openness—“I made a mistake, I hurt you, and I’m sorry”—could have real consequences. Apology laws run the gamut In 1986, Massachusetts adopted the first law designed to encourage physicians to apologize without having to worry that their words would be used against them. A total of 38 states now have apology laws on the books. But the laws are anything but standard, meaning that your state’s apology law mileage may vary. Thirty-two states have so-called “partial” apology laws and six have “full” apology laws. “Partial and full apology laws differ in the type of communication protected, the sentiments protected, the types of providers that are protected, to whom the protected communication may be made, and the context in which a communication will be protected,” Dr. McKenna explained. The six states with full apology laws—Wisconsin, South Carolina, Georgia, Connecticut, Colorado, and Arizona—provide the most protection to physicians. Wisconsin’s 2014 apology law, for example, allows statements of “apology, benevolence, Getty Images/iStock/Getty Images Plus/26ISO THOMAS H. GALLAGHER, MD UrologyTimes.com ∣ ❳ Cover Feature ❲ JUNE 2016 compassion, condolence, fault, liability, remorse, responsibility, or sympathy.” The statements, however, must be made “before the commencement of the civil action, administrative hearing, disciplinary proceeding, mediation, or arbitration.” What you can (and shouldn’t) say The Wisconsin law seems clear and easy to understand. But apology laws can be maddeningly complex and vague too. “Partial and full apology laws differ in the type of communication protected, the sentiments protected, the types of providers that are protected, to whom the protected communication may be made, and the context in which a communication will be protected.” PATRICK MCKENNA, MD For example, Florida’s partial apology law says “the portion of statements, writings, or benevolent gestures expressing sympathy or a general sense of benevolence relating to the pain, suffering, or death of a person involved in an accident and made to that person or to the family of that person shall be inadmissible as evidence in a civil action.” Clear as mud, it seems. Do medical mishaps count as “accidents”? It’s not clear. If they do count, can a urologist, for example, apologize and go on to admit responsibility for missing obvious signs of cancer? No: The law says a statement of fault is admissible. How well do apology laws work? Researchers have been trying to understand the effects of apology laws, but their findings have been mixed. In an October 2011 study published in the Journal of Risk and Uncertainty (2011; 43:141), researchers reported that apology laws seemed to reduce average malpractice payments and settlement time, especially in cases involving the worst harm. However, a 2016 Vanderbilt University study that has been presented to several academic audiences found that, “In general, apology laws increase the probability of malpractice lawsuits... Overall, the evidence suggests that apology laws do not effectively limit medical malpractice liability risk.” Now, a new study co-authored by a urologist, 37 Dr. McKenna, offers a contrasting opinion. The study analyzed malpractice cases from 1991 to 2014. In states with apology laws, litigation length was 4.4±3.3 years before the laws were enacted (N=165,556) and 3.3±2.0 years afterwards (N=38,940) (p<.001). Litigation length was shorter (2.6±1.4 years, N=2,281) in states Please see APOLOGY, on page 38 Practice Management Leadership Forum Structuring the Urology Practice for Success Presented by: Mark Painter - and Larry A. Kemp, FACHE When September 16th and 17th, 2016 Where "3 Tampa Airport Tampa, FL What to Expect &osition your practice for the future & $""%# tice &$""!%# "! Register Now! Limit 50 attendees, don’t miss out on this unique experience from PRS. Special Early Bird Pricing ends June 28th (800) 972 - 9298 45"8 .com/uacrs P R S network Coding, Reimbursement, and Practice Management Solutions 38 ❳ Cover Feature ❲ JUNE 2016 ∣ Urology Times ‘APOLOGY’ DILEMMA Confirm mistake before apologizing to patient continued from page 37 with full apology laws than in states with partial laws (3.3±2.0, N=36,659; p<.001). Why might there be a connection? According to other research, patients and their relatives say “an explanation and apology would prevent them from litigating,” Dr. McKenna said. “Additionally, apologies decrease patients’ anger toward their doctor and increase patients’ trust, strengthening the doctor-patient relationship.” Not so fast, says Dr. Cotton, the anti-apology attorney. Yes, he practices law in a state— Pennsylvania—that has a partial apology law. But he doesn’t think it’s worth anything. Empathy, compassion, and caring are part of doctoring, he believes. However, he said, “The idea that a doctor who inadvertently injures a nerve during a complex, 6-hour surgery has committed a moral wrong that violates the trust of the doctor-patient relationship is insulting.” “The idea that a doctor who inadvertently injures a nerve during a complex, 6-hour surgery has committed a moral wrong that violates the trust of the doctor-patient relationship is insulting.” VICTOR COTTON, MD, JD As for apologizing, he said, “It is very hard to find a real physician who has tried this approach. They value their licenses and careers.” Steps before you apologize What if a doctor does actually want to apologize and wants to do it right? “Don’t apologize unless you know a mistake has been made,” Dr. McKenna advised. “Wait until the evidence clearly indicates a medical mistake before giving an apology.” But keep in mind that “a patient deserves to know what happened in the event of a medical error,” Dr. McKenna said. “At the least, the doctor should disclose the error, as this is ethical.” Then check your state’s law. Going beyond the apology “I’ve found that patients really appreciate an open and honest conversation and, when the harm was caused by an error, a really frank apology.” THOMAS H. GALLAGHER, MD “In states with partial apology laws, physicians should be cognizant that giving an apology without admitting fault is still better than giving no apology at all,” he said. “In states with full apology laws, it is important to know that patients want to understand what happened, why it happened, how the error could impact their health, and plans for preventing future errors. All of this information should be offered in the apology.” You may also wish to look at relevant codes of ethics. An opinion from the American Medical Association says “physicians must offer professional and compassionate concern toward patients who have been harmed” and offer a “general explanation” regarding what happened and how future errors will be prevented. The ethics code of the AUA tells urologists to “render services to humanity with full respect for human dignity.” But expressions of condolence, sympathy, and responsibility aren’t enough. “The majority of them want to know that this error will never happen again to anyone else,” Armstrong said. But too often, she said, “patients are left to wonder how an error happened and whether it will happen again.” Indeed, apologies focus on resolving a problem from the past, not fixing the future. That’s one reason why some health systems are embracing communication-and-resolution programs, which encourage medical professionals to do more than say they’re sorry. These programs promote apologies, explanations, and— in some cases—compensation. In May 2016, the federal Agency for Healthcare Research and Quality introduced the CANDOR (Communication and Optimal Resolution) tool kit, which encourages hospitals to be open to patients about errors. The kit is based in part on policies at the University of Michigan Health System in Ann Arbor, which “In all cases, [patients] want empathy and understanding. They want someone to care.” SARAH ARMSTRONG, RN, MSN, JD ‘I’m sorry’: How to apologize Dr. Gallagher, the University of Washington professor who is a general internist, says he frequently apologizes to patients and uses the words “I’m sorry,” often repeatedly. “I’ve found that patients really appreciate an open and honest conversation and, when the harm was caused by an error, a really frank apology,” he said. But be aware, he says, that just because patients appreciate an apology doesn’t mean they’re happy. Also understand that acknowledging an error could bring it to a patient’s attention and potentially prompt legal action. So what do patients want? “In all cases, they want empathy and understanding. They want someone to care,” said Sarah Armstrong, RN, MSN, JD, a health care communication and conflict resolution consultant at the University of Washington. says it’s seen reductions in lawsuits, malpractice cases that reach court, and settlement payments. Critics question whether these programs intend to divert patients with valid cases from suing. But others believe they not only prevent lawsuits but also lead to change because they emphasize preventing future errors. “No liability reform holds as much promise for improving safety,” Armstrong said. So which approach is best: No apologies, apologies, or apologies-plus? Dr. Cotton points to words attributed variously to Hippocrates and tuberculosis pioneer Edward Livingston Trudeau, MD: “To cure sometimes, to relieve often, to comfort always.” Comfort, as always, will be the hardest of those three verbs to define. UT UrologyTimes.com ∣ ❳ Cover Feature ❲ JUNE 2016 HIF U continued from page 1 The new study findings are being released as urologists continue to debate the value of HIFU in light of the FDA rulings. It’s not a new controversy: In January 2014, a Urology Times online poll found that 46% of respondents didn’t believe HIFU for prostate cancer had a future in the United States. The other 54% thought it did. The 24-month, prospective, non-randomized study enrolled 135 patients aged 50 years and over with low-risk, localized prostate cancer (stage T1-T2a, PSA <10.0 ng/mL, Gleason score <6) and prostate AP diameter <25 mm. The patients were treated with HIFU via Ablatherm and analyzed via prostate biopsy for cause, 24-month post-HIFU biopsy, and serum PSA. The biopsies are unusual, Dr. Robertson said, since surgeons typically rely on PSA results after procedures. inflammatory changes on urinalysis since you’ll get some shedding of some cells,” Dr. Robertson told Urology Times. “Most of the patients didn’t really have any real issues. They had their treatments and a temporary indwelling catheter, and they had that taken out.” What should urologists take from the research? The relevance is limited due to the patient population. According to Dr. Robertson, patients with low-risk, low-grade prostate cancer are “not considered a great treatment category” for HIFU. EDAP TMS says HIFU “is generally recommended for patients with localized prostate cancer (stages T1-T2) who are not candidates for surgery or who prefer an alternative option, or for patients who failed radiotherapy treatment.” Dr. Robertson is a consultant and principal investigator for EDAP TMS. UT Reduction in positive cores observed The results: Of 1,251 baseline pre-HIFU biopsy cores, 365 (29.2%) were positive for prostate cancer. After the procedure, 87 (7.7%) of 1,127 biopsy cores were positive. Before the procedure, mean PSA was 4.60 ng/mL. At 6 months after the procedure, the mean PSA nadir was 0.53 ng/mL. As for side effects, “Some patients had ❳ UT Figure ❲ HIFU: Change in positive Bx cores 30 29.2% #BLOODEQUALITY Positive biopsy cores 20 10 7.7% 0 Baseline pre-HIFU Source: Cary Robertson, MD 24 months post-HIFU 39 When I tried to donate blood, they turned me away because I’m a gay man. The FDA’s latest policy says that gay and bisexual men can’t be blood donors unless they remain celibate for a year. Yet the blood supply is always tested to ensure safety. So why are they typecasting my blood? Blood is blood. And discrimination is discrimination. That’s why it’s time for science, not stigma. BloodEquality.com In partnership with 40 JUNE 2016 Speak Out What should the AUA’s legislative priorities be? “A s a private practice urologist coming up on my 29th year of doing this, there have been a lot of changes. What the AUA can do for those of us in the trenches, so to speak, is to lessen some of the regulatory burdens that have been put on us, specifically the [Physician Quality Reporting System] and jumping through all these additional hoops. We’ve been forced into elecDr. Piser tronic medical records, which have increased our clerical time tremendously. Some people just kind of give up and do poor, cookie-cutter notes, and that goes against the grain of a lot of docs who take pride in taking care of patients—which means good documentation. But this adds things that are really who are doing the screenings, and I think we’re going to see cases of people presenting with late metastatic disease. The other two things that apply to all of medicine are access to medication, especially generics that we use but that frequently go on shortage because manufacturers stop Dr. Broghammer producing it because there’s no oversight or regulation in terms of drugs. There’s less access and periods where some drugs aren’t available at all. The issue is, if we want to give guideline-directed care, we’re not able because the medication is not there. We need some sort of regulation. The other issue is the Affordable Care Act. Although I support the idea in principle of providing coverage, it hasn’t really accomplished that. There needs to be some kind of alternative solution.” Joel Piser, MD Kansas City, KS ’ve been here for 21 years in a 15-mangroup, with several of us in our 50s and very busy. We try to be politically active. One thing that really worries me is that we’re all about ‘quality’ work—and paying for quality is kind of a misnomer for me. How are you going to pay urologists to do quality work when much of what we do is episodic interventions for people with bladder cancer, kidney stones, prostate cancer? We do some Dr. Weisner primary care, but we don’t have a lot of preventive medicine to provide. I’m worried you’re already seeing it with fewer PSAs being done, with fewer people being referred for elevated PSAs. Unfortunately, people are getting diagnosed later with more aggressive prostate cancer. How do urologists fit into this integrated network or an accountable care organization when we’re such a small part of the health care dollar and we’re not on the front lines? But we’re important and necessary, and I would like for the AUA to confirm our seat at the table so we’re not excluded from any pay for performance. I think the [U.S. Preventive Services Task Force] is a bunch of hooey. They should have had urologists’ input. They made a false decision that hurt urology and our patients. Anything the AUA can do to tamp down meaningful use—some of it’s OK, but so much of it is not urology pertinent. The other thing I hate is preauthorization for imaging and medications. We spend hours on the phone every day. I love my job. Just the regulations drive me bonkers.” Berkeley, CA ontinued access to PSA testing is something that needs to be looked at and advocated for by the AUA. So far, it’s still being covered by insurance, but we’ve seen kind of a blanket decrease in the primary care physicians “C Companies featured in this issue To obtain additional information about products advertised in this issue, use the contact information below. (Regional ads are marked with an asterisk.) This index is provided as an additional service. The publisher does not assume any liability for errors or omissions. Brand/Product Page # Website Lipshultz Epididymovasostomy Microdissection Scissors 15 www.accuratesurgical.com XTANDI 45-CV4 www.xtandihcp.com Flexor Parallel 11 www.cookmedical.com Endo Pharmaceuticals XIAFLEX 24-27 www.xiaflex.com Genentech Tecentriq 13 www.gene.com Decipher Prostate Cancer Classifier 9, 33 www.genomedx.com ZYTIGA 16 A-F* www.zytigahcp.com Lumenis FemTouch 31 www.lumenis.com NeoTract UroLift 5 www.urolift.com Narrow Band Imaging (NBI) 21 www.olympusamerica.com Physician Reimbursement Systems – 37 www.prsnetwork.com Sagent Pharmaceuticals Glydo CV2-3 www.glydo.com Accurate Surgical & Scientific Instruments Astellas Cook Medical GenomeDx Biosciences Janssen Biotech Olympus America Inc. Urology Times unnecessary, so it takes a lot of unnecessary time. I personally have given up and have a scribe. That costs more money but makes my personal time more available. The AUA needs to advocate strongly against repealing the in-office ancillary service exemption, especially ultrasonography. It’s also so much more expensive to send out cultures rather than doing our own. Study after study have shown we deliver care less expensively when it’s administered in our office as compared to the hospital or even the hospitalbased urologists. If a patient in the office needs a catheter, Medicare pays me a minimal fee and doesn’t reimburse for the cost of the catheter. (We do it for existing patients because I won’t make them go sit in the ER for 4 hours when we’re here.) The AUA can do a lot to support the independent private practitioner that would be good for patient care, would be most cost effective to do, and really be the right thing to do for patients.” Advertisers Index Advertiser Name ∣ Joshua Broghammer, MD “I Bradley Weisner, MD Matthews, NC UrologyTimes.com | Marketplace JUNE 2016 Careers K ANSAS THE UNIVERSITY OF KANSAS MEDICAL CENTER DEPARTMENT OF UROLOGY CONNECT with qualified leads and career professionals The Department of Urology at the University of Kansas is seeking a board certified (or eligible) general urologist. Our Department of Urology has full time faculty members in all subspecialty areas and we are seeking urologists to cover a very busy general urology practice. Responsibilities include managing a busy clinical practice and teaching medical students and residents, with minimal administrative duties. Academic rank, salary will be commensurate with experience. Academic rank and salary will be commensurate with experience. Interested applicants should contact Jessica McCullough at [email protected] An EO/AA employer. Post a job today THE UNIVERSITY OF KANSAS MEDICAL CENTER DEPARTMENT OF UROLOGY The Department of Urology at the University of Kansas Medical Center is seeking a board certified or eligible urologist. We have full time faculty members in all subspecialty areas and are seeking a urologist specializing in female urology, urinary incontinence, voiding dysfunction, and neurourology. ZZZPRGHUQPHGLFLQHFRPSK\VLFLDQFDUHHUV Joanna Shippoli Responsibilities include managing a busy clinical practice and teaching medical students and residents, with minimal administrative duties. This position will also present research opportunities. Fellowship training for this staff position is preferred. Academic rank and salary will be commensurate with experience. Interested applicants should contact Jessica McCullough at [email protected]. An EO/AA employer. RECRUITMENT MARKETING ADVISOR (800) 225-4569, ext. 2615 [email protected] GET FAST ACTION WITH THE DYNAMICS OF MARKETPLACE ADVERTISING! 41 42 Marketplace JUNE 2016 | Urology Times Careers NEW JERSEY UROLOGIST - CENTRAL New Jersey Seeking General Urologist and Pediatric Urologist Garden State Urology (GSU), located in Morris County, has an outstanding opportunity for a General Urologist and Pediatric Urologist with proven and respected leadership skills to join our team of talented physicians. Specialties within GSU include but are not limited to Minimally Invasive Robotic Surgery, Treatment for Stones, Prostate Care, Reconstructive Urology, Female Urology and Men’s Health, and Pediatric Urology. All positions are aligned with the integration of complex clinical care with teaching and research to support the vision of GSU. Candidates may be Board Eligible or Board Certified. Fellowship trained candidates preferred but not required. New grads strongly encouraged to apply, as we have current and future needs. About GSU Garden State Urology was formed in 2008, the result of a merger of five of the busiest urology practices in Morris County. We joined on the principle that by working cooperatively, we could provide more cost-effective and higher quality care than we did individually. Our mission statement, created at our inception, reflects these beliefs and directs our future growth: To provide comprehensive and compassionate urologic care at the highest possible level. By coming together, we have embraced a national trend to coordinate care. Most important to each of the members of Garden State Urology is to keep the practice of medicine patientfocused. We believe in the integrated model of patient care. Somerset Urological Associates, a premier, busy, well-established private practice with state-of-the-art office and highly regarded hospital and surgery center with access to a daVinci robot seeks two energetic and personable urologists, one who is fellowshiptrained in female and reconstructive urology, and one general urologist. We offer a compensation package with defined short path to partnership. Live in community noted for great schools with close proximity to NYC, Philadelphia and the NJ shore. Opportunity is available June 2017. www.somerseturological.com Please email: NHY`JHZPUV'Y^QWLJVT Equal Opportunity Employer Please submit your CV and letter of interest to: [email protected] Please include a cover sheet and salary requirements. Other information on GSU may be found on our website www.gsunj.com Content Licensing for Every Marketing Strategy Marketing solutions fit for: FOR PRODUCTS & SERVICES RECRUITMENT PLEASE CONTACT: JOANNA SHIPPOLI at 800-225-4569 x 2615 or E-mail: [email protected] Outdoor Print Advertising Social Media Direct Mail Tradeshow/POP Displays Radio & Television Logo Licensing | Reprints Eprints | Plaques Leverage branded content from Urology Times to create a more powerful and sophisticated statement about your product, service, or company in your next marketing campaign. Contact Wright’s Media to find out more about how we can customize your acknowledgements and recognitions to enhance your marketing strategies. For more information, call Wright’s Media at 877.652.5295 or visit our website at www.wrightsmedia.com UrologyTimes.com ∣ ❳Washington and You❲ JUNE 2016 MACRA proposed rule brings new decisions Details provided on meaningful use program replacement Washington—Urologists and other physicians who serve Medicare patients face some new decisions now that the Centers for Medicare & Medicaid Services (CMS) has proposed new regulations implementing last year’s fee schedule reform law, while also replacing the existing meaningful use program with a more flexible approach to technology and electronic health records. “We have more work to do, but we are committed to implementing this important legislation and creating a health care system that works better for doctors, patients, and taxpayers alike,” said Health and Human Services Secretary Sylvia M. Burwell, referring to the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA), which reforms the Medicare physician payment system and ends the troubling pay cut crises that occurred year after year. single framework to help physicians transition from volume-based payments to those based on value. The new rule, for which CMS is accepting comments until June 27, 2016, implements those changes by establishing the Quality Payment Program, giving physicians two options for Medicare reimbursement. They can participate either in the merit-based incentive payment system (MIPS) or Advanced APMs. “Our goal with Advancing Care Information is to support the vision of a simpler, more connected, less burdensome technology.” ANDY SLAVITT Rule streamlines payment programs The proposed rule, issued April 27, streamlines a patchwork of programs that are designed to measure the value and quality of care provided by doctors and other clinicians. Some physicians participate in alternative payment models (APMs) such as accountable care organizations, the Comprehensive Primary Care Initiative, and the Medicare Shared Savings Program, and most participate in such programs as the Physician Quality Reporting System, the Value-Based Payment Modifier Program, and the Medicare Electronic Health Record Incentive Program. MACRA streamlined these programs into a Fast Facts A proposed rule implementing the Medicare Access and CHIP Reauthorization Act of 2015 would: ❯❯ establish the Quality Payment Program, giving physicians two options for Medicare reimbursement: the merit-based incentive payment system (MIPS) or Advanced Alternative Payment Models ❯❯ increase clinician flexibility by allowing them to choose MIPS measures and activities appropriate to the type of care they provide ❯❯ replace the Medicare Electronic Health Record Incentive Program with a MIPS measure called Advancing Care Information Acting CMS Administrator In its announcement of the rule, CMS said most Medicare clinicians will initially participate through MIPS. The agency said the proposed rule would increase clinician flexibility by allowing them to choose measures and activities appropriate to the type of care they provide. MIPS provides for payment through these performance categories: Quality, Advancing Care Information, Clinical Practice Improvement Activities, and Cost. Those categories break down as follows: Quality (50% of total score in year 1). Clinicians would choose to report six measures from a range of options that accommodate differences among specialties and practices. Advancing Care Information (25% of total score in year 1). Clinicians would choose to report cus- tomizable measures that reflect how they use technology in their day-to-day practice, with emphasis on interoperability and information exchange. Clinical Practice Improvement Activities (15% of total score in year 1). This category rewards clinical practice improvements, such as care coordination, beneficiary engagement, and patient safety. Clinicians may select activities that match their practices’ goals from a list of more than 90 options. Cost (10% of total score in year 1). The score would be based on Medicare claims, so there would be no reporting requirements for clinicians. The category would use 40 episode-spe- 43 Bob Gatty UT Washington Correspondent Bob Gatty, a former congressional aide, covers news from Washington for Urology Times. cific measures to account for differences among specialties. Meaningful use replacement ‘simpler’ CMS’s action to replace the meaningful use program was based on comments from more than 6,000 physicians and patients about their experience with health information technology, according to Andy Slavitt, acting administrator at CMS. “Our goal with Advancing Care Information is to support the vision of a simpler, more connected, less burdensome technology,” said Slavitt. The new regulation would: allow physicians and other clinicians to choose to select the measures that reflect how technology best suits their day-to-day practice simplify the process for achievement and provide multiple paths for success align with the Office of the National Coordinator for Health Information Technology’s 2015 Edition Health IT Certification Criteria emphasize interoperability, information exchange, and security measures and require that patients have online access to their health information simplify reporting by no longer requiring all-or-nothing EHR measurement or quality reporting reduce the number of measures to 11 from 18, and no longer require reporting on the Clinical Decision Support and Computerized Provider Order Entry measures exempt certain physicians from reporting when EHR technology is less applicable to their practice and allow physicians to report as a group. CMS would begin measuring performance through MIPS in 2017, with payments based on those measures beginning in 2019. Medicare physicians who participate to a sufficient extent in Advanced APMs would be exempt from MIPS reporting requirements and qualify for financial bonuses. CMS said it expects the number of clinicians who qualify as participating in Advanced APMs to grow as the program matures. r r r r r r r Feedback Send your comments to Bob Gatty c/o Urology Times, at [email protected] 44 ❳Malpractice Consult❲ JUNE 2016 ∣ Urology Times Could necrotizing fasciitis have been diagnosed sooner? Defendant claims consult, reliance on MRI scan compliant with standard of care A 57-year-old Tennessee man presented to an emergency room in 2006 with complaints of severe groin pain. Testing indicated a high white blood cell count, but a magnetic resonance imaging scan was negative for infection. Two days later, a surgeon was called to consult. She reviewed the medical records, ruled out infection, and left for the weekend. Four days later, the patient’s condition worsened and he was then diagnosed with necrotizing fasciitis of his groin and penis. The surgeon was called in to perform an operation to excise the area, including removal of skin from the penis and removal of the scrotum with the testicles implanted in the upper thigh. The result of the infection and surgery was described as a horrendous and deforming injury. In medical malpractice cases, the caregivers are held to the “standard of care” expected in the particular situation and are judged as to whether that standard was met. The man sued the consulting surgeon and alleged she failed to make a timely diagnosis of the infection or perform a biopsy; rather, she relied on the MRI and ignored the clear clinical signs of infection. He argued that if the infection were caught earlier, an effective treatment would have prevented the subsequent injury. He also claimed the surgeon failed to communicate with other medical team members before leaving for the weekend. The man died a year after filing the lawsuit, and his estate pursued the case to trial. The surgeon contended that her consult and reliance on the MRI and communication were all compliant with the standard of care and that at the time of her consult, the patient did not yet have the infection. A defense judgment was entered. LEGAL PERSPECTIVE: In medical malpractice cases, the caregivers are held to the “standard of care” expected in the particular situation and are judged as to whether that standard Malpractice Consult pletely without any scarring. The jury returned a defense verdict. Dawn Collins, JD Failure to diagnose torsion alleged Ms. Collins is an attorney specializing in medical malpractice in Long Beach, CA. She welcomes your feedback on this column at [email protected]. was met. In our legal system, a “reasonable person” standard is used, meaning would a reasonable physician with the same or similar training, in a same or similar situation, have performed similarly as the defendants in the particular lawsuit? In this case, the plaintiff introduced what he called the “gold standard” for diagnosing this particular infection, claiming that the gold standard was to perform a biopsy at the time of consult instead of relying on the MRI findings. The physician prevailed in showing that her care was compliant with the required standard of care. Allergic reaction to antiseptic solution A New Jersey man in his 40s was admitted to a hospital for a cystoscopy to examine his bladder lining and urethra. After the procedure, the patient had complaints of inflammation and pain to his penis and was seen by several urologists, but with no treatments performed. As a result, he developed scarring to his penis and complained of tenderness and some functional deficit. The man sued the urologist, his nurse, and his medical group, claiming that the antiseptic solution on the equipment used for the cystoscopy caused a severe allergic reaction, with severe inflammation and pain to his penis. The man alleged the urologist and a nurse who assisted in the procedure negligently failed to provide appropriate medical care and failed to properly clean the equipment prior to the procedure, which resulted in the allergic reaction and injuries. The defense denied any negligence, contending that any negative reaction the patient experienced to the antiseptic material was one that could not have been anticipated. They argued that the inflammation and related conditions were temporary and had since resolved com- A 14-year-old male from Illinois presented to an emergency room in 2008 with complaints of lower left abdominal pain and was examined and treated by a pediatric ER physician. A subsequent lawsuit alleged that those involved with his care failed to diagnose leftsided testicular torsion, failed to perform a testicular examination to rule out torsion, and failed to surgically fix the right testicle to prevent a right-sided torsion. As a result, the patient developed a right-sided torsion 6 months later that was treated at a second hospital. There, the medical personnel surgically removed the right testicle, discovered an atrophied left testicle, and surgically fixed that testicle to the scrotum in an attempt to salvage hormone production. The teen is now sterile and requires testosterone replacement therapy for the rest of his life. The lawsuit alleged that those involved with the patient’s care failed to diagnose left-sided testicular torsion, failed to perform a testicular examination to rule out torsion, and failed to surgically fix the right testicle to prevent a right-sided torsion. The defense maintained that the patient did not suffer from testicular torsion at the time of the first ER visit, that he had none of the classic symptoms such as painful/swollen testicles, and that the physician found no reproducible symptoms when he examined the testicles. The plaintiff further asserted that presenting complaints for testicular torsion in an adolescent can be limited to lower quadrant pain without testicular pain, so the defense should have investigated further, especially after other diagnostic tests came back normal and the source of the abdominal pain was not found. The jury found in favor of the patient and awarded $351,000. UT XTANDI® (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION The following is a brief summary. Please see the package insert for full prescribing information. INDICATIONS AND USAGE XTANDI is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). CONTRAINDICATIONS Pregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. WARNINGS AND PRECAUTIONS Seizure In Study 1, which enrolled patients who previously received docetaxel, 7 of 800 (0.9%) patients treated with XTANDI experienced a seizure and no patients treated with placebo experienced a seizure. Seizure occurred from 31 to 603 days after initiation of XTANDI. In Study 2, 1 of 871 (0.1%) chemotherapy-naive patients treated with XTANDI and 1 of 844 (0.1%) patients treated with placebo experienced a seizure. Patients experiencing seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizure. Limited safety data are available in patients with predisposing factors for seizure because these patients were generally excluded from the trials. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, and brain arteriovenous malformation. Study 1 excluded the use of concomitant medications that may lower the seizure threshold, whereas Study 2 permitted the use of these medications. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment. Posterior Reversible Encephalopathy Syndrome (PRES) There have been reports of posterior reversible encephalopathy syndrome (PRES) in patients receiving XTANDI. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). Discontinue XTANDI in patients who develop PRES. ADVERSE REACTIONS Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Two randomized clinical trials enrolled patients with metastatic prostate cancer that has progressed on androgen deprivation therapy (GnRH therapy or bilateral orchiectomy), a disease setting that is also defined as metastatic CRPC. In both studies, patients received XTANDI 160 mg orally once daily in the active treatment arm or placebo in the control arm. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids. The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over placebo) in the XTANDI-treated patients from the two randomized clinical trials were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. Study 1: Metastatic Castration-Resistant Prostate Cancer Following Chemotherapy Study 1 enrolled 1199 patients with metastatic CRPC who had previously received docetaxel. The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids. Grade 3 and higher adverse reactions were reported among 47% of XTANDI-treated patients and 53% of placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in Study 1 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm. Table 1. Adverse Reactions in Study 1 XTANDI Placebo N = 800 N = 399 Grade Grade Grade Grade a 3-4 1-4 3-4 1-4 (%) (%) (%) (%) General Disorders Asthenic 50.6 9.0 44.4 9.3 Conditionsb Peripheral 15.4 1.0 13.3 0.8 Edema Musculoskeletal And Connective Tissue Disorders Back Pain 26.4 5.3 24.3 4.0 Arthralgia 20.5 2.5 17.3 1.8 Musculoskeletal 15.0 1.3 11.5 0.3 Pain Muscular 9.8 1.5 6.8 1.8 Weakness Musculoskeletal 2.6 0.3 0.3 0.0 Stiffness Gastrointestinal Disorders Diarrhea 21.8 1.1 17.5 0.3 Vascular Disorders Hot Flush 20.3 0.0 10.3 0.0 Hypertension 6.4 2.1 2.8 1.3 Nervous System Disorders Headache 12.1 0.9 5.5 0.0 9.5 0.5 7.5 0.5 Dizzinessc Spinal Cord Compression and Cauda 7.4 6.6 4.5 3.8 Equina Syndrome Paresthesia 6.6 0.0 4.5 0.0 Mental Impairment 4.3 0.3 1.8 0.0 Disordersd Hypoesthesia 4.0 0.3 1.8 0.0 Infections And Infestations Upper Respiratory 10.9 0.0 6.5 0.3 Tract Infectione Lower Respiratory 8.5 2.4 4.8 1.3 Tract And Lung Infectionf Psychiatric Disorders Insomnia 8.8 0.0 6.0 0.5 Anxiety 6.5 0.3 4.0 0.0 Renal And Urinary Disorders Hematuria 6.9 1.8 4.5 1.0 Pollakiuria 4.8 0.0 2.5 0.0 Injury, Poisoning And Procedural Complications Fall 4.6 0.3 1.3 0.0 Non-pathologic 4.0 1.4 0.8 0.3 Fractures Skin And Subcutaneous Tissue Disorders Pruritus 3.8 0.0 1.3 0.0 Dry Skin 3.5 0.0 1.3 0.0 Table 1. Adverse Reactions in Study 1 (cont.) Respiratory Disorders Epistaxis 3.3 0.1 1.3 0.3 a b c d CTCAE v4 Includes asthenia and fatigue. Includes dizziness and vertigo. Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. e Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. f Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection. Study 2: Chemotherapy-naive Metastatic CastrationResistant Prostate Cancer Study 2 enrolled 1717 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 1715 received at least one dose of study drug. The median duration of treatment was 17.5 months with XTANDI and 4.6 months with placebo. Grade 3-4 adverse reactions were reported in 44% of XTANDI-treated patients and 37% of placebo-treated patients. Discontinuations due to adverse events were reported for 6% of XTANDI-treated patients and 6% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was fatigue/asthenia, which occurred in 1% of patients on each treatment arm. Table 2 includes adverse reactions reported in Study 2 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm. Table 2. Adverse Reactions in Study 2 Placebo XTANDI N = 844 N = 871 Grade Grade Grade Grade a 1-4 3-4 3-4 1-4 (%) (%) (%) (%) General Disorders Asthenic 46.9 3.4 33.0 2.8 Conditionsb Peripheral 11.5 0.2 8.2 0.4 Edema Musculoskeletal And Connective Tissue Disorders Back Pain 28.6 2.5 22.4 3.0 Arthralgia 21.4 1.6 16.1 1.1 Gastrointestinal Disorders Constipation 23.2 0.7 17.3 0.4 Diarrhea 16.8 0.3 14.3 0.4 Vascular Disorders Hot Flush 18.0 0.1 7.8 0.0 Hypertension 14.2 7.2 4.1 2.3 Nervous System Disorders 11.3 0.3 7.1 0.0 Dizzinessc Headache 11.0 0.2 7.0 0.4 Dysgeusia 7.6 0.1 3.7 0.0 Mental 5.7 0.0 1.3 0.1 Impairment Disordersd Restless Legs 2.1 0.1 0.4 0.0 Syndrome Respiratory Disorders 11.0 0.6 8.5 0.6 Dyspneae Infections And Infestations Upper 16.4 0.0 10.5 0.0 Respiratory Tract Infectionf Lower Respiratory 7.9 1.5 4.7 1.1 Tract And Lung Infectiong Psychiatric Disorders Insomnia 8.2 0.1 5.7 0.0 Renal And Urinary Disorders Hematuria 8.8 1.3 5.8 1.3 Injury, Poisoning And Procedural Complications Fall 12.7 1.6 5.3 0.7 Non-Pathological 8.8 2.1 3.0 1.1 Fracture Metabolism and Nutrition Disorders Decreased 18.9 0.3 16.4 0.7 Appetite Investigations Weight 12.4 0.8 8.5 0.2 Decreased Reproductive System and Breast Disorders 1.4 3.4 0.0 0.0 Gynecomastia Table 2. Adverse Reactions in Study 2 (cont.) a b c d CTCAE v4 Includes asthenia and fatigue. Includes dizziness and vertigo. Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. e Includes dyspnea, exertional dyspnea, and dyspnea at rest. f Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. g Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection. Laboratory Abnormalities In the two randomized clinical trials, Grade 1-4 neutropenia occurred in 15% of patients treated with XTANDI (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with XTANDI (0.3% Grade 3-4) and 5% of patients treated with placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with XTANDI (0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4). Infections In Study 1, 1% of patients treated with XTANDI compared to 0.3% of patients treated with placebo died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death. Falls and Fall-related Injuries In the two randomized clinical trials, falls including fallrelated injuries, occurred in 9% of patients treated with XTANDI compared to 4% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas. Hypertension In the two randomized trials, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm. Post-Marketing Experience The following additional adverse reactions have been identified during post approval use of XTANDI. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Neurological Disorders: posterior reversible encephalopathy syndrome (PRES) DRUG INTERACTIONS Drugs that Inhibit CYP2C8 Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold. Coadministration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI. Drugs that Induce CYP3A4 Co-administration of rifampin (strong CYP3A4 inducer and moderate CYP2C8 inducer) decreased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 37%. Co-administration of strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) with XTANDI should be avoided if possible. St John’s wort may decrease enzalutamide exposure and should be avoided. If co-administration of a strong CYP3A4 inducer with XTANDI cannot be avoided, increase the dose of XTANDI. Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring. USE IN SPECIFIC POPULATIONS Pregnancy– Pregnancy Category X. Risk Summary XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no human data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. Enzalutamide caused embryofetal toxicity in mice at exposures that were lower than in patients receiving the recommended dose. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XTANDI. Animal Data In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15). Findings included embryo-fetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at ≥ 10 mg/kg/day, and cleft palate and absent palatine bone at 30 mg/kg/day. Doses of 30 mg/kg/day caused maternal toxicity. The doses tested in mice (1, 10 and 30 mg/kg/day) resulted in systemic exposures (AUC) approximately 0.04, 0.4 and 1.1 times, respectively, the exposures in patients. Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/day (approximately 0.4 times the exposures in patients based on AUC). Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established. Geriatric Use Of 1671 patients who received XTANDI in the two randomized clinical trials, 75% were 65 and over, while 31% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic CRPC and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment (30 mL/min ≤ creatinine clearance [CrCL] ≤ 89 mL/min) compared to patients and volunteers with baseline normal renal function (CrCL ≥ 90 mL/min). No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed. Patients with Hepatic Impairment Dedicated hepatic impairment trials compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild, moderate, or severe hepatic impairment (ChildPugh Class A, B, or C, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild, moderate, or severe baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild, moderate, or severe hepatic impairment. OVERDOSAGE In the event of an overdose, stop treatment with XTANDI and initiate general supportive measures taking into consideration the half-life of 5.8 days. In a dose escalation study, no seizures were reported at ≤ 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizure following an overdose. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide. Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay. Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4-, 13-, and 39-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day (0.3 times the human exposure based on AUC). Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716 Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Medivation, Inc., San Francisco, CA 94105 Revised: October 2015 15C018-XTA Rx Only © 2015 Astellas Pharma US, Inc. XTANDI® is a registered trademark of Astellas Pharma Inc. 076-1200-PM XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). Important Safety Information Contraindications XTANDI is not indicated for women and is contraindicated in women who are or may become pregnant. XTANDI can cause fetal harm when administered to a pregnant woman. Warnings and Precautions Seizure In Study 1, conducted in patients with metastatic castration-resistant prostate cancer (CRPC) who previously received docetaxel, seizure occurred in 0.9% of XTANDI patients and 0% of placebo patients. In Study 2, conducted in patients with chemotherapy-naive metastatic CRPC, seizure occurred in 0.1% of XTANDI patients and 0.1% of placebo patients. There is no clinical trial experience re-administering XTANDI to patients who experienced a seizure, and limited safety data are available in patients with predisposing factors for seizure. Study 1 excluded the use of concomitant medications that may lower threshold; Study 2 permitted the use of these medications. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity during which sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment. Posterior Reversible Encephalopathy Syndrome (PRES) In post approval use, there have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES. Adverse Reactions The most common adverse reactions (≥ 10%) reported from two combined clinical studies that occurred more commonly (≥ 2% over placebo) in XTANDI patients were asthenia/ fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. In Study 1, Grade 3 and higher adverse reactions were reported among 47% of XTANDI patients and 53% of placebo patients. Discontinuations due to adverse events were reported for 16% of XTANDI patients and 18% of placebo patients. In Study 2, Grade 3-4 adverse reactions were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to adverse events were reported for 6% of both study groups. • Lab Abnormalities: Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). Grade 1-4 thrombocytopenia occurred in 6% of XTANDI patients (0.3% Grade 3-4) and 5% of placebo patients (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of XTANDI patients (0.2% Grade 3-4) and 16% of placebo patients (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients (0.1% Grade 3-4) and 2% of placebo patients (no Grade 3-4). • Infections: In Study 1, 1% of XTANDI patients compared to 0.3% of placebo patients died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death. • Falls (including fall-related injuries), occurred in 9% of XTANDI patients and 4% of placebo patients. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients, and included non-pathologic fractures, joint injuries, and hematomas. • Hypertension occurred in 11% of XTANDI patients and 4% of placebo patients. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of all patients. Drug Interactions Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration is necessary, reduce the dose of XTANDI. Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If co-administration is necessary, increase the dose of XTANDI. Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring. Please see adjacent pages for Brief Summary of Full Prescribing Information. © 2016 Astellas Pharma US, Inc. All rights reserved. Printed in USA. 076-1306-PM 1/16 XTANDI, Astellas, and the flying star logo are trademarks of Astellas Pharma Inc. patient lives 94% ofareinsured covered for XTANDI* 2 *As of February 2015. A product’s placement on a plan formulary involves a variety of factors known only to the plan and is subject to eligibility. To learn more, please visit XtandiHCP.com XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). bilatera *Or after l orchiecto 1 my. patient lives 94% ofareinsured covered for XTANDI †2 †As of February 2015. A product’s placement on a plan formulary involves a variety of factors known only to the plan and is subject to eligibility. Select Safety Information To learn more, please visit XtandiHCP.com XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. Seizure occurred in 0.9% of patients receiving XTANDI who previously received docetaxel and in 0.1% of patients who were chemotherapy-naive. Permanently discontinue XTANDI in patients who develop a seizure during treatment. There have been post approval reports of posterior reversible encephalopathy syndrome (PRES), a neurological disorder which can present with rapidly evolving symptoms and requires confirmation by brain imaging. Discontinue XTANDI in patients who develop PRES. References: 1. XTANDI [package insert]. Northbrook, IL: Astellas Pharma US, Inc. 2. Data on file, Medivation, Inc. Please see inside page for additional Important Safety Information. Please see adjacent pages for Brief Summary of Full Prescribing Information.