April 2014

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gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

ASCO GI

IBS AWARENESS MONTH

Surveillance in Barrett’s Lacking

Physicians, Patients Becoming More Aware of Effects of Diet in IBS

BY CAROLINE HELWICK BY MONICA J. SMITH

see Barrett’s Surveillance, page 23

Blood Test for Pancreatic Cancer BY CAROLINE HELWICK SAN FRANCISCO— —The presence of even one circulating tumor cell (CTC) appears to be diagnostic of pancreatic ductal adenocarcinoma, according to research conducted at the University of California, Los Angeles (UCLA), and presented at the see Pancreatic Cancer, page 34

SAN DIEGO—Nearly all patients with gastrointestinal (GI) distress wonder if their problems stem from what they eat or don’t eat, and if they might feel better on the right diet. This is especially true in patients with irritable bowel syndrome (IBS), two-thirds of whom report symptomatic responses to food. With the rising popularity of specialized diets and heavy marketing of the notion that wellbeing depends on eating specific foods, it’s no surprise that many people view their plate as a potential friend or foe. An average of three tons of food is consumed over a lifetime. A small proportion of this amount gives rise to food poisoning, food allergies and food sensitivities, with the latter two being reported with increasing frequency. In a presentation at the 2013 American College of Gastroenterology (ACG) Annual Scientific

Endoluminal Devices For GERD The Struggle To Arrive and Thrive BY MAUREEN SULLIVAN It is about 14 years since the CSM Stretta System (Mederi Therapeutics) was launched as the first endoluminal treatment for patients with gastroesophageal reflux disease (GERD). Its introduction

Meeting entitled “Food Intolerances and IBS: Coexistent or Separate Entities?” Sheila Crowe, MD, professor of medicine and director of research at the University of California, San Diego, in La Jolla, discussed the influence of diet on symptoms of IBS. see IBS, page 14

I N S I D E FROM THE BENCH TO THE BEDSIDE see pages 8-9

Maximizing Bowel Preparation for Colonoscopy: The Patient Component Lawrence B. Cohen, MD

Pancreatic Exocrine Insufficiency FDA Regulations on Pancreatic Enzyme Products Questioned .................... page 36

CORPORATE SPOTLIGHT

CLINICAL REVIEW

see pages 16-17

see insert after page 70

Medivators Inc.

Pancreatic Exocrine Insufficiency Part 1 of 2: Treatment Approaches

Your best practice is our promise.

By Vivek Kadiyala, MD, Shadeah Laila Suleiman and Darin L. Conwell, MD, MS

see GERD, page 20 PROCEDURAL BREAKTHROUGH

FROM THE BENCH TO THE BEDSIDE

see pages 24-25

see pages 38-39

Use of FibroScan for Noninvasive Assessments of Liver Disease

Switching From 5-ASA to Mesalamine Granules in Patients With Ulcerative Colitis in Remission

David Bernstein, MD

Gary R. Lichtenstein, MD

Switching From 5-ASA to Mesalamine Granules in Patients With Ulcerative Colitis in Remission Faculty Gary R. Lichtenstein, MD Professor of Medicine Director, Center for Inflammatory Bowel Disease Department of Medicine Division of Gastroenterology Raymond and Ruth Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania

Indication for APRISO APRISO® (mesalamine) is a locally acting aminosalicylate indicated for the maintenance of remission of ulcerative colitis in patients 18 years and older. The use of APRISO for treating ulcerative colitis beyond 6 months has not been evaluated in controlled clinical trials.

Important Safety Information About APRISO APRISO extended-release capsules are contraindicated in patients with hypersensitivity to salicylates or aminosalicylates (sulfasalazine) or to any of the components of APRISO capsules. It is recommended that patients have an evaluation of renal function prior to initiation of APRISO therapy and periodically while on therapy. Exercise caution when using APRISO in patients with known renal dysfunction or a history of renal disease. Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from a flare of inflammatory bowel disease. Symptoms include cramping, acute abdominal pain and bloody diarrhea, sometimes fever, headache, and rash. If acute intolerance syndrome is suspected, promptly discontinue treatment with APRISO. There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine. Caution should be exercised when administering APRISO to patients with liver disease. Because dissolution of the coating of APRISO granules depends on pH, APRISO should not be coadministered with antacids. Caution should be taken to closely monitor blood cell counts during mesalamine therapy in patients ages 65 and older. Patients with phenylketonuria should be aware that APRISO contains aspartame, equivalent to 2.24 mg of phenylalanine per day.

The most common treatment-related adverse events occurring in at least 3% of adult patients taking APRISO and at a rate greater than placebo in clinical trials were headache (11%), diarrhea (8%), upper abdominal pain (5%), nausea (4%), nasopharyngitis (4%), influenza and influenzalike illness (4%), and sinusitis (3%).

Introduction Primary goals in the treatment of ulcerative colitis (UC) include maintenance of remission.1 Reduction in the need for corticosteroids also is important to avoid the long-term adverse effects otherwise associated with such therapy.1 Although mesalamine (5-aminosalicylic acid, 5-ASA) is an effective nonsteroid for maintenance of remission in patients with UC, one popular mesalamine formulation (ASACOL 400 mg) was recently discontinued thus requiring physicians to choose another mesalamine formulation for their patients who were formerly receiving this medication.1,2 This clinical scenario requires a review of the available data to help guide the transition of patients in remission from one formulation to another, including an investigation of whether flare-ups may occur while transitioning to the new regimen. This article will discuss available data regarding the efficacy and safety of a switch from one mesalamine formulation to another mesalamine formulation with once-daily dosing (mesalamine extendedrelease [ER] granules [APRISO]) for maintenance of remission.

Mesalamine Extended-Release Granules Mesalamine ER granules (APRISO, Salix Pharmaceuticals) are a once-daily 5-ASA preparation approved by the FDA in October 2008 for maintenance of remission of UC in patients aged 18 years and older.3 Mesalamine ER capsules possess Intellicor® technology that allows both delayed-release and ER delivery of mesalamine to areas of the gastrointestinal tract affected in patients with UC.3,4 Once ingested, the gelatin capsules dissolve, releasing thousands of granules that provide a large surface area from which mesalamine is released. Each granule has a delayed-release, gastric acid–resistant coating that allows it to travel intact until a pH of 6.0 is reached. Intestinal fluids dissolve the coating to initiate ER delivery. Each granule’s polymer matrix core then swells as intestinal fluid is

absorbed, forming channels through which mesalamine is delivered in an extended release, providing once-daily protection throughout the colon.3 Clinical investigation also revealed that 32%±11% (mean ± SD) of the administered dose was systemically absorbed under fasting conditions and that a high-fat meal did not affect peak concentration for 5-ASA, indicating that APRISO can be taken without regard to food.3

Clinical Studies of Mesalamine Granules Double-blind, placebo-controlled trials have described the efficacy of mesalamine granules for the maintenance of remission of UC.5 In the 2010 study, patients with UC were randomized to receive either mesalamine granules (1.5 g once daily; n=209) or placebo (n=96) for up to 6 months. The percentage of relapse-free patients at the end of the treatment period was significantly higher for the group receiving mesalamine granules than for those receiving placebo (78.9% vs 58.3%; P<0.001). Furthermore, patients receiving mesalamine granules had positive outcomes in terms of secondary end points, including improvement in rectal bleeding, stool frequency, physician’s disease activity rating, and the Sutherland Disease Activity Index.

Probability of remaining relapse-free

SAN FRANCISCO—Surveillance of patients with Barrett’s esophagus (BE) requires a more systematic approach that incorporates risk stratification, and although that paradigm is still a work in progress there are ways that endoscopists can make the

Headaches (11%), diarrhea (9%), abdominal pain (7%), nasopharyngitis (5%), upper abdominal pain (4%), abnormal feces (3%), back pain (3%), and nausea (3%) were the most frequently reported adverse events in patients receiving mesalamine granules.5 A subanalysis of patients with UC from the 2010 study as well as patients from another randomized, double-blind, placebo-controlled 6-month study of identical design (N=487) was performed.6 The specific patients examined were those who had switched to mesalamine granules (1.5 g once daily) or to placebo from other 5-ASA formulations. The results were remarkably similar to those seen in the larger group of patients in the 2010 study; the relapse-free rate after 6 months was significantly higher for those who had switched from other 5-ASA formulations to mesalamine granules compared with those who switched from other 5-ASA formulations to placebo (78.3% vs 58.8%; P<0.001) (Figure).6 Furthermore, rectal bleeding, stool frequency, and the physician’s rating of disease activity remained unchanged after 6 months in a higher percentage of patients who switched to mesalamine granules compared with those who had switched to placebo (P<0.004 for each end point). Of note, withdrawal due to UC flare-ups in the group receiving mesalamine

1.0 MG 1.5 g qd (N=322)

0.80 0.60

Placebo (N=165)

0.40 0.20

MG vs placebo 55% reduction in risk of relapse (P<0.001)

0 0

50

N at risk, MG: N at risk, placebo:

100 150 200 Relapse-free duration, d Month 1 322 165

Month 3 299 135

250

Month 6 267 114

Figure. Kaplan–Meier estimates of time to relapse during the treatment period in patients who switched from other 5-ASA formulations to either APRISO 1.5 g daily or placebo. Based on Lichtenstein G, et al. Aliment Pharmacol Ther. 2012;36(2):126-134, with permission. 5-ASA, 5-aminosalicylic acid; MG, mesalmine granules; qd, daily

300

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GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

Vol. 65, No. 4 MEDICAL ADVISORY BOARD MANOOP S. BHUTANI, MD

GARY R. LICHTENSTEIN, MD

Houston, Texas

Philadelphia, Pennsylvania

ALAN F. CUTLER, MD

NIRMAL S. MANN, MD, BSC, MS, PHD, DSC

Farmington Hills, Michigan

FREDRIC DAUM, MD Mineola, New York

STEVEN M. FABER, MD Elizabeth City, North Carolina

RONNIE FASS, MD Cleveland, Ohio

BARBARA B. FRANK, MD Philadelphia, Pennsylvania

FRANK G. GRESS, MD New York, New York

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St. Charles, Illinois

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4

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

The New York Times, Rebuked Re: “Colonoscopy—Facts The New York Times Omitted,� by Farid Naffah, MD, MS. Gastroenterology & Endoscopy Newss March 2014;65:1,6,8,13. Kudos to Dr. Naffah! What gives me a chill is the profuse amount of misstatements, allegations, unsubstantiated “facts� and blather that pours out of the mainstream media daily. We, as doctors, are responsible and accountable for our actions; the media is not. I remember years ago in Waterbury, Conn., doctors rushing to their offices as soon as possible on the days when The New York Times was delivered so that they would have time to review the front page, which usually had a comment on the most recent lead article in The New England Journal of Medicine so that they could try to answer their patients’ questions. And when the Times stated that too many hysterectomies were being done, they had no responsibility for any woman suffering from ovarian cancer because she read and believed the Times. pbals March 13, 2014

This is a great rebuttal to the article. Please send it to the editors at The New York Times. renen March 13, 2014

You should be commended for a comprehensive, well-presented, balanced response to a New York Times reporter who has repeatedly chosen to conveniently disparage not only gastroenterologists, but other medical professionals with a litany of misinformation that ultimately harms the unsuspecting consumer of medical services. The fact that she herself is a physician is shameful, considering that she has deliberately betrayed our profession with numerous demeaning and false accusations that are grounded in false information. Instead of trying to repair the distrust embodied by insurance companies’ blatant attempts to undermine the scared patient–physician relationship, Ms. Rosenthal has decided to lead the charge by providing misleading inaccuracies about the proven benefit of colonoscopies in reducing morbidity and mortality. She should be ashamed of herself for violating the trust of the unsuspecting readers of The New York Times. We, on the other hand, will continue to care for our patients based on compassion, medical facts and evidence-based information to provide the quality of medicine that our society deserves and that attracts patients from around the globe to our medical facilities. fedid March 15, 2014

The criticism voiced in The New York Times article was brought upon us by ourselves. It is hard to deny the professional and professional societies’ bias that played into the current situation, denying the benefits of objectivity offered by a simple annual fecal occult blood test. That there is a 10% to 15% incidence of interval colorectal cancer that is almost always picked up by blood in stool (occult or overt), has been glaring at us for decades. By doing unnecessary colonoscopies, we ended up neglecting the ones that really needed to be done. Not to mention subjecting patients to the risks of sedation and invasive procedures. Dr. Naffah’s criticism of flexible sigmoidoscopy is not justified: He needs to review the prevalence of lesion location and the justification of removing miniscule polyps and then branding the patients for lifelong colonoscopies every three to five years. Granted, a lot of wh hat was said in The Ne ew York Times article wa as gastro endone sensationalism, bu ut ws co as we are dictated byy professional bias, so is Ms. Rosenthal.

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I think the American Association for the Study of Liver Diseases (AASLD) missed a golden opportunity for using an Internet-based “smart forms� registry, which also automatically generates a billable visit note for the physician and provides real-time data open to alll participants. So often it is hard to replicate in real-life practice what is reported as “outstanding success of prescriptions� in the sales literature by opinion leaders. When you are asking me to prescribe medications worth $100,000, I need to know what the efficacy and toxicity of the drug is in real-world patients with hepatitis C and multiple other comorbidities. To that end, doctors like me would be willing to input anonymous basic clinical data and detailed side effects into a central database as a part of our workflow. There should be some way of capturing laboratory data directly into the database without manual

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entry. A portion of the money collected by Big Pharma should be passed on to the physicians for doing this boring and time-consuming work for them: I would say about $1,000 to $1,500 per hepatitis C patient treated, and more when complications have to be reported. It takes up enormous amounts of time for which we are paid a pittance. All related lab work should be included in medication cost to allow unified billing. This makes sense because the treatment of hepatitis C is essentially “protocolized.� Unlike university centers, which care little about costs and routinely hire dozens of para-clinical staff to do paperwork for their glorious electronic records, for a busy private solo physician like me, time and money are valuable. I run a lean office. I expect to be compensated for my time because the insurance reimbursement for visit codes does not even come close to our operational costs. As far back as 2008, I sensed what was coming and wrote a blog on sermo.com: Physicians can access it at https://app.sermo. com/posts/posts/21459.

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Re: “ASGE Unveils New Training Facility,� by Brigid Duffy. Gastroenterology & Endoscopy News March 2014;65:1,28,30,31. Although this facility is designed to train physicians, it looks to me to be the perfect spot to develop a new certification for endoscopy technicians (with the cooperation of the Society of Gastroenterology Nurses and Associates). Maybe a week of classroom and a week of hands-on with endoscopes and cleaning techniques, followed by written and practical exams. Hospitals and ambulatory care units in California here would pay dearly to get the technicians a new certification so that we could petition the state to allow them to assist us during procedures. (Last year, the state decided to interpret the Centers for Medicare & Medicaid Services guidelines to require only RNs to assist doctors during biopsies and snaring). Please consider doing this! rpech March 13, 2014

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6

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

Tailored Diet for Crohn’s Disease

Hemorrhoid Ligation: Full Disclosure

Re: “Popular IBD Diet Associated With Increased Microbial Diversity,� by David Wild. Gastroenterology & Endoscopy News January 2014;65:35.

Re: “Approach to Hemorrhoids: A Primer for Gastroenterologists,� by Harry Sarles Jr., MD. Gastroenterology & Endoscopy News January 2014;65(suppl):1-4. Has Dr. Sarles fully disclosed his financial links to CRH Medical, such as equity? Gastroenterologists who wish to perform hemorrhoid ligation must be prepared to deal with the complications, such as delayed hemorrhage, severe pain, urinary retention and deep pelvic sepsis. These complications are rare, until they happen; then they can be a nightmare, even leading to litigation. Fairness dictates that this article, unless clearly displayed as advertising, should advise gastroenterologists that they also could band hemorrhoids at a fraction of the overhead using reusable banding devices. I have been banding hemorrhoids for more than 30 years and pay about 15 cents per band. The reusable devices I use now are the same ones I started with, and I inherited them from a retiring surgeon. rgold. February 18, 2014

It’s gratifying to see a structured diet very similar to the one I’ve gravitated toward over time with Crohn’s disease. My own criteria follow the “legal� diet outlined by the specific carbohydrate diet, but with another layer. The source of any food must be carefully considered because there may be sensitivity to animal feeds and any agricultural sprays used before food production begins. A local food co-op is now labeling produce as “unsprayed� if it is known to come from fields untreated with any commercial sprays, organic or otherwise. Meat and dairy products are a little trickier because farm sources tend to be pooled

and any one farm may or may not be spraying; certain brands are less irritating than others, it’s just a matter of trial and error. mom@m February 12, 2014

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Compassionate Care Above All Else Re: “Dear Professor Flexner: Medicine Is a Business, as Well as a Public Trust,� by Nicholas V. Costrini, MD, PhD, MBA. Gastroenterology & Endoscopy News January 2014;65:6. Regarding Dr. Costrini’s piece in the January issue, although I think it is anyone’s right to acquire an MBA, Trust we should not lose sight of Public l as a exner: as Wel ssor Fl r Profe a Business, ea D the multiple factors that are ine Is Medic destroying our ability to efficiently and compassionately render patient care. Outside forces are conspiring to create a perfect storm that we, as physicians, mustt repel in order to carry out our moral and ethical responsibilityy to our patients. What we nee ed to do is to reject the constrain nts -/

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on delivering the kind of care we were al all trained to give, much as a soldierr should reject orders from superiors that violate moral standards. These forces include: • lac ck of pricing power with eve er-declining rates; • increased and ineffective regulations, such as HIPAA; • d draconian endoscopy center documentation mandates; d • EMR [electronic medical record] adoption with childish meaningful use standards;

loroentero those gastour game in ity. To ice qual dy on top of our endosel of serv alrea built wed the gaps mod believe we are : When we this we follo t would h Flexner gists who consider decades, Tha althoug ssary e matters, the past two scopy vendors. Company es that er opin rt that were necees fac- thes units over s of the endo , by Ludmer dyear Tire repo issu tion - copy ng Goo surprising thatated Kenneth tions in his predicted the enda aski Lud e,â€? Car y. Mr. recomm ta Airlines have mmenda It is not overestim MBA made reco he could not icine toda with the be like Del needed! py of units pment. It is , PhD, and med addressed tires it time, osco equi trini, MD practice rnment t be at that r—as the how many ed dur25% end age and/or s V. Cos ety, gove matters mus the consume ssment, foot units closa lack of all ing soci ist in solo Group, PC Nichola i.e., ber of my asse s for square ge. y said that the public— nterolog lar num s is a result of ent. n and chan merer Gastroe Gastroenterolog their need that a simi rests of of adaptatio n. Thi environm r worthy best inte downtur care business g the future rgia c ivato ne Georgia note iGeo omi mot dici th med ah, ary Me the econ g of the health mism regardin challenges of heal Savann since the al and prim iness of future service ing of ndin century t for opti of the the Bus myriad d soci ined r, of the understa driver been a fee-forargumen is that the bracing or othe has face central It has tices of doctor– The best were dest1910, Em g some, e. The current th care munity al prac ent, the vidual applyin of heal In cal com nal issues that At pres The tradition and indi le value. 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Conjecture in NEJM Re: “FOBT Shows ‘Striking’ Results for Long-Term Reduction in CRC Mortality,� by Monica Smith. Gastroenterology & Endoscopy Newss March 2014;65:1,18,19. When reading this interesting study published in The New England Journal of Medicine (NEJM),

one is left with the impression that there are more data in the study that were not put in that would have been very interesting and relevant, including: • the timing of polyp detection and outcomes of these patients versus patients who did not have any polyps; • the timing of colorectal cancer in relationship to the study conclusion (after the 11 years); • the effect of a four-year hiatus; and

• complex ICD-10; • unending insurance authorizations and verifications that increase costs; • payments based on patient satisfaction; • Medicare payments to hospitals with our fees bundled; • payment for outcomes using short-term and poorly designed metrics; and • federal boards that determine best practices (data always in flux). Let’s not take our eye off the ball with MBA speak. We can hire MBAs, but our role in life is to give empathetic and competent care, one patient at a time. Ronald E. Feldman, MD Gastroenterologist Escondido, Calif.

• the incidence (if any) of interval cancers not detected by fecal occult blood test, etc. It is surprising that the NEJM M editors did not ask for these data. The conjecture of the effect of polypectomy is therefore left as just that, and again it is surprising that NEJM M did not question the conjecture statement. dines March 13, 2014

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

7

Pyramids, Pancakes an nd Presidents: Lessons for Crohn’s Diisease Nicholas V. Costrini, MD, PhD, MBA Gastroenterologist in solo practice Georgia Gastroenterology Group, PC Savannah, Georgia I am like many physicians. Medicine is my nucleus, no matter how much I might strive for what in the current lifestyle vernacular is called a “balanced” life. Balance seems reasonable, but like a tuxedo, it is not quite natural. I don’t spend every waking hour thinking about medicine. That is not because I find other things more interesting or challenging. Rather, it is because other arenas of human discourse have ways of influencing how I think about what is most important to me, namely medical care. Take, for instance, the history of the presidents. History is a funny thing. Rather than being a static appraisal of the past, it is quite like medicine in that it is constantly being revisited and corrected as new information percolates through parchment archives. The life of Thomas Jefferson is a telling example. In 1974, the very highly regarded UCLA historian, Fawn M. Brodie, reported in her book, “Thomas Jefferson: An Intimate Life,” that there is impressive circumstantial evidence that our nearly glorious third president had an intimate relationship with his house servant and slave Sally Hemings. The reaction of the academic history gaggle was swift and harshly critical. One might have thought that the religious affiliation of the pope had been challenged. Two decades later, historian Willard Sterne Randall, in his book, “Thomas Jefferson, A Life,” concluded that for practical, political and reasons of honor, Mr. Jefferson did not have a personal, private, intimate life with Sally. He wrote, “the whole chain of suppositions was preposterous.” Not so fast, Willard. In 2012, Pulitzer Prize–winning historian Jon Meacham, in his “Thomas Jefferson: The Art of Power,” presented the issue in the most unambiguous and unemotional manner, with the cold analytical tool of DNA analysis. Thomas Jefferson and Sally Hemings had an intimate relationship and progeny. I enjoy history for itself and for how it informs medicine. Take for example, the past several decades of Crohn’s disease treatment recommendations. For nearly as long as I can remember, the management of Crohn’s disease has been presented with that pyramid that places mesalamine at the base, affixes the immunomodulators at the next tier or step, followed by steroids, then the biologics. Surgery sits on top. Assuming the pyramid is still meritorious, a rather distracting debate has been one of “bottom-up versus top-down” therapy. In truth, we spent an embarrassing two decades believing that mesalamine was a good treatment for the disease. There is abundant evidence that, although mesalamine is a mainstay for patients with ulcerative colitis, it has precious little merit for patients with Crohn’s. Yet for more than a decade, mesalamine and its variations have remained at the base of the pyramid. In a similar manner and with as much discord as the “Jefferson matter,” the immunomodulators have been recommended as a standard of care in the management of Crohn’s disease. It remains as the second pyramid tier. We entered 2014 with the American Gastroenterological Association (AGA) recommending “thiopurines over no immunomodulator therapy” for maintenance therapy in patients with Crohn’s disease (Terdiman JP et

For nearly as long as I can remember, the management of Crohn’s disease has been presented with that pyramid that places mesalamine at the base, affixes the immunomodulators at the next tier or step, followed by steroids, then the biologics. Surgery sits on top. al. Gastroenterology 2013;145:1459-1463). The AGA is softening the importance of short- and long-term risks, as well as the current reports that this class of drugs is no better than placebo in preventing relapses. Specifically, in the October 2013 issue of Gastroenterology, two respected studies, one by the AZTEC (Azathioprine for Treatment of Early Crohn’s disease in adults) group (Panés J et al. Gastroenterology 2013;145:766-774) and a second by the GETAID (Groupe d’Etude Thérapeutique des Affections Inflammatoires du Tube Digestif ) group (Cosnes J et al. Gastroenterologyy 2013;145:758-765), provide data that most strongly call into question the merits of the azathioprine immunomodulators in preventing relapses, steroid sparing or, for that matter, inducing remission. All that remains for this group of medications is that they improve clinical effectiveness and reduce immunogenicity of the biologics and maybe, just maybe, reduce postoperative relapses. (This point has not been investigated with rigor.) As of this moment, the scientific data should require us to dismantle the holy pyramid. It should be changed to, rather, a double stack of pancakes—namely, biologics and/or steroids for induction and maintenance. Surgery could be a pat of butter seated on top. The other drugs can receive their useful boutique mention. At a time when the bar has been raised from the purely clinical Crohn’s Disease Activity Index to that of mucosal healing, reduction of steroids and surgery, and advancement of quality of life, the pyramid is a misdirected pictorial history of Crohn’s disease care. Regarding the October Gastroenterology publications, experts offer that the immunomodulators will remain in use because the biologics are too expensive. Astonishingly, such comments imply that practicing gastroenterologists should offer patients placebo and indeed dangerous care because effective treatments are too expensive. What would the genius, philosopher-politician Thomas Jefferson advise? The biologics are indeed expensive. However, it is not all the fault of the pharmaceutical industry. Big Pharma has recognized the problem to some extent. Programs exist to aid patients with limited incomes, high copays or no insurance. However, nearly 40% of eligible patients are not participating in these programs. There are, of course,

numerous reasons for this; but it has to be said that many gastroenterologists do not take the time or extend the required effort to provide successful enrollment for their patients. If they did, the cost issue would be blunted. The most vigorous tack is to work directly with (i.e., lobby) the relevant pharmaceutical companies to lower the cost of the biologics. What? Why would the companies do that? Consider that the biosimilar biologics will be here in probably a few years. They will likely cost 15% less than the originals and will likely be equally effective. (In Europe, the first equi-effective biosimilar has been approved for the treatment of rheumatoid arthritis.) If the prices were cut now for the originals, any merit of the marketed biosimilars would be dampened if not eliminated, and more patients could be given effective medications now. This would be a win–win situation for patients and for the current drug makers who would enjoy an even higher market share over the biosimilars. These companies have made blockbuster profits over the past 15 years and have worked constructively with the gastroenterology community. Only the gastroenterology community can encourage them to step up now, as they own the only effective nonsteroid treatment for Crohn’s disease. Finally, the gastroenterology leadership can work with biosimilar drug companies and the FDA in order to ensure a fast-track program of approval. (Actually, these drugs already are in fast-track mode.) Rather than saying there is nothing to do, Thomas Jefferson would likely address the problem with his political genius by pushing available cost-reduction programs; showing the real corporate merit, financially and ethically, of dropping the entire cost now by at least 15%; and by working with FDA. If we do nothing, I will be ashamed because it will reflect a lost opportunity for our specialty to very effectively honor a serious commitment to our patients. If the drug companies do nothing, I will have a good memory when the biosimilars come to the market. I am no genius, but I know the difference between placebos, pyramids and pancakes. Only the last has a taste of merit. ■ Dr. Costrini can be reached via email at ncostrini@georgiagi.com.

THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Maximizing Bowel Preparation for Colonoscopy: The Patient Component Lawrence B. Cohen, MD, FACG, FASGE, AGAF Clinical Professor of Medicine Division of Gastroenterology Icahn School of Medicine at Mount Sinai New York, New York

Introduction It has been demonstrated that colonoscopy is the most effective strategy employed in clinical practice for the prevention and early detection of colorectal cancer (CRC). The systematic detection and removal of colon adenomas during colonoscopy is estimated to prevent 53% of deaths that would otherwise be associated with progression of polyps to colon cancers.1 However, success using this highly technical procedure is dependent on a host of variables working in concert, including the operator, the operator’s experience

with colonoscopy, and the appropriate use of surveillance and screening intervals.2 Closely related with the success of colonoscopy is the quality of bowel preparation. 2 Inadequate bowel preparation is estimated to occur in 20% to 25% of cases and results in a reduction in adenoma detection rate (ADR), and often, the need for a second attempt at bowel preparation and colonoscopy (Figure 1).2,3 This phenomenon can contribute to higher direct as well as indirect costs of care related to lost physician appointment time, time spent by patients and their escorts, and sometimes, the need for a second procedure.4 The revised 2012 United States MultiSociety Task Force Guidelines on Colorectal Cancer suggest monitoring the quality of bowel preparation with the goal of achieving preparations adequate for detection of lesions greater than 5 mm in size. The adequacy of bowel preparation should be assessed afterr efforts to clean the mucosa during examination have been completed.

All lesions (P<0.0001) Polyps ≤9 mm (P<0.0001) Cancer/polyp >9 mm (P=0.82)

35% 30% 25% 20% 15% 10% 5% 0% Adequate prep

Inadequate prep

Figure 1. Colonic lesion detection rates according to preparation quality. Reprinted from Harewood GC, Sharma VK, de Garmo P. Impact of colonoscopy preparation quality on detection of suspected colonic neoplasia. Gastrointest Endosc. 2003;58(1):76-79, with permission from Elsevier.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

Furthermore, the guidelines state that patients found to have poor bowel preparation during colonoscopy should undergo repeat examination within 1 year.5 However, the guidelines do not provide direction in terms of how to optimize bowel preparation for patients with a history of poor bowel preparation or for those at high risk for poor bowel preparation.

Factors Related to Poor Colonoscopy Preparation Identification of factors that could predict poor colonoscopy preparation would help target additional education or proactive interventions toward the appropriate population. Nguyen et al studied 300 consecutive patients who underwent screening colonoscopy and who were instructed to use a standard preparation of 2,000 mL of polyethylene glycol bowel preparation.6 Approximately 15% of patients had inadequate bowel preparation, and the majority of patients (n=45) with poor colonoscopy preparation (86.7%) reported either failure to complete the preparation or failure to follow written instructions concerning timing or dietary restrictions.6 Multivariate analysis showed the primary contributors to poor colonoscopy were single status, an interpreter requirement, Medicaid insurance, and having more than 8 active prescription medications.6 Additionally, Borg et al studied the adequacy of bowel preparation in 1,588 unique colonoscopy procedures at a tertiary referral center.7 The authors reported that body mass index (BMI) of at least 25 kg/m2 was an independent predictor of inadequate bowel preparation.7 In fact, each unit increase in BMI increased the likelihood of an inadequate composite outcome score by 2.1%.7 In their review of bowel preparation failure, Romero et al found that patient-related factors, such as increased age, male gender, presence of a comorbidity (particularly diabetes mellitus, stroke, and dementia), and lower patient socioeconomic status, were associated with poor bowel preparation among adults undergoing routine outpatient colonoscopy.8 Procedure-related factors, such as poor adherence to bowel preparation instructions, erroneous timing of bowel purgative administration, and longer appointment waiting times for colonoscopy were associated with poor bowel preparation (Table).8 Lastly, Hassan et al studied 2,811 consecutive patients who underwent colonoscopy examinations. They determined that factors associated with inadequate bowel preparation included

obesity (odds ratio [OR], 1.1), male gender (OR, 1.2), previous colorectal surgery (OR, 1.6), cirrhosis (OR, 5), Parkinson’s disease (OR, 3.2), and diabetes (OR, 1.8).9 Despite these data, however, no group yet has validated a predictive algorithm with high sensitivity and specificity for the identification of patients who would experience poor bowel preparation. For example, Hassan et al studied a predictive model that included older age, male gender, increased BMI, Parkinson’s disease, and previous colorectal surgery. Their algorithm for predicting a poor preparation was only 60% sensitivity, 59% specificity, 41% positive predictive value, and 76% negative predictive value for the prediction of patients who would experience poor preparation.9

Improving Bowel Preparation Quality Although identification of patients who are at risk for poor-quality bowel preparation is an important step toward improving outcomes, a key question remains: What interventions might help improve the quality of bowel preparation in these patients? One important determinant of bowel preparation success is the type and degree of communication when instructing patients regarding a bowel preparation regimen.10 Patients should be instructed as to the clear relationship among compliance with the prescribed bowel preparation regimen, adequacy of bowel preparation, and the subsequent safety and efficacy of the colonoscopy procedure. Furthermore, each aspect of the bowel preparation, including timing, dietary restrictions (with specific examples), expected side effects, and office contacts in the event that the patient has questions, should be reviewed explicitly and in detail. All members of the clinical team and office staff, including nurses, medical assistants, and appointment schedulers, should be prepared to answer questions and guide patient efforts during clinical visits or when contacted by patients with questions or requests for guidance. For today’s busy clinician, conveying this depth of information can be challenging. Durable educational materials and instructions with simple checklists can be useful. For example, a booklet produced by the University of California, Los Angeles and US Veterans Affairs health systems entitled “Preparing for Your Colonoscopy” provides detailed instructions with pictures, diagrams, and answers to common patient questions. The booklet also contains a

Supported by

Patient-Related Factors

Procedure-Related Factors

Age >65 y

Bowel preparation instruction adherence

Male gender

Purgative administration timing

Presence of comorbidity:

Waiting time until appointment

Dementia Diabetes Inpatient status Stroke Prior gastrointestinal and/or pelvic surgery Low socioeconomic status Adapted from reference 8.

Group A Group B

90% 76.5

80% 70% 60%

56.2

50%

43.8

40% 30%

23.5

20% 10% 0% Satisfactory S ti f t

Unsatisfactory U ti f t

Figure 2. Adequacy of bowel preparation with a single-dosing (group A) versus split-dosing (group B) strategy. Reprinted from Aoun E, Abdul-Baki H, Azar C, et al. A randomized single-blind trial of split-dose PEGelectrolyte solution without dietary restriction compared with whole dose PEG-electrolyte solution with dietary restriction for colonoscopy preparation. Gastrointest Endosc. 2005;62(2):213-218, with permission from Elsevier.

simple checklist detailing the steps patients should take the day before and the day of the scheduled colonoscopy.11 In a study of the effect of this booklet on the adequacy of bowel preparation, a “good” bowel preparation was achieved in 76% of patients who received standard counseling plus the booklet compared with 46% of patients who received standard counseling alone.12 The American Gastroenterological Association also has produced a video that explains what patients can expect before, during, and after colonoscopy, including information regarding bowel preparation.13 The video can be viewed in the doctor’s office or at home via the Internet, and may be particularly helpful for patients with lower degrees of literacy. Some patients who are provided a booklet or access to a video may not take advantage of this information, and thus may require additional motivation and reminders. Liu et al studied the effect of telephone-based re-education the day before colonoscopy. The telephone call included a review of the importance of bowel preparation and its directions for use and side effects, the proper food type to be eaten before the procedure, and the start time of the procedure. Patients in the control group received education and a booklet the day of the appointment only.14 Adequate bowel preparation was more common in the group that received the telephone-based education (81.6%) compared with those who received standard counseling and a booklet (70.3%).14 Compliance and tolerability of the prescribed regimen also has a marked effect on the success of bowel preparation. The revised 2012 US Multi-Society Task Force Guidelines on Colorectal Cancer state that there is substantial evidence that splitting the dose of bowel preparation results in better quality, and they strongly encourage use of this strategy.5,15 Split-dosing preps might be associated with better compliance and increased tolerability and hence can improve the rate of successful bowel preparation (Figure 2).16

Conclusion Improving bowel preparation may lead to an increased ADR, decreased rate of complications, and decreased costs of care. Identification of patients who are at risk for poor bowel preparation and institution of intensive education are important, potentially preventative tactics to ensure bowel preparation quality improvement.

References 1.

Zauber AG, Winawer SJ, O’Brien MJ, et al. Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths. N Engl J Med. 2012;366(8):687-696.

2.

Rex DK, Petrini JL, Baron TH, et al. Quality indicators for colonoscopy. Gastrointest Endosc. 2006; 63(4 suppl):S16-S28.

3.

Harewood GC, Sharma VK, de Garmo P. Impact of colonoscopy preparation quality on detection of suspected colonic neoplasia. Gastrointest Endosc. 2003;58(1):76-79.

4.

Hendry PO, Jenkins JT, Diament RH. The impact of poor bowel preparation on colonoscopy: a prospective single centre study of 10,571 colonoscopies. Colorectal Dis. 2007;9(8):745-748.

5.

Lieberman DA, Rex DK, Winawer SJ, et al; United States Multi-Society Task Force on Colorectal Cancer. Guidelines for colonoscopy surveillance after screening and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology. 2012;143(3):844-857.

6.

Nguyen DL, Wieland M. Risk factors predictive of poor quality preparation during average risk colonoscopy screening: the importance of health literacy. J Gastrointestin Liver Dis. 2010;19(4):369-372.

7.

Borg BB, Gupta NK, Zuckerman GR, et al. Impact of obesity on bowel preparation for colonoscopy. Clin Gastroenterol Hepatol. 2009;7(6):670-675.

8.

Romero RV, Mahadeva S. Factors influencing quality of bowel preparation for colonoscopy. World J Gastrointest Endosc. 2013;5(2):39-46.

9.

Hassan C, Fuccio L, Bruno M, et al. A predictive model identifies patients most likely to have inadequate bowel preparation for colonoscopy. Clin Gastroenterol Hepatol. 2012;10(5):501-506.

10. Rosenfeld G, Krygier D, Enns RA, et al. The impact of patient education on the quality of inpatient bowel preparation for colonoscopy. Can J Gastroenterol. 2010;24(9):543-546. 11. UCLA Health System. Preparing for your colonoscopy. www.uclahealth.org/workfiles/documents/ brochures-programs/preparing-colonoscopy-en. pdf. Accessed February 11, 2014. 12. Spiegel BM, Talley J, Shekelle P, et al. Development and validation of a novel patient educational booklet to enhance colonoscopy preparation. Am J Gastroenterol. 2011;106(5):875-883. 13. American Gastroenterological Association. Preparing for a colonoscopy. http://youtu.be/ Yrw8geYQSQg. Accessed February 11, 2014. 14. Liu X, Luo H, Zhang L, et al. Telephone-based re-education on the day before colonoscopy improves the quality of bowel preparation and the polyp detection rate: a prospective, colonoscopist-blinded, randomised, controlled study. Gut. 2014;63(1):125-130. 15. Kilgore TW, Abdinoor AA, Szary NM, et al. Bowel preparation with split-dose polyethylene glycol before colonoscopy: a meta-analysis of randomized controlled trials. Gastrointest Endosc. 2011;73(6):1240-1245. 16. Aoun E, Abdul-Baki H, Azar C, et al. A randomized single-blind trial of split-dose PEG-electrolyte solution without dietary restriction compared with whole dose PEG-electrolyte solution with dietary restriction for colonoscopy preparation. Gastrointest Endosc. 2005;62(2):213-218.

Disclosures BB149

Table. Factors Predictive of Bowel Preparation Quality Independent of Colon-Cleansing Agent Used

Dr. Cohen reported that he is a consultant for and has received speaker fees from Braintree and Salix.

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

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OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

Better Patient Care Requires a New Way of Thinking How ‘Complexity Science’ Can Improve Health Care and Provide Better Value to Our Patients Bruce Ramshaw, MD Chairman and Chief Medical Officer Transformative Care Institute (nonprofit) Surgical Momentum LLC (for profit) Co-director, Advanced Hernia Solutions Daytona Beach, Florida

the law and led to significant emotional harm for family members of the involved children. This event resulted in a Congressional hearing on the misinterpretation of HIPAA. On April 26, 2013, Leon Rodriguez, JD, director of the Office of Civil Rights under the Department of Health and Human Services (HHS), testified, “We have never taken enforcement action because [a] provider decided that the best interest of the patient [was] to disclose information to a third party. In fact, of the 80,000 complaints of HIPAA violations that HHS has received, only twelve have resulted in monetary penalties.”

Last year, I was in Gdansk, Poland, for the annual meeting of the European Hernia Society. In a session on guidelines, Dr. Jaap Bonjer presented a paper that looked at expert consensus regarding guidelines published by the International Endo Hernia Society. Guidelines were presented based on levels of evidence, with Level 1 evidence being Because we tend to accept the highest quality and Level 5 being the lowest. Interestsimple explanations for events ingly in this review, Level 5 and concepts that sometimes guidelines were evaluated as appropriate by experts about are quite complicated, we often 85% of the time (a solid B end up misinterpreting and grade), but amazingly, Level misunderstanding phenomena 1 guidelines were judged as appropriate only about 60% that are not simple. of the time, a near-failing grade. How could that be? Based on our current understanding and interpretation of medical guidelines, this makes no sense. But, if we allow ourselves to understand how this could possibly happen, it might help us to understand why our health care system is struggling, and what we might be able to do to improve it. Because we tend to accept simple explanations for events and concepts that sometimes are quite complicated, we often end up misIn an article by David Pittman in MedPage Today, interpreting and misunderstanding phenomena that which covered the hearing, Mark Rothstein, JD, director are not simple. Our health care system is one trou- of the Institute for Bioethics, Health Policy and Law at bling example of this. And because the science we have the University of Louisville, in Kentucky, was quoted: applied to health care, with its hierarchy of evidence, “Physicians frequently misinterpret what they’re allowed is based on the investigation of isolated or mechani- to share under HIPAA. The outcome is that some use of cal systems rather than complex biologic systems, we disclosures permitted by the privacy rule are not allowed often are left with incomplete and inaccurate results by some covered entities, perhaps out of ignorance or an and interpretations. I believe our misinterpretations overabundance of caution.” and misunderstandings of medical evidence and health Although one would think that a daylong Congrescare laws have contributed to the current problems in sional hearing would lead to changes in hospital and health care. physician policies, and that there would be more transLet me try to explain. parency with patients and family members regarding the use of their information, that has not happened. In Misinterpretation fact, I have not found anyone who even knows there was Misinterpretation of a law can lead to unintended a Congressional hearing on the misinterpretation of harm and consequences. The misinterpretation of HIPAA. What’s more, this was not even the first hearHIPAA is a prime example. A gut-wrenching dem- ing on the misinterpretation of the law. On Sept. 23, onstration of this error occurred in December 2012, 2003, Richard Campanelli, the director of the Office after the Sandy Hook Elementary School shootings in for Civil Rights at that time, testified, “A number of Newtown, Conn. Many parents were denied informa- concerns that have come to our attention actually are tion about their children by the hospital, with HIPAA not a problem with the rule itself, but rather, misconcited as the reason. This is a clear misinterpretation of ceptions about the rule.” He continued to explain that

the rule “specifically allowed doctors and other providers to share this information for treatment purposes, to obtain payment, or to carry out their day-to-day operations without first having to obtain a patient’s written approval.” It is my belief that the problem has been one in which the rule was interpreted by organizations out of fear of how it could harm them, rather than how it could help patient and their families have access to medical information. Improving the value of patients’ care should be our focus when interpreting laws and rules. Laws and rules must be made and used to continuously improve the value of care for patients and their families.

Misunderstanding Another challenge is to really understand the massive amount of information that is being produced in health care, including information from traditional medical research. If we apply only simplistic levels of understanding to medical problems, we can end up with good intentions that result in unexpected harm and waste. One example of this arises out of the wonderful research done by Drs. Atul Gawande and Peter Pronovost and others. Patient safety and quality improvement have been significant areas of research focus for these physician scientists. In fact, some of the studies they have led have resulted in central-line and operating room (OR) checklists. In work done with the World Health Organization, a surgical safety checklist has been created and used with varying degrees of success around the world. The problem is not that a multidisciplinary team developed a tool (a checklist) to address a problem (patient safety/need to improve quality). The problem is the simplistic thinking that a tool such as a checklist can be generalized and be the solution for all hospital ORs, intensive care units, etc., in all locations and for every condition. From the perspective of complexity science, the actual solution was the process of getting a diverse team together to come up with a solution and to implement it locally. The solution was not the checklist, but a diverse local team given the authority and resources to implement ideas for process improvement. It is my belief that to make optimum use of this valuable concept, if a checklist is determined to be an appropriate tool, teams need to modify the checklist to take into consideration the local differences and conditions that exist in every hospital setting. The aviation industry often is cited as an example of how to use checklists to improve safety. I have had the see Complexity Science, page 12

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12

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

Complexity Science continued from page 10

privilege of working with Dr. Jerry Berlin, one of the There is another harm done when simplistic early pioneers in the development of new methods for understanding is applied by forcing the implemenimproving aviation safety. Dr. Berlin has recounted tation of a checklist, as in the example of mandatthe pain he experienced as he investigated commer- ing the use of antibiotics before all operations. The cial and military accidents of the 1960s, 1970s and problem is there is a gradual change in focus, espe1980s. Checklists had been used for years with some cially when the goal is tied to reimbursement, from significant success, but there were also many accidents improving the value to the patient to achieving the involving risk variables, especially complicated ones, target goal or benchmark. that were entirely inappropriate for inclusion in checkA friend of mine was the CEO of a chemical comlists. A good example of this was the horrific airport pany in California. He recently recounted a story from disaster in Tenerife, Canary Islands, in 1977, when two his industry that he related to the situation in health 747s collided on a runway. It was the deadliest accident in aviation history. The cause, like many previous accidents, was the human factors related to communication within the cockpit and between the cockpit and air traffic control. The solution to the communicaWe are approaching the law of diminishing tion problem was a long painful process to transform the returns using current traditional research and relationships and the hierarorganizational management methods in health chy of the traditional aviation culture. care. The billions of dollars spent on traditional The term “cockpit (or crew) research methods and technologies, such as resource management” was electronic medical records, and our current medical a process of change in how the pilot and crew interacted training have not led to much improvement of with one another. (By the patient value in our system. way, Jerry, an organizational design psychologist, always says pilots and surgeons are very similar psychologically.) Aircraft commanders and captains had to go through a significant behavioral change and understand that protectiveness of their authority led to either their not listening to a co-pilot or engineer who discovered a problem or the co-pilot or engineer becoming afraid care. He used to sell large amounts of cyanide to goldof speaking up because of an anticipated punitive mining companies. The mining companies used the response. I have heard many of these recordings and cyanide to erode rock quarry to facilitate extraction it is chilling to hear one human being reject another’s of the gold. They encountered a problem with ducks plea to be heard just minutes or seconds before a fatal dying from exposure to the cyanide after landing on crash. the tubs. A wildlife foundation discovered this and Each airline subsequently developed its own check- levied fines for each duck that was killed. Spotters lists and crew resource training. There is no standard- would count the number of ducks that were killed. ized, one-size-fits-all solution. In fact, in a recent This amounted to a large sum of money each year. The article in the Scandinavian Journal of Trauma, Resusci- mining company addressed the problem by putting up tation and Emergency Medicine, the authors interviewed nets and noisemakers, and this method worked. Fewer experts from a variety of highly reliable organizations, ducks were killed. But instead of being happy about including the aviation industry, about the use of check- the success of their efforts, spotters for the wildlife lists. Their message was consistent and clear: Check- foundation began to use duck calls to entice the ducks lists are tools, not solutions unto themselves. Checklists to the cyanide tubs. They were missing their revenue should be implemented and used locally by those who from the fines. I cannot vouch for the accuracy of this do the work. None of the authors recommended that story, but I believe the analogy to the current state of a checklist be developed in a standardized way. In fact, our health care system is an apt one. they noted that the local group had to have the authority and resources to adapt the checklist over time. This Complexity Science is not the current simplistic understanding of our govI would like to start a dialogue about the science of erning bodies and organizational leaders in health care. complexity, or complex systems, as applied to patient This lack of understanding in health care continues to care. Just as Einstein discovered the incompleteness lead to patient harm and death, the extent of which is of Newtonian physics, we are only just beginning unknown and perhaps unknowable. to understand the incompleteness of our traditional

research and management methods in medicine. I will use the terms “simple” or “simplistic” to describe our traditional thinking, management and research principles, which are based on the understanding of isolated or mechanical systems. In these systems, a cause is always followed by a predictable effect. I will use the terms “complexity” or “complex systems” to describe our complex biological world, in which the same cause (or causes) can have multiple results, some of which are not predictable. I first began to understand this concept of complex systems when our mesh lab group studied the effects of the body on hernia mesh. We have explanted and studied hundreds of mesh, and we learned that the same mesh (the cause) can have very different effects in different bodies (unpredictable results). This finding helped me to better understand the science of complexity. To learn more about complexity science applied to health care, I refer you to Appendix B of Crossing the Quality Chasm: A New Health System for the 21st Century, written by Paul Plsek (2001, Institute of Medicine; National Academy Press). In this article, “Redesigning Health Care with Insights from the Science of Complex Adaptive Systems,” Mr. Plsek outlined what he saw to be the key components of establishing a health care system based on the theory of complex systems. We are approaching the law of diminishing returns using current traditional research and organizational management methods in health care. The billions of dollars spent on traditional research methods and technologies, such as electronic medical records, and our current medical training have not led to much improvement of patient value in our system. A better understanding of complexity science will allow us to apply new concepts of research and management as a natural part of caring for patients. Interestingly, some of these concepts are contained in the HIPAA law from 1996, but we have yet to interpret and apply them. Continuous improvement research and care coordination in patient care management have the potential to focus on the goal of improving the value of care for our patients. That also will improve the value for all the parts of our system that contribute to that value. This will take effort at the level of all local environments. There is no single right answer to our health care problem and no simple fix. One of the first objections I heard about implementing a new approach to patient care and research is that we cannot afford to do it. My response is that clearly, we cannot afford nott to. ■

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

13

CMS Directives: Hat or Miss By Lauren A. Kosinski, MD, MS Assistant Professor of Surgery Division of Colorectal Surgery Medical College of Wisconsin Milwaukee, Wisconsin In response to deficiencies reported by the Centers for Medicare & Medicaid Services (CMS), following a recent survey of my hospital, the operating room administration mandated that the traditional surgeon’s cap (referred to in that correspondence as a “skullcap”) could be worn no longer. Only disposable bouffant caps provided by the hospital would be acceptable attire, and all surgeons’ caps were removed from hospital procedural areas. Surgeons (male and female alike) were dumbfounded. The rollout of the new hat policy offered no scientific evidence to justify the decree. This rule affected more than physicians, but nonetheless was received as just one more of the rapidly proliferating, apparently capricious rules governing physician performance, reinforcing the perception that we are being policed by administrators and nurses to prevent us from harming our patients. This new mandate struck a nerve: Wiping out a surgical icon—the long white coat and scrubs signify “doctor,” but the skullcap signifies “surgeon.” Not only that, the comfort of the familiar was jettisoned without warning. Somehow this chafes, because despite earning a decent income and reveling in the technical performance of an operation, we have all made, and will continue to make, generous sacrifices of our time and personal comfort in the service of our patients. Many of us have shared the view that CMS surveys result in more particular and yet arbitrary citations than those generally issued by The Joint Commission (TJC)—formerly the Joint Commission on Accreditation of Healthcare Organizations ( JCAHO)—which has tended to

take a self-improvement approach, establishing guidelines rather than specific approaches to satisfy established standards. This theme is expressed in TJC’s mission “to continuously improve health care for the public, in collaboration with other stakeholders, by evaluating health care organizations and inspiring them to excel in providing safe and effective care of the highest quality and value.” Historically, JCAHO accreditation paved the way for CMS accreditation. Although our hospital received exemplary ratings from TJC approximately two years ago, subsequent CMS survey citations seemed contradictory to our favorable TJC rating. The CMS survey of our surgery center preceded that of the main hospital and led to citations for double-gloving during operations and for using any sort of extension cord even with hospital standard mobile plug towers. This led to the disappearance of all extension cords despite the fact that there were no substitute long cord options for frequently used operating room (OR) equipment. We wondered if we were required to move the OR table over to the wall outlet in order to use a lighted, rigid proctosigmoidoscope, one of the more ancient instruments in use and never associated, to my knowledge, with setting patients, drapes or staff on fire or electrocuting anyone after more than 50 years of use! The double-gloving citation was unintelligible until the main hospital survey clarified that the under-glove could not be regarded as sterile once the outer glove was removed. Of course, anyone who has double-gloved for an operation and changed the outer glove when a hole developed in it knows that a major reason for double-gloving is the risk for single-glove failure. Regarding the surgeon’s cap, deeper investigation into the recommendations by the Association of Operating Room Nurses (AORN) on head coverings in the OR (that formed the basis of the CMS directive), revealed no convincing evidence that hair or scalp exposure in the

Only disposable bouffant caps provided by the hospital would be acceptable attire, and all surgeons’ caps were re removed from hospital procedural area areas. The rollout of the new hat polic policy offered no scientific evidence evidenc to justify t e decree. th the

OR constitutes an infection riskk for patients (2010 Perioperative Staandards and Recommended Practicces. Aseptic Practice. Recommendeed Practices for Surgical Attire, Reccommendation II: “Personneel should cover head and facial hair,

No systematic comparison on was o ascertain made among cap styles to whether the sanctioned bouffant creases style more effectively decreases geon’s hair, patient exposure to a surgeon’s dandruff or scurf (flakes of exfoliated epidermis) than other hat styles. including sideburns and necklines, when in the semi-restricted and restricted areas of the surgical suite,” page 69. AORN, Inc.). Whether data support the necessity of a hat at all, common sense would dictate that keeping hair out of the operative field—and out of the operator’s eyes— is reasonable. Even a short-order cook knows that. The question is “how?” No systematic comparison was made among cap styles to ascertain whether the sanctioned bouffant style more effectively decreases patient exposure to a surgeon’s hair, dandruff or scurf (flakes of exfoliated epidermis) than other hat styles. Nor has the “one hat fits all” standard been evaluated. Long hair slips out of bouffants. I can attest to this personally since during my training, a scrub nurse once instructed the circulator to pull out a few hairs that strayed from my cap! On that occasion (and many others), loose strands have been gently tucked back under the cap during a long case by kinder OR staff. Conversely, what holds the bouffant in place on the near-bald male surgeon? The question of whether we wear a traditional surgeon’s cap or a bouffant bonnet is not just about cap style. Will we choose to step up to the plate and wear the hat of the leader or don the hat of the subordinate? Will we—through our thoughtful dedication to patient care— set the example in the OR, or resign ourselves to being recalcitrant employees who bitterly swallow whatever pill we are administered for fear of diminishing our earnings? Greed; loss of autonomy; preferring to circumvent policies rather than authoring and being the custodians of them; longstanding indulgence of a “boys will be boys” perception of surgeons’ demeanors; failure to reckon with our human limitations so that we become resentful of our demanding work; and loss of connection

with the sacred intention that inspired us to pursue our calling to be doctors: These are the ways we undermine ourselves personally and professionally and diminish our financial value when we withdraw from the system. We sacrifice our integrity and our credibility when we disengage and sidestep meaningless policies rather than challenging and reshaping them to reflect our expertise and values. We fuel the characterization of surgeons as disruptive, childish and disagreeable, and justify the ever-intensifying micromanagement of our performance and policing by administrators, nurses, and nearly anyone else inside or outside the hospital. We must find the character and conviction to creatively reinvigorate the culture of surgery, our guild, and find meaningful connections with the other professionals whose scope of work overlaps our own. We must understand that our ability, not only to respond to pointless legislation but also to assume our appropriate place in the determination of sound surgical practices, will serve us well. It will enhance our gratification by deepening our connection to our calling and make us value our work and ourselves, so that we stop agreeing to do more and more with less and less. Although the CMS hat initiative at our hospital apparently has not affected many others yet, it will. The cap is a fitting emblem of our specialty and our identity. At the end of the day, whether we figure out that one cap does or does not fit all, I intend to think critically about my value as a surgeon and an educator and to encourage my associates to do the same, and to remember our original, sacred intention that led each of us down this arduous but amazing path. Let’s think carefully every day about what hat we choose to wear. ■

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IBS AWARENESS MONTH

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

IBS continued from page 1

Of the many different studies investigating the associations between diet, GI symptoms and IBS, Dr. Crowe focused on two of the most prominent studies. The first, which involved about 200 patients, found that the 20% of patients who met the Rome III criteria for IBS consumed more canned foods, processed meats, legumes, whole cereals, sweets and fruit compotes— foods recognized as fermentable oligo-, di-, and monosaccharides and polyols (FODMAPs; Chirila I et al. J Gastrointestin Liver Dis 2012;21:357-362). “Many of these individuals were eating foods that might be giving them symptoms,” Dr. Crowe said. The second study, a questionnaire of patients meeting diagnostic criteria for IBS, found that 84% reported symptoms associated with at least one type of food (Böhn L et al. Am J Gastroenterol 2013;108:634-641). “Many were carbohydrates, and some were the type we would classify as FODMAPs, and also histaminereleasing foods that can simulate allergic types of reactions,” Dr. Crowe said. Fried and fatty foods also were associated with symptomatic responses in this survey. The role of diet and its influence in IBS is a complicated one and often oversimplified, but not just by patients, noted William Chey, MD, of the University of Michigan, Ann Arbor. “It’s understandable for patients—how would they know anything beyond what they can find online? But what’s really frustrating is that a lot of physicians don’t know much about it either.” When he first started lecturing about the role of food in IBS five years ago, Dr. Chey surveyed an audience of listeners at a postgraduate meeting and found their awareness of the low-FODMAPs diet to be almost nil. “There were maybe a few hands out of thousands; people had no idea this even existed,” he said. Physicians do, however, appear to be catching on, at least in terms of knowledge. When Dr. Chey posed the same question about six months ago, nearly two-thirds of the audience raised their hands. “It’s amazing that in five years, there’s been such an increase in awareness,” Dr. Chey said. But when he asked how many were actually directing patients in the use of a low-FODMAPs diet, the number shrank precipitously. “I’d say fewer than half were using the low-FODMAPs diet with their IBS patients. It’s not to say that that’s right or wrong; it’s just an observation,” Dr. Chey noted. “I’m thrilled that nearly 40% of gastroenterologists are now using specific dietary interventions in their clinical management plans of patients with IBS,” he added. “That’s a huge leap forward, but there’s room for improvement.”

Is it IBS or Something Else? Given that about 4% of the U.S. population experiences some kind of food allergy, it’s likely that some patients with IBS have one; however, that may not be the mechanism of the IBS. “A good history will be able to tease this apart, but it can be difficult in patients who have multiple sensitivities as well as allergies,” said Dr. Crowe, noting that it’s now preferred to refer to non-allergic mechanisms as food sensitivities rather than intolerances, and to allergies as being any type of immune-mediated food intolerance, including celiac disease. Eosinophilic gastroenteritis is another disorder that

‘I’m thrilled that nearly 40% of gastroenterologists are now using specific dietary interventions in their clinical management plans of patients with IBS. That’s a huge leap forward, but there’s room for improvement.’ —William Chey, MD

can present with symptoms that resemble IBS. “One should be looking for increased peripheral eosinophils, and the patient may have food allergies as well as an underlying condition,” Dr. Crowe said. “This is something you would be able to [discern] on the labs.” Of course, many studies have shown an increasing prevalence of celiac disease in patients meeting IBS criteria, and many celiac patients report symptoms that resemble IBS. “There’s clearly some overlap there,” Dr. Crowe said. The ACG recommends testing for celiac disease in patients with diarrhea-predominant IBS. Not to be overlooked are the physiologic food reactions that everyone has. These experiences (e.g., flatus) are augmented in many IBS patients, but can be mitigated to some extent by choosing foods and amounts that will be less distressing. “Simple things like asking your patients not to go to buffet restaurants or not to finish their whole Mexican dinner would help them a great deal,” Dr. Crowe said. “I think this is largely choice of food, not just altered receptors; it could be enhanced by visceral sensitivity, fat-delayed gastric emptying and many other factors.”

Gluten and Wheat As dietary fads go, avoiding gluten is clearly the new black. Whatever the mechanism, a lot of people report feeling better when they avoid gluten, including people with IBS. But it isn’t clear whether their improvement is because of gluten avoidance or steering clear of other components associated with gluten-containing items. In a recent study, 37 patients with IBS and non-celiac gluten sensitivity (NCGS) adhered to a low-FODMAPs diet for two weeks, after which all subjects reported a significant relief of symptoms and fatigue. They were

then given a high-gluten, low-gluten or control capsule to ingest. There were no significant differences between the three groups in terms of symptomatic or biologic changes, leading the researchers to suggest that the patients’ sensitivity was to FODMAPs and not gluten, as they had suggested in a previous study (Biesiekierski JR et al. Gastroenterologyy 2013;145:320-328; Biesiekierski JR et al. Am J Gastroenteroll 2011;106:508-514). “The patients all got better on the low-FODMAPs diet; and although there were no significant differences between the different doses of gluten and the control capsule, there was an increase in symptomatology in all patients, suggesting there might be something else in the capsules, a placebo response or it may be the wearing off of the low-FODMAPs diet over time,” Dr. Crowe said. Non-celiac wheat sensitivity has been reported by a number of groups in Spain and Italy in wheat-sensitive patients with IBS-like symptoms. “They also found other sensitivities in some subjects who had antibodies to gliadin, and inflammation [indicated by] eosinophils in the duodenal and colonic biopsies,” Dr. Crowe said. “The proposed mechanism of non-celiac gluten or wheat sensitivity is broad, and I think NCGS or wheat sensitivity is a big factor in many of our patients with IBS,” she noted. “It may not be a separate entity. It may just be widespread food sensitivities through different mechanisms, including the microbiome having effects on certain foods, such as fructans and other fermentable components of the diet.”

Evaluation and Management When patients with functional GI disorders or other symptoms visit Dr. Crowe, she evaluates them see IBS, page 18

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IBS AWARENESS MONTH

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

IBS continued from page 14

for celiac disease, eosinophilic GI syndromes, and if their medical history indicates, specific food allergies. The evaluation may include having patients keep a diet diary and trying a hypoallergenic diet, as well as endoscopy and biopsy. Laboratory tests for evaluating immune-mediated adverse reactions to food include complete blood count, eosinophil count, quantitative immunoglobulin (Ig) count, and tests for specific IgE levels (e.g., radioallergosorbent test, enzyme-linked immunosorbent assay). Other tests are largely for research, including basophil histamine release assay, basophil leukotriene release assay and others for non–IgE-mediated reactions. The IgG assay should no longer be used, and none of the many food sensitivity assays on the market have been scientifically proven. “Many of the food antigen challenges that are done are not accepted, but skin prick testing remains very useful, and hopefully new tests will become available,” Dr. Crowe said. Dr. Chey often asks new patients to keep a food diary so that they can evaluate symptomatic trends and establish whether their symptoms are related to food. “One thing I think is confusing for patients is that they often think symptoms need to occur right away— during or immediately after the meal. But symptoms may not occur until hours later,” he said. “The association may not be that apparent until it is mapped out in a diary. If there is indeed a relationship between eating and symptoms, you have a couple of different evidencebased approaches.” Dr. Chey prefers to start patients on a low-FODMAPs diet, which he considers a bit of a shotgun approach. “Low FODMAPs is a gluten-restricted diet, but it also restricts a variety of other short-chain, poorly absorbable, highly fermentable carbohydrates that can be associated with symptoms in IBS patients,” he said. If a patient responds favorably to a low-FODMAPs diet after four to six weeks, he or she can begin a structured reintroduction of gluten-containing foods and other types of carbohydrates. The other, and more specific, strategy is to eliminate gluten-containing foods. “There is some evidence to suggest that both of these

‘One thing I think is confusing for patients is that they often think symptoms need to occur right away—during or immediately after the meal. But symptoms may not occur until hours later. The association may not be that apparent until it is mapped out in a diary.’ —William Chey, MD

diets offer benefits to some IBS patients,” Dr. Chey said. “But it’s a bit of a dealer’s choice right now in terms of what you choose. Sometimes you’ll get lucky and patients will be able to identify the foods that cause problems. Most of the time, that’s not the case.”

What’s Next? Food-induced symptoms are very common in patients with IBS and other GI disorders, and just as celiac disease and eosinophilic gastroenteritis can mimic or coexist with IBS and other disorders, so can food allergies. “Many food-induced symptoms are sensitivities, but some—particularly the highly fermentable

carbohydrates—may be a mechanism to produce IBS symptoms,” Dr. Crowe said. Patients may benefit from eliminating gluten, wheat and other fermentable carbohydrates, but there are few studies that prove a benefit of any particular dietary intervention. “I think we need a lot more investigation and a lot more research,” Dr. Crowe said. A better understanding of how the gut microbiome ferments certain substrates, giving rise to symptoms, may lead to personalized treatments. “Potentially fecal transplant—but I think that is overkill at the present time, since we don’t have data to support this approach for treating food sensitivities.” ■

Diets for IBS and Functional GI Disorders BY MONICA J. SMITH Many different dietary treatments have been used in patients with irritable bowel syndrome (IBS) and other functional gastrointestinal (GI) disorders, but there is little to no evidence to support their use or effectiveness. • Low-fat: This was a popular diet, but it has little influence on IBS symptoms. Limited evidence. • Gluten-free: Many IBS patients report feeling better when they

go gluten-free, which may be attributable to gluten or to other components of foods that contain gluten. Limited evidence. • Specific carbohydrate diet: “This is a very restrictive diet and there is little to no evidence for IBS, or for any other disorder, in my opinion,” Dr. Crowe said. • Low-FODMAPs diet: Many patients experience decreased symptoms when they restrict fructose and fructans, sorbitol, sucrose and lactose. Dr. Crowe

noted that a significant portion of the world’s population has difficulty digesting lactose, and pointed out that even people with lactose intolerance need not forgo dairy products completely. “They’re not allergic to the protein, due to lactase deficiency— they’re only sensitive to lactose, which is not found in all dairy products, so they can eat hard cheeses, yogurt and kefir.” • Paleolithic: “This is primarily protein—meat—and some

vegetables, with little grain or fruit, and it does seem to help some patients with IBS,” Dr. Crowe said. Minimal evidence. • Candida: This diet reduces carbohydrates and gluten. No evidence.

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20

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

GERD continued from page 1

offered an alternative to long-term medical treatment with proton pump inhibitors (PPIs) and an alternative to a Nissen fundoplication, considered major surgery for those more severely affected with the disease. During this time, several other endoluminal devices entered the GERD market—and most of them failed. In a 2005 review, the Agency for Healthcare Research and Quality (AHRQ) evaluated the efficacy of four endoluminal GERD devices that were on the market at that time: Stretta (Curon Medical, FDA-approved in 2000), Endocinch Suturing System (C.R. Bard, Inc., FDA-approved in 2001), Enteryx

of Mederi. “One would think that if the FDA has approved a device … that it is proven to be safe and effective … that that would be good enough for an insurance company. But it is not. Even the federal government—the Centers for Medicare & Medicaid Services that governs Medicare—does not view FDA approval as sufficient for covering Medicare constituents, even though the FDA is a branch of the federal government [as well]. There is no participation or cooperation between these two entities. Incredible, isn’t it?” Mr. Rutan said. Although medical devices that first enter the market will have enough clinical data to satisfy the FDA that they are

technologies go off the market: They are unable to meet the very, very high hurdles required by the insurance companies to gain leverage, because such long-term data are [required],” Mr. Rutan said. “And they require Level I clinical data, which are randomized controlled trials, and they require society support in the form of guidelines … so gathering all that is required to get widespread insurance coverage is a 10- to 12-year proposition, and very, very few new technologies have investors who are patient enough to fund it [for that long]. “For that reason [the funding sources] for start-up medical devices are almost gone. Most of the traditional venture cap-

“Both ADVAMED [Advanced Medical Technology Association] and the MDMA [Medical Device Manufacturers Association] have been attempting to get the FDA to loosen up some, because [it has] tightened up what are already stringent requirements,” said Mr. Rutan. All of the endoluminal devices that have launched since 2000 for the treatment of GERD were approved for commercial use through the FDA’s 510(k) preapproval process, which classifies medical devices as Class II or of moderate risk to patients. (A Class III product, such as the Linx surgical procedure, is considered “high risk” and must go through a different and stricter

How the Stretta System works. Left: Controlled radiofrequency energy is delivered to tissue. Middle: Multi-level thermal treatment remodels muscle in the lower esophageal sphincter and gastric cardia. Right: Function is improved; fewer transient lower esophageal sphincter relaxations occur. Source: SAGES Guidelines—Endoluminal Treatments for Gastroesophageal Reflux Disease, www.sages.org.

(Enteric Medical Technologies, FDAapproved in 2002) and the Endoscopic Plication System (NDO Surgical Inc., FDA-approved in 2003). Of these, Stretta alone survives. By the time the AHRQ published an updated review in 2011, Enteryx had been pulled from the market due to serious adverse events (AEs) and the Plication System was no longer in use. As of October 2013, the manufacturers of Endocinch confirmed that it too is no longer in production.

Why So Many Failed Attempts? Although Stretta has lasted the course where others have not, it also has withstood many challenges. Originally owned by Curon Medical, the company eventually went bankrupt and its assets, including Stretta, were taken over by Mederi Therapeutics. “Curon went bankrupt simply because they were unable to get widespread insurance coverage,” said Will Rutan, CEO

“safe and effective,” it is very rare for any of them to have supporting studies longer than two years. “If you ask 10 people [for their definition] of a ‘long-term’ study, you’ll get 10 different answers,” Mr. Rutan said, “but if a product is new, then ‘long-term’ is one year.” The litmus test of a device is its application in the real world, but the irony is that many of the endoluminal devices that launched did not survive long enough for their efficacy to be established. “Insurance companies by and large judge four years—48 months—to be long term, which is the conundrum of new technology, particularly in the United States,” said Mr. Rutan, who explained that it can take several years to progress from a new idea to a finished device due to the necessity for bench testing, animal testing, meeting FDA requirements for approval and obtaining long-term data. “That is why so many good

italists that would have backed new medical technologies have shifted their focus to technology investments like Instagram and Twitter,” Mr. Rutan said. Unlike the pharmaceutical industry, most medical device companies are small start-ups with limited financial resources. Raising capital to fund a device is no less difficult in the current climate, according to Mr. Rutan. “We have just completed fundraising and even with the derisking we have done—we have regulatory approval, long-term Level I data, society support and tremendous unmet [market] need— even with all that, it was far and away the hardest time that I’ve ever had raising money for a medical device,” he said.

FDA Standards Too High? Adding to this challenge is the belief of some industry stakeholders that the FDA’s requirements for market approval are excessive.

premarket approval [PMA] process). Under the 510(k) pathway, a manufacturer must prove that its device is “safe and effective,” by determining that it is “substantially equivalent” to a similar or “predicate” device previously approved by the FDA, and which is supported by the manufacturer’s clinical research. For example, in its application to the FDA for approval of its SRS Endoscopic Stapling System, the manufacturer, Medigus, cited the NDO Plicator and EsophyX (EndoGastric Solutions) as predicate devices because they used similar mechanisms of action to perform a partial fundoplication. Chris Rowland, CEO of Medigus, agreed that the FDA approval process is quite strict but in his opinion, it is necessary. “The FDA is doing its job … there are thresholds in place and the FDA holds companies accountable; [the FDA’s] first [responsibility] is patient safety,” he said.

21

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

But the FDA’s reach does not stop with granting PMA: It also has the authority to make postmarketing demands such as device registration, mandatory reporting of AEs, and stipulating certain standards in the manufacturing process. Device manufacturers must consistently be vigilant to ensure that they adhere to these regulations. “The [FDA has the] ability to look and see how the device is [performing in the market] and say ‘you know, I think we made a mistake—maybe this device shouldn’t have been out there,” said Kenneth K. Wang, MD, president of the American Society for Gastrointestinal Endoscopy (ASGE).

profession tend to be a little older in age (late 40s to early 50s). “I think most [of us] evaluate the data that’s out there conservatively, concerning the efficacy of a device. I think [we] examine … if the device makes physiologic sense, [as well as] its efficacy,” he said. “If you look at Enteryx, the injective device that was pulled from the market voluntarily by the manufacturers … [the procedure] was relatively easy to do … it was a technique that most of us were familiar with … but once it developed some serious complications with patients … you know endoscopists kind of shied away from that technology,” Dr. Wang said.

‘I think most [of us] evaluate the data that’s out there conservatively, concerning the efficacy of a device. I think [we] examine … if the device makes physiologic sense, [as well as] its efficacy.’ —Kenneth K. Wang, MD

“The 510(k) process has become much more difficult. Now the FDA is requiring more efficacy data to the point where a lot of [medical device] companies are saying ‘well, why bother with a 510(k)? Why not go in with a full PMA [application] for a new device because pretty much, you have to show the same things. If [the FDA] is making the 510(k) that much more onerous, then what’s the advantage of having that pathway?’” As president of the ASGE, Dr. Wang has witnessed firsthand the difficulties inherent in launching new devices. “New technology like GERD antireflux devices is often very challenging. It’s almost the same kind of thing you see with drugs. There is usually an attempt to try to market these very quickly, and a lot of it has to do with the way funding is for medical devices: Usually these are not big companies with a lot of resources,” he said. Insurance companies, as well as physicians, also view securing an endorsement from a professional society such as the ASGE favorably, and the publication of guidelines on a particular device or procedure bodes well for its success. The guidelines, Dr. Wang explained, “is an evidence-based document that looks over a given technology and makes recommendations based on available literature.” However, endoscopists tend to be conservative in their evaluation of new devices because, on average, members of that

Acceptance in the Field The publication of guidelines is not in itself a ticket to success. Recommendations come with varying degrees of emphasis, a case in point being the “Clinical Spotlight Review” published by the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES), in February 2013. Although it gave Stretta the highest (“strong”) recommendation due to the extent and the quality of its long-term data, it gave a “weak” recommendation to EsophyX, an endoluminal GERD treatment that was FDA-approved in 2009. Dr. Wang explained that in addition to writing guidelines they deem appropriate, the professional societies give advice about the kinds of studies that may help to provide evidence of effectiveness and good outcomes, whether or not the new developments have already gone before the FDA. “[Companies] don’t need to go through societies,” Dr. Wang said, “but generally, societies do a better job of vetting what the evidence is for their devices. You know we can present a more unbiased view than they can.” Despite the market challenges and the time-consuming process of obtaining insurance coverage, devices can still gain a foothold in the market, albeit slowly, as manufacturers target early adopters of new devices and techniques. “Some [physicians] require less [clinical]

data and some require more, depending on their comfort level—on their ability to adopt a new technology, just like some physicians have iPhones and some still have flip phones,” Mr. Rowland said. Mr. Rutan also found that the medical profession is open to new technology but that a very limited window exists to get a new product in the door. “The fact that [devices] are not covered is not an obstacle initially because the market loves new technologies. Many times, it involves doctors and hospitals losing money on [new devices] but they are willing to do that for a short period of time. … [However,] it’s a short-term proposition because before long, you have to have insurance coverage or the product will fail,” Mr. Rutan said. Even with insurance, the success of a new medical procedure also depends on whether it is fully embraced by the medical profession as an effective, safe and durable treatment option for patients. Ronnie Fass, MD, chair, Division of Gastroenterology and Hepatology and head of the Esophageal and Swallowing Center at MetroHealth Medical Center in Cleveland, said, “At the beginning, we had a rush of endoluminal approaches. For some of them, I don’t think there were significant data to support their long-term effect and some of them … ended up in the hands of people who were not experienced in using them, resulting in some terrible side effects. To convince people that a technique is effective and durable in the long term, you need at least five years [of data].” Robert Fanelli, MD, chief of minimally invasive surgery and chief of surgical endoscopy at The Guthrie Clinic, Sayre, Pa., said GERD experts are “searching for a continuum along which to treat patients at various stages of the disease,” and endoluminal therapies offer valid treatment alternatives. “We [tend to] hold them up against the standards established by surgery and I’m not sure that it makes a lot of sense for us to look at endoluminal therapy as competition with a Nissen fundoplication.” In carefully selected patients, he said, “a nicely performed, low-risk, endoluminal procedure might be just exactly the thing that they would benefit from,” said Dr. Fanelli, who co-authored the SAGES’ Clinical Spotlight Review. In July 2013, Medigus, an Israel-based company, received its first order for the SRS in the United States from NewYork-Presbyterian/Columbia University Medical Center. The unique advantage of the SRS over the endoluminal devices that have tried and failed is its

simple approach, Mr. Rowland said. “We know that a Nissen fundoplication works. We know that the partial wrap or the full wrap actually is successful, so we’re not trying to recreate that surgical procedure,” Mr. Rowland said. “Instead we are recreating the direction in which it is performed, so instead of going laparoscopic, we are going endoscopic.” Interestingly, Mr. Rutan said the reason Stretta has lasted well over a decade is that, in contrast, it did not seek to emulate a fundoplication, relying instead on radiofrequency ablation. “All the other treatments [that failed] were a variation on a fundoplication … whether you suture it, staple it or put an implant around it, it’s still surgery and there are complications associated with it. Stretta is the least invasive, longest lasting … and has the lowest complication rate.” Ultimately, a device must survive long enough in the market to have a chance to prove its commercial success. The reasons why so many endoluminal technologies have failed to date could simply be explained as insufficient financing and challenging market forces. “None of them achieved insurance coverage; none of them was around long enough to get the quality of data … or society support that is necessary,” Mr. Rutan said. “It’s very difficult to get something approved or cleared, and it’s next to impossible to get it paid for, regardless of clinical efficacy.” ■ Drs. Fanelli, Fass and Wang reported no relevant conflicts of interest.

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ASCO GI

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

PPIs Protective for Esophageal Cancer BY CAROLINE HELWICK

SAN FRANCISCO—Patients with Barrett’s esophagus (BE) who are treated with proton pump inhibitors (PPIs) have a significantly decreased risk for progression to high-grade dysplasia or esophageal adenocarcinoma (EAC), a recent systematic analysis presented at the 2014 American Society for Clinical Oncology Gastrointestinal Cancers Symposium showed.

“This effect seems to be independent of the use of nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin or statins, or the presence of erosive esophagitis,” said the study’s lead author, Preet Paul Singh, MD, of Mayo Clinic, Rochester, Minn. “Long duration of use—more than two to three years—may provide a greater benefit than short duration.” Preclinical studies suggest that PPIs may prevent or delay the progression of dysplasia in patients with BE; however,

the development of hypergastrinemia induced by acid suppression has raised concerns about the oncogenic potential of acid-suppressive agents, Dr. Singh explained. “Epidemiologic studies of the association between acid-suppressive therapy and EAC risk have been small, with conflicting results, and have been limited by small number of events, precluding a robust estimation of the true association,” he said. “We performed this systematic

review and meta-analysis to better understand the issue.” The meta-analysis included studies published through June 2013, along with abstracts from major conferences, that investigated the association between acid-suppressive medications (PPIs, H2 receptor antagonists [H2RAs]) and EAC and/or BE with high-grade dysplasia in patients with preexisting BE. Inclusion criteria were: 1) clearly defined exposure to PPIs or H2RAs; 2) reported EAC and/or BE with high-grade dysplasia risk in patients with established BE; and 3) reported hazard ratio, relative risk or odds ratio, or the existence of data allowing for their calculation.

‘We believe, based on these

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results, that in patients with BE with multiple risk factors for progression to EAC (e.g., long-segment BE, central adiposity, smoking, advanced age), PPI therapy should be considered for its primary chemopreventive potential.’ —Preet Paul Singh, MD

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Seven studies, including 2,813 patients (ranging from 77 to 812 patients per study) met the study criteria. Five were cohort studies, and two were case–control studies. The studies were conducted in the United States, the Netherlands and Australia. The analysis revealed that PPI use was associated with a decreased risk for EAC. “The use of PPIs, as compared to nonuse, was associated with a decreased risk for EAC and/or high-grade dysplasia in BE,” Dr. Singh said. The adjusted odds ratio (OR) for the use of PPIs was 0.29 (95% confidence interval [CI], 0.12-0.71). There was considerable heterogeneity in the overall analysis, observed primarily because of two case–control studies with divergent results, Dr. Singh noted. Even on restricting the analysis to studies that adjusted for the concomitant use of NSAIDs, aspirin and statins, the protective effect of PPI therapy persisted (adjusted OR, 0.44; 95% CI, 0.24-0.83), suggesting an independent protective association for PPIs. In three studies that accounted for the presence of erosive esophagitis or reflux symptoms, PPI use also was protective against EAC (adjusted OR, 0.15; 95% CI, 0.04-0.55). see PPIs, page 34

ASCO GI

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

Barrett’s Surveillance continued from page 1

most of the tools they currently have, said Rebecca Fitzgerald, MD, of the MRC Cancer Unit, University of Cambridge, United Kingdom, in a presentation at the 2014 American Society for Clinical Oncology Gastrointestinal Cancers Symposium. Dr. Fitzgerald chaired the recent revision of the guidelines on BE diagnosis and management of the British Society of Gastroenterology (Fitzgerald RC et al. Gutt 2014;63:7-42). “Both the American Gastroenterological Association and the British Society of Gastroenterology agree that endoscopic surveillance is recommended for Barrett’s, but our evidence is rather weak,” Dr. Fitzgerald said.

who went on to develop cancer, almost half had previous dysplasia, including patients who underwent surveillance. In spite of multiple prior endoscopies, eight had a negative endoscopy just 10 months prior to a cancer diagnosis. “The study tells us that, in practice, surveillance doesn’t work. However we are doing it, we are not doing it right,” she continued. “We should not look at the Corley paper and think that surveillance is a waste of time, but we need to find a better way. Meanwhile, we need to make the most of the tools we have.”

She suggested that outcomes can be improved with a more stringent approach to patient selection, optimization of current endoscopic tools, and better pathology reporting and use of biomarkers. “I hope in the future we will see more risk stratification, taking into account clinical and demographic characteristics. Perhaps in time we can also take into account inherited genotypes and molecular biomarkers,” she said.

Deciphering Intestinal Metaplasia Intestinal

metaplasia

confers

an

23

increased risk for cancer and is present in the vast majority of long-segment BE, according to many studies. “Perhaps we can use this somehow for risk stratification,” Dr. Fitzgerald said. The correlation with other risk factors, such as male gender, is less clear, and recommendations should not be based on those data, she said. A meta-analysis (Desai TK et al. Gut 2012;61:970-976) and a large study from Ireland (Bhat S et al. J Natl Cancer Inst 2011;103:1049-1057) reported an annual see Barrett’s Surveillance, page 26

‘Both the American Gastroenterological Association and the British Society of Gastroenterology agree that endoscopic surveillance is recommended for Barrett’s, but our evidence is rather weak.’

with the best-read gastroenterology publication.

—Rebecca Fitzgerald, MD Although the “rationale is straightforward” (i.e., detection of esophageal cancer at an early stage improves survival), studies of surveillance are largely retrospective, vary in size, use poor methodology and lack quality control. “Therein lies part of the problem with the quality of the data,” she said. “Nevertheless, studies generally show some association between performing surveillance and diagnosing cancer at an earlier stage, and some association with improved survival,” Dr. Fitzgerald noted.

Surveillance Setback Recently, a study from Corley et al (Gastroenterologyy 2013;145:312-319) sounded a somber note. These researchers evaluated 38 patients who died of esophageal cancer after a diagnosis of BE and matched them with 101 living patients with BE. They found that surveillance within three years of a diagnosis of esophageal cancer was nott associated with a reduction in cancer-related deaths. “A closer look at the data showed that nearly half had advanced disease, and clearly that is a problem,” Dr. Fitzgerald said. “Of those with a prior diagnosis of BE, only half had undergone surveillance, showing that all patients eligible for surveillance are not getting it. Of patients

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average page exposures Based on data from Kantar Media, June 2013

THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Use of FibroScan for Noninvasive Assessments Of Liver Disease Faculty David Bernstein, MD Chief, Division of Hepatology North Shore-LIJ Health System Manhasset, New York

Introduction The prevalence of chronic liver diseases continues to rise worldwide. The obesity epidemic has led to significant rates of nonalcoholic fatty liver disease (NAFLD), affecting approximately 27% to 34% of individuals in the United States; furthermore, 6 million are expected to have progressed to nonalcoholic steatohepatitis (NASH), and roughly 600,000 have developed NASH-related cirrhosis.1 Moreover, between 3 and 4 million individuals in the United States have chronic hepatitis C virus (HCV) infections and many of these individuals are unaware of their serostatus.2 In August 2012, the Centers for Disease Control and Prevention recommended that all baby boomers, a high-risk population of individuals born between 1946 and 1964, undergo HCV testing at least once in their lifetime.3 In June 2013, the US Preventive Services Task Force made a similar recommendation.4 As a result, the number of individuals diagnosed with HCV has increased considerably.3,4 For patients with chronic liver disease, the early identification of liver fibrosis is critical, particularly for those with cirrhosis who are more likely to develop hepatocellular carcinoma (HCC).5 Clinical guidelines recommend that cirrhotic patients undergo an ultrasound liver examination every 6 months.5 Of concern, the annual incidence of HCC between 2001 and 2010 rose from 2.7 to 7.7 cases per 100,000 population, causing 5.5 deaths per 100,000 population.6 The most common cause of HCC is infection, typically from viral hepatitis, followed by alcoholic liver disease and NAFLD.7 Liver biopsy has long been the gold standard to stage liver fibrosis, but it has wellknown downsides. It is a costly, invasive procedure that requires patients to miss at least 1 day of work and to avoid strenuous activities for several days thereafter (this has a greater effect on individuals with physically demanding jobs). Biopsies also can be painful and carry a risk for bleeding.8 Additionally, the accuracy of biopsy results depends on the size of the sample and the pathologist reading it—sampling errors occur in 25% to 30% of liver biopsies.8 Due to the increasing rates of liver diseases and the shortcomings of biopsy, alternative diagnostic procedures have been investigated. This article will discuss

24

recent developments in the evaluation of liver fibrosis, including the FibroScan® 502 Touch (Echosens, Sandhill Scientific), which received 510(k) clearance from the FDA in April 2013.

Alternative Diagnostics for Liver Fibrosis As previously mentioned, several noninvasive tests for staging liver disease have been developed. One such option involves serum biomarker tests that measure variations in biomarkers caused by changes in liver stiffness. In a recent study, researchers compared the diagnostic accuracy of several liver-staging blood tests with that of liver biopsy and concluded that many were “moderately useful” for identifying fibrosis and cirrhosis.9 The most useful tools were FibroTest™ (LabCorp), FibroIndex (Janssen), simple platelet counts, aspartate aminotransferase/platelet ratio index (APRI), and the Forns Index.9 Studies have shown that these blood tests work well for staging patients with zero or minimal fibrosis as well as those who have advanced fibrosis or cirrhosis, but they are less helpful for assessing mid-range liver disease or for tracking fibrosis.8,9 Another method that clinicians can use to stage liver disease is measuring liver stiffness through transient elastography. This includes ultrasound elasticity imaging and magnetic resonance elasticity imaging. Although these new imaging techniques have a high degree of accuracy for measuring liver stiffness, they are expensive and require sending a patient for scanning at a separate facility, which can delay diagnosis.9

FibroScan: A Novel, Noninvasive Technique FibroScan is a noninvasive test that assesses liver stiffness by employing vibration-controlled transient elastography (VCTE™) to emit a shear wave through the liver and measure its velocity via ultrasound.8 Although this technology was approved for marketing in the United States in April 2013, it has been available in Europe since 2003, in China since 2008, and in Japan since 2011. It is easy to administer at the point of care, takes only 5 to 7 minutes to conduct, and results are available within 10 minutes. FibroScan is not painful, does not require sedation, and evaluates 100 times more liver volume than biopsy.8,10 During the procedure, clinicians induce a 50-Hz shear wave into the liver from a small mechanical actuator on the end of an ultrasound probe during patient expiration. The technology measures the velocity of the shear wave passing through the liver, in meters per second, and then converts the

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

measurement into a liver stiffness value, which is expressed in kilopascals (kPa).8 Higher kPa values indicate more extensive fibrosis. Results are offered following 10 or more successful measurements and a median interquartile range/median ratio less than 0.30.8 FibroScan can be used as a standalone tool or as an adjunct to liver biopsy, and it is particularly useful for identifying patients who have very advanced liver disease or cirrhosis.8 FibroScan is often the first test clinicians order when a patient presents with liver disease. FibroScan comes with 2 different probes: M and XL. The XL probe, which is indicated for use in obese patients, employs a 2.5-MHz ultrasonic transducer for improved vibration amplitude and measurement depth for accurate measurements in this patient population; the M probe is intended for use in the general population.11 Clinicians need to be aware of a few subtleties when conducting the test: Patients should be instructed to not consume any food or liquid 2 hours before testing; measurements may be taken anytime during a patient’s respiratory cycle; and the physician should be seated on a stool, not standing. Because FibroScan has not yet received a current procedural terminology (CPT) code,

some clinicians are batching the tests, putting their billing in a holding pattern. For patients paying out of pocket, the test costs approximately $131 (North Shore-LIJ Health System charges $375), which is much cheaper than biopsies that may cost $1,255 or more once all clinician fees are factored in.12 In early 2014, FibroScan was included in joint HCV management guidelines from the Infectious Diseases Society of America and the American Association for the Study of Liver Diseases as a point-of-care option for measuring liver stiffness in order to distinguish the presence of cirrhosis.13 Doctors are also using it in patients with other types of liver disease, including NAFLD, alcoholic fatty liver disease, hepatitis B virus (HBV) infection, and cholestatic liver disease.14

Clinical Data on FibroScan The most thorough clinical testing of FibroScan has been conducted in patients with chronic HCV. In a prospective multicenter study of 327 patients with chronic HCV, investigators compared results from FibroScan and liver biopsy. FibroScan results were well correlated with fibrosis stage (Kendall correlation coefficient, 0.55; P<0.0001).13 The investigators generated cutoff values with a high degree of accuracy for more

Table 1. Accuracy of FibroScan in Patients With Chronic Hepatitis C Metavir Score

Cutoff Value, kPa

AUROC

14.6

0.97

Advanced fibrosis (≥F3)

9.6

0.91

Significant fibrosis (≥F2)

8.8

0.79

AUROC, area under the receiver-operator characteristic curve; kPa, kilopascal From reference 15.

Table 2. Recommended Cutoff Values for Different Stages of Fibrosis Fibrosis Stage and Cutoff Value Disease

F0-F1, kPa

≥F2, kPa

≥F3, kPa

F4, kPa

HBV infection

≤6

7.2

8.1

11

HCV infection

≤7

8.8

9.6

14.6

HIV/HCV coinfection

–

>7

≥11.5

≥14

Cholestatic liver disease

≤7

7.3

9.8

17.3

NAFLD/NASH

≤7

≥7.5

≤10

≥14

HBV, hepatitis B virus; HCV, hepatitis C virus; kPa, kilopascal; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis Based on references 14, 15, 18, 19, and 21.

Supported by

serious Metavir fibrosis stages: 8.8 kPa for stage F2 or greater, 9.6 kPa for stage F3 or greater, and 14.6 kPa for stage F4 (Table 1).15 Another study involved 109 patients with chronic HCV who underwent a FibroScan test within 6 months of liver biopsy at the National Institutes of Health from 2006 to 2011. With a cutoff value of 13.1 kPa, there was a negative predictive value of 1.0 for the diagnosis of cirrhosis.16 The specificity of 0.89 resulted in a positive predictive value of 0.58, but 7 of 10 patients with increased liver stiffness consistent with cirrhosis had a noncirrhotic biopsy result.16 This cohort, however, had other clinical and radiologic features of cirrhosis, which suggests that liver biopsy had understaged the disease.16 Other researchers have identified the optimal cutoff value for cirrhosis in patients with HCV as 12 kPa.17 FibroScan has shown similar utility for patients with HIV/HCV coinfection. One investigation compared the diagnostic accuracy of FibroScan with 4 other noninvasive serum markers for predicting fibrosis among 100 patients with HIV/HCV coinfection: APRI, Forns Index, FIB-4, and HGM2.18 FibroScan was more accurate for the diagnosis of advanced fibrosis (≼F3) and cirrhosis, resulting in significantly higher area under

the receiver-operating characteristic curves compared with FIB-4 (0.92 vs 0.69; P=0.06), APRI (0.93 vs 0.77; P=0.007), HGM2 (0.92 vs 0.80; P=0.03), and the Forns Index (0.92 vs 0.75; P=0.002).18 Additionally, prospective studies have demonstrated that VCTE is reliable for the evaluation of fibrosis or cirrhosis in patients with HBV, with cutoff values similar to those observed for HCV.14,19 Research also supports the use of FibroScan for assessing liver fibrosis in patients with cholestatic liver disease and alcoholic liver disease, with precision comparable to that observed in patients with viral hepatitis.20,21 At Beth Israel Deaconess Medical Center in Boston, clinicians have been using liver stiffness values between 12 and 15 kPa to indicate a high probability of cirrhosis and a value greater than 15 kPa as a diagnosis of definite cirrhosis.14 Table 2 provides cutoff values for fibrosis staging across several chronic liver diseases.14,15,18,19,21 A diagnostic algorithm for the assessment of liver fibrosis is provided in the Figure.

Institute for Health and Care Excellence, the European Association for the Study of the Liver, and the Asian Pacific Association for the Study of the Liver recommend using FibroScan technology for the initial evaluation of liver diseases.8 The procedure has been validated in more than 760 peerreviewed publications and has been administered to over 100,000 patients. The primary benefit of this procedure is the exclusion or inclusion of advanced fibrosis and cirrhosis, but FibroScan also can be used for serial testing to assess disease progression or treatment response; additionally, it can serve as an adjunct to liver biopsy as well as clinical, radiologic, and serum marker testing.

References 1. World Gastroenterology Organisation Global Guidelines. Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. http://www.worldgastroenterology.org/assets/export/userfiles/2012_ NASH%20and%20NAFLD_Final_long.pdf. Accessed March 9, 2014. 2. Naggie S. Management of hepatitis C virus infection: the basics. Top Antivir Med. 2012;20(5):154-161.

Conclusion

3. Smith BD, Morgan RL, Beckett GA, et al. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 19451965. MMWR Recomm Rep. 2012;61(RR-4):1-32.

FibroScan has been used extensively as a point-of-contact test in liver clinics throughout Europe. Guidelines from the National

4. U.S. Preventive Services Task Force. Screening for hepatitis C virus infection in adults. http://www. uspreventiveservicestaskforce.org/uspstf12/hepc/ hepcfinalrs.htm. Accessed March 9, 2014.

5. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53(3):1-35. 6. Rahman R, Hammoud GM, Almashhrawi AA, et al. Primary hepatocellular carcinoma and metabolic syndrome: an update. World J Gastrointest Oncol. 2013;5(9):186-194. 7. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132(7):2557-2576. 8. Afdhal N. Fibroscan (transient elastography) for the management of liver fibrosis. Gastroenterol Hepatol. 2012;8(9):605-607. 9. Chou R, Wasson N. Blood tests to diagnose fibrosis or cirrhosis in patients with chronic hepatitis C virus infection: a systematic review. Ann Intern Med. 2013; 158(11):807-820. 10. de Ledinghen V, Vergniol J. Transient elastography (FibroScan). Gastroenterol Clin Biol. 2008;32(6 suppl 1): S58-S67. 11. Armstrong MJ, Corbett C, Hodson J, et al. Operator training requirements and diagnostic accuracy of Fibroscan in routine clinical practice. Postgrad Med J. 2013;89(1058):685-692. 12. Carlson JJ, Kowdley KV, Sullivan DS, et al. An evaluation of the potential cost-effectiveness of non-invasive testing strategies in the diagnosis of significant liver fibrosis. J Gastroenterol Hepatol. 2009;24(5): 786-791. 13. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org/fullreport-view. Accessed March 9, 2014. 14. Bonder A, Afdhal N. Utilization of FibroScan in clinical practice. Curr Gastroenterol Rep. 2014;16(2):372-379. 15. Ziol M, Handra-Luca A, Kettaneh A, et al. Non-invasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Hepatology. 2005;41(1):48-54. 16. Gara N, Zhao X, Kleiner DE, et al. Discordance among transient elastography, aspartate aminotransferase to platelet ratio index, and histologic assessments of liver fibrosis in patients with chronic hepatitis C. Clin Gastroenterol Hepatol. 2013;11(3):303-308.

<10 kPa APRI <1 Platelets >150,000 featu es of No clinical c ca features of cirrhosis c os s

Low probability of cirrhosis

No liver biopsya Follow up or treat according to disease

10 kPa to <14 kPa APRI 1-2 l l Platelets 100,000 - 150,000 No clinical c ca ffeatures eatu es of of cirrhosis c os s

>14 kPa APRI >2 Platelets <100,000 Cl C ca ffeatures Clinical eatu es of of cirrhosis c osis

F3 to F4 High probability of cirrhosis

a

No liver biopsy Treat as cirrhosis Screen for HCC Screen for varices with EGD

High probability of cirrhosis

17. Malik R, Lai M, Sadiq A, et al. Comparison of transient elastography, serum markers and clinical signs for the diagnosis of compensated cirrhosis. J Gastroenterol Hepatol. 2010;25(9):1562-1568. 18. Sanchez-Conde M, Montes-Ramirez ML, Miralles P, et al. Comparison of transient elastography and liver biopsy for the assessment of liver fibrosis in HIV/hepatitis C virus co-infected patients and correlation with noninvasive serum markers. J Viral Hepat. 2010;17(4): 280-286. 19. Marcellin P, Ziol M, Bedossa P, et al. Non-invasive assessment of liver fibrosis by stiffness measurement in patients with chronic hepatitis B. Liver Int. 2009;29(2):242-247. 20. Nguyen-Khac E, Chatelain D, Tramier B, et al. Assessment of asymptomatic liver fibrosis in alcoholic patients using fibroscan: prospective comparison with seven non-invasive laboratory tests. Aliment Pharmacol Ther. 2008;28(10):1188-1198.

a

No liver biopsy Treat as cirrhosis Screen for HCC Screen for varices with EGD

21. Corpechot C, El Naggar A, Poujol-Robert A, et al. Assessment of biliary fibrosis by transient elastography in patients with PBC and PSC. Hepatology. 2006;43(5):1118-1124. Disclosures: Dr. Bernstein reported that he has received grant support from AbbVie, Bristol-Myers Squibb, Gilead, Merck, and Vertex. He has also served as a consultant for AbbVie, Gilead, and Merck.

Figure. Procedural workup for assessing fibrosis at North Shore-LIJ Health System.

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

BB1412

APRI, aspartate aminotransferase/platelet ratio index; EGD, esophagogastroduodenoscopy; HCC, hepatocellular carcinoma; kPa, kilopascal a Patients receive an annual FibroScan until cirrhosis is detected. The risks of biopsy outweigh the benefits gained from annual HCC screening and a single EGD screening for varices.

25

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Barrett’s Surveillance continued from page 23

risk of 0.33% and 0.38%, respectively, for the progression of intestinal metaplasia to cancer. A Danish study reported a lower risk (0.12%), but this population likely included many patients with shortsegment BE. Short-segment BE was associated with a much lower risk for progression in the meta-analysis and the Irish study (0.19% and 0.11%, respectively). The characteristics of Barrett’s tissue (e.g., presence of intestinal metaplasia, BE segment length) should be a component of risk stratification, as stated by the British Society guidelines.

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

the assessment of dysplasia, and also has been incorporated into the revised guidelines.

Commentary Thomas L. Vaughan, MD, MPH, professor of epidemiology at the Fred Hutchinson Cancer Research Center, in Seattle, commented on Dr. Fitzgerald’s remarks. He noted that of approximately 10,000 esophageal adenocarcinomas diagnosed annually in the United States, only 500 are identified as a result of current

approaches to cancer control. “There are numerous extrinsic and intrinsic risk factors with substantial effects,” Dr. Vaughan said. “Most of these appear to act in the development of BE. Drivers of progression to esophageal adenocarcinoma are less clear, but are likely to be inflammation-related,” he said. Dr. Vaughan agreed with Dr. Fitzgerald that approaches to screening and surveillance can greatly benefit from more accurate risk stratification. “We cannot afford to put so many individuals under surveillance, but we

could use information we already have to risk-stratify them.” He said efforts are under way to determine how best to incorporate risk factors into a screening and surveillance algorithm. ■ Dr. Fitzgerald developed the Cytosponge and assays, which have been licensed by the UK Medical Research Council to Covidien for commercialization. Dr. Vaughan reported no conflicts of interest.

‘For the first time we have begun to introduce some concept of risk into these guidelines.’ —Rebecca Fitzgerald, MD “We don’t say that intestinal metaplasia is a prerequisite but we do say that if the segment is short—less than 3 cm— and you only have gastric metaplasia on biopsy, you should be suspicious that you have biopsied a hiatal hernia and you should repeat the endoscopy,” she said. If the results are confirmed, the patient probably has no increased risk for progression to cancer and can be dismissed. When intestinal metaplasia is confirmed, the BE segment length should dictate surveillance intervals: Endoscopy should be repeated every three to five years for short segments, and every two to three years for long segments. “For the first time, we have begun to introduce some concept of risk into these guidelines,” Dr. Fitzgerald said.

1978

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36th Anniversary — 2 0 1 4 2014

The Independ Independent Monthly Newspaper for Gastroenterologists

For almost four decades, Gastroenterology & Endoscopy News has been providing gastroenterology health care professionals with specialty-specific news and reviews, offering comprehensive and objective information for the practicing clinician.

Optimizing Current Technologies Although current technologies should be sufficient for surveillance, they are not always used appropriately, Dr. Fitzgerald pointed out. “The key thing is to use our current tools—white light, high resolution— well. Perform a high-quality endoscopy, look for recognizable landmarks and use the Prague classification to document BE length. Look carefully for visible lesions, which can be subtle and easily missed, and use the Paris classification for these.” Pathologic assessment can be made more accurate through consensus reporting of dysplasia, as the British guidelines now recommend. “You need to know your pathologist. In my opinion, this is specialist’s work,” she said. Abnormal p53 by immunohistochemical staining can be a useful adjunct in

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Optimal Approach for Early Esophageal Cancer Still Debated BY CAROLINE HELWICK SAN FRANCISCO—A number of papers and presentations at the 2014 American Society for Clinical Oncology Gastrointestinal Cancers Symposium sought to better define the role of endoscopic resection and the optimal endoscopic approach for early-stage esophageal cancer. Gastroenterology & Endoscopy News captured the news and perspectives.

‘Although surgery used to be the gold standard and holds the promise of cure when performed by an experienced group, it is also limited by high morbidity and mortality.’ —Michel Kahaleh, MD

Endoscopy Versus Esophagectomy

role of endoscopic treatment versus esophagectomy. His conclusion: T0 and T1a cancers are appropriate for endoscopic treatment and selected patients

Michel Kahaleh, MD, of Weill Cornell Medical College, New York City, focused on the ongoing debate surrounding the

with T1b disease can also be considered for endoscopic treatment, provided they are carefully staged, the techniques are advanced and there has been a multidisciplinary discussion of the case. In situations not satisfying these criteria, surgery should be the treatment. “The management of superficial esophageal cancers, defined as lesions limited to the mucosa and submucosa, has been subject to debate,” Dr. Kahaleh see Esophageal Cancer, page 29

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H E PAT O L O G Y IN F O C U S

Guidance Equivocal On HCV Screening Of Baby Boomers

Despite Above Average Income, Gastros Report Job Dissatisfaction BY VICTORIA STERN

BOSTON—Recent evidence suggests that nonalcoholic fatty liver disease (NAFLD) is emerging as a significant public health problem. One study revealed an “alarming” rate of HCC related to NAFLD, even among

Gastroenterologists are the fourth most highly compensated physicians compared with doctors in 24 other medical specialties, according to an online survey conducted by Medscape in February 2013. Average annual income for gastroenterologists was up 13% in 2012 compared with 2011, coming in at $342,000. The three specialties that beat out gastroenterology in average yearly compensation were orthopedists at $405,000, cardiologists at $357,000 and radiologists at $349,000 (see Figure 1, page 28). But despite robust earnings, less than half (48%) of the gastroenterologists surveyed said they felt fairly compensated, the same percentage as that of physicians of all specialties who said they felt fairly compensated. The findings were based on responses collected in a third-party online survey of 21,878 U.S. physicians, 2% of whom were gastroenterologists. Most gastroenterologists who responded were men (84%) and board certified (96%), and 62% were aged 45 years or older.

see NAFLD, page 14

see Income, page 28

BY CHRISTINA FRANGOU Hepatologists have added their voices to the debate over screening for hepatitis C virus (HCV) infection and are urging the U.S. Preventive Services Task Force (USPSTF) to upgrade its current recommendation see HCV Screening, page 18

NAFLD Threatening Public Health BY KATE O’ROURKE

I N S I D E

Cost Sharing for Polyp Removal During Colonoscopy Waived for Some Patients

H E PAT O L O G Y

I N

FOCUS

Investigational Device Prolongs Survival of Livers For Transplantation .................................................page 8

BY MONICA J. SMITH

tor

Ma Vis it y DD 19-2 us W bo 1, 20 oth 13 15 31

Effect of Preexisting Cardiovascular Disease On Outcomes After Liver Transplantation May Be Underestimated..........................................page 9

Patients with private insurance will no longer be responsible for any cost sharing in the event that a polyp is removed during a screening colonoscopy, according to a recent clarification, issued by the federal government, on preventive screening benefits under the Affordable Care Act (ACA). “This is very good news,” said Durado Brooks, MD, MPH, direcof Prostate and Colorectal Cancers at the American Cancer Society in

Retreatment of Hepatitis C With Interferon Alone May Increase Mortality ..........................................«>}iÊ£È Statins Linked to Reduction in Mortality From Liver Cancer .................................................«>}iÊÓ{

see Cost Sharing, page 32 PRINTER FRIENDLY VERSION AT GASTROENDONEWS.COM

CLINICAL REVIEW see insert between pages 20 and 21

Ulcerative Colitis: Treatment Strategies By Ellen J. Scherl, MD, Arun Swaminath, MD, Brian Bosworth, MD, and Vinita Jacob, MD

PRODUCT ANNOUNCEMENT

Ulcerative Colitis:

Optimizing Mesalamine Sttrategies ELLEN J. SCHERL, MD Director, Jill Roberts Center for Inflammatory Bowel Diseasea Jill Roberts Center for Inflammatory Bowel Disease Director of Researchb Jill Roberts Associate Professor of Inflammatory Bowel Diseaseb Associate Professor of Clinical Medicineb Adjunct Associate Professor of Medicinec

T

see page 63 for product information

he e greatest ch hallenge for clinicians who

treat pattients with inflamma atory bowel disease (IBD) is to move from symptomoriented (step--up) strategies toward preventio on-orie ented (early intervention) strategies aimed

ARUN SWAMINATH, MD

at tight inflammation control and alteration of the natural

Assistant Attending Physiciana Assistant Professor of Clinical Medicinec

history of IBD. This review focuses on a personalized

BRIAN BOSWORTH, MD

acid (5-ASA) agents.

approach to the treatment of IBD using 5-aminosalicylic

Assistant Attending Physiciana Assistant Professor of Medicineb Anne and Ken Estabrook Clinical Scholar in Gastroenterologyb

VINITA JACOB, MD Assistant Attending Physiciana Assistant Professor of Medicineb

DANA J. LUKIN, MD, PHD Gastroenterology Fellowc a

b

c

NewYork-Presbyterian Hospital/ Weill Cornell Medical Center New York, New York Weill Cornell Medical College New York, New York Columbia University College of Physicians and Surgeons New York, New York

Challenging the Traditional IBD Diagnosis Traditionally, IBD has been divided into 2 distinct entities: ulcerative colitis (UC) and Crohn’s disease (CD). A nuanced view presents IBD as an immunoinflammatory spectrum of chronic and recurring diseases of the intestines defined by individual molecular signatures. This newly gained perspective holds the promise of moving treatment in a more proactive, personalized direction, toward targeting molecules and risk assessment, rather than treating symptoms of the disease. One of the major questions facing clinicians is whether IBD is a single entity or a spectrum of multiple disorders. This distinction becomes particularly difficult to make when attempting to

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Esophageal Cancer continued from page 27

Table. Tailored Approach in Superficial Esophageal Adenocarcinoma

said. “This debate is rooted in the lack of sufficient clinical trials comparing longterm outcomes of esophagectomy and endoscopic resection. Although surgery used to be the gold standard and holds the promise of cure when performed by an experienced group, it is also limited by high morbidity and mortality.” Few studies have suggested that endoscopic treatment and surgery are equally effective in patients with high-grade dysplasia and intramucosal carcinoma. Although endoscopic treatment is successful in 80% of patients, it is also associated with a higher rate of recurrence (6%-12%) compared with surgery (0%2%), Dr. Kahaleh noted. “The price we pay for this is the need for close follow-up and repeat endoscopic resection,” he said. But for some patients, endoscopic resection is warranted. Cancer that is limited to the mucosa is rarely associated with nodal metastases (0%-2%). “That’s the concept behind endoscopic treatment—cancer limited to the mucosa, and no nodal metastasis,” he said. On the other hand, recurrence rates are 20% or higher in patients with submucosal lesions, poorly differentiated tumors, tumors greater than 2 cm and those with lymphatic or venous infiltration. “These patients are at high risk and obviously need surgery,” Dr. Kahaleh said. “The problem in our field is that no randomized clinical trials have compared these techniques, and they are likely not going to. We have to come up with the best guidelines to make sure our patients are channeled down the right treatment path.”

Patient Population

Recommended Treatment

Older, poor FEV, high risk

Endoscopic therapies

Unsalvageable esophagus (e.g., esophageal strictures, giant hiatal hernia)

Esophagectomy

Young, good FEV, good risk

Patient must be educated; decision is complex. Consider esophagectomy for: • Multifocal vs. unifocal disease • High-risk factors from endoscopic resection specimen (T1b, size >2 cm, grade 3 histology, lymphovascular invasion)

FEV, forced expiratory volume

The chief debate regarding optimal treatment focuses on cancer that “touches” the muscularis, Dr. Kahaleh noted. “There is no question that if cancer involves the deep layer of the muscularis, those patients should be offered surgery.”

Two Recent Studies Two studies from 2013 and 2014 compared endoscopic therapy and surgery, and concluded they have equivalent survival outcomes. The first study was a population-based comparison of 430 patients who underwent endoscopic treatment and 1,586 who underwent esophagectomy. No differences were found in esophageal cancer–related mortality at years 2 and 5 of follow-up (Wani S et al. Gastrointest Endoscc 2014;79:224-232). The overall higher mortality rate in the endoscopy group was attributed to other causes, including comorbidity and older age. Similar results were noted when comparisons were limited to patients with stage T0 and T1a disease and esophageal adenocarcinoma. The second study, based on data from the Surveillance, Epidemiology, and End

Results database of 1,618 patients with superficial cancers, revealed that fiveyear overall survival rates were higher in patients who underwent surgery. However, outcomes were similar between the treatment groups adjusting for patient demographics and tumor characteristics; esophageal cancer–specific survival rates were also similar (Ngamuengphong S et al. Clin Gastroenterol Hepatol 2013;11:1424-1429). Also, the study documented the increasing use of endoscopic therapy, from 3% to 29% in 1998 compared with 2009. “The rise of endoscopic treatment is evident. I predict that moving forward, we will see a shifting paradigm of decreasing use of ablative treatments and increased use of endoscopic resection,” Dr. Kahaleh said.

A Surgeon’s Perspective Hiran C. Fernando, MBBS, of Boston Medical Center, added the surgeon’s perspective to the debate. He agreed that for T1aN0 (intramucosal) cancers, endoscopic therapies can be considered, since the incidence of occult nodal disease is very low in these superficial tumors. He cited one study of 100 carefully selected

Piecemeal Mucosal Resection as Effective as En Bloc For Early Esophageal Cancer BY CAROLINE HELWICK SAN FRANCISCO—For endoscopic treatment of early esophageal cancers, piecemeal and en bloc resections yield similar outcomes, Mayo Clinic investigators reported at the 2014 American Society for Clinical Oncology Gastrointestinal Cancers Symposium. Lesions smaller than 1.5 cm are often removed with en bloc resection, whereas those larger than 1.5 cm often require piecemeal resection. En bloc resection removes the entire lesion, whereas piecemeal resection removes the lesion in pieces but

still with the same level of sampling of depth. The current study aimed to determine if the type of resection affected five-year overall and cancer-free survival rates. To do so, researchers performed a retrospective examination of 138 patients with early esophageal cancer treated between 1998 and 2012. “With the advent of techniques such as endoscopic submucosal dissection (ESD) that can remove large lesions en bloc, it is important to determine if performing piecemeal resections of intramucosal cancers is detrimental,” said Chuanlian Chu, PhD, of Mayo Clinic, Rochester, Minn.

No statistically significant differences in outcomes were observed: Complete remission rates were 92.1% for the en bloc resection group and 93.6% for the piecemeal resection group; local recurrence rates were 7.9% and 6.4%, respectively; time to recurrence was 22 months and 11 months, respectively; and five-year survival was 83.2% and 80.9%, respectively. Complications were rare in both groups, Dr. Chu reported. Donald E. Low, MD, head of Thoracic Surgery and Thoracic Oncology at Virginia Mason Medical Center, Seattle, commented that advanced

patients that showed five-year survival to be 98% (Ell C et al. Gastrointest Endosc 2007;65:3-10). Other studies also have confirmed the appropriateness of an esophageal-sparing approach for selected patients, Dr. Fernando said. In another study of “low-risk” T1bN0 (submucosal) cancers, 28% of tumors recurred at almost five years; five-year survival was 66%, but no deaths were tumor-related (Manner H et al. Am J Gastroenterol 2008;103:2589-2597). “But these results were achievable in a highly specialized single center, and this approach would not be applicable to most centers,” Dr. Fernando noted. “The pendulum has shifted to endoscopic therapies for selected patients with T1aN0 cancers,” he concluded. “Although its use has been applied to submucosal tumors as well, this approach is not justified in most centers, and esophagectomy should remain the standard of care for these deeper invading cancers.” Dr. Fernando recommended a tailored approach to treatment (Table). ■ Drs. Kahaleh, Chu and Low reported no conflicts of interest. Dr. Fernando has served in an advisory role for CSA Medical.

Western centers are moving toward ESD, which is common in many centers in Japan, Korea and China. Currently, the majority of U.S. interventional endoscopists are performing standard endoscopic mucosal resection (EMR). The choice between en bloc ESD and piecemeal EMR resection has mostly to do with endoscopist experience, although those trained in ESD are now using that approach more routinely, Dr. Low said. “Piecemeal dissections remove and stage cancer completely, and this is a significant improvement over previous standard practice which was small pinch biopsies,” he said. “This study showed that local recurrence rates and overall survivorship is virtually identical between the two approaches,” he added.

IN THE TREATMENT OF CHRONIC HEPATITIS B (CHB) IN ADULTS WITH COMPENSATED LIVER DISEASE

TAKE A CLOSER LOOK AT LAMIVUDINE (LAM) RESISTANCE MORE THAN NEARLY Not an actual patient, but is representative of a real patient type. Models are used for illustrative purposes only.

50% 70% 70% 2%

of Americans living with CHB are Asian and Pacific Islanders1

of Asian Americans were born or have parents born in countries where CHB is common1

of patients receiving lamivudine develop resistance at 5 years2

of patients in the United States use lamivudine; up to 88% in Asia3

Indication and Usage VIREAD® (tenofovir disoproxil fumarate) is indicated for the treatment of chronic hepatitis B in adults and pediatric patients 12 years of age and older. The following points should be considered when initiating therapy with VIREAD for the treatment of HBV infection: s The indication in adults is based on data from treatment of subjects who were nucleoside–treatment-naïve and treatment-experienced with documented resistance to lamivudine. Subjects were adults with HBeAgpositive and HBeAg-negative chronic hepatitis B with compensated liver disease s VIREAD was evaluated in a limited number of subjects with chronic hepatitis B and decompensated liver disease s The numbers of subjects in clinical trials who had adefovir resistance-associated substitutions at baseline were too small to reach conclusions of efficacy

Important Safety Information BOXED WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS s Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases cases, have been reported with the use of nucleoside analogs, analogs including VIREAD, in combination with other antiretrovirals s Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including VIREAD. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy, including VIREAD. If appropriate, resumption of anti-hepatitis B therapy may be warranted

Warnings and Precautions s New onset or worsening renal impairment: Cases of acute renal failure and Fanconi syndrome have been reported with the use of VIREAD. In all patients, assess estimated creatinine clearance (CrCl) prior to initiating and during therapy. In patients at risk for renal dysfunction, including those

who previously experienced renal events while receiving adefovir dipivoxil, additionally monitor serum phosphorus, urine glucose, and urine protein. In patients with CrCl <50 mL/min, adjustt dosing interval and closely monitor renal function. Avoid concurrent or recent use with a nephrotoxic agent. Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after initiation of high dose or multiple NSAIDs in HIV-infected patients with risk factors for renal dysfunction; consider alternatives to NSAIDs in these patients. Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function s Coadministration with other products: – Do not use in combination with other products containing tenofovir disoproxil fumarate – Do not administer in combination with adefovir dipivoxil s Patients coinfected with HIV-1 and HBV: Due to the risk of development of HIV-1 resistance, VIREAD should only be used in HIV-1 and HBV coinfected patients as part of an appropriate antiretroviral combination regimen. HIV-1 antibody testing should be offered to all HBV-infected patients before initiating therapy with VIREAD s Bone effects: Decreases in bone mineral density (BMD) and mineralization defects, including osteomalacia, have been seen in patients treated with VIREAD. C VIREAD Consider id assessmentt off BMD in i adult d lt andd pediatric di t i patients ti t who h have h a history of pathologic bone fracture or other risk factors for bone loss. In a clinical trial conducted in pediatric subjects 12 to <18 years of age with chronic hepatitis B, total body BMD gain was less in VIREAD-treated subjects as compared to the control group. In patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms, hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered

Adverse Reactions s In HBV-infected subjects with compensated liver disease: Most common adverse reaction (all grades) was nausea (9%). Other treatmentemergent adverse reactions reported in >5% of patients treated with VIREAD included: abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain, and skin rash

TAKE A CLOSER LOOK AT VIREAD LAM-resistant VIREAD patients (Study 121) achieving viral suppression (HBV DNA <400 copies/mL) at 96 weeks of treatment 4,5 VIREAD

100 90

89%

(n=126)

Patients (%)

80 70 60 50 40

s As a secondary endpoint, no HBV resistance (0%) was detected at 96 weeks in CHB patients with LAM resistance4

30 20 10 0

Study 121 was a randomized, double-blind, active-controlled 96-week trial evaluating the safety and efficacy of VIREAD (n=141) compared to an unapproved antiviral regimen (n=139) in subjects with CHB, persistent viremia (HBV DNA ≥1000 IU/mL), and genotypic evidence of LAM resistance. The primary endpoint in Study 121 was HBV DNA <400 copies/mL (69 IU/mL) at Week 96.4,5

0

4

8

12 16

24

32

40

48

60

72

Important Safety Information (cont’d) s In HBV-infected subjects with decompensated liver disease: Most common adverse reactions (all grades) reported in ≥10% of patients treated with VIREAD were abdominal pain (22%), nausea (20%), insomnia (18%), pruritus (16%), vomiting (13%), dizziness (13%), and pyrexia (11%)

Drug Interactions s Didanosine: Coadministration increases didanosine concentrations. Use with caution and monitor for evidence of didanosine toxicity (e.g., pancreatitis, neuropathy). Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions. In patients weighing >60 kg, the didanosine dose should be reduced to 250 mg once daily when it is coadministered with VIREAD and in patients weighing <60kg, the didanosine dose should be reduced to 200 mg once daily when coadministered with VIREAD s HIV-1 protease inhibitors: Coadministration decreases atazanavir concentrations and increases tenofovir concentrations; use atazanavir given with ritonavir. Coadministration of VIREAD with atazanavir and ritonavir, darunavir and ritonavir, or lopinavir/ritonavir increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity s Drugs affecting renal function: Coadministration of VIREAD with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of tenofovir

Dosage and Administration s Recommended dose, in adults and pediatric patients ≥12 years of age (≥35 kg), for the treatment of chronic hepatitis B: one 300 mg tablet, once daily, taken orally, without regard to food s In the treatment of chronic hepatitis B, the optimal duration of treatment is unknown

84

96 Weeks

s Safety and efficacy in pediatric patients <12 years of age or weighing <35kg with chronic hepatitis B have not been established s The dosing interval of VIREAD should be adjusted (using recommendations in the table below) and renal function closely monitored in patients with baseline creatinine clearance <50 mL/min Dosage Adjustment for Patients with Altered Creatinine Clearance Creatinine clearance (mL/min)a ≥50 Recommended 300 mg dosing interval

Every 24 hours

30-49

Every 48 hours

10-29

Every 72 to 96 hours

Hemodialysis patients Every 7 days or after a total of approximately 12 hours of dialysisb

a

Calculated using ideal (lean) body weight. Generally once weekly assuming three hemodialysis sessions a week of approximately 4 hours duration. VIREAD should be administered following completion of dialysis.

b

s The pharmacokinetics of tenofovir have not been evaluated in nonhemodialysis patients with creatinine clearance <10 mL/min; therefore, no dosing recommendation is available for these patients s No dose adjustment is necessary for patients with mild renal impairment (creatinine clearance 50-80 mL/min). Routine monitoring of estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein should be performed in these patients s No data are available to make dose recommendations in pediatric patients with renal impairment

Please see Brief Summary of full Prescribing Information, including BOXED WARNING, on the adjacent pages. References: 1. CDC Web site. CDC Features-August 2011: Chronic hepatitis B and Asian & Pacific Islanders. Centers for Disease Control and Prevention. http://www.cdc.gov/Features/ChronicHepatitisB/. Accessed June 26, 2013. 2. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of chronic hepatitis B virus infection. J Hepatol.l 2012;57:167-185. 3. Data on file, Gilead Sciences, Inc. Gilead HBV LAM assessment, IMS MIDAS data. May 2013. 4. Data on file, Gilead Sciences, Inc. 0121 CSR. 5. VIREAD Prescribing Information, Foster City, CA: Gilead Sciences, Inc.; October 2013.

VIREAD® (tenofovir disoproxil fumarate) tablets Brief summary of full Prescribing Information. Please see full Prescribing Information including Boxed WARNING. Rx only WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS @ Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, in combination with other antiretrovirals (See Warnings and Precautions) @ Severe acute exacerbations of hepatitis have been reported in HBVinfected patients who have discontinued anti-hepatitis B therapy, including VIREAD. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy, including VIREAD. If appropriate, resumption of anti-hepatitis B therapy may be warranted (See Warnings and Precautions) INDICATIONS AND USAGE: VIREAD is indicated for the treatment of chronic hepatitis B in adults and pediatric patients 12 years of age and older The following points should be considered when initiating therapy with VIREAD for the treatment of HBV infection: J The indication in adults is based on safety and efficacy data from treatment of subjects who were nucleoside-treatment-naïve and subjects who were treatment-experienced with documented resistance to lamivudine. Subjects were adults with HBeAg-positive and HBeAg-negative chronic hepatitis B with compensated liver disease (See Adverse Reactions) J VIREAD was evaluated in a limited number of subjects with chronic hepatitis B and decompensated liver disease (See Adverse Reactions) J The numbers of subjects in clinical trials who had adefovir resistance-associated substitutions at baseline were too small to reach conclusions of efficacy DOSAGE AND ADMINISTRATION: For the treatment of chronic hepatitis B the recommended dose, in adults and pediatric patients ≥12 years of age (≥35 kg), is one 300 mg tablet, once daily, taken orally, without regard to food. In the treatment of chronic hepatitis B, the optimal duration of treatment is unknown. Safety and efficacy in pediatric patients <12 years of age with chronic hepatitis B weighing <35 kg have not been established. Dose Adjustment for Renal Impairment in Adults: Significantly increased drug exposures occurred when VIREAD was administered to subjects with moderate to severe renal impairment. Therefore, the dosing interval of VIREAD tablets 300 mg should be adjusted in patients with baseline creatinine clearance <50 mL/min using the recommendations in Table 1. These dosing interval recommendations are based on modeling of single-dose pharmacokinetic data in non-HIV and non-HBV infected subjects with varying degrees of renal impairment, including end-stage renal disease (ESRD) requiring hemodialysis. The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated in patients with moderate or severe renal impairment, therefore clinical response to treatment and renal function should be closely monitored in these patients (See Warnings and Precautions). No dose adjustment of VIREAD tablets 300 mg is necessary for patients with mild renal impairment (creatinine clearance 50–80 mL/min). Routine monitoring of estimated creatinine clearance, serum phosphorus, urine glucose and urine protein should be performed in patients with mild renal impairment (See Warnings and Precautions). Dosage Adjustment for Adult Patients with Altered Creatinine Clearance

Recommended 300 mg dosing interval

Creatinine clearance (mL/min)a ≥50 30-49 10-29

Hemodialysis patients

Every 24 Every 48 Every 72 to hours hours 96 hours

Every 7 days or after a total of approximately 12 hours of dialysisb

a. Calculated using ideal (lean) body weight. b. Generally once weekly assuming three hemodialysis sessions a week of approximately 4 hours duration. VIREAD should be administered following completion of dialysis. The pharmacokinetics of tenofovir have not been evaluated in non-hemodialysis patients with creatinine clearance <10 mL/min; therefore, no dosing recommendation is available for these patients. No data are available to make dose recommendations in pediatric patients with renal impairment. CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS: Lactic Acidosis/Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with VIREAD should be

suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). Exacerbation of Hepatitis after Discontinuation of Treatment: Discontinuation of anti-HBV therapy, including VIREAD, may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinue VIREAD should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of anti-hepatitis B therapy may be warranted. New Onset or Worsening Renal Impairment: Tenofovir is principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of VIREAD (See Adverse Reactions). It is recommended that estimated creatinine clearance be assessed in all patients prior to initiating therapy and as clinically appropriate during therapy with VIREAD. In patients at risk of renal dysfunction, including patients who have previously experienced renal events while receiving adefovir dipivoxil, it is recommended that estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of VIREAD, and periodically during VIREAD therapy. Dosing interval adjustment of VIREAD and close monitoring of renal function are recommended in all patients with creatinine clearance <50 mL/min (See Dosage and Administration). No safety or efficacy data are available in patients with renal impairment who received VIREAD using these dosing guidelines, so the potential benefit of VIREAD therapy should be assessed against the potential risk of renal toxicity. VIREAD should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple nonsteroidal anti-inflammatory drugs (NSAIDs)) (See Drug Interactions). Cases of acute renal failure after initiation of high dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on tenofovir DF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction. Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients. Coadministration with Other Products: VIREAD should not be used in combination with the fixeddose combination products ATRIPLA®, COMPLERA®, STRIBILD® or TRUVADA® since tenofovir disoproxil fumarate is a component of these products. VIREAD should not be administered in combination with adefovir dipivoxil (See Drug Interactions). Patients Coinfected with HIV-1 and HBV: Due to the risk of development of HIV-1 resistance, VIREAD should only be used in HIV-1 and HBV coinfected patients as part of an appropriate antiretroviral combination regimen. HIV-1 antibody testing should be offered to all HBV-infected patients before initiating therapy with VIREAD. It is also recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B before initiating treatment with VIREAD. Bone Effects Bone Mineral Density:: In clinical trials in HIV-1 infected adults, VIREAD was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving VIREAD (See Adverse Reactions). Clinical trials evaluating VIREAD in pediatric and adolescent subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects aged 2 years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the VIREAD-treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic hepatitis B infected adolescent subjects aged 12 years to less than 18 years. In all pediatric trials, skeletal growth (height) appeared to be unaffected (See Adverse Reactions). The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for adults and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained. Mineralization Defects:: Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of VIREAD (See Adverse Reactions). Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir DF (See Warnings and Precautions). ADVERSE REACTIONS: Clinical Trials in Adult Subjects with Chronic Hepatitis B and Compensated Liver Disease: Treatment-Emergent Adverse Reactions:: In controlled clinical trials in subjects with chronic hepatitis B (0102 and 0103), more subjects treated with VIREAD during the 48-week double-blind period experienced nausea: 9% with VIREAD versus 2% with adefovir dipivoxil. Other treatmentemergent adverse reactions reported in >5% of subjects treated with VIREAD included: abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain, and skin rash. No significant change in the tolerability profile was observed with continued treatment with VIREAD for up to 240 weeks. Laboratory Abnormalities:: in Studies 0102 and 0103 (0–48 Weeks) laboratory

Brief Summary (cont’d) abnormalities (Grades 3–4) reported in ≥1% of subjects treated with Viread (n=426) and adefovir dipivoxil (n=215), respectively, were: any ≥Grade 3 laboratory abnormality (19%, 13%); creatine kinase (M: >990 U/L; F: >845 U/L) (2%, 3%); serum amylase (>175 U/L) (4%, 1%); glycosuria (≥3+) (3%, <1%); AST (M: >180 U/L; F: >170 U/L) (4%, 4%); and ALT (M: >215 U/L; F: >170 U/L) (10%, 6%). Laboratory abnormalities (Grades 3–4) were similar in subjects continuing VIREAD treatment for up to 240 weeks in these trials. The overall incidence of on-treatment ALT flares (defined as serum ALT >2 × baseline and >10 × ULN, with or without associated symptoms) was similar between VIREAD (2.6%) and adefovir dipivoxil (2%). ALT flares generally occurred within the first 4-8 weeks of treatment and were accompanied by decreases in HBV DNA levels. No subject had evidence of decompensation. ALT flares typically resolved within 4-8 weeks without changes in study medication. The adverse reactions observed in subjects with chronic hepatitis B and lamivudine resistance who received treatment with VIREAD were consistent with those observed in other hepatitis B clinical trials in adults. Clinical Trial in Adult Subjects with Chronic Hepatitis B and Decompensated Liver Disease:: In a small randomized, double-blind, active-controlled trial (0108), subjects with CHB and decompensated liver disease received treatment with VIREAD or other antiviral drugs for up to 48 weeks. Among the 45 subjects receiving VIREAD, the most frequently reported treatment-emergent adverse reactions of any severity were abdominal pain (22%), nausea (20%), insomnia (18%), pruritus (16%), vomiting (13%), dizziness (13%), and pyrexia (11%). Two of 45 (4%) subjects died through Week 48 of the trial due to progression of liver disease. Three of 45 (7%) subjects discontinued treatment due to an adverse event. Four of 45 (9%) subjects experienced a confirmed increase in serum creatinine of 0.5 mg/dL (1 subject also had a confirmed serum phosphorus <2 mg/dL through Week 48). Three of these subjects (each of whom had a Child-Pugh score ≥10 and MELD score ≥14 at entry) developed renal failure. Because both VIREAD and decompensated liver disease may have an impact on renal function, the contribution of VIREAD to renal impairment in this population is difficult to ascertain. One of 45 subjects experienced an ontreatment hepatic flare during the 48 week trial. Clinical Trials in Pediatric Subjects 12 Years of Age and Older with Chronic Hepatitis B: Assessment of adverse reactions is based on one randomized study (0115) in 106 pediatric subjects (12 to less than 18 years of age) infected with chronic hepatitis B receiving treatment with VIREAD (N = 52) or placebo (N = 54) for 72 weeks. The adverse reactions observed in pediatric subjects who received treatment with VIREAD were consistent with those observed in clinical trials of VIREAD in adults. In this study, both the VIREAD and placebo treatment arms experienced an overall increase in mean lumbar spine BMD over 72 weeks, as expected for an adolescent population. The BMD gains from baseline to Week 72 in lumbar spine and total body BMD in VIREAD-treated subjects (+5% and +3%, respectively) were less than the BMD gains observed in placebo-treated subjects (+8% and +5%, respectively). Three subjects in the VIREAD group and two subjects in the placebo group had significant (greater than 4%) lumbar spine BMD loss at Week 72. At baseline, mean BMD Z-scores in subjects randomized to VIREAD were −0.43 for lumbar spine and −0.20 for total body, and mean BMD Z-scores in subjects randomized to placebo were −0.28 for lumbar spine and −0.26 for total body. In subjects receiving VIREAD for 72 weeks, the mean change in BMD Z-score was −0.05 for lumbar spine and −0.15 for total body compared to +0.07 and +0.06, respectively, in subjects receiving placebo. As observed in pediatric studies of HIV-infected patients, skeletal growth (height) appeared to be unaffected (See Warnings and Precautions). Postmarketing Experience: The following adverse reactions have been identified during postapproval use of VIREAD. Because postmarketing 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: allergic reaction, including angioedema, lactic acidosis, hypokalemia, hypophosphatemia, dyspnea, pancreatitis, increased amylase, abdominal pain, hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT), rash, rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy, acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria, asthenia. The following adverse reactions listed above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia. DRUG INTERACTIONS: Didanosine: Coadministration of VIREAD and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions. When administered with VIREAD, Cmaxx and AUC of didanosine increased significantly. The mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy. Suppression of CD4+ cell counts has been observed in patients receiving VIREAD with didanosine 400 mg daily. In patients weighing >60 kg, the didanosine dose should be reduced to 250 mg once daily when it is coadministered with VIREAD. In patients weighing <60 kg, the didanosine dose should be reduced to 200 mg once daily when it is coadministered with VIREAD. When coadministered, VIREAD and didanosine EC may be taken under fasted conditions or with a light meal (<400 kcal, 20% fat). For additional information on coadministration of VIREAD and didanosine, please refer to the full Prescribing Information for didanosine.

HIV-1 Protease Inhibitors: VIREAD decreases the AUC and Cmin of atazanavir. Viread should not be coadministered with atazanavir without ritonavir. Lopinavir/ritonavir, atazanavir coadministered with ritonavir, and darunavir coadministered with ritonavir have been shown to increase tenofovir concentrations. Tenofovir disoproxil fumarate is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) transporters. When tenofovir disoproxil fumarate is co-administered with an inhibitor of these transporters, an increase in absorption may be observed. Patients receiving VIREAD concomitantly with lopinavir/ritonavir, ritonavir-boosted atazanavir, or ritonavir-boosted darunavir should be monitored for VIREAD-associated adverse reactions. VIREAD should be discontinued in patients who develop VIREAD-associated adverse reactions. Drugs Affecting Renal Function: Since tenofovir is primarily eliminated by the kidneys, coadministration of VIREAD with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of tenofovir and/or increase the concentrations of other renally eliminated drugs. Some examples include, but are not limited to cidofovir, acyclovir, valacyclovir, ganciclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs (See Warnings and Precautions). In the treatment of chronic hepatitis B, VIREAD should not be administered in combination with adefovir dipivoxil. USE IN SPECIFIC POPULATIONS: Pregnancy: Pregnancy Category B:: There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, VIREAD should be used during pregnancy only if clearly needed. Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to VIREAD, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263. Animal Data: Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir. Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Samples of breast milk obtained from five HIV-1 infected mothers in the first post-partum week show that tenofovir is secreted in human milk. The impact of this exposure in breastfed infants is unknown. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving VIREAD. Geriatric Use: Clinical studies of VIREAD did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for the elderly patient should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Patients with Impaired Renal Function: It is recommended that the dosing interval for VIREAD be modified in patients with estimated creatinine clearance <50 mL/min or in patients with ESRD who require dialysis (See Dosage and Administration). For detailed information, please see full Prescribing Information. To learn more call 1-800-GILEAD-5 (1-800-445-3235) or visit www.VIREAD.com. COMPLERA, EMTRIVA, GSI, HEPSERA, STRIBILD, TRUVADA, and VIREAD are trademarks or registered trademarks of Gilead Sciences, Inc., or its related companies. ATRIPLA is a registered trademark of Bristol-Myers Squibb & Gilead Sciences, LLC. All other trademarks referenced herein are the property of their respective owners.

©2013 Gilead Sciences, Inc. All rights reserved. VIRP0103 12/13

34

ASCO GI

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

‘Our current diagnostic procedure is inconvenient, requires sedation,

Pancreatic Cancer continued from page 1

2014 American Society for Clinical Oncology Gastrointestinal Cancers Symposium. “We were able to discriminate between pancreatic ductal adenocarcinoma and non-adenocarcinoma diseases using CTC presence as a marker,” said Jacob S. Ankeny, MD, a surgical oncology fellow who conducted the research. “If we find a CTC in a patient, using our definition and our system, it’s virtually diagnostic of pancreatic cancer, though we caution that this is a small study population.” The process involves detection of CTCs in 2 mL of blood using NanoVelcro technology with anti-EpCAM antibody enrichment. As blood moves through a serpentine microfluidic channel, tumor cells (and white cells) are captured on the surface of a silicone nanowire due to topographic interactions between the cell membrane and the nano surface, similar to the adhesive interactions of Velcro; antibodies on the surface preferentially interact with epithelial cells, and tumor cells ultimately are confirmed through cytokeratin staining. “Currently, we diagnose pancreatic cancer with endoscopic ultrasound and fine-needle aspiration (FNA), which is successful approximately 90% of the time. However, in order to achieve that success rate, we often need to do repeat biopsies and almost always need to repeat needle passes to obtain adequate tissue for diagnosis,” Dr. Ankeny said. “As a result, our current diagnostic procedure is inconvenient, requires sedation, is relatively expensive and is not without risk. So, we are evaluating the use of CTCs up front, to obtain the diagnosis in a manner that avoids FNA in some patients.” Using this system, Dr. Ankeny and his colleagues evaluated 61 consecutive patients with suspected pancreatic cancer or who were diagnosed recently with pancreatic cancer but not treated. With tissue biopsy, 41 patients were found to have cancer and 20 patients had nonmalignant pathology. “We had only one false positive, for a specificity of 95%, and a positive predictive value of almost 97%. This was for one CTC in the presence of a suspicious pancreatic lesion on CT [computed tomography].” Once pancreatic cancer is confirmed, the system also can aid in staging the disease. In this study, seven patients with presumed stage II disease diagnosed by CT were found, instead, to have metastatic disease at surgery, and five of these patients were found to have at least two CTCs. The CTC test, therefore, would have more accurately staged these patients, the investigators concluded. CTC enumeration was able to discriminate between stages II, III and IV disease (P=0.013) P and between local/regional disease and metastatic disease (P<0.001). Using a cutoff of two or more CTCs per 2 mL of blood, the sensitivity of the test was 68.8%, the specificity was 96%, and the positive predictive value was 92.3% for the presence of metastases. CTCs had more discriminating power than CA 19-9 levels. “If we find just two CTCs in a patient with cancer, it is virtually diagnostic of metastatic disease. This was consistent and statistically robust. Even one additional CTC was very specific for having metastatic disease,” he said.

Validation of CTCs as a Biomarker Senior investigator James S. Tomlinson, MD, PhD, a surgical oncologist at UCLA, noted that the researchers

is relatively expensive and is not without risk. So, we are evaluating the use of CTCs up front, to obtain the diagnosis in a manner that avoids FNA in some patients.’ —Jacob S. Ankeny, MD

wanted to confirm that the CTCs actually originated from the tumor, and thus were a valid biomarker of malignancy. To do so, they showed that KRAS mutations, which are present in almost 100% of pancreatic tumors, were present in the CTCs and matched the tumor tissue from the primary tumor, but not the white cells. “We can therefore be confident in calling a CTC a tumor cell,” he said. Dr. Tomlinson emphasized that CTCs could not only be a useful adjunct in the workup of patients suspected of having pancreatic cancer, but could help to optimize cancer treatment. “We are looking for a biomarker that will be used at the time of disease presentation and will inform our first-line therapy, so that we treat more appropriately, based on more accurate staging,” he said. Rebecca Miksad, MD, MPH, of Harvard Medical School and Beth Israel Deaconess Medical Center, both in Boston, was the discussant of the study at the meeting. Dr. Miksad noted that CTCs are rare and difficult to detect, and they have been relatively understudied in pancreatic cancer. In the largest study to date, using nested polymerase chain reaction, CTCs were identified in about one-third of pancreatic cancer patients and were associated with lower survival rates. In another study using immunohistochemistry, CTCs were found more frequently in patients with metastatic disease than in patients with resectable cancer. “The reasons for the challenges in identifying CTCs in pancreatic cancer are multiple, and involve both biological and technical issues,” Dr. Miksad said. The current study is by far the largest and it demonstrated a high specificity, she said, but the difference between cancer and no cancer was just one CTC found in the sample. Similarly, the difference between metastatic and locoregional disease was one CTC. “Because CTCs are only detected in whole numbers, the close cutoffs raise questions about accuracy, reliability and reproducibility. In other words, will the same result be found in repeated analyses of the same sample and in different samples from the same patient?” she asked.

“CTCs in pancreatic cancer are intriguing, but their role remains unclear,” Dr. Miksad concluded. ■ Drs. Ankeny and Tomlinson reported no conflicts of interest. Dr. Miksad has served as a consultant or in an advisory role for OptumInsight, and has received research funding from Bayer/Onyx, NewLink Genetics and Sanofi Pasteur.

PPIs continued from page 22

Duration of PPI use also appeared to be important. In the three studies where PPI exposure was less than three years, the adjusted OR was 1.09, compared with 0.45 for the three studies whose patients took PPIs for a longer duration. “The present study provides relatively good evidence that PPI use prevents progression to EAC in BE patients,” Dr. Singh concluded. “A total of 2,813 patients with BE in seven studies were evaluated, and we believe, based on these results, that in patients with BE with multiple risk factors for progression to EAC (e.g., long-segment BE, central adiposity, smoking, advanced age), PPI therapy should be considered for its primary chemopreventive potential.” Thomas L. Vaughan, MD, MPH, professor of epidemiology at the University of Washington and program head of epidemiology at Fred Hutchinson Cancer Research Center, in Seattle, was less convinced. He indicated that the potential effect of PPI use on BE and cancer is complex. “It’s hard to comment about such a difficult area of study,” he told Gastroenterology & Endoscopy News, “with treatment indications, and frequency and duration of treatment with PPIs tightly linked with underlying risk factors and clinical predictors of progression to EAC.” ■

As d te Ci in e Th y og ol nc O et nc La

™

™

See what you could be missing. Experience Fuse at DDW 2014 - EndoChoice Booth #2333 and Hands-On at the ASGE Learning Center Colonoscopy and gastroscopy are widely accepted as the gold standards for screening, surveillance, and diagnosis of GI diseases. However, endoscopy technology has not changed significantly in decades and misses still occur1, 2. In a multi-center tandem study recently published in The Lancet Oncology, the Fuse™ endoscope system demonstrated the miss rate on adenomas with Standard, Forward Viewing (SFV) colonoscopes was 41%. Conversely, when the patient received a colonoscopy with Fuse first, followed by SFV, the researchers had an adenoma miss rate of

Standard Colonoscope

only 7%3. Overall, Fuse enabled this international team of endoscopists to find 76% more

Limited 170° Field of View

polyps after SFV had been used. How was this achieved? Traditional endoscopes provide endoscopists only a limited forward view ((up p to 170 degrees) g ) causing g them to p potentially y miss adenomas that hide behind folds. Leveraging a proprietary design of three lenses and three monitorrs, Fuse Full Spectrum Endoscopy provides a panoramic field of view (330° Colonos scope / 2 245° Gastroscope) thus

Fuse™ Colonoscope

enabling endoscopists to see forward and on each side of the colon noscope.

Panoramic 330° Field of View Adenoma Miss Rate Standard, Forward Viewing (SFV) Colonoscope

41%

Miss Rate

7%

Miss Rate

76 %

Incremental polyp find rate with Fuse™

To schedule a Fuse experience, call your EndoC Choice e sales representative, or the EndoChoice Headquarters, at 888.682.3636 x.5 5, or em mail fuse@endochoice.com. EndoChoice.com/Fuse (1) Rex et al. Gastroenterology, 1997; (2) Siersema et al. World Journal of Gastroenterology, 2012; (3) Gralnek et al. The Lancet Oncology, 2014

36

GASTROENTEROLOGY & ENDOS OS SC COP CO OPY OP O PY Y NE N EW NEW E W S • APR AP PRII L 20 PR 2 0 14 14

FDA Regulations on Pancreatic Enzyme Products Que estioned ‘Our primary outcome was the cost of prescriptions one year before and one year after the FDA NDA requirement was put into place. We found … the total

BY MONICA J. SMITH SAN DIEGO—Patient advocacy groups may have been operating with the best of intentions in 2004 when they pressured the FDA to mandate pancreatic enzyme therapies to submit new drug approval (NDA) applications and undergo approval. At this point, however, those actions seem to have resulted only in a reduction of available products and a spike in nongeneric prescription costs, while the publication of postmarketing safety data supporting the products’ safety and efficacy has yet to occur. Pancreatic enzyme products are essential for individuals with exocrine pancreatic insufficiency, a condition most commonly found in patients with cystic fibrosis or chronic pancreatitis. This is a lifelong treatment, and typically comprises three to four daily doses. Without pancreatic enzyme replacement products, malnutrition and osteoporosis are common. “Up until about seven years ago, there were around 30 different prescription-based formulations for pancreatic enzyme therapy,” said Timothy B. Gardner, MD, director, pancreatic disorders, Dartmouth–Hitchcock Medical Center, Lebanon, N.H., who presented research on these products at the 2013 American College of Gastroenterology Annual Scientific Meeting. “This is because prior to the FDA coming into existence in 1938, these enzyme products were already in place; they were grandfathered in, and didn’t have to undergo FDA approval,” he said. “Anecdotally, because children who have cystic fibrosis often have very robust insurance programs, their prescriptions are covered. In my experience, this is not necessarily the case in patients with chronic pancreatitis,” he said. To determine the effect of the FDA NDA requirement on the cost of and access to pancreatic enzyme products, Dr. Gardner and his colleague Stuart L. Gordon consulted the IMS Health Product Report Database, which tracks total prescriptions and total sales of individual drugs. “We obtained the cost per prescription by dividing the total [number of ] prescriptions by the total amount of sales during the period from 2008 to 2012,” Dr. Gardner explained, noting that the four-year span captured time periods before and after the NDA requirement went into effect in 2009-2010. “Our primary outcome was the cost of prescriptions one year before and one year after the FDA NDA requirement was put into place. We found … the total sales for nongeneric pancreatic enzyme replacement products were $281 million before this was put in place. In 2012, [the year] for which the most recent data is available, it was up to $632 million,” Dr. Gardner said. The total number of prescriptions, however, did not change—only the amount spent in sales. Concerning the number of products available, in 2008, before the NDA requirement, approximately 16 enzymatic therapies were being tracked by the IMS database. “We now have six products approved,” Dr. Gardner said. “If we look at the cost per prescription before and after the NDA requirement, the cost for each individual prescription in 2008 was $247. By 2012, the cost had increased to $577.”

sales for nongeneric pancreatic enzyme replacement products were $281 million before this was put in place. In 2012, [the year] for which the most recent data is available, it was up to $632 million.’ —Timothy B. Gardner, MD

‘If we look at the cost per prescription before and after the NDA requirement, the cost for each individual prescription in 2008 was $247. By 2012, that cost had increased to $577.’ —Timothy B. Gardner, MD

Essentially, there is an inverse relationship between the number of products available and the total cost per prescription. Dr. Gardner acknowledged the study’s limitations: It is based on administrative data, which does not keep track of all the pancreatic enzyme products available, such as generic products. Also, because the NDA requirement went into effect in 2010, there are only two years of data available at this time. “But we have concluded that the NDA requirement for these products resulted in universal prescription price increases and in more nongeneric prescriptions for these products. Also, at this point, three years after this requirement, there has been no postmarketing safety data published, which was the original goal of this requirement,” Dr. Gardner said. Christopher E. Forsmark, MD, professor of medicine and chief of the Division of Gastroenterology, Hepatology and Nutrition, University of Florida College of Medicine,

Gainesville, noted that previous analyses of pancreatic enzyme products revealed that the content was often incorrect, but tended to be more than the packaging suggested. The new enzymes have the same level of porcine enzyme content, but undergo a better manufacturing process. “The issue is that most patients with chronic pancreatitis are not treated with enzymes, and those that are often receive an inadequate dosage. The inadequate dose is partly the fault of physicians lacking knowledge about dosing, but many patients just can’t afford the products,” Dr. Forsmark said. “Patients who receive inadequate dosages are at particular risk for fat-soluble vitamin deficiencies and osteoporosis, which occurs in up to 60% of patients, so this issue is very important and has very substantial clinical indications,” Dr. Forsmark concluded. ■ Drs. Garner and Forsmark reported no relevant conflicts of interest.

EXPERT ROUNDTABLE

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37

COMPILED AND WRITTEN BY COLLEEN HUTCHINSON

Yuman Fong, MD

Daniel Jones, MD, MS

Omar Yusef Kudsi, MD, MBA

Murray F. Brennan Chair in Surgery Memorial Sloan-Kettering Cancer Center New York, New York

Chief of Minimally Invasive & Bariatric Surgery Beth Israel Deaconess Medical Centerr Professor of Surgery Harvard Medical School Boston, Massachusetts

Martin Makary, MD, MPH

Frank Rosato, MD

Noel N. Williams, MD

Health Policy Johns Hopkins University Director of Minimally Invasive HPB Surgery Johns Hopkins Hospital Baltimore, Maryland

Director of Gastrointestinal Ga Surgery Capitall Health He Hospital Penn ennington, New Jersey

Professor of Surgery, Perelman School of Medicine University of Pennsylvania Director, Penn Metabolic and Bariatric Surgery Program Philadelphia, Pennsylvania

Assistant Professor of Surgery Tufts University School of Medicine Boston, Massachusetts

n his blog, Toby Cosgrove, CEO of Cleveland Clinic Foundation, recently referenced two studies

I

don ne within his institution comparing robotic surgery with traditional methods for mitral valve repair and d prostatectomy. The first study found that technical complexity and longer surgical time were

balanced by the benefits of shorter hosptial stays and smaller incisions; the second study showed that robotic surgery was no better or worse than traditional surgery. I’ve tested the waters to see how surgeonss feel about this new surgical approach. The time has come to hear from surgeons beyond sound bytess and to tackle the issues in a dedicated column column. While both sides are effectively represented here, and with more objectivity and balance in each individual perspective than one might expect, I was surprised to see agreement on a few major aspects of robotics—most interestingly, the opinion that robotics doesn’t necessarily mean greater risk for inadvertent injury than open or laparoscopic surgery. Robotics will continue to be a subject for which spirited debate and technological advancement progress in parallel. General consensus also was reached on one more important point—the robot is not only here to stay, but will continue to advance, and surgeons would be wise to advance with it. Otherwise, as Dan Jones, MD, said, the robotic surgeon may soon be eating your lunch!

The mechanisms and three-dimensional (3D) vision of the robot allow for maneuvering in tight spaces and enhanced viewing of smaller areas compared with the laparoscopic approach, and it provides the surgeon the benefits of the ability to manipulate tissue and provide for improved performance of surgery, as well as reducing surgeon fatigue. Additionally, it has been proven to provide clinical patient benefits of less

pain, less recovery time (and shorter hospital stay and less postoperative pain medication), generally less blood loss and improved cosmesis. Dr. Jones: Disagree. Despite 3D and maneuverability, there is no proven benefit for most operations. The bigger SILS [single-incision laparoscopic surgery] port may actually cause more pain and more hernias and be more disfiguring than needle laparoscopy. Dr. Williams: Agree. In transoral robotic surgery [TORS], radical prostatectomy and most gynecologic procedures, the robot is far superior to traditional open and laparoscopic approaches.

Dr. Makary: 3D vision and added degrees of freedom may benefit patients undergoing select operations in which tight spaces cannot otherwise be reached by standard laparoscopy (e.g., posterior pharynx surgery). Future versions of the robot will expand these select indications. The benefit to a surgeon’s spine is noteworthy in some operations (e.g., prostatectomy) where bending over to perform standard laparoscopy is known to cause occupational injury. The framing of the question of whether robotic surgery is proven to yield less pain, recovery time and blood loss is precisely the problem with the robotic surgery controversy—the question of superiority lacks a comparison group (is it open or standard laparoscopic surgery?), does not specify for which operation type, and ignores the publication bias of underreporting of the rare but catastrophic complications associated with the lack of haptic feedback. Sound byte claims of robotic superiority are largely unfounded, unfairly crediting the robot with minimally invasive surgery [MIS] benefits over open surgery. Dr. Fong: Agree. There is no doubt that the 3D vision and the articulated instruments offer technical advantages and allow more complicated operations to be performed in an MIS environment. Proving that this translates to better patient outcomes has been more difficult because of a lack of studies and poor outcome parameters. Dr. Rosato: Disagree. Today’s laparoscopic articulating instruments and scopes provide the ability to navigate in tight spaces with enhanced visualization see Robotics Roundtable, page 41

THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Switching From 5-ASA to Mesalamine Granules in Patients With Ulcerative Colitis in Remission Gary R. Lichtenstein, MD Professor of Medicine Director, Center for Inflammatory Bowel Disease Department of Medicine Division of Gastroenterology Raymond and Ruth Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania

Indication for APRISO APRISO® (mesalamine) is a locally acting aminosalicylate indicated for the maintenance of remission of ulcerative colitis in patients 18 years and older. The use of APRISO for treating ulcerative colitis beyond 6 months has not been evaluated in controlled clinical trials.

Important Safety Information About APRISO APRISO extended-release capsules are contraindicated in patients with hypersensitivity to salicylates or aminosalicylates (sulfasalazine) or to any of the components of APRISO capsules. It is recommended that patients have an evaluation of renal function prior to initiation of APRISO therapy and periodically while on therapy. Exercise caution when using APRISO in patients with known renal dysfunction or a history of renal disease. Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from a flare of inflammatory bowel disease. Symptoms include cramping, acute abdominal pain and bloody diarrhea, sometimes fever, headache, and rash. If acute intolerance syndrome is suspected, promptly discontinue treatment with APRISO. There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine. Caution should be exercised when administering APRISO to patients with liver disease. Because dissolution of the coating of APRISO granules depends on pH, APRISO should not be coadministered with antacids. Caution should be taken to closely monitor blood cell counts during mesalamine therapy in patients ages 65 and older. Patients with phenylketonuria should be aware that APRISO contains aspartame, equivalent to 2.24 mg of phenylalanine per day.

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The most common treatment-related adverse events occurring in at least 3% of adult patients taking APRISO and at a rate greater than placebo in clinical trials were headache (11%), diarrhea (8%), upper abdominal pain (5%), nausea (4%), nasopharyngitis (4%), influenza and influenzalike illness (4%), and sinusitis (3%).

Introduction Primary goals in the treatment of ulcerative colitis (UC) include maintenance of remission.1 Reduction in the need for corticosteroids also is important to avoid the long-term adverse effects otherwise associated with such therapy.1 Although mesalamine (5-aminosalicylic acid, 5-ASA) is an effective nonsteroid for maintenance of remission in patients with UC, one popular mesalamine formulation (ASACOL 400 mg) was recently discontinued thus requiring physicians to choose another mesalamine formulation for their patients who were formerly receiving this medication.1,2 This clinical scenario requires a review of the available data to help guide the transition of patients in remission from one formulation to another, including an investigation of whether flare-ups may occur while transitioning to the new regimen. This article will discuss available data regarding the efficacy and safety of a switch from one mesalamine formulation to another mesalamine formulation with once-daily dosing (mesalamine extendedrelease [ER] granules [APRISO]) for maintenance of remission.

Mesalamine Extended-Release Granules Mesalamine ER granules (APRISO, Salix Pharmaceuticals) are a once-daily 5-ASA preparation approved by the FDA in October 2008 for maintenance of remission of UC in patients aged 18 years and older.3 Mesalamine ER capsules possess Intellicor® technology that allows both delayed-release and ER delivery of mesalamine to areas of the gastrointestinal tract affected in patients with UC.3,4 Once ingested, the gelatin capsules dissolve, releasing thousands of granules that provide a large surface area from which mesalamine is released. Each granule has a delayed-release, gastric acid–resistant coating that allows it to travel intact until a pH of 6.0 is reached. Intestinal fluids dissolve the coating to initiate ER delivery. Each granule’s polymer matrix core then swells as intestinal fluid is

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

absorbed, forming channels through which mesalamine is delivered in an extended release, providing once-daily protection throughout the colon.3 Clinical investigation also revealed that 32%±11% (mean ± SD) of the administered dose was systemically absorbed under fasting conditions and that a high-fat meal did not affect peak concentration for 5-ASA, indicating that APRISO can be taken without regard to food.3

Clinical Studies of Mesalamine Granules Double-blind, placebo-controlled trials have described the efficacy of mesalamine granules for the maintenance of remission of UC.5 In the 2010 study, patients with UC were randomized to receive either mesalamine granules (1.5 g once daily; n=209) or placebo (n=96) for up to 6 months. The percentage of relapse-free patients at the end of the treatment period was significantly higher for the group receiving mesalamine granules than for those receiving placebo (78.9% vs 58.3%; P<0.001). Furthermore, patients receiving mesalamine granules had positive outcomes in terms of secondary end points, including improvement in rectal bleeding, stool frequency, physician’s disease activity rating, and the Sutherland Disease Activity Index.

Probability of remaining relapse-free

Faculty

Headaches (11%), diarrhea (9%), abdominal pain (7%), nasopharyngitis (5%), upper abdominal pain (4%), abnormal feces (3%), back pain (3%), and nausea (3%) were the most frequently reported adverse events in patients receiving mesalamine granules.5 A subanalysis of patients with UC from the 2010 study as well as patients from another randomized, double-blind, placebo-controlled 6-month study of identical design (N=487) was performed.6 The specific patients examined were those who had switched to mesalamine granules (1.5 g once daily) or to placebo from other 5-ASA formulations. The results were remarkably similar to those seen in the larger group of patients in the 2010 study; the relapse-free rate after 6 months was significantly higher for those who had switched from other 5-ASA formulations to mesalamine granules compared with those who switched from other 5-ASA formulations to placebo (78.3% vs 58.8%; P<0.001) (Figure).6 Furthermore, rectal bleeding, stool frequency, and the physician’s rating of disease activity remained unchanged after 6 months in a higher percentage of patients who switched to mesalamine granules compared with those who had switched to placebo (P<0.004 for each end point). Of note, withdrawal due to UC flare-ups in the group receiving mesalamine

1.0 MG 1.5 g qd (N=322)

0.80 0.60

Placebo (N=165)

0.40 0.20

MG vs placebo 55% reduction in risk of relapse (P<0.001)

0 0

50

N at risk, MG: N at risk, placebo:

100 150 200 Relapse-free duration, d Month 1 322 165

Month 3 299 135

250

Month 6 267 114

Figure. Kaplan–Meier estimates of time to relapse during the treatment period in patients who switched from other 5-ASA formulations to either APRISO 1.5 g daily or placebo. Based on Lichtenstein G, et al. Aliment Pharmacol Ther. 2012;36(2):126-134, with permission. 5-ASA, 5-aminosalicylic acid; MG, mesalmine granules; qd, daily

300

Supported by

APRISO 1.5 g/d, %

Placebo, %

Headache

11

8

Diarrhea

8

7

Upper abdominal pain

5

3

Nausea

4

3

Nasopharyngitis

4

3

Influenza and influenza-like illness

4

—

Sinusitis

3

3

Based on reference 3.

granules was almost 2-fold lower than the placebo group (10.9% vs 19.8%, respectively), largely due to a lower incidence of UC flare-ups in the mesalamine granule-treated group. The most frequently reported adverse events for patients receiving mesalmine granules were headaches (11.3%), diarrhea (7.8%), upper abdominal pain (5.3%), abdominal pain (5%), nausea (3.8%), and nasopharyngitis (3.1%).6 These studies also investigated safety parameters of the mesalamine granule formulation. In the 2 placebo-controlled trials, 59% of mesalamine granule–treated patients experienced an adverse reaction compared with 64% of placebo patients.3 However, most adverse reactions with mesalamine granules were mild or moderate in severity, and the incidence of severe adverse reactions was not significantly different when comparing mesalamine granule–treated patients with placebo-treated patients (6% vs 5%). Furthermore, the proportion of patients discontinuing treatment due to adverse reactions was lower in the mesalamine granule-treated patients than in the placebo-treated group (11% vs 17%). This finding is likely a consequence of the fact that the most common adverse reaction resulting in study discontinuation was recurrence of UC (mesalamine granules vs placebo: 6% vs 14%). The most common adverse reactions reported with mesalamine granules were

headache (11%), diarrhea (8%), upper abdominal pain (5%), nausea (4%), nasopharyngitis (4%), influenza or influenzalike illness (4%), and sinusitis (3%) (Table).3 Each mesalamine formulation is uniquely designed and varies in delivery, dosage, and schedule, thereby preventing simple doseto-dose comparisons across formulations.6 Regardless, the data from the pooled analysis suggest that patients may be switched successfully to mesalamine granules at 1.5 g once daily without regard to prior 5-ASA formulations or the doses used previously for the maintenance of UC remission. More patients remained relapse-free after switching to mesalamine granules at 1.5 g once daily (when compared with placebo), despite their prior 5-ASA formulations, dosages, or dosing schedule.

Conclusion Mesalamine is an effective nonsteroid firstline therapy for maintenance of remission in patients with UC. With the recent discontinuation of one common mesalamine formulation, physicians were challenged to identify a replacement therapy for their patients for the maintenance of UC remission. Extended-release mesalamine capsule (APRISO), which contains mesalamine granules, is a once-daily preparation approved by the FDA for the maintenance of remission of UC in patients aged 18 years and older. Data from a randomized double-blind, placebo-controlled trial suggests that patients

Contraindications APRISO® (mesalamine) extended-release capsules are contraindicated in patients with hypersensitivity to salicylates or aminosalicylates (sulfasalazine), or to any of the components of APRISO capsules.

References 1. Kornbluth A, Sachar DB; Practice Parameters Committee of the American College of Gastroenterology. Ulcerative colitis practice guidelines in adults: American College Of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2010;105(3):501-523. 2. American Society of Health-System Pharmacists. Mesalamine 400 mg Delayed-Release Tablet (Asacol). http://www.ashp.org/DrugShortages/ NotAvailable/Bulletin.aspx?id=1017. Accessed March 11, 2014. 3. APRISO [prescribing information]. Raleigh, NC: Salix Pharmaceuticals, Inc.; 2012. http://www. salix.com/assets/pdf/prescribe_info/apriso-pi. pdf. Accessed March 11, 2014. 4. Lawlor G, Ahmed A, Moss AC. Once-daily mesalamine granules for ulcerative colitis. Expert Rev Clin Immunol. 2010;6(4):521-526. 5. Lichtenstein GR, Gordon GL, Zakko S, et al. Clinical trial: once-daily mesalamine granules for maintenance of remission of ulcerative colitis—a 6-month placebo-controlled trial. Aliment Pharmacol Ther. 2010;32(8):990-999. 6. Lichtenstein GR, Zakko S, Gordon GL, et al. Mesalazine granules 1.5 g once-daily maintain remission in patients with ulcerative colitis who switch from other 5-ASA formulations: a pooled analysis from two randomised controlled trials. Aliment Pharmacol Ther. 2012;36(2):126-134.

Disclosures: Dr. Lichtenstein reported that he has served as a consultant for Abbott Corporation/ Abbie, Alaven, Elan Pharmaceuticals, Inc., Ferring Pharmaceuticals, Hospira, Janssen Ortho Biotech, Millennium Pharmaceuticals, Ono Pharmaceuticals, Pfizer Inc., Prometheus Laboratories Inc., Salix Pharmaceuticals, Inc., Santarus, Inc., Shire Pharmaceuticals, Takeda Pharmaceuticals, UCB Pharma, Inc., and Warner Chilcott. He has received grant support for clinical research from Bristol-Myers Squibb, Ferring Pharmaceuticals, Janssen Ortho Biotech, Prometheus Laboratories Inc., Salix Pharmaceuticals, Inc., UCB Pharma, Inc., and Warner Chilcott.

APR45-0314

Adverse Reaction

may be switched successfully to mesalamine granules at 1.5 g once daily without regard to prior 5-ASA formulations or the doses used previously for the maintenance of UC remission without any increase in the risk for relapse.

BB1122

Table. Treatment-Emergent Adverse Reactions During Clinical Trials Occurring in at Least 3% of APRISO-Treated Patients and at a Greater Rate Than With Placebo

Please See Accompanying Brief Summary.

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

39

BRIEF SUMMARY Please consult package insert for full prescribing information. INDICATIONS AND USAGE APRISO is a locally acting aminosalicylate indicated for the maintenance of remission of ulcerative colitis in patients 18 years and older. DOSAGE AND ADMINISTRATION The recommended dose for maintenance of remission of ulcerative colitis in adult patients is 1.5 g (four APRISO capsules) orally once daily in the morning. APRISO may be taken without regard to meals. APRISO should not be co-administered with antacids. An evaluation of renal function is recommended before initiating therapy with APRISO. CONTRAINDICATIONS APRISO is contraindicated in patients with hypersensitivity to salicylates or aminosalicylates or to any of the components of APRISO capsules. WARNINGS AND PRECAUTIONS Renal Impairment Renal impairment, including minimal change nephropathy, acute and chronic interstitial nephritis, and, rarely, renal failure, has been reported in patients given products such as APRISO that contain mesalamine or are converted to mesalamine. It is recommended that patients have an evaluation of renal function prior to initiation of APRISO therapy and periodically while on therapy. Exercise caution when using APRISO in patients with known renal dysfunction or a history of renal disease. In animal studies, the kidney was the principal organ for toxicity. Mesalamine-Induced Acute Intolerance Syndrome Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from a flare of inflammatory bowel disease. Although the exact frequency of occurrence has not been determined, it has occurred in 3% of patients in controlled clinical trials of mesalamine or sulfasalazine. Symptoms include cramping, acute abdominal pain and bloody diarrhea, sometimes fever, headache, and rash. If acute intolerance syndrome is suspected, promptly discontinue treatment with APRISO. Hypersensitivity Some patients who have experienced a hypersensitivity reaction to sulfasalazine may have a similar reaction to APRISO capsules or to other compounds that contain or are converted to mesalamine. Hepatic Impairment There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine. Caution should be exercised when administering APRISO to patients with liver disease. ADVERSE REACTIONS APRISO was studied in two placebo-controlled trials (n=367 treated with APRISO) and in one open-label, long-term study (n=190 additional patients). The population consisted of patients with ulcerative colitis; the mean age was 47 years, 54% were female, and 93% were white. Patients received doses of APRISO administered orally once per day for six months in the placebo-controlled trials and for up to 24 months in the open-label study. In the two placebo-controlled trials, 59% of APRISO-treated patients experienced an adverse reaction compared with 64% of placebo patients. Most adverse reactions with APRISO were mild or moderate in severity. Severe adverse reactions occurred in 6% of APRISO-treated patients and 5% of placebo-treated patients. Discontinuations due to adverse reactions occurred in 11% of APRISO-treated patients and 17% of placebo-treated patients; the most common adverse reaction resulting in study discontinuation was recurrence of ulcerative colitis (APRISO 6%, placebo 14%). The most common treatment-related adverse events occurring in at least 3% of adult patients taking 1.5 g/day of APRISO and at a rate greater than placebo were headache (11% vs 8% for placebo), diarrhea (8% vs 7% for placebo), upper abdominal pain (5% vs 3% for placebo), nausea (4% vs 3% for placebo), nasopharyngitis (4% vs 3% for placebo), influenza and influenza-like illness (4% vs 4% for placebo), and sinusitis (3% vs 3% for placebo).

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B. Reproduction studies with mesalamine have been performed in rats at oral doses up to 320 mg/kg/day (about 1.7 times the recommended human dose based on a body surface area comparison) and rabbits at doses up to 495 mg/ kg/day (about 5.4 times the recommended human dose based on a body surface area comparison) and have revealed no evidence of impaired fertility or harm to the fetus due to mesalamine. 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. Mesalamine is known to cross the placental barrier. Nursing Mothers Low concentrations of mesalamine and higher concentrations of its N-acetyl metabolite have been detected in human breast milk. The clinical significance of this has not been determined and there is limited experience of nursing women using mesalamine. Caution should be exercised when APRISO is administered to a nursing woman. Pediatric Use Safety and effectiveness of APRISO capsules in pediatric patients have not been established. Geriatric Use Clinical studies of APRISO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing APRISO. Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher incidence of blood dyscrasias, i.e., neutropenia, pancytopenia, in patients who were 65 years or older who were taking mesalamine-containing products such as APRISO. Caution should be taken to closely monitor blood cell counts during mesalamine therapy. Mesalamine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken when prescribing this drug therapy. (see WARNING AND PRECAUTIONS) Phenylketonuria Patients with phenylketonuria should be aware that APRISO contains aspartame, equivalent to 0.56 mg of phenylalanine. CLINICAL STUDIES Two similar, randomized, double-blind, placebo-controlled, multi-center studies were conducted in a total of 562 adult patients in remission from ulcerative colitis. Ulcerative colitis disease activity was assessed using a modified Sutherland Disease Activity Index1 (DAI), which is a sum of four subscores based on stool frequency, rectal bleeding, mucosal appearance on endoscopy, and physician’s rating of disease activity. Patients were randomized 2:1 to receive either APRISO 1.5 g or placebo once daily in the morning for six months. In both studies, the proportion of patients who remained relapse-free at six months was greater for APRISO than for placebo. In study 1 (N=305), 68% of subjects taking APRISO were relapse-free at 6 months EOT vs 51% with placebo (P<0.001). In study 2 (N=257), 71% of subjects in the APRISO group were relapse-free at 6 months EOT vs 59% for placebo (P=0.046). HOW SUPPLIED APRISO is available as light blue opaque hard gelatin capsules containing 0.375 g mesalamine and with the letters “G” and “M” on either side of a black band imprinted on the capsule. NDC 65649-103-02 NDC 65649-103-01

Bottles of 120 capsules Bottles of 4 capsules

STORAGE AND HANDLING Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). See USP Controlled Room Temperature. Reference: 1. Sutherland LR, Martin F, Greer S, Robinson M, Greenberger N, Saibil F, et al. 5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis. Gastroenterology. 1987;92:1894-1898.

Salix Pharmaceuticals, Inc. Raleigh, NC 27615

GM 08/22-1

MANUFACTURED FOR:

EXPERT ROUNDTABLE

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Robotics Roundtable continued from page 37

‘Robotic surgery versus

similar to the robot. Furthermore, the robot’s lack of tactile feedback is a major concern. The initial studies quantifying the benefits of robotic surgery were based on claims made in comparison with open approaches. More recent studies comparing the robot with laparoscopic surgery show no difference related to pain, recovery time, blood loss or cosmesis. Patients need to understand that it is who does your surgery, and not how they do it that is important. Dr. Kudsi: Agree. I believe that the surgeon’s skill, training and incremental learning are determining factors to successful outcomes in the field of surgery, and in particular, robotic surgery. In regard to robotics, we, as surgeons, have the chance to shape the future, craft it and define it using our values as our moral compass. And, most importantly, when comparing robotics outcomes, experience is the No. 1 criterion a surgeon should consider prior to judging the results (3D vision, suturing, stability and control). There isn’t a single surgical tool that wasn’t dependent on practice and on a skilled surgeon to achieve the very best results. In the words of Dr. [Francis] Sutter, a robotic cardiac surgeon, “Surgical excellence revolves around one basic principle—improving upon the existing procedure, making surgery safer and easier for the patient and surgeon.” Robotic surgery versus laparoscopic surgery is an ongoing comparison, but those judging are missing the point that robotics is another tool that, in the right hands of dedicated surgeons and programs, could deliver phenomenal outcomes. Robotics is an instrument to achieve excellence.

laparoscopic surgery is an

The effectiveness of the robot is proven in many operations but it is clearly more expensive. As we are a society with ample resources, the extra cost of this technology should be paid by third-party payors so that it is available to all. Dr. Fong: Disagree. The way to make this technology available to all is not to just pass it off into the “thirdparty payor pool.” To make it available to all, we need to optimize robot use by using standard laparoscopy for those MIS procedures where robotics adds no advantage but does add cost. Because surgical robotic products are currently a monopoly, we should consider having it regulated as such. All essential services that are monopolies are usually regulated by the government for charges. Dr. Williams: On the fence. Clearly there are operations where the robot is far superior to standard laparoscopic approaches. In these instances, they should be reimbursed by the third-party payors. Dr. Jones: Disagree. No reason to jack up health care costs and insurance premiums. Technology must prove to be cost-effective. Dr. Makary: Any medical intervention that benefits our patients should be paid for, but is it really better for gallbladder surgery? As a society, how do we justify doing robotic cholecystectomy when there is an established, safe laparoscopic approach that costs thousands less per operation? We should remember that we currently have rationing of health care in America. Arizona has let, and continues to let, patients die on transplant waitlists simply because the state insurance program cannot afford the expensive procedure. We should consider our larger mission to the public.

ongoing comparison, but those judging are missing the point that robotics is another tool that, in the right hands of dedicated surgeons and programs, could deliver phenomenal outcomes.’ —Omar Yusef Kudsi, MD, MBA

Dr. Rosato: Disagree. Although the effectiveness of the robot has been shown in a myriad of surgical procedures, its superiority over more traditional and less costly approaches has never been proven. The goal of every physician should be to deliver effective and efficient health care. The robot adds expense to every case performed. Using it for surgeries in which there is no proven superiority is not cost-effective. We are not a society of unlimited resources, and although third-party payors are covering the added expense of robotic cases currently, it will be only a matter of time before that extra cost will be passed along to patients. Dr. Kudsi: Agree. Most famous institutions and schools in the United States have a fair amount of their resources paid by third parties (donations), and many surgical centers in Europe, Middle East and Asia were donated. I do believe that [robotics] shouldn’t be considered as the only approach, but the percentage for the next decade will definitely grow.

Institutions and surgical societies need to establish a standard resident and attending curriculum for learning robotic skills to proficiency—and to not do so is to allow for a continuation of the current environment of the self-made robot expert. Residents and fellows should be trained in the technology so that they can apply it rationally and help develop the next generation of robotic interfaces. Dr. Fong: Agree. This is where a society such as SAGES [Society of American Gastrointestinal and Endoscopic Surgeons] could be quite helpful, providing guidelines similar to those drafted for laparoscopy. We need sensible guidelines that provide for patient safety while allowing room for innovation. Having experts in the field preemptively define these will prevent onerous guidelines that may result from a reaction to an untoward event. Dr. Jones: Agree. Next-generation robots are the future. We will realize technological breakthroughs sooner if we get the robots into the hands of trainees and multiple vendors. Dr. Kudsi: Agree. The pace of innovation in surgery change has increased substantially over the past decade, and it will continue to accelerate in the near future. We as surgeons and surgical trainees are faced with the dilemma of whether to adopt robotics. We should consider four basic questions: What is the

learning curve in robotics? How much commitment is needed to achieve excellent results? Does robotics add value to the existing options? Is it financially viable? From the point of view of a robotic surgeon, and someone who has done hundreds of robotics in the field of general surgery, I could simply say that it is a phenomenal tool that permits the surgeon to deliver stateof-the-art results to his or her patients. The potential of robotics is yet to be discovered, especially with the new generation of motivated surgeons in the field of robotic surgery. In regard to teaching facilities, robotics might provide a more controlled environment with the teaching console in comparison to laparoscopic surgery. Dr. Williams: Agree. In our institution, all the residents are required to do a standard simulation curriculum before sitting at the console. We also have a simulation lab with Box Trainers stomach models to do full simulated operations before patient exposure at the console. Dr. Makary: I agree, for everything we do in surgery. Dr. Rosato: Agree. If we continue to allow industry to define training criteria and determine proficiency standards, the true indications for robotic use and the maximum benefit of this technology will never be realized.

Regarding safety, in the event of an acute life-threatening iatrogenic bleed, the entire surgical team needs to respond quickly to remove the robot. Several case reports in the literature now detailing the patient being stuck under the robot call for quick team response to be regularly practiced, yet this practice need is not being met currently within institutions or within the larger scope of surgical education. Dr. Williams: Agree. If a hospital has a major robotic program, there should be a dedicated OR [operating room] staff that knows how to handle emergencies in an expeditious manner to allow for rapid conversion to an open procedure. This scenario should be practiced in a simulation setting on a regular basis or when new staff members join the team. Teamwork is very important between OR staff and the surgeons. Dr. Makary: Agree, and it’s for this reason—the need for quick conversion—that I have a preference to not use the robot for laparoscopic Whipples, where major portal vein bleeding can require rapid conversion. Dr. Rosato: Disagree. At the institutions where I have worked, there has always been a dedicated operating room team for robotics. Each member, from anesthesia through circulating nurse, is well aware of the unique safety concerns presented while performing robotic procedures. Furthermore, for high-risk procedures with the potential for massive hemorrhage, I meet with our robotic team 24 hours before [the procedure] to review the case and expectations of all members should an emergency arise. As the applications of the robot are being applied to more complex and high-risk procedures, the importance of the rapid response will only increase. I am sure that I am not unique in my approach to these cases. Ultimately, see Robotics Roundtable, page 42

42

EXPERT ROUNDTABLE

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

Robotics Roundtable continued from page 41

it is the responsibility of the surgeon to assure that the team is prepared for any type of robotic emergency. Dr. Fong: Agree. The essentials for a rapid and potentially lifesaving emergency conversion to an open operation are 1) immediate availability of open instruments and self-retaining open retractors; 2) rehearsal of emergency conversion and emergency time-out at beginning of case to define; and 3) document each participant’s role. Dr. Jones: Agree. We recently had a robot stuck over a patient when a medical student tripped over the electrical plug. We have simulation labs to practice scenarios as teams. We should mandate that all teams must practice crisis response. Dr. Kudsi: Agree. Despite the fact that many hospitals have formed robotic committees with rigid restrictions, some of these features are very useful. As surgeons, we should be the most experienced in the room with regard to the machine and troubleshooting. Commitment to understand and go beyond just technical skills will demonstrate leadership skills. Understanding how to dock, drive and position trocars is as important as performing the surgery to prevent instruments and arms collisions. That’s why troubleshooting and emergency conversion should be part of the team training.

Inadvertent injury to a major structure is a risk inherent in robotics compared with both laparoscopic and open approaches.

IBM’s Watson Worst abuse of the robot right now

Dr. Rosato: Disagree. Inadvertent injury to a major structure is an inherent risk for all surgical approaches. Dr. Jones: On the fence. Although the surgeon may be able to see better, one gives up haptic feedback. Dr. Kudsi: Disagree. Robotics might provide a more controlled environment with the teaching console in comparison with laparoscopic surgery, almost similar to open surgery. Injury to a major structure could happen in any approach; it’s related to technical and judgment skills. You can’t blame the slave robot. Dr. Makary: Agree, but the added risk is minimal, even negligible in the hands of a good robotic surgeon. Robotic surgery can be safe when the surgeon is experienced and is the right surgeon for that operation. Patients should choose a good surgeon first and the approach second. Dr. Fong: Disagree. Inadvertent enterotomies occur in open, laparoscopic and robotic surgery. It will be important to document those injuries that would not have occurred with open surgery (e.g., trocar, vascular and traction injuries because of excessive robotic force). These should be graded according to 1) no immediate or longterm adverse outcome, 2) immediate adverse outcome but no long-term disability and 3) both immediate and longterm adverse outcome. Dr. Williams: Disagree. There is a risk for inadvertent injury during all forms of surgery and no more so in robotic surgery if an appropriate training model proctoring has taken place.

American College of Surgeons (ACS)

Society of American Gastrointestinal and Endoscopic Surgeons (SAGES)

As we continue to learn more regarding safety from SAGES Fundamental Use of Surgical Energy program, we need to appreciate the potential from stray currents and iatrogenic burns with use of the robot and instruments in parallel. Dr. Fong: Agree. These should be tracked for all forms of surgery: open, laparoscopic and robotic. The lateral spread of heat for each energy instrument in open, CO2 environment and air insufflation environment at common settings should be part of the package insert for each instrument. Education curriculum should teach use of each of these instruments in open, laparoscopic and robotic deployment. Dr. Kudsi: On the fence. This is the greatest point of all. As a FUSE member and a robotic surgeon, I emphasized this point from day 1 in practice. In robotic surgery you are zoomed in more in comparison with laparoscopic surgery, where you usually have a larger surgical view. In being zoomed in and having long instruments, often you don’t get to see the whole instrument and adjacent structures. We have to be aware and educated about SAGES [FUSE], and I invite all surgeons to take the course and the actual test. Dr. Rosato: Agree. This applies to all minimally see Robotics Roundtable, page 44

Best advice to the community surgeon on robot adoption

FDA’s approval process for medical devices

The one thing residents and fellows forget most is …

The one thing patients forget most is …

Importance of It’s just another setup of room tool.

The one thing I forget most is …

Yuman Fong, MD

Get to work.

Small procedures Need to Need to help with where advocate for guidelines laparoscopy is reimbursement equivalent

Need to be educated

Reasonable

Daniel Jones, MD, MS

Not Apple

Lap chole

Too conservative

Replaces first assistant

Innovation with Duty hours competition

Medications

ICD-10

Noel N. Williams, MD

Loser

None

Great organiza- Great organization Proper prepation ration and proctoring

Fair

To follow up

My jawbone, up at the gym

Frank The beginRosato, MD ning of SkyNet

Transaxillary thyroidectomy

Should develop curriculum for robotic certification

Typical govern- Use both ment agency hands when operating

Martin A good start Makary, MD

Omar Yusef da Vinci Kudsi, MD, surgery MBA

Too little

To come to clinic

How hard laparoscopy was

Should develop curriculum for robotic certification

Practice; do easy cases, then more practice

Cholecystectomy Inspiring quality

Futuristic

Consider it on Is better than The value of a case-by-case their postvisiting other basis. approval moni- centers toring process

The name of their What book anesthesiologist chapter deadline just passed

Giving credential to everyone who asks

FLS/FUSE

You are either all in or out.

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44

EXPERT ROUNDTABLE

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

Robotics Roundtable continued from page 42

invasive approaches used for treating surgical problems. Limiting the use of monopolar energy in favor of bipolar or alternative energy devices is paramount for patient safety. Dr. Jones: Agree. Especially when doing SILS, where instruments are closer together, there is a potential danger. Take FUSE and you will change the way you do SILS forever, if ever again. Dr. Williams: Agree. The understanding of energy sources is mandatory for all surgeons performing robotic and laparoscopic surgery. Dr. Makary: I agree; this is true for all minimally invasive surgery.

Although robots will one day replace many precision human tasks in the OR, currently very few operations are really done better with a robot when performed by a skilled surgeon. Therefore, currently many surgeons and medical centers are really using the robot to gain a marketing edge against competition and to attract new patients, rather than to provide for safer, improved operations and clinical outcomes for their patients.

Dr. Jones: Agree. I usually can do two laparoscopic cholecystectomies and have a cup of coffee in the doctors’ lounge in the time my colleague does one robotic cholecystectomy. But he may soon be eating my lunch since the photo opportunity is with the milliondollar robot and not the laparoscope these days. Dr. Makary: On the fence. Some surgeons and hospitals may use the robot for marketing, evidenced by robot debuts at community half-time events and shopping malls. And although some even mislead the public with unethical marketing to patients who are in a vulnerable state and shopping for quality surgery, I believe many surgeons are simply trying to be proficient with a futuristic technology. As new robot versions come out and new companies introduce next-generation robots, surgeons are smart to keep an open mind and evaluate the application for their practice mix. Dr. Kudsi: Disagree. I can say in all confidence that it would take me less time to perform robotassisted laparoscopic cholecystectomy than laparoscopic cholecystectomy on a personal level—skin to skin in less than 30 minutes with room turnover time less than 15 minutes from a team perspective. It was recently published in HBR [Harvard Business Review] that once you have a dedicated surgical team, the whole day becomes efficient, your outcomes are excellent and it is more fun! It is similar to many surgeons in their surgical centers. Robotic surgery will not cause less pain and lead to faster recovery, but it will provide control over the operation where you are doing 100% of the cases, whereas in other cases you are dependent on the assistant performance and skill level. How many of us will change his or her face when a lesser-skilled assistant shows up for a morbidly obese male patient who has an acute gallbladder?

should be on excellence—you better choose one surgeon and make him the robotic expert. At the end of the day, it will be a more expensive option; thus, we should find a dedicated surgeon who would ensure superb results.

There is catch-up work to be done: Generally speaking, at centers where the robot is currently used, protocols that both ensure proper patient selection and fully inform patients of risks and benefits of all surgical options are lacking.

Dr. Fong: Disagree. At most academic medical centers, robotic surgical time is a valuable commodity. It is usually assigned to the procedures and programs of greatest promise. Credentialing processes are rigorous and include auditing of outcomes. Patients certainly must give informed consent before undergoing such an operation. Dr. Jones: The robot is marketed as “cool” and “cutting-edge.” The surgeons who use it say it makes their operations easier and possibly better; so, no surprise, the patient signs. If the patient, rather than the insurance company were paying part of the added costs, the patient might have more questions or find a surgeon who does as well without the need for costly Dr. Rosato: Agree. A 2011 study published robotic assistance. in the Journal for Healthcare Quality [33:48-52] and Dr. Kudsi: I agree, despite the fact that many conducted by Johns Hopkins School of Medicine hospitals have formed robotic committees with rigid [Baltimore] researchers found 41% of hospital webrestrictions and details beyond practicality at some sites described robotic surgery. Among these, 37% prehospitals and others driven by media and fear of sented robotic surgery on their home page; 73% used lawsuits. Developing high-performance robotic surmanufacturer-provided stock images or text; and 33% gery teams requires leadership—not the authoritarlinked to a manufacturer website. Statements of cliniian leadership of the past, but the kind of leadership cal superiority were made on 86% of webthat fosters exceptional communicasites, with 32% describing improved cancer tion, mutual respect and support, and control, and 2% described a reference group. the development of the best and most None of the hospital websites mentioned straightforward to achieve the goals of ‘Although it is true that some medical centers will risks. These investigators concluded that our surgical society. Recently, SAGES materials provided by hospitals regarding created Minimally Invasive Robotic form robotic surgery programs to be “competitive,” the surgical robot overestimate benefits and Association guidelines, and it will conthe truly innovative centers that have invested tinue to evolve. largely ignore risks, and are strongly influenced by the manufacturer. [Editor’s note: Dr. Makary: The key is for in large academic programs in robotic surgery patients to be fully informed of all their Dr. Makary was an author on this paper]. have included technical development, outcomes Dr. Fong: Agree and disagree. options. Stakeholders should have creAlthough it is true that some medical cenated a robust, “capture-all” registry for research and education as part of the program.’ ters will form robotic surgery programs to all robotic surgery patient outcomes 12 —Yuman Fong, MD be “competitive,” the truly innovative years ago when the robot was FDAcenters that have invested in large approved. This endeavor would have academic programs in robotic surallowed researchers to evaluate the gery have included technical development, benefit or harm to patients in real outcomes research and education as part of time. National registries in health care the program. Developing new tools, defining the advanAlthough many centers are marketing themselves to require a broad investment, but are badly needed. tage and disseminating the knowledge are key to truly gain a marketing edge, it’s a false hope because this road Dr. Rosato: Agree. It is time for a national innovative programs. will lead nowhere. database for robotic procedures. This will allow for the Dr. Williams: On the fence. This statement As I previously stated, robotic versus laparoscopic evaluation of proper indications, as well as short- and applies to lap cholecystectomy. But for example, for surgery is an ongoing point of comparison, but misses long-term outcomes. ■ cases of patients undergoing laparoscopic sleeve gas- the point that robotics is a tool that, in the hands of trectomy who have a very high BMI [body mass index], dedicated surgeons and programs, can deliver remarkI feel it is safer and more precise to use the robot. In our able outcomes—an instrument to achieve excellence. —Colleen Hutchinson is a communications consultant who specializes in the areas of general surgery and bariatrics. institution, robot setup time does not add any time to Hundreds of robots have been sold worldwide and the She can be reached at colleen@cmhadvisors.com. the overall procedure. approach is being adopted across the universe. Focus

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OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

The Surgical Robot: A Tool? A Toy? An Advance? Gary H. Hoffman, MD, Eiman Firoozmand, MD, Liza M. Capiendo, MD, Stephen Yoo, MD, and Allen Kamrava, MD Los Angeles Colon and Rectal Surgical Associates Division of Colon and Rectal Surgery Colorectal Surgery Fellowship Cedars-Sinai Medical Center Los Angeles, California

[[A caveatt: This is an overview of a relatively new technology and a new surgical endeavor. r It is not an exhaustive review and it is not meant as a substitute for a scientific evaluation. It is a practical look at a new surgical world. d Most importantly, what follows is an attempt to raise many questions and provide a few answers. The article is part fact, part observation and part editorial.]

The mere mention of robotic-assisted surgery evokes strong passions. “Love” and “hate” are words heard when discussions turn toward the robot in the operating room. Logic becomes murky as the debate rages. But one thing is clear: The technology works. And not only does it work, it works beautifully in every sense of the word. The surgical robot represents the intersection of science and art;

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a surgeon-controlled machine directed toward delicate human dissection. Talk about “no touch” technique. This is it. To watch one robotic operation, guided by a skilled surgeon, is to see surgery at its finest, to see it as we picture it. The technology works. So what? To ask whether the technology works, or whether we should allot dollars to robotic surgery, is to ask important questions. However, these may not be the bigger, more important questions. Let’s look first at surgical history, and at the smaller questions.

Confusion and Fear If you are a “traditional” surgeon (insert your own age here), then you may feel somewhat antiquated in the present-day, high-tech operating room. Fast forward. It gets worse. You are about to feel like a dinosaur. Stand in an operating room with an operating robot docked comfortably at the side of the patient who is lying on the operating table. Watch as the surgeon, dressed in a traditional sterile surgical gown and gloves, places several instruments and readies the operative field. So far, so good. But just as you are beginning to feel comfortable in this new world, beginning to think that you are not really the ghost of the operating room past, and that you might actually fit in here, the surgeon abruptly turns, walks away, removes the sterile gown, snaps off the gloves and sits down at a console in the corner. Before you blurt out “Where are you going?” you realize that you have just stepped far out of your comfort zone and through the door marked “tomorrow,” today. If you are a “young” surgeon (insert your own age here), this new world is the same old world of your present-day operating room. The transition likely will be but a small blip on your lifetime learning curve. But, if you are that “traditional” surgeon, you are going to begin to ask yourself a lot of questions. The answers to these questions may bother you or elate you. The answers are as much about your mind as they are about the operating room. The answers are about more than the date on your residency certificate or the date on your maintenance of certification certificate. You are about to find out if you are “traditional” or “young.” Perhaps you are both. And should you become concerned that you, the surgeon, are about to become expendable, take heart. With all of the automation in our modern aircraft cockpits, two pilots guide and control the plane. Two pilots make sure that each of us arrives safely at our destination. The pilot, not the robot, is responsible for

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

our safety. As with aircraft avionics, the surgical robot works for us. You are not expendable ‌ yet.

How Did We Arrive at the Present? Or Is This the Future? The confined space of the human pelvis can hamper visibility and maneuverability in the operative field. Both laparoscopic and robotic systems are touted as helping the surgeon overcome this space limitation. This has spurred the explosive growth of minimally invasive technologies. Robotic surgery was originally developed by the military for remote surgical use. Subsequently, its use was found to be more applicable as an on-site tool. The first robotic procedure, a prostate operation, was performed in 1992. To date, more than 1.5 million robotic procedures have been performed worldwide. In 2000, the FDA approved the da Vinci robotic system for use in intraabdominal surgery. The initial popularity of robotic systems was for use in urologic and gynecologic procedures. Robotic colorectal surgery was first performed in 2001. Only six reported robotic colectomies were performed between December 2001 and April 2002, despite literature demonstrating the feasibility and safety of the da Vinci system. Fifty-three robotic colorectal procedures were performed between 2001 and 2003, with 22 of these cases being for malignancy. The general consensus was that robotic techniques could achieve the same operative and postoperative results when compared with conventional laparoscopic techniques. According to one review, the use of robotic surgery in colorectal operations increased by 100% from 1,188 cases in 2009 to 2,380 cases in 2010. In contrast, the use of laparoscopy increased only by 1.15%. Colorectal surgeons were thoughtfully slow to adopt robotic technology. Questions arose as to what, if any, were the advantages of robot-assisted colorectal surgery. In contradistinction to the improved, hand-sewn, robot-guided urethral anastomosis, the stapled colorectal anastomosis performed during robot-assisted surgery was no different than the stapled anastomosis performed during laparoscopic procedures. And then, there was the issue of cost. New systems were expensive to purchase or lease, and to maintain, to say nothing of the cost of the disposable items for each case. And, what about the steep learning curve? With the inevitable development of new equipment and experience, coupled with a never-ending drive to advance in fertile directions, surgeons and industry have begun to look again at robotic technology. Costs have come down and instruments are being made to better fit the

needs of the colorectal surgeon and the general surgeon, as well as various other surgical specialists. The surgical community has begun to re-evaluate roboticassisted technology and operative strategies. Does the improved experience

in urologic surgery translate to colorectal surgery? To other specialties? Specifically, in colorectal surgery, current robotic techniques are focused on the treatments of rectal cancer, rectal prolapse, enterocele repair and diverticulitis.

The surgical community has begun to re-evaluate roboticassisted technology and operative strategies. Does the improved experience in urologic surgery translate to colorectal surgery?

47

Similarities Between Laparoscopic And Robotic Systems As in laparoscopic surgery, robotic surgery makes use of small incisions. In both techniques, patients recover faster compared with recovery times following open operations. With a more rapid recovery, needed chemotherapy can begin sooner when laparoscopic or robotic surgery is used for rectal cancer. In surgery for very low rectal tumors, the increased visibility using modern optic systems and improved precision and access to the most distal see Robotic Surgery, page 48

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OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

Robotic Surgery continued from page 47

surgical sites—allowing for increased rates of sphincter-sparing procedures—could potentially decrease the permanent ostomy rate. Additionally, postoperative pain is minimized by an extraction site incision of just 6 to 8 cm (and in some cases even shorter) compared with an incision length of 15 to 20 cm in open surgery. Large, comparative clinical trials are under way, and results thus far indicate that robotic surgery is as effective as open surgery, and

yields results “no worse” than the results in laparoscopic surgical procedures.

The (Advertised) Bells and Whistles Of Robots The robotic system has certain benefits for both the surgeon and the patient. These are: Three-dimensional high-definition vision. The robotic system has two

high-definition cameras that provide the surgeon with a magnified, stereoscopic view of the surgical site, combining accurate depth perception with a sharp image. An additional arm. This additional arm, which can be used to hold a retractor or other surgical instruments, gives the surgeon 50% more operating capability. Instant image referencing (“TilePro”). This feature allows the surgeon to

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display up to two diagnostic ultrasound or computed tomographic (CT) images taken before surgery, inside the da Vinci console monitor, directly alongside the view of the real-time procedure, providing a critical extra reference when necessary. Extra-mobile “wrist action.”” The mechanical wrists, which can hold a wide array of specialized instruments, function just like a human wrist, but with even greater range of motion. This facilitates a relative ease of intracorporeal suturing. Scalability and dexterity. This innovation allows the surgeon to calibrate the robot’s arm to move a fraction of an inch for every inch that the surgeon’s hand moves, simplifying the most complex movements, including delicate resections, suturing and knot-tying. With the robotic system, movements are smooth and without awkwardness. Natural tremor is eliminated. Anastomotic vascular perfusion. Following the injection of indocyanine green, vascularized tissues are seen as green under fluorescent light, whereas underperfused or nonperfused tissues are seen as gray or black. (Presently, it is not known whether this technology is predictive of the anastomotic leak rate and more study is needed to evaluate this technology.) A related technology, real-time, fluorescent, nearinfrared cholangiography also may image the biliary tree. Visualization of the pelvic nerve plexus. Using the high-definition magnification of the robotic optical system, the pelvic plexus of nerves can be seen and protected. The thought is that protecting this delicate and critical latticework of autonomic nerves will preserve continence and sexual functioning. This has yet to be proven in clinical trials. Laparoscopic surgeons will point out that the nerves are seen during laparoscopic interventions as well, thus negating the promoted critical view of the autonomic plexus in robotic procedures. More study is needed to clarify this point.

Weaknesses and Drawbacks

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The robotic system has a few drawbacks. An important clinical drawback is the lack of both tactile sensation and tensile feedback to the surgeon. Thus, tissue damage can occur unintentionally during traction by the robotic arm and during movement of the robotic instrument. Learning safe robotic surgery is associated with a steep learning curve. Importantly, robotic technology seems to put the eyes of the surgeon closer to the operative field; an advantage and a drawback as the view of the operative field is often “too close” and a

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

larger frame of reference is required in order to get the “big picture.” Ureteral catheters may be placed before beginning the robot-assisted operation. As robot-assisted procedures are associated with limited tactile sensation, lighted catheters may better improve ureteral identification. The catheters may assist in visual confirmation, identification and added protection of the ureters. This practice varies by institution and by surgeon, depending on factors related to training and personal preference. The use of catheters also may be related to the surgeon’s initial comfort with robot-assisted procedures. The use of ureteral catheters may decrease over time. More study is needed to evaluate the use and safety of robotic colon procedures with respect to genitourinary complications. A dedicated team must be assembled and trained to allow for consistency, safety and reliability in the conduct of the operation. The robot is an expensive system. A new system can cost up to $1.5 million to purchase, and, as in laparoscopic surgery, each operation can require the use of more expensive, single-use equipment. Service contracts are required. As of now, the manufacturer has no competitor and no competitive pricing pressure beyond the current regulatory forces. Clearly, there is a financial impact of added operating time, materials and personnel needs.

are unrivaled. In many instances, the robotic optical view is improved over the view during laparoscopic procedures. Dissection is delicate and atraumatic. How-

Unlike a urethral anastomosis, the colorectal anastomosis is no different between laparoscopic and robotic techniques, negating an important potential advantage of the robotic system. ever, is one technology better than the other? Is robotic colorectal technology an

the cusp of another surgical revolution? Is robotic surgery a fancy gimmick and sales

tool, or perhaps a technology looking for another diseased organ system to repair? Many questions, few answers … so far.

The Big Questions In science, a properly framed question is worth more than a king’s ransom. It is worth more than all of the equipment in all of the labs in all of our research facilities. Frame your question wrong, and you might as well not even take the first step down the road of experimentation. The game is over before the first reagent hits see Robotic Surgery, page 50

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There are studies showing that the results after robotic procedures are “no worse” than laparoscopic procedures. However, there are no prospective, randomized controlled trials demonstrating a clear-cut advantage of this new technology when compared with the now “traditional” laparoscopic technology. Unlike a urethral anastomosis, the colorectal anastomosis is no different between laparoscopic and robotic techniques, negating an important potential advantage of the robotic system.

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The Smaller Questions Surgeons are now performing most colorectal procedures using either laparoscopic or robotic technology. Our surgical group is transitioning to performing an ever-increasing number of robotic-assisted operations. New technologies usually engender new questions. Are there challenges in colorectal procedures that can be overcome, or clinical outcomes that can be improved by using robotic techniques? In both laparoscopic and robotic systems, the technical aspects of the operation are similar. Surgical principles remain unchanged. It is our (mechanical) hands that are different in robot-assisted operations. The view and clarity of the operative field and the precision of the surgeon’s movements

advance? Are we improving the results for our patients? Can hospitals and society afford the expensive robotic system? And, specifically in colorectal surgery, are we on

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OPINION

Robotic Surgery continued from page 49

the first test tube. But, frame your question well, frame it in your mind before even putting pen to paper or fingers to keyboard, and the results will jump out at you in ways almost unimaginable. And so it is with robotic surgery. Everyone has an opinion and an answer. To be sure, all questions about patient care are important. And, as robotic technology spreads into new arenas, new questions must be asked as old questions resurface. However, the top-level questions must be asked first in order to appropriately frame the subsequent debate and evaluation. So, here are the top-level questions: Should the robot be allowed into our surgical thinking and then into our operating rooms?

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

Here are the top-level answers: Yes and yes. And here is why: It does not matter at all what the robot can do for us today. It matters a heck of a lot what the robot might do for us tomorrow. We explore space, we explore the ocean’s depths and we explore our bodies down to our electrons. We do these things because we are curious and because we can. And, from this curiosity we have penicillin and x-rays. We have stethoscopes and ophthalmoscopes, and all of the incredible tools of our craft. We have automobiles, although horses worked just fine. We have computers and software for all kinds of problems. We have telescopes in space. And we have pacemakers, electron microscopes, CT scanners and magnetic resonance scanners. We have artificial joints coated with Trabecular Metal. The list is endless and is a catalogue of human advances. In fact,

everything that we have today is because we invented it all yesterday. Think of robotic-assisted surgery as an experiment: an experiment that may or may not yield results. It might prove meaningless. Or, it might lead to the development of artificial intelligence algorithms that will save lives, maybe even save lives in remote locations or remote planets. Who knows? But it is worth trying. It matters that in developing robotic technologies, we might just invent something totally unexpected, something that none of us can see now through our shortterm lenses. We must think longer term. We must look further. We must go beyond small questions to big questions, to huge questions. And from this questioning will come small and large advances for all of us. We need to advance. To stand still is … to stand still. We need to keep moving forward, because we can. Robotic technologies are a part of this progress.

Robots R Us? A Few More Answers (Beginning With the Big Answer) Should we be using the robot in the operating room? Yes. We may not know where this technology will lead us, but the story of mankind runs in lockstep with invention and exploration of all of our frontiers. Is performing a robotic colorectal procedure exciting and fun? Yes. Are robotic-assisted procedures being performed in our community and at our hospital? Yes. Surgeons of many specialties are in various stages of learning and adoption, and are evaluating the clinical applications of robotic-assisted operations. It is an intense learning process, and the field of robotic surgery is a rapidly evolving work in progress at both the national and personal levels. Is robotic surgery safe? Yes, in trained surgical (Remember, first do no harm.)

hands.

What about the learning curve? It is steep, very steep. For “traditional” surgeons, it involves didactic training, much practical training and “muscle memory” retraining. The curve is likely not as steep for the “younger” surgeons who already live in a high-tech surgical and video game world. Is laparoscopic surgery presently the most commonly used surgical system in minimally invasive general surgical and colorectal operations? Yes. The da Vinci Surgical System by Intuitive Surgical.

Will laparoscopic, minimally invasive surgery remain the most commonly used system in minimally invasive general surgical and colorectal operations for some time to come? Yes. Is today’s robotic colorectal surgery an advance over our current laparoscopic techniques? Yes, in certain clinical situations. Does robotic surgery have the potential to become the procedure of choice for the resection of pelvic tumors, left-sided tumors and complicated resections or reoperative resections, as well as in intraabdominal rectocele repair and enterocele repair? Yes. Do colorectal robotic systems allow for better clinical outcomes when compared with laparoscopic procedures? Possibly, for certain clinical applications. Much study is needed to clarify this point, however. Are the results using robotic tools “no worse” than the results in laparoscopic surgery? Yes. (Remember, first do no harm.) Is the promoted advantage of “greater visibility” using robotic technology an operating room advance when used in colorectal surgery? Possibly, especially if it turns out that nerve visualization and protection, and intraoperative vascular anastomotic perfusion evaluation are found to relate to improved clinical outcomes. Again, more study is needed to look at clinical outcomes. Finally, is someone, somewhere working on an artificial intelligence program that will guide the robot-surgeon (or surgeon-robot) through an operation? Yes.

A Tool, a Toy and an Advance Ultimately, as with any new intervention, the decision to use a robotic system in the operating room will depend on a clinical benefit analysis. There appears to be increasing acceptance and use of robotic technologies in many common operative interventions. The technology has improvements and advances over open surgical procedures and laparoscopic technologies as well. However, it will take the combined evaluations of both “traditional” and “young” surgeons to decide if the robot is a tool, a toy or an advance. ■ The authors reported no financial relationship with Intuitive Surgical.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

Spotting Spin and Bias in Clinical Trials ‘You can’t look at specificity BY KATE O’ROURKE CHICAGO—In recent years, doctors have adopted standards of care based on clinical trial data that are not always scientifically solid. In some cases, new practice patterns may have caused more harm than good. At the 2013 annual meeting of the American Society of Clinical Oncology (ASCO), three clinicians discussed how doctors can approach reports

of clinical trial data more critically and spot spin and bias. According to Mike Glantz, MD, professor of neurosurgery and oncology at Penn State College of Medicine in Hershey, Pa., a recent trial that compared memantine with placebo in patients undergoing whole brain radiation therapy is a good example of a lapse in critical appraisal. The study, designed with 80% power and a significance of

P<0.025, had a primary end point of cognitive improvement at six months. The researchers accrued a large number of patients, but only one-third were evaluable at six months (primarily because of attrition from death), and the study failed to achieve its primary end point. In the study’s conclusion, the researchers focused instead on the secondary observation that a lower percentage of patients in the memantine group

and sensitivity in isolation. … If they add up to 100%, the test is useless.’ —Gary Gronseth, MD

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had cognitive decline at six months, and clinicians would only have to treat nine people with memantine, a relatively benign intervention, to prevent one case of cognitive decline. Reports of the study that followed, including one in the National Cancer Institute’s Cancer Bulletin, stated that memantine would likely become the standard of care. Clinicians also should have paid attention to the wide 95% confidence interval (relative risk, 0.65-1.07). “This study is equally consistent with a 35% benefit from memantine or a 7% harm,” Dr. Glantz said. Generally, studies can be misleading because of random error (caused by unrepresentative sampling) or because of bias and confounding (caused by study design flaws). Clinicians can spot statistical mistakes, spin and bias by examining a study’s methodology, scrutinizing sample sizes, P values, confidence intervals, randomization strategies, patient characteristics and loss to follow-up. In determining a study’s reliability, clinicians should reflect on how a study influences their post-study conviction compared with their pretest conviction, Dr. Glantz said. For example, he estimated that because roughly 10% of oncology drugs entering Phase III trials are ultimately approved for the proposed indication, 10% is a reasonable pretest conviction that a therapy will work in a Phase III study. Dr. Glantz analyzed three months of Phase III randomized

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GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

The test for prostate-specific antigen (PSA) has a sensitivity of 91% and a specificity of 20%. The test is only slightly better than useless, but its widespread application wasn’t disastrous because prostate cancer is very prevalent, and prevalence affects predictive value. “The positive predictive value of the PSA test isn’t horrible, mainly because prostate cancer is so common, but you don’t get a lot out of the test,” Dr. Gronseth said. “With a positive PSA, you go from a 16% probability of prostate cancer in a population with this kind of prevalence to a 22% [post-test] probability.” The

trials comparing two treatments published in the Journal of Clinical Oncology. Of the 28 trials identified, 17 were not only statistically nonsignificant, but had confidence intervals that included the possibility of both clinically meaningful benefit and clinically meaningful harm. Thus, the studies were completely uninformative. Half of the remaining nine studies afforded a post-study conviction of, at most, 60%. “They were statistically significant, but poorly powered. We are left with less than one in five studies that we have seen in the last three months in the JCO that we can really hang our hats on,” Dr. Glantz said. According to Gary Gronseth, MD, professor and vice chair of neurology at the University of Kansas Medical Center in Kansas City, and an evidence-based methodologist for the American Academy of Neurology, one mistake that clinicians sometimes make is believing that the probability of having a disease decreases if a patient has a negative result from a test that has a sensitivity of, for example, 90%. “You can’t look at specificity and sensitivity in isolation,” he said. For diagnostic tests, sensitivity is the proportion of patients with the disease that the test is positive for, and specificity is the proportion of patients without the condition who have a negative result. “The trick to correct the flawed heuristic in your head is to add up the specificity and sensitivity. If they add up to 100%, the test is useless,” Dr. Gronseth said.

damage from using such a test is the falsepositive results and the consequences that come from them. In analyzing medical literature, Dr. Gronseth said, some clinicians fail to recognize the effect that false positives can have on patients. Other studies may be faulty in not recognizing overdiagnosed patients—those who would have the same outcome whether or not they receive treatment. Dr. Gronseth also pointed out that researchers need to be cautious about studies that focus on relative measures

of benefit instead of absolute numbers. This can inflate benefit. According to Ian Tannock, MD, PhD, professor of medicine and medical biophysics at the University of Toronto Princess Margaret Cancer Centre, in Ontario, Canada, clinicians should expect that a clinical trial has a primary end point that reflects benefit to patients and is explicitly defined in a study abstract, that an abstract should include a statement of major toxicity, and that the abstract’s concluding sentence see Spotting Spin, page 54

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GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

Spotting Spin continued from page 53

should relate to the primary end point. “Unfortunately, many reports, both in high-level journals and at the ASCO meetings, do not meet these simple requirements,” Dr. Tannock said. In a recent study, Dr. Tannock and his colleagues searched PubMed to identify randomized trials of breast cancer that involved more than 200 patients and were published between 1995 and 2011 (Vera-Badillo FE et al. Ann Oncol

2013;24:1238-1244). In 59% of the 92 trial reports, the abstract’s concluding statement used secondary end points to suggest benefit. One-third of the studies reported the frequency of grade 3/4 toxicities in the abstract. Positive results for the primary end point were associated with underreported toxicity. Dr. Tannock pointed out that the only two ways that a new treatment benefits a patient are by helping patients live longer or live better. “End points such as tumor response show biological activity, but are poorly correlated with survival,”

he said. A 2008 study that surveyed adjuvant breast cancer trials from 1996 to 2006 found that early differences in disease-free survival (DFS) predict for much smaller, if any, differences in overall survival (OS; Ng R et al. Ann Oncol 2008;19:481-486). “We have a huge problem in the literature with surrogate end points,” Dr. Tannock said. “As long as the FDA and EMA [European Medicines Agency] allow registration of drugs on the basis of surrogate end points, we are going to have this continuous problem.”

Optimizing the Prevention and Management of Postsurgical Adhesions To participate in this FREE CME activity, log on to

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Jon Gould, MD Chief, Division of General Surgery Alonzo P. Walker Chair in Surgery Associate Professor of Surgery Medical College of Wisconsin Senior Medical Director of Clinical Affairs Froedtert Hospital Milwaukee, Wisconsin

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Michael J. Rosen, MD Associate Professor of Surgery Division Chief, General Surgery University Hospitals Case Medical Center Cleveland, Ohio

Statement of Need Adhesions are the most common complication of abdominopelvic surgery, developing postoperatively in 50% to 100% of all such interventions. They can lead to serious medical complications, substantial morbidity, high monetary costs, large surgical workloads, dangerous and difficult reoperations, and an increasing number of medicolegal claims. An official definition of the Sponsored by

Expiration date: September 1, 2014 condition has not been established, and an unequivocally effective prevention method has not been identified. A standardized classification for adhesion assessment and scoring also is lacking, as are guidelines for diagnosis and management. To close these gaps, clinician education is necessary.

Goal The goal of this educational activity is to provide surgeons with up-to-date, clinically useful information concerning the prevention and management of postoperative adhesions.

Learning Objectives 1 Review the pathophysiology and complications of postoperative adhesion formation. 2 Summarize current strategies used to prevent postoperative adhesion formation. 3 Describe the various types of barrier materials used to prevent postoperative adhesion formation.

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Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Medical College of Wisconsin and Applied Clinical Education. The Medical College of Wisconsin is accredited by the ACCME to provide continuing medical education for physicians.

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He said some clinicians may argue that BOLERO-2 proves that exemestane plus everolimus (Afinitor, Novartis) should be used for postmenopausal women with hormone receptor–positive breast cancer who have progressed on a nonsteroidal aromatase inhibitor, but the combination hasn’t been proven to improve OS, and it increases adverse events (AEs; Baselga J et al. N Engl J Medd 2012;366:520-529). Twenty-four percent of patients receiving the combination therapy discontinued the trial because of serious AEs or withdrawn consent. Clinical trials often don’t provide an accurate assessment of a drug’s toxicity. “To get into a clinical trial, you need to be an Olympic athlete with cancer,” he said. “We are highly selective, yet we apply those results to people who have all sorts of other comorbidities.” A recent study concluded that 58% of potentially fatal AEs are not in the initial FDA drug label and 39% are not reported in any published randomized trial (Seruga B et al. J Clin Oncoll 2009;29:174-185). Many trials detect trivial differences that are statistically, but not clinically, significant. These small differences in treatment outcomes may disappear— and toxicities increase—when a treatment is used in the general population. When clinicians read a study, they should ask themselves how trial results fit with other study results and clinical experience, and whether the results are relevant to theirr patients. Doctors also need to be on guard to detect intentional spin. For example, Dr. Tannock said, the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial group has published roughly 30 papers concluding that aromatase inhibitors are superior to tamoxifen for postmenopausal women with estrogen receptor–positive breast cancer, based on an end point of recurrence-free survival. “I cannot find a single plot of overall survival in that data,” Dr. Tannock said. The cynic in him thinks that perhaps AstraZeneca, the maker of Arimidex, may have had some influence in the reporting of studies, and perhaps the survival curves of the patient groups are superimposable. A metaanalysis, he said, shows the curves are identical (Dowsett M et al. J Clin Oncol 2010;28:509-518). In other words, “newly approved” does not always mean “new and improved.” ■ Dr. Glantz has received honoraria and research funding from Enzon, and has relationships with the American Academy of Neurology and the American Association of Neurological Surgeons. Drs. Gronseth and Tannock had no relevant conflicts of interest.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

IOM Report Warns of Impending Cancer Care Crisis BY KATE O’ROURKE The growing demand for cancer care, combined with increasingly complex treatments, a shrinking workforce and rising costs, now constitutes “a crisis” for the field, according to a new report from the Institute of Medicine (IOM). Health care experts have been warning that the cancer care system needs improvements. The new report, from one of the most respected organizations in health care policy, effectively pours gasoline on the fire.

and an oncologist and the director of palliative care at Johns Hopkins’ Sidney Kimmel Comprehensive Cancer Center in Baltimore, says the following recommendations may make the most impact: that patients have written care plans; that clinicians provide detailed information to patients about benefits, risks and costs of treatment; and that any seriously ill patient has access to palliative care alongside usual oncology care. “Palliative care is the home run of

American medicine,” Dr. Smith said. “First, people have better symptom management and quality of life. Second, people have fewer hospital days and hospitalizations at the end of life. Third, people live at least as long, if not longer, with both hospice and palliative care. And fourth, it is care that we can actually afford.” Another important recommendation is removing reimbursement barriers to team-based care. Some insurance

companies do not pay for a patient to see more than one physician per day, when oftentimes the ideal is to meet with a team of caregivers. Dr. Smith said new care models may remedy this, including bundled payments, accountable care organizations and oncology patient– centered medical homes. To align clinical trial populations with those most commonly seen in a community clinic, the IOM recommends see Cancer Care, page 56

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According to Matthew Farber, director of provider economics and public policy at the Association of Community Cancer Centers (ACCC), “none of the problems or solutions listed in the report are incredibly shocking,” but the study “is a call to arms.” The report proposes a conceptual framework for making improvements, outlines 10 goals and issues several recommendations (Table, page 56). Tom Smith, MD, one of the report’s authors,

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OPINION

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Two Miserable Extra Months: Not Worth Very Much! And Not Very Worthy of Pursuit! Steven Vogl, MD Medical Oncologist New York, New York Each year sees the approval and marketing of new, ever more expensive drugs that prolong the largely miserable lives of dying cancer patients by one to three months. Erlotinib (Tarceva, Astellas) was probably the first—prolonging life (median survival) as second- or third-line therapy for non-small cell lung cancer by about two months and for pancreatic cancer by about 12 days. Regorafenib (Stivarga, Bayer) for colon cancer is one of the most recent—prolonging life by six weeks at the cost of considerable toxicity and no obvious improvement in the already severely impaired quality of life of the suffering patients.1 Similar data exist for ixabepilone (Ixempra, BristolMyers Squibb) and eribulin (Halaven, Eisai) for breast cancer, pazopanib (Votrient, GlaxoSmithKline) for sarcomas, the latter of which provides seven weeks longer median survival and 13 weeks longer progression-free survival based

on evaluation with every-six-week computed tomography. Although these drugs have some obvious benefits, their costs embody many of the most undesirable aspects of U.S. medical care. They are massively overpriced for the benefits they confer, and the cost is borne largely by two overlapping groups: American taxpayers and American consumers. The price is completely dissociated from any significant market pressure. Rather, successive generations of drugs are priced higher and higher each year as the gall of drug companies increases. Indeed, one can fairly confidently guess the year of a drug’s approval by its monthly cost—a cost that relates more to Big Pharma’s estimate of the price ceiling beyond which society would be outraged than to the cost of drug development or the costs of manufacture and marketing. Thus, erlotinib was priced at about $2,400 per month in 2000 and regorafenib at about $9,350 per month in 2012. The level just “below outrage levels” has apparently risen to about $40,000 per month for threemonth courses of immune therapies like sipuleucel-T (Provenge, Dendreon) for

Cancer Care continued from page 55

rewarding companies with a six-month patent extension when they conduct drug trials in older patients or individuals with multiple comorbidities. This is a tool used to encourage trials in pediatric populations. Another important recommendation is for payors to implement payment models that incentivize discussions about clinical options, cost of care and end-of-life care issues. Robert Arnold, MD, chief of palliative care and medical ethics at the University of Pittsburgh School of Medicine, says physicians who have end-of-life care discussions currently bill their time under general counseling Current Procedural Terminology, or CPT, codes. He thinks having specific CPT codes for an end-of-life conversation will help. “It’s an uncomfortable conversation and it’s a financial loser, so everything is against it,” Dr. Arnold said. “I think if you tell doctors we support it [by having a specific code], the symbolism is really important. It says, ‘this is something from a societal point of view that we want you to do.’” According to Virginia Vaitones, MSW, the president of the ACCC, educating patients about all aspects of chemotherapy treatment takes at least an hour. It is not reimbursable if undertaken by nurses and only partially reimbursable when done by doctors. She thinks having more thorough discussions up front will save money in the

The high prices paid for drugs that delay progression for very sick patients by only a few months, and the large profits they generate, divert drug company research funds from trials that seek prolonged high-quality remission or cure.

prostate cancer and ipilimumab (Yervoy, Bristol-Myers Squibb) for melanoma. The high prices paid for drugs that delay progression for very sick patients by only a few months, and the large profits they generate, divert drug company research funds from trials that seek prolonged high-quality remission or cure.

Table. IOM Cancer Care Goals Provide patients with understandable information on cancer prognosis, treatment benefits and harms, palliative care, psychosocial support, and estimates of total and out-of-pocket costs. Provide end-of-life care consistent with patients’ needs, values and preferences. Ensure that members of the cancer care team coordinate with one another and with primary/geriatric and specialist care teams to implement patient care plans and deliver comprehensive, efficient and patient-centered care. Ensure the cancer care team has core competencies. Expand breadth of cancer research data collected on cancer interventions for older adults and individuals with multiple comorbid conditions. Expand the depth of data available for assessing interventions. Develop an ethically sound health care information technology system that can “learn” by enabling real-time analysis of data from cancer patients in a variety of care settings. Develop a national quality-reporting program for cancer care as part of a learning health care system. Reduce disparities in access to cancer care among vulnerable and underserved populations. Improve the affordability of cancer care by leveraging existing efforts to reform payment and eliminate waste. IOM, Institute of Medicine

How Did This Come To Be? Big Pharma and its lobbyists—with deep pockets that support many election campaigns—have succeeded in inducing the U.S. Congress and state legislatures to pay the asking price for any approved drug. By law, Medicare Part D prescription plans are forbidden from bargaining see High Costs, page 58

long run, and she sees the new codes coming to fruition within the next five years. A precedent for having specialized consultation codes has been set—an existing diabetes management code can be used as an example. Many clinicians hope the report’s focus on patient-centered care will encourage research in this area. Current clinical trials are rarely designed to provide information to a patient who is going to live with treatment-related side effects and long-term sequelae. “The older oncology literature is really focused on things like survival and recurrence,” said Benjamin Smith, MD, associate professor of radiation oncology at the University of Texas MD Anderson Cancer Center in Houston. “Those are helpful, but they don’t tell the whole story of the way a patient experiences an illness.” Dr. Smith, who also is a health services researcher, believes the IOM report will make waves. “I think IOM reports carry quite a bit of weight,” he said. As evidence, he pointed to a 1999 IOM report that concluded the gaps in cancer care need further study. “There has been a dramatic proliferation of cancer-related health services research between the time that report was published and the present day,” he said. “Given there is a historical precedent, I am hopeful that this IOM report will have an impact.” ■

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*Demonstrated non-inferiority with both split-dose and day-before regimens, evaluated in randomized trials using the validated Aronchick scale. Superior cleansing efficacy of split-dose regimen demonstrated vs day-before regimen comparator (84% vs 74%, respectively, achieving “excellent or good” visualization). The comparator was 2L PEG with electrolytes (PEG+E) plus 2x 5 mg bisacodyl tablets, dosed as labeled. The primary efficacy endpoint was the proportion of patients with successful colon cleansing defined as bowel preparations with >90% of the mucosa seen and mostly liquid stool, assessed by blinded colonoscopists. [Prepopik: n=256/304; comparator: n=221/297].1-3 SUPERIOR CLEANSING

PATIENT PREFERENCE

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Percentage of patients achieving excellent or good visualization in the split-dose trial

Patient reactions to bowel prep regimens in the split-dose trial

Colon segment

Prepopik

2L PEG+E plus 2x 5 mg bisacodyl tablets

Overall

84%

74%

(n=256/304)

Ascending Mid (Transverse and Descending)

Rectosigmoid

90%

(n=272/304)

92%

(n=221/297)

79%

10%

86%

(n=255/297)

92%

87%

Completed preparation

DIFFERENCE

(n=234/297)

(n=281/304) (n=281/304)

Patient perspective

(n=259/297)

Prepopik

99%

(n=304/305)

96%

Would ask for the prep again in the future

(n=290/302)

Was very easy or easy to take

(n=270/302)

89%

2L PEG+E plus 2x 5 mg bisacodyl tablets

91%

(n=267/292)

55%

(n=162/296)

29%

(n=86/296)

SPLIT-DOSE OR DAY-BEFORE REGIMEN4

INDICATION AND IMPORTANT SAFETY INFORMATION Prepopik ® for oral solution is indicated for cleansing of the colon as a preparation for colonoscopy in adults. • Prepopik is contraindicated in the following conditions: patients with severely reduced renal function, gastrointestinal obstruction or ileus, bowel perforation, toxic colitis or toxic megacolon, gastric retention, or in patients with a known allergy to any of the ingredients in Prepopik. Patients should be advised on the importance of adequate hydration, and post-colonoscopy lab tests should be considered if a patient develops significant vomiting or signs of dehydration after taking Prepopik • Patients with electrolyte abnormalities should have them corrected before treatment. Use caution when prescribing for patients who are at risk for seizures, or arrhythmias, including those patients with a history of prolonged QT, recent myocardial infarction, unstable angina, congestive heart failure, or cardiomyopathy. Caution should also be used in patients with impaired gag reflex, regurgitation or aspiration, severe active ulcerative colitis, impaired renal function or patients taking medications that may affect renal function, electrolyte imbalance and/or water retention • Oral medication administered within one hour of the start of administration of Prepopik solution may be flushed from the GI tract and the medication may not be absorbed. Prior or concomitant use of antibiotics with Prepopik may reduce its efficacy. Tetracycline and fluoroquinolone antibiotics, iron, digoxin, chlorpromazine and penicillamine, should be taken at least 2 hours before and not less than 6 hours after administration of Prepopik to avoid chelation with magnesium. Osmotic laxatives may produce colonic mucosal aphthous ulcerations and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Concurrent use of additional stimulant laxatives with Prepopik may increase this risk • Prepopik should not be used if gastrointestinal obstruction or perforation is suspected. Prepopik is not for direct ingestion. Each packet must be dissolved in 5 ounces of cold water and administered at separate times, in addition to additional clear fluids, according to the dosing regimen. In randomized, multicenter, controlled clinical trials, nausea, headache, and vomiting were the most common treatment-emergent adverse reactions (>1%) following Prepopik administration

Please see brief summary of Prescribing Information following this advertisement. †

The SEE CLEAR I and SEE CLEAR II studies were phase 3, randomized, multicenter, assessor-blinded, noninferiority studies in patients preparing for colonoscopy. The primary endpoints were evaluation of overall colon cleansing with Prepopik vs a comparator using modified Aronchick and Ottawa scales. Patients were also required to complete a questionnaire, which included the questions: “How easy or difficult was it to consume the prescribed bowel preparation?” and “Would you ask your doctor for this preparation again if you needed another colonoscopy in the future?”1,3

‡

The Ottawa bowel preparation scale assesses bowel cleanliness by section, based on numeric scores of 0-4. A score of 0 denotes “excellent” cleansing with ascending numbers denoting “good,” “fair,” “poor,” and “inadequate.” Additional numeric value is assigned based on the amount of fluid present (small, moderate, or large). [Prepopik: n=272/304; comparator: n=234/297].1,2

Visit prepopik.com/testimonials to hear what patients and healthcare professionals have to say about Prepopik! References: 1. Rex DK, Katz PO, Bertiger G, et al. Split-dose administration of a dual-action, low-volume bowel cleanser for colonoscopy: the SEE CLEAR I study [published online ahead of print]. Gastrointest Endosc. 2013. http://dx.doi.org/10.1016/j.gie.2013.02.024. 2. Data on file. Ferring Pharmaceuticals Inc. Parsippany, NJ 07054, USA. 3. Katz PO, Rex DK, Epstein M, et al. A dual-action, low-volume bowel cleanser administered the day before colonoscopy: results from the SEE CLEAR II study. Am J Gastroenterol. 2013;108:401-409. http//dx.doi. org/10.1038/ajg.2012.441. 4. Prepopik® Prescribing Information, July 2012. Ferring Pharmaceuticals Inc. Parsippany, NJ 07054, USA. PREPOPIK® is a registered trademark of Ferring B.V. © 2013 Ferring B.V. All rights reserved. PK/1219/2013/US(1)

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OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

High Costs continued from page 56

over the prices of approved drugs. As a consequence, both American taxpayers and American consumers pay higher prices for drugs than anywhere else in the world. The Medicare prescription plan’s deductible and copay provisions, which are designed to discourage the use of marginally beneficial drugs, have been effectively nullified by the creation of bogus charities and foundations through

which Big Pharma pays the copay and deductible to itself, and still makes huge sums by collecting 80% to 95% of the posted price from Medicare and private insurers. At the same time, insurance companies have consolidated, so most are dominant in their market and can pass the increasing cost of drugs through to the purchasers of the insurance as much higher premiums. It seems this leaves enough

Aspiration Patients with impaired gag reÀex and patients prone to regurgitation or aspiration should be observed during the administration of PREPOPIK. Use with caution in these patients. Not for Direct Ingestion Each packet must be dissolved in 5 ounces of cold water and administered at separate times according to the dosing regimen. The following is a brief summary only; see full Prescribing Ingestion of additional water is important to patient tolerance. Direct Information for complete product information. ingestion of the undissolved powder may increase the risk of nausea, vomiting, dehydration, and electrolyte disturbances. INDICATIONS AND USAGE PREPOPIK® (sodium picosulfate, magnesium oxide and anhydrous ADVERSE REACTIONS citric acid) for oral solution is indicated for cleansing of the colon as a preparation for colonoscopy in adults. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, CONTRAINDICATIONS adverse reaction rates observed in the clinical trials of a drug cannot PREPOPIK is contraindicated in the following conditions: be directly compared to rates in clinical trials of another drug and may • Patients with severely reduced renal function (creatinine clearance not reÀect the rates observed in practice. less than 30 mL/minute) which may result in accumulation of In randomized, multicenter, controlled clinical trials, nausea, headache, magnesium and vomiting were the most common adverse reactions (>1%) • Gastrointestinal obstruction or ileus following PREPOPIK administration. The patients were not blinded to • Bowel perforation the study drug. Since abdominal bloating, distension, pain/cramping, • Toxic colitis or toxic megacolon and watery diarrhea are known to occur in response to colon cleansing • Gastric retention preparations, these effects were documented as adverse events in • An allergy to any of the ingredients in PREPOPIK the clinical trials only if they required medical intervention (such as a change in study drug or led to study discontinuation, therapeutic or WARNINGS AND PRECAUTIONS diagnostic procedures, met the criteria for a serious adverse event), Serious Fluid and Serum Chemistry Abnormalities or showed clinically signi¿cant worsening during the study that was Advise patients to hydrate adequately before, during, and after the not in the frame of the usual clinical course, as determined by the use of PREPOPIK. Use caution in patients with congestive heart investigator. failure when replacing Àuids. If a patient develops signi¿cant vomiting PREPOPIK was compared for colon cleansing effectiveness with or signs of dehydration including signs of orthostatic hypotension a preparation containing two liters (2L) of polyethylene glycol plus after taking PREPOPIK, consider performing post-colonoscopy electrolytes solution (PEG + E) and two 5-mg bisacodyl tablets, all lab tests (electrolytes, creatinine, and BUN) and treat accordingly. administered the day before the procedure. Table 1 displays the most Approximately 20% of patients in both arms (PREPOPIK, 2L of PEG common adverse reactions in Study 1 and Study 2 for the PREPOPIK + E plus two x 5-mg bisacodyl tablets) of clinical trials of PREPOPIK Split-Dose and Day-Before dosing regimens, respectively, each as had orthostatic changes (changes in blood pressure and/or heart rate) compared to the comparator preparation. on the day of colonoscopy. In clinical trials orthostatic changes were documented out to seven days post colonoscopy. Table 1: Treatment-Emergent Adverse Reactions observed in at Fluid and electrolyte disturbances can lead to serious adverse events Least (>1%) of Patients using the Split-Dose Regimen and Dayincluding cardiac arrhythmias or seizures and renal impairment. Fluid Before Regimen** and electrolyte abnormalities should be corrected before treatment with PREPOPIK. In addition, use caution when prescribing PREPOPIK Adverse Study 1: Split-Dose Regimen Study 2: Day-Before Regimen for patients who have conditions or who are using medications that Reaction increase the risk for Àuid and electrolyte disturbances or that may PREPOPIK 2L PEG+E* PREPOPIK 2L PEG+E* increase the risk of adverse events of seizure, arrhythmia, and renal with 2 x (N=296) with 2 x 5-mg (N=305) impairment. n (% = n/N) 5-mg n (% = n/N) bisacodyl Seizures There have been reports of generalized tonic-clonic seizures with the use of bowel preparation products in patients with no prior history of seizures. The seizure cases were associated with electrolyte abnormalities (e.g., hyponatremia, hypokalemia, hypocalcemia, and hypomagnesemia) and low serum osmolality. The neurologic abnormalities resolved with correction of Àuid and electrolyte abnormalities. Use caution when prescribing PREPOPIK for patients with a history of seizures and in patients at risk of seizure, such as patients taking medications that lower the seizure threshold (e.g., tricyclic antidepressants), patients withdrawing from alcohol or benzodiazepines, patients with known or suspected hyponatremia. Use in Patients with Renal Impairment As in other magnesium containing bowel preparations, use caution when prescribing PREPOPIK for patients with impaired renal function or patients taking concomitant medications that may affect renal function (such as diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, or non-steroidal anti-inÀammatory drugs). These patients may be at increased risk for renal injury. Advise these patients of the importance of adequate hydration before during and after the use of PREPOPIK. Consider performing baseline and post-colonoscopy laboratory tests (electrolytes, creatinine, and BUN) in these patients. In patients with severely reduced renal function (creatinine clearance < 30 mL/min), accumulation of magnesium in plasma may occur.

bisacodyl tablets (N=302) n (% = n/N) Nausea 8 (2.6) 11 (3.7) 9 (3.0) 13 (4.3) Headache 5 (1.6) 5 (1.7) 8 (2.7) 5 (1.7) Vomiting 3 (1.0) 10 (3.4) 4 (1.4) 6 (2.0) * 2L PEG + E = two liters polyethylene glycol plus electrolytes solution. **abdominal bloating, distension, pain/cramping, and watery diarrhea not requiring an intervention were not collected tablets (N=298) n (% = n/N)

Stakeholders in the Status Quo Drug companies and venture capital firms have learned the current system, lobbied to modify it to their advantage, adapted to it, and proven themselves capable of prospering in this absurd environment. If society changes the rules, stakeholders will push back to defend

arrhythmias, and prolonged QT in the setting of Àuid and electrolyte abnormalities. This includes patients receiving drugs which may be associated with hypokalemia (such as diuretics or corticosteroids, or drugs where hypokalemia is a particular risk, such as cardiac glycosides) or hyponatremia. Use caution when PREPOPIK is used in patients on nonsteroidal anti-inÀammatory drugs (NSAIDS) or drugs known to induce Antidiuretic Hormone Secretion (SIADH), such as tricyclic antidepressants, selective serotonin re-uptake inhibitors, antipsychotic drugs and carbamazepine, as these drugs may increase the risk of water retention and/or electrolyte imbalance. Consider additional patient evaluations as appropriate. Potential for Altered Drug Absorption Oral medication administered within one hour of the start of administration of PREPOPIK solution may be Àushed from the GI tract and the medication may not be absorbed. Tetracycline and Àuoroquinolone antibiotics, iron, digoxin, chlorpromazine and penicillamine, should be taken at least 2 hours before and not less than 6 hours after administration of PREPOPIK to avoid chelation with magnesium. Antibiotics Prior or concomitant use of antibiotics with PREPOPIK may reduce ef¿ f cacy of PREPOPIK as conversion of sodium picosulfate to its active metabolite BHPM is mediated by colonic bacteria. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B Reproduction studies with PREPOPIK have been performed in pregnant rats at oral doses up to 2000 mg/kg/day (about 1.2 times the recommended human dose based on the body surface area), and did not reveal any evidence of impaired fertility or harm to the fetus due to PREPOPIK. The reproduction study in rabbits was not adequate, as treatment-related mortalities were observed at all doses. A pre and postnatal development study in rats showed no evidence of any adverse effect on pre and postnatal development at oral doses up to 2000 mg/kg twice daily (about 1.2 times the recommended human dose based on the body surface area). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, PREPOPIK should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PREPOPIK is administered to a nursing woman. Pediatric Use The safety and effectiveness of PREPOPIK in pediatric patients has not been established.

Geriatric Use In controlled clinical trials of PREPOPIK, 215 of 1201 (18%) patients were 65 years of age or older. The overall incidence of treatmentemergent adverse events was similar among patients 65 years of age ( 3%) and patients <65 years of age ( 1%). Among all patients 65 years of age, the proportion of patients with successful colon cleansing Electrolyte abnormalities was greater in the PREPOPIK group (81.1%) than in the comparator In general, PREPOPIK was associated with numerically higher rates group (70.9%). of abnormal electrolyte shifts on the day of colonoscopy compared to the preparation containing 2L of PEG + E plus two x 5-mg bisacodyl Renal InsufÀ f ciency tablets. These shifts were transient in nature and numerically similar Patients with impaired renal function or patients taking concomitant between treatment arms at the Day 30 visit. medications that may affect renal function (such as diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor Postmarketing Experience blockers, or non-steroidal anti-inÀammatory drugs) may be at The following foreign spontaneous reports have been identi¿ed during increased risk for further renal injury. Advise these patients of the use of formulations similar to PREPOPIK. Because these events are importance of adequate hydration before during and after the use reported voluntarily from a population of uncertain size, it is not always of PREPOPIK. Consider performing baseline and post-colonoscopy possible to reliably estimate their frequency or establish a causal laboratory tests (electrolytes, creatinine, and BUN) in these patients. relationship to drug exposure. In patients with severely reduced renal function (creatinine clearance < 30 mL/min), accumulation of magnesium in plasma may occur. The Allergic reactions signs and symptoms of hypermagnesemia may include, but are not Cases of hypersensitivity reactions including rash, urticaria, and limited to, diminished or absent deep tendon reÀexes, somnolence, purpura have been reported. hypocalcemia, hypotension, bradycardia, muscle, respiratory paralysis, complete heart block, and cardiac arrest. Electrolyte abnormalities There have been reports of hypokalemia, hyponatremia and OVERDOSAGE hypermagnesemia with the use of PREPOPIK for colon preparation The patient who has taken an overdose should be monitored carefully, prior to colonoscopy. and treated symptomatically for complications.

Cardiac Arrhythmias There have been rare reports of serious arrhythmias associated with the use of ionic osmotic laxative products for bowel preparation. Use caution when prescribing PREPOPIK for patients at increased risk of arrhythmias (e.g., patients with a history of prolonged QT, uncontrolled arrhythmias, recent myocardial infarction, unstable angina, congestive heart failure, or cardiomyopathy). Pre-dose and post-colonoscopy Gastrointestinal ECGs should be considered in patients at increased risk of serious Abdominal pain, diarrhea, fecal incontinence, and proctalgia have been reported with the use of PREPOPIK for colon preparation cardiac arrhythmias. prior to colonoscopy. There have been isolated reports of reversible Colonic Mucosal Ulceration, Ischemic Colitis and Ulcerative Colitis aphthoid ileal ulcers. Ischemic colitis has been reported with the use Osmotic laxatives may produce colonic mucosal aphthous ulcerations of PREPOPIK for colon preparation prior to colonoscopy. However, a and there have been reports of more serious cases of ischemic colitis causal relationship between these ischemic colitis cases and the use requiring hospitalization. Concurrent use of additional stimulant of PREPOPIK has not been established. laxatives with PREPOPIK may increase this risk. The potential for mucosal ulcerations should be considered when interpreting Neurologic colonoscopy ¿ndings in patients with known or suspected inÀammatory There have been reports of generalized tonic-clonic seizures associated with and without hyponatremia in epileptic patients. bowel disease. Use in Patients with SigniÀcant Gastrointestinal Disease If gastrointestinal obstruction or perforation is suspected, perform appropriate diagnostic studies to rule out these conditions before administering PREPOPIK. Use with caution in patients with severe active ulcerative colitis.

money for very large salaries and bonuses for upper-echelon executives.

DRUG INTERACTIONS

We need to modify the current system to encourage drug companies to fund studies that seek better and more beneficial uses for their drugs, and discourage studies seeking statistically significant but biologically minor advantages.

Manufactured by: Ferring Pharmaceuticals (China) Co., Ltd. No. 6 HuiLing Lu (Ferring Road) National Health Technology Park Zhongshan City, Guangdong Province, CHINA Manufactured for: Ferring Pharmaceuticals Inc. Parsippany, N.J. 07054

www.ferringusa.com 1-888-FERRING Drugs That May Increase Risks of Fluid and Electrolyte Abnormalities Use caution when prescribing PREPOPIK for patients with conditions ©2014 Ferring Pharmaceuticals Inc. or who are using medications that increase the risk for Àuid and All rights reserved. Printed in USA. electrolyte disturbances or may increase the risk of seizure, PK/069/2014/US

their current business models. Any changes will be resisted by political action committees, “Harry and Louise” advertisements, positive and negative political pressure, and public relations campaigns that call value pricing “death panels.”

Should We Pay More for Drugs That Work Better and Help the Sick More? The intuitive answer is yes. Just as one would be willing to pay more for a bigger car, a faster car, a safer car or a more attractive car, one would pay more for a drug that offered many extra years of good life than one that offered an extra few months of poor-quality life just before death. Why do these simple market concepts not apply to medications? The market no longer functions. The very high cost for each dose means that few consumers can afford to pay on their own, regardless of how much they value the benefits of the drug, assuming they have the knowledge and judgment to estimate that value. Either society as a whole, or insurance companies, thus participate in whatever market exists to determine drug pricing. Society has set some rules to allow developers of approved drugs to reap profits from their investment—years of exclusive rights to sell based on the drug’s patent. Eventual expiration of the patent allows price-lowering competition. While the patent is valid, it is almost impossible to get drug prices on the Internet—these have become closely guarded industrial secrets. Many new, expensive drugs are marketed through a single or a very limited number of “specialty pharmacies.” I do not know for

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

HMOs that automatically pay solo physicians half what they pay for the same service done in a large group or hospital practice with more negotiating clout. The provided service is judged on absurd “bullet points” emphasizing “boilerplate” and easily fabricated and largely irrelevant lists of present or absent symptoms.

It Is Possible To Charge More For Better Drugs and Less for Marginal Ones

certain why this happens, but I suspect this allows the drug company to charge different prices to different customers, and to maintain discounts given to specific customers, either because of their size or negotiating acumen, and keep them secret from other customers, some of whom may be government or other buyers that forbid discounting below the prices they pay.

The Patient Is Not the Purchaser Intermediaries separate the beneficiary of insurance from the purchaser of insurance, often the government or an employer, who chooses the limits of the policy. The insurer often chooses the drugs for which it will pay, determines the additional cost to beneficiaries and determines what price it will pay, if any. Some states require insurers to pay for approved drugs for approved indications. This is often astute policy for state lawmakers, although not always the wisest use of limited resources. In contrast, the National Institute for Health and Care Excellence (NICE) in Britain evaluates drugs not only for safety and efficacy, but critically on the benefit as it relates to the cost.

Drug Prices Should Be Based On Benefits to the Patient Because what may be a lifesaving drug for one condition may be a poor drug for another, it makes sense to charge more for the drug in the situation in which it is more valuable to the patient.

Can the Same Drug Have Two Prices? Of course it can! A single drug often has many prices, but we are just not used

to having two prices based on the drug’s value; we are used to two or many prices based on the market clout of the purchaser and how this affects the profits of the seller.

Small Purchasers Are at a Big Disadvantage A number of drugs purchased by small practices cannot be obtained for prices at or below reimbursement by Medicare or private insurance companies. If the price I must pay as a solo practitioner with no volume discount is above 106% of average sales price, some other entity is getting a discount I cannot obtain. So, we already have many prices for the same drug made by the same manufacturer. These are not dictated by a free market, nor by the extent of the benefit to patients (the ultimate users); rather, manufacturers manipulate the retail price to maximize profits and avoid the appearance of violating government insurance regulations. Drugs are occupying an ever-bigger chunk of the medical care budget, which already represents about 17% of the U.S. economy. The magnitude of funds being drained from the system for so little return in health, life or function begs for correction.

Bizarre Pay Patterns Dominate For Physicians as Well as Drugs— Both Reflect Economic and Political Clout Bizarre drug-pricing patterns have a parallel in the rules governing physicians’ compensation. It makes sense to pay more for better service, better care, more compassion, better availability and better communication. Instead, we have

This already happens, although the charges are varied not by benefit, but by expense to the insurer. Medication insurers already charge much higher copays for expensive, brand-name drugs than for cheap generics. Some very expensive drugs are not covered at all, or are covered under exceptional circumstances known only to the insurer (listed on the computer screens in front of the clerks we are obliged to call for “prior approvals”). A benevolent and wise insurer, one interested in the care of the sick as well as the cost to society, would charge a small copay for erlotinib to a patient with a lung adenocarcinoma with an exon 19 EGFR deletion, where response for about a year could be expected in 75% of treated patients, and a huge copay for third-line erlotinib in patients with lung cancer with wildtype EGFR, where erlotinib barely has any benefit at all. If the United States had a legislature capable of deliberation based on the needs of the country and its citizens, surely it would replace the current chaotic system—one that produces riches for drug manufacturers, insurance companies and the marketers of both drugs and insurance—with a system that rewards innovation and the development of effective drugs, and with prices somehow tied to both costs and benefits, rather than campaign contributions, access to politicians and skill at smear advertising. The prices paid for very good drugs may have to be very high to compensate for randomized trials with very long follow-up to demonstrate long-term safety and efficacy. Adjuvant therapy for breast cancer is an important example; because rates of death from metastases are already very low for the largest subgroups of patients, any benefits for those few who now still relapse and die must be shown to outweigh toxicity among those who already enjoy long and healthy lives with currently available therapy. In contrast, society would suffer little if the criteria became less stringent for approving marginal drugs for the very ill near the end of their lives, or for diseases that have few effective treatments

59

available, and thus allow faster and lessexpensive drug development. The FDA has already made major strides in this area. Society should demand lower prices as compensation for the lower development costs for these drugs.

The FDA Already Picks Likely ‘Winner’ Drugs for Expedited Development The FDA already has a program to decide which drugs it will support preferentially for development, to help the drug industry bring them to market sooner. The good drugs are designated as likely filling an “unmet need,” and the really good drugs as “breakthroughs.” If the United States had a single-payor system, with the right to bargain with drug companies on price (as do single payors in Canada and the United Kingdom), I suggest that the payor would be unwilling to pay much for poor drugs, and would be willing to pay more for drugs that benefit citizens more and for longer periods. Negotiations could include price; patent protection (there is no reason that drug patent protection must be the same for bad drugs as for good ones); price increases if company-sponsored studies discover a new indication that substantially benefits sick members of society, like a major decrease in relapses when given as adjuvant therapy or major activity against a different disease; and higher prices paid for situations in which the benefit is great, such as years of improved survival without disease.

The Proposal We need to modify the current system to encourage drug companies to fund studies that seek better and more beneficial uses for their drugs, and discourage studies seeking statistically significant but biologically minor advantages. This would be far easier in the setting of a single payor or a very small number of payors. If the government is the single payor, there is no antitrust issue. If there are a small number of private companies acting as negotiators, they need a legislatively mandated negotiating body to shield them from antitrust liability. Wouldn’t it be wonderful if the United States had a Congress that could effectively deal with these issues? ■

Reference 1. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:303-312.

GILEAD, the GILEAD Logo, SOVALDI, and the SOVALDI Logo are trademarks of Gilead Sciences, Inc., or its related companies. Š2013 Gilead Sciences, Inc. All rights reserved. GILP0074 12/13

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62

F D A U P D AT E & P R O D U C T N E W S

GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

Trials, Data Needed To Guide Biosimilar Adoption BY BEN GUARINO Effectively integrating biosimilar drugs into the U.S. market will require careful collaboration between manufacturers and regulators, according to clinicians who spoke during a recent web conference hosted by the Institute for Safe Medication Practices (ISMP). For a number of blockbuster biologic drugs, the road ahead leads to the socalled patent cliff. Several drugs will lose their market protection within the next decade, including adalimumab in 2016 (Humira, Abbott) and trastuzumab in 2019 (Herceptin, Genentech). At the same time, the market for biologics is booming, with worldwide sales climbing from $46 billion in 2002 to $169 billion in 2012, an IMS Health report estimated. As the demand for biologics continues to grow, physicians, regulators and patients are looking to biosimilars, the off-patent compounds that are comparable to biologics—although not identical copies— to help rein in costs. “We definitely need biosimilars as a strategy to reduce our health care costs,” said Edward Li, PharmD, associate professor in the Department of Pharmacy Practice at the University of New England, in Portland, Maine, who spoke during the ISMP seminar. The pathways to approval for biosimilars and generic drugs run parallel, although there are a few important distinctions. Under the Biologics Price Competition and Innovation (BPCI) Act, part of the Affordable Care Act, a manufacturer can apply for a shortened approval process through the FDA. Previously, in 1984, the U.S. Drug Price Competition and Patent Term Restoration Act had paved the way for a standard method of approving nonbranded medication through an Abbreviated New Drug Application. At that time, however, Congress excluded biologic drugs from the abbreviated pathway, citing the difficulty of manufacturing these compounds. “When you consider small molecule drugs,” Dr. Li said during the ISMP conference, “those are relatively simple [to produce] compared to a biologic manufacturing process.”

Big—but Not Easy Part of the challenge arises from the extreme disparity in size of the compounds. With a sequence of 165 amino acids, epoetin, for example, has a molecular mass of about 30,000 Da, hundreds of times larger than inorganic compounds such as the chemotherapy agent cisplatin. And unlike the chemical production of a small molecule compound, creating

a large biologic drug requires living cells. “It’s not quite like synthesizing something in a test tube,” said Leonard Zwelling, MD, MBA, a clinical oncologist and professor of medicine and pharmacology at the University of Texas MD Anderson Cancer Center in Houston, who was not involved with the ISMP web seminar. Because biosimilars are the product of living systems, it will be impossible for other manufacturers to perfectly match the structure of a brand-name biologic. Although a biosimilar could have the majority of the same chemical constituents as a reference drug, post-translational modifications such as protein folding or other biological quirks of a cell line may affect a biosimilar agent’s efficacy. Dr. Li noted that the complexity of producing biosimilars would keep the costs of these drugs higher than the price of traditional generic pharmaceuticals. “But we are going to see some savings compared to the reference product,” he said during the web conference. “Hopefully, that will increase access to expensive therapies.” John Mbagwu, PharmD, a clinical pharmacist for the medical consulting group Optum, said that, on the high end, estimates for the manufacture of a biosimilar would be about $250 million. Although this is a fraction of the average $1.2 billion cost of bringing a new drug to market, manufacturing is not the only expense that the biosimilar approval process will incur. Compared with a generic drug, a biosimilar requires more rigorous safety and efficacy data to earn approval.

Ensuring Biosimilar Safety Approval for generic drugs must show bioequivalence in form, safety and route of administration, and the agents are not required by the FDA to undergo comparative clinical trials. Biosimilars, in contrast, must demonstrate that they are “highly similar” (Figure). To guide manufacturers looking to bring biosimilars to market, the FDA has released three draft recommendations. In a 2012 draft guidance, the agency said that approval of a biosimilar must be based on “data derived from analytical studies, animal studies and a clinical study or studies,” under the BPCI Act. Because biologic drugs are manufactured in cells derived from hamsters, rabbits and other organisms, they pose varying risks for immunogenicity. A patient’s immune system may produce antibodies that neutralize the biologic, or develop antibodies that trigger antibody-mediated disease or other adverse reactions. Dr. Li cited an increase in the number of cases of pure red cell aplasia linked to biologic erythropoietin

Figure. Biosimilar development approach. Adapted from Clin Pharmacol Ther. 2012;91:409-417; http://1.usa.gov/L62id7.

products in the 1990s. “The whole point of this abbreviated biosimilar [approval] pathway is [to allow] the FDA [to] prospectively review these agents, so we don’t have immunogenicity issues in the future,” Dr. Li said. To that end, the FDA has recommended comparative parallel studies in its guidances. But the requirement for clinical data increases the projected costs of biosimilars. Although generic drugs can be purchased at cost reductions of up to 80% of the price of branded versions, a 2011 review reported that estimates for biosimilars prices would be 15% to 30% less than the reference drug (Simoens S. Clinicoecon Outcomes Ress 2011;3:29-36). In June, the CEO of Celltrion announced that the biosimilar version of infliximab, Remsima, would be more than 30% cheaper than Johnson & Johnson’s Remicade. Celltrion is seeking approval for Remsima in Europe, where more than a dozen biosimilars have been approved by the European Medicines Agency. In the European Union, biosimilars saved an estimated $2.6 billion (1.9 billion euros) in 2009, according to the European Generic Medicines Association.

Overcoming Prescriber Skepticism When biosimilars become available in the United States, a large body of clinical data will be needed to help overcome another hurdle—prescribers’ skepticism. Biosimilars of infliximab, such as Remsima, have been studied in patients with rheumatoid arthritis and may rely on “indication extrapolation” to be approved and/or used for inflammatory bowel

disease and other indications. A 2013 study conducted by the market research firm BioTrends found that about 70% of the 90 gastroenterologists surveyed would not prescribe a biosimilar that had only been tested in patients with rheumatoid arthritis. Additional clinical data also will enable certain biosimilars to be labeled “interchangeable,” a term that has already come under fire in the United States. Under a provision of the BPCI, biosimilars deemed interchangeable by the FDA can be substituted without a pharmacist notifying the prescribing physician. A bill passed by California’s state Senate would have voided that provision, requiring pharmacists to notify prescribers which biosimilar drug they had dispensed. Responding to calls from the Generic Pharmaceutical Association and other critics, Gov. Edmund G. Brown vetoed the bill. In a letter to the state Senate, Mr. Brown pointed out that the FDA has not yet determined the standards for interchangeability, writing, “to require physician notification at this point strikes me as premature.” The question to ask becomes not when biosimilars will become available in the United States, Dr. Zwelling said, but when doctors will prescribe them. “Until I see a trial in which the biosimilar and the [reference] drug are compared head to head, in real patients with real cancer,” he said, “I wouldn’t prescribe it, and I wouldn’t let my mother take it.” ■

Dr. Zwelling reported no relevant conflicts of interest. Dr. Li has served on advisory boards for Amgen and Hospira.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

FDA Creates Plan To Combat Drug Shortages BY BEN GUARINO Over the past few years, the FDA has made significant strides in the prevention of drug shortages, circumventing 200 shortages in 2011 and more than 280 in 2012. By the end of December 2012, however, 300 drugs remained in short supply. In October, the FDA outlined a plan to mitigate ongoing drug shortages while averting future supply problems.

“Preventing drug shortages before they begin is a top priority for the FDA,” said FDA Commissioner Margaret A. Hamburg, MD, during a media briefing last fall. “Drug shortages pose a significant public health threat because they can result in serious, or even deadly, outcomes.” Although the FDA currently prevents a large number of shortages each year, the scarcities are occurring at higher frequencies than a decade ago. There were about 60 new drug shortages in 2005, according

to the FDA. By 2011, the number of new shortages had increased to more than 250. In response, Washington took two actions that would provide the impetus for the FDA’s newest plan: an executive order issued by President Obama in 2011 and the passage of the FDA Safety and Innovation Act (FDASIA) in 2012, which gave more muscle to the agency’s regulatory capabilities. At the heart of the FDA’s new strategy are improved lines of communication,

Advances in Probiotic Therapy For Diarrhea-Associated Illness To participate in this FREE CME activity, log on to

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Release Date: February 10, 2014 Chair William D. Chey, MD Professor of Internal Medicine Director, Gastrointestinal Physiology Laboratory Co-Director, Michigan Bowel Control Program H. Marvin Pollard Institute Scholar Division of Gastroenterology University of Michigan Health System Ann Arbor, Michigan

Faculty Brooks Cash, MD

Statement of Need

Intended Audience

Probiotics can be powerful tools in managing a number of medical conditions. However, effi fficacy may be suboptimal if these agents are not used appropriately. As public interest in the benefi fits of probiotics increases, so does the need for clinical education. Many physicians and patients are unfamiliar with the nuances of probiotic pharmacology, or—with many probiotics available for over-the-counter purchase— may not be aware that their patients are selecting ineff ffective therapies. Thus, it is important for health care professionals to familiarize themselves with the latest research data on probiotic use.

Gastroenterologists, primary care physicians, nurse practitioners, nurses, physician assistants, pharmacists, and other health care professionals involved in the care of patients who may benefit fi from the use of probiotic therapy.

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Shanti Eswaran, MD

Learning Objectives

Clinical Assistant Professor Division of Gastroenterology University of Michigan Health System Ann Arbor, Michigan

Expiration Date: February 10, 2015

The goal of this educational activity is to provide clinicians with current evidence and strategies for effecff tive probiotic therapy in a variety of disease states. Upon completion of this activity, the participant will be better prepared to do the following: 1 Review key differentiating ff characteristics of various probiotic therapies, including mechanism of action. 2 Describe the importance of strain specificity fi in the clinical applicability of probiotic therapies.

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with respect to both drug manufacturers and the public. In the short term, the agency plans to streamline its internal response whenever a manufacturer gives notice about a supply problem. Through a proposed rule, any company that produces “medically necessary” drugs must alert the FDA about a discontinuance or interruption in the production of a drug. That way, the agency will be able to provide information about drug shortages to the public. “It might help individual purchasers make plans for the future,” said William L. Greene, PharmD, the chief pharmaceutical officer of St. Jude Children’s Research Hospital, in Memphis, Tenn. “If [the FDA] can update that information quickly, that would probably be a benefit.” A potential hitch, however, could be a discrepancy between what the FDA considers a shortage and a hospital pharmacist’s definition. “If premixed heparin bags are in short supply, it can be tremendously difficult for hospital pharmacies,” said Erin R. Fox, PharmD, director of the Drug Information Service at University of Utah Health Care, in Salt Lake City. “The FDA may not see that as a true shortage.” Patients have been harmed when hospitals mix heparin improperly, Dr. Fox said. Clinicians seeking information about drug shortages have two primary options: a list of shortages and other resources maintained by the American Society of HealthSystem Pharmacists (bit.ly/I834FR), and a drug shortages database maintained by the FDA (1.usa.gov/1bXUZy9). “I tend to not use the FDA database as frequently as I use the [ASHP] database,” Dr. Greene said. “There’s more

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what is “a slam dunk” for purchasers. Under such a program, the price of medications may increase—but drug shortages also contribute to higher costs of medication, Dr. Greene said. The FDA warned that pharmaceuticals purchased from the secondary gray market might worsen the effects of a shortage because these products may be improperly stored or handled. “It troubles me that we have people who are willing to purchase drugs from the gray market,” Dr. Greene said. “I just can’t believe we actually do that.”

Dr. Fox said the University of Utah made a decision in 2001 to prohibit the purchase of drugs from the gray market. “If no one was buying from the gray market,” she said, “it wouldn’t exist.” Dr. Fox said she is “hopeful” that the FDA’s methods will prioritize manufacturing quality. “What’s evident in the plan is the tremendous amount of work the FDA has done. Kudos to them for doing what they can.” ■ The sources had no relevant financial conflicts of interest.

your opinion? Gastroenterology & Endoscopy News is now accepting opinion pieces. Send your thoughts

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information that’s more meaningful to me there.” As part of a long-term approach, the FDA laid out plans to tackle the underlying cause of shortages. “The majority of drug shortages, an estimated 70%, are the result of a breakdown in quality and manufacturing,” Dr. Hamburg said. Under some life-threatening circumstances, the FDA will exercise regulatory discretion as a temporary fix to quality issues. When rubber particles were discovered in Genentech’s Cathflo Activase (alteplase) in March 2013, for example, the FDA allowed the drug to be distributed with a warning that it must be filtered before administration. But such regulatory discretion is not sufficient when drugs are contaminated with bacteria and fungus, or when the production of a drug has been halted. An estimated 30% of U.S. drug-manufacturing capacity is currently offline as a result of FDA actions, Dr. Fox noted. “We cannot solve the challenges of drug shortages alone,” said Douglas Throckmorton, MD, deputy director of the FDA’s Center for Drug Evaluation and Research. He called for a greater emphasis on the quality and stability of the drug supply. “As the FDA has indicated, the current supply chain does not reward manufacturers for quality,” Dr. Greene said. Although the FDA is limited in what it can accomplish, he said, the agency could help the marketplace make decisions that would reward manufacturers for quality. FDASIA asks the FDA to consider the creation of a qualified manufacturing partner program, which Dr. Greene called

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GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

New Acetaminophen Warnings Build on Previous FDA Actions BY DONALD M. PIZZI Following the FDA’s recent announcement that it is asking physicians and other health care professionals to stop prescribing combination drugs that include more than 325 mg of the analgesic and fever reducer acetaminophen, medical professionals, journalists, patients and members of the general population alike took to the Web to weigh in on the ruling. “Acetaminophen doses over 325 mg might lead to liver damage?” wrote one individual on a social media site. “It’s been on the market for 50 YEARS and it took TIL NOW to tell us it DAMAGES the LIVER?” Actually, it was 60 years ago when McNeil first marketed paracetamol (the better known generic name of acetaminophen at the time) in combination with sodium butabarbital, under the trade name Algoson. And liver toxicity from high doses of acetaminophen has been chronicled in the medical literature for years. Overuse of acetaminophen is far and away the most common cause

of acute liver damage in the United States: It is believed that taking higher-than-recommended doses of acetaminophen is quite common, with one study reporting that almost 40% of patients with acute liver failure related to unintentional acetaminophen overuse were taking two or more preparations of the painkiller simultaneously (Myers RP et al. Clin Gastroenterol Hepatol 2008;6:918-925). In its Jan. 14 press statement, the FDA acknowledged that multiple acetaminophen sources taken simultaneously have led to the majority of the toxicity cases. Furthermore, the agency said, there are no data showing that doses greater than 325 mg “provide additional benefit that outweighs the added risks for liver injury.” The FDA also warned against taking more than the recommended dose over a 24-hour period, and against drinking alcohol in combination with acetaminophen. These actions are the next step in the agency’s ongoing effort to reduce the risk for potentially fatal liver damage with acetaminophen use.

A Record of Action Many of the moves the FDA has made over the past five years with regard to acetaminophen have been made with the dangers of high doses of the drug in mind. For example, in 2009, the FDA required manufacturers of over-thecounter (OTC) painkillers and fever reducers to post a warning on their labels of the potential for stomach bleeding and liver damage. That same year, an advisory committee to the FDA recommended strengthening the warning about severe liver injury on the drug labels of prescription products containing acetaminophen. The 2009 panel also voted in favor of

lowering the maximum daily dose of acetaminophen to less than the current 4,000 mg recommendation; reducing the maximum single adult dose from 1,000 to 650 mg; making the 500-mg pill obtainable by prescription only; and, in perhaps its most controversial recommendation, eliminating all prescription products that combine acetaminophen with certain other drugs, like narcotics, from the market. In January 2011, the FDA followed two of the advisory panel’s recommendations: It issued a black box warning regarding liver toxicity for prescription combination products that contained acetaminophen; it also moved to limit the amount of acetaminophen in each see Acetaminophen, page 68

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FDA Seeks Electronic Records for Drug Safety Data BY BEN GUARINO As part of the FDA’s ongoing efforts to evaluate the safety of drugs and biological products, the agency quietly began a search for access to electronic health records (EHRs) in December. The agency plans to use the information gleaned from EHR data to augment its MedWatch reporting system and other actions taken by the FDA’s Office of Surveillance and Epidemiology. In a notice posted to Federal Business Opportunities, a website used by government agencies looking to contract outside vendors, the FDA wrote that it is seeking direct and continued access to EHR data. The agency said it is “not interested [in] developing this database,” because the successful contractor would have to provide the health information for at least 10 million patients. At a minimum, 5 million of these patients would be currently active in the EHR system, and the majority of patients must have been continuously enrolled in the system for three years or longer. The FDA emphasized

that the identities of all patients would be obscured. The Prescription Drug User Fee Act (PDUFA) gives the FDA the legal authority to compile this database information, the agency said in the notice. It cited a provision in PDUFA that enables the FDA to “continue the Agency’s efforts on the standards-based information systems to support how FDA obtains and analyzes post-market drug safety data and manages emerging drug

safety information.” The data provided by the contractor will allow reviewers to “evaluate drug-related safety issues of high regulatory priority in a timely manner” and assess several risk factors. In the notice, the FDA said it sees benefit from access to longitudinal information regarding the patient population. The agency is looking for real-time access to a database that includes demographic and diagnostic information; laboratory test orders and

results; drug and biological agent use; the National Death Index; and health history, including visits to hospitals and specialists. On Jan. 8, the response date for the EHR notice had passed, and three contractors had posted to the website expressing their interest. In a separate notice, the FDA also sought database access to demographic information regarding over-the-counter drug purchases. ■

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GASTROENTEROLOGY & ENDOSCOPY NEWS • APRIL 2014

US Endoscopy Releases New Carr--Locke Injectio on Needle US Endoscopy recently released the new 1.8-mm Carr-Locke Injection Needle, allowing endoscopists to use the Carr-Locke technology across a broader range of smaller-channel endoscopes. The original Carr-Locke needle was introduced in 2001. The new 1.8-mm Carr-Locke Injection Needle provides increased suction capability in standard or larger-channel endoscopes. “Listening and delivering solutions

to our customerrs is what we continue to do best,” said Tony Siracusa, vice president and general manager of US Endoscopy in a press release. “I am thrilled to provvide another offering Locke needle portfolio within the Carr-L that customers can count on.” For more inforrmation about the CarrLocke Injection Needle and other produsendoscopy.com. ucts, visit www.u

Image courtesy of US Endoscopy

—Bassed on a press release from US Endoscopy

Acetaminophen continued from page 66

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pill to 325 mg, setting Jan. 14, 2014 as the deadline by which to comply. In its Jan. 14 statement, the FDA said that roughly half of manufacturers have voluntarily complied with the requirement, adding that “in the future, FDA intends to institute proceedings to withdraw approval of prescription combination drug products containing more than 325 mg of acetaminophen per dosage unit that remain on the market.” Additionally, in October 2013, the FDA issued warnings on potential serious, life-threatening rashes associated with acetaminophen use, including Stevens-Johnson syndrome and toxic epidermal necrolysis. The agency required prescription drugs containing acetaminophen to include a warning about potential skin reactions, and announced it would do so with OTC agents in the future.

Exceptions Can Be Made, More Action To Come The FDA’s warning came with the caveat that in some cases physicians could prescribe up to two tablets containing a maximum of 650 mg of acetaminophen, if appropriate, but stressed the need to consider both the amount of acetaminophen and the prescription painkiller (e.g., opioid) in the tablet being prescribed. The agency also stressed that pharmacists who receive a prescription totaling more than 350 mg acetaminophen should contact the prescribing physician and discuss lower-dose alternatives. The FDA will continue to monitor acetaminophen toxicity, writing in the press statement that it will “address OTC acetaminophen products in another regulatory action.” More information and a list of the products affected by the new ruling can be found at www.fda.gov/acet■ aminophen.

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PillCam Colon Receives FDA Clearance

Image courtesy of Given Imaging

Given Imaging has received clearance from the FDA for PillCam Colon to be used for the detection of colon polyps in patients for whom optical colonoscopy with adequate bowel preparation was incomplete, and complete evaluation of the colon was not technically possible. PillCam Colon received clearance under the direct de novo classification for devices with low to moderate risk that have no predicate on the market.

The PillCam Colon video capsule measures 12 mm × 33 mm and is equipped with two miniature color video cameras, one on each end, a battery and an LED light source. It is designed to be ingested by the patient, and transmits four or 35 frames of data per second to a recording device worn by the patient, for approximately 10 hours. Video images are transferred from the device to a computer, where the physician can review and report the results. Approval of the PillCam Colon was based on data from an 884-patient, 16-site clinical trial studying the accuracy and safety of PillCam Colon compared with optical colonoscopy for the detection of adenomas 6 mm or larger. Sensitivity and specificity of the PillCam were 88% and 82%, respectively. For hyperplastic polyps and adenomas, the positive percent agreement for PillCam Colon and optical colonoscopy was 69%, and the negative percent agreement was 81%. “PillCam Colon will improve patient care by offering a new and effective colon imaging option for patients who have experienced an incomplete colonoscopy,” said Douglas Rex, MD,

Distinguished Professor of Medicine and Chancellor’s Professor, Indiana University School of Medicine, and director of endoscopy, Indiana University Hospital, in Indianapolis. “Among the limited alternatives available after incomplete colonoscopy, PillCam Colon gives us a minimally invasive, radiation-free option that provides endoscopic images of the same basic type that have made colonoscopy so useful.”

According to Given Imaging, incomplete colonoscopies occur in approximately 750,000 patients annually in the United States (Rex DK et al. Am J Gastroenteroll 2006;101:873885; Seeff LC et al. Gastroenterology 2004;127:1670-1677). “Colonoscopy is the most comprehensive option, but for up to 10% of individuals, achieving a complete colonoscopy may not be possible. For those individuals, PillCam Colon

capsule endoscopy could be an effective option to allow their gastroenterologist to complete a colon examination,” said Eric Hargis, CEO, Colon Cancer Alliance. PillCam Colon is commercially available in more than 80 markets, including Japan, Europe, Latin America, Canada, Australia, and parts of Asia and Africa. —Based on a press release from Given Imaging

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Pancreatic Exocrine Insufficiency Part 1 of 2: Treatment Approaches

VIVEK K KADIYALA, MDa SHAD DEAH LAILA SULEIMANAa b DARW WIN L. CONWELL, MD, MS a

Cente er for Pancreatic Disease Brigham m and Women’s Hospital Division n of Gastroenterology, H atology, Hepa t l and d Endoscopy E d Harvarrd Medical School Boston n, Massachusetts b

Professsor of Medicine Ohio State University College of Medicine e Directo or, Division of Gastroenterology, Hepa atology, and Nutrition Ohio State University Wexner Medical Cen nter Columb bus, Ohio

Author Disclosures—Ms. Suleiman and Drs. Conw well and Kad diyala have no conflicts of interest.

I

n Part 1 of this 2-part review, treatment approaches fo or patients with pancrea atic exocrine insufficienc cy (P PEI) are discussed, inclu uding the proper use of

currently FDA-approved pancrelipase preparationss.

Treatment of diagnosed PEI is vital to maintaining nutritional status, thereby preventing exacerbation of complications related to cystic fibrosis (CF) and chronic Nutrition t iti and d lung l health h lth are closely l l pancreatitis titi (CP) (CP).1 N linked; for example, PEI exacerbates pulmonary disease and negatively affects quality of life.1,2 Evidence indicates that maldigestion and malabsorption, secondary to CP and other pancreatic diseases, are associated with serious and potentially fatal complications, such as cardiovascular events associated with low plasma concentrations of high-density lipoprotein cholesterol, apolipoprotein A-I, and lipoprotein A.3 A prospective study of 23 patients recovering from acute pancreatitis and experiencing significant weight loss, demonstrated

that PEI developed in 86% of patients classified d with severe pancreatitis as defined by preset criteria.4 In these patients, pancreatic enzyme replacement therapy 4 (PERT) may hasten h t recovery off pancreatic ti function. f ti Patients who have been diagnosed with pancreatic cancer will require PERT for the remainder of their lives, regardless of concomitant therapies, to improve their level of nutrition and to potentially reduce pain associated with high cholecystokinin levels.5-8 Clinical pancreatic malabsorption may remain despite the use of PERT and therefore requires individualized therapy and monitoring. In addition to PERT, treatment of PEI also should encompass dietary modifications and fat-soluble vitamin supplementation.

G A ST R O E N T E R O LO GY & E N D O S CO P Y N E WS • A P R I L 2 0 1 4

1

Table. FDA-Approved Pancreatic Enzyme (Pancrelipase) Preparations Product

Enzyme Content/Unit Dose, United States Pharmacopeia Units Lipase

Amylase

Protease

Viokace 10,440

10,440

39,150

39,150

Viokace 20,880

20,880

78,300

78,300

Immediate-release capsule Non–enteric-coated

Delayed-release capsules Enteric-coated minimicrospheres Creon 3,000

3,000

15,000

9,500

Creon 6,000

6,000

30,000

19,000

Creon 12,000

12,000

60,000

38,000

Creon 24,000

24,000

120,000

76,000

Creon 36,000

36,000

180,000

114,000

Ultresa 13,800

13,800

27,600

27,600

Ultresa 20,700

20,700

41,400

41,400

Ultresa 23,000

23,000

46,000

46,000

Enteric-coated minitablets

Goals of PERT PERT is the standard therapy for PEI; 93% of patients in the US Cystic Fibrosis Registry are treated with pancreatic enzyme replacements.9 Clinical therapeutic goals of enzyme replacement include optimizing quality of life by correcting macronutrient and micronutrient malabsorption, and reducing or eliminating abdominal symptoms associated with maldigestion.8 In adults, PERT should prevent weight loss and wasting when accompanied by a normal diet.10 The pharmacokinetic objective of PERT is to optimize the nutritional value of each meal by achieving an

2

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

adequate and timely concentration of active enzymes in the duodenal lumen for proper digestion. 5,11-13 Despite the diverse armamentarium of available pancreatic enzyme replacement products (differing in enzyme content, dosage formulation, and coating) individual response to therapy is highly variable and limited, restoring fat absorption to only 80% to 85% of normal function.5,11-14

Pancreatic Enzyme Replacement Products Pancreatic enzyme replacement products were first marketed as powders, tablets, and capsules. All were

Table. FDA-Approved Pancreatic Enzyme (Pancrelipase) Preparations (cont.) Product

Enzyme Content/Unit Dose, United States Pharmacopeia Units Lipase

Amylase

Protease

Delayed-release capsules (cont.) Enteric-coated beads Zenpep 3,000

3,000

16,000

10,000

Zenpep 5,000

5,000

27,000

17,000

Zenpep 10,000

10,000

55,000

34,000

Zenpep 15,000

15,000

82,000

51,000

Zenpep 20,000

20,000

109,000

68,000

Zenpep 25,000

25,000

136,000

85,000

Pancreaze 4,200

4,200

17,500

10,000

Pancreaze 10,500

10,500

43,750

25,000

Pancreaze 16,800

16,800

70,000

40,000

Pancreaze 21,000

21,000

61,000

37,000

Enteric-coated microtablets

Bicarbonate-buffered enteric-coated microspheres Pertzye 8,000

8,000

30,250

28,750

Pertzye 16,000

16,000

60,500

57,500

comprised of porcine pancreatic extracts of lipase, amylase, and protease because of their similar composition to human pancreatic enzymes.15 The United States Pharmacopeia (USP) previously defined standards for 2 pancreatic enzyme preparations—pancreatin and pancrelipase—which are measured in units of lipase activity, as lipase is the lead enzyme.5 Pancreatin, a conventional preparation obtained from ox or swine pancreas, contained no less than 2 USP units of lipase activity and no less than 25 USP units of amylase and protease activity in each milligram.5 Pancrelipase, the newer preparation obtained from swine

pancreas, contains no less than 24 USP units of lipase activity and no less than 100 USP units of amylase and protease activity per milligram.5 Because of the greater number of tablets required to achieve appropriate enzymatic concentration in the duodenum with pancreatin, the newer pancrelipase formulation has replaced the older preparation as the standard for PERT.5 The Table displays the commercially available, FDAapproved pancrelipase enzyme replacement products. Previously, a wide array of unapproved products were available in 2 formulations: uncoated, conventional

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immediate-release and enteric-coated microencapsulated enzymes.5 As of April 2010, only FDA-approved pancreatic enzyme replacement products are commercially available in the United States; at press time, 6 products meet those requirements.16 There are no approved powdered formulations, nor are there any approved generic enzyme preparations. Creon is an appropriate first-line agent as it is approved for use in CP, pancreatectomy, and CF.16 Because of the acidic environment of the stomach, Viokace, the lone uncoated immediate-release preparation, is susceptible to inactivation before reaching the duodenum17,18; its efficacy has been established only when coadministered with proton pump inhibitors (PPIs). Enteric coating with acid-resistant film only allows the pancreatic enzyme replacements to be released from the microencapsulation when the pH exceeds 5.5, targeting release into the small intestine only.5 First introduced in the 1970s, one of the initial challenges with enteric-coated tablets was their inability to dissolve.15 The development of variably sized, enteric-coated microspheres with small diameters (<2 mm) was an attempt to circumvent this issue by facilitating more even distribution within chime throughout gastric emptying.5 However, this theoretical advantage has never been evaluated.5 Taken correctly with food, enzymes last for approximately 1 hour following ingestion.19 When protected from acid degradation either by microencapsulation or by concomitant administration of acid-suppressive therapy, pancrelipase preparations can survive transit through the stomach and effectively decrease steatorrhea.20 CF patients with PEI exhibit a marked decrease in the pancreatic secretion of bicarbonate needed to neutralize gastric acid. Suboptimal bicarbonate secretion results in increased acidity in the gastrointestinal tract, including the duodenum, which may prevent or slow the dissolution of enteric-coated microcapsules, which dissolve over a variable period of time at a pH exceeding 5.5 to 6.0.6,21 Bicarbonate-buffered enzyme preparations have been shown to be effective in CF and may improve activity of delivered enzymes.22,23 The role of bicarbonate is to increase the duodenal pH to 8.5 to 9.0, potentially allowing optimal lipase bioactivity and consequently decreased doses of PERT.24,25 These theoretical advantages require further clinical study and documentation before being recommended as standard initial therapy.

Dosing Strategies and Guidelines PERT should be individualized to achieve a balance between minimizing steatorrhea and maximizing nutritional status.26 Guidelines for the dosing of PERT have

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been issued by the Cystic Fibrosis Foundation (CFF). Weight-based dosing recommendations for PERT, promulgated by the CFF, require adjustment in relation to disease severity and clinical response to optimize fat absorption.26 Pancreatic lipase enzymes are susceptible to acidic deactivation; in order to restore nutrient digestion in patients with PEI, enzymes must be delivered into the duodenal lumen in sufficient quantities and synchronized with meals.26 In adults, intraluminal lipase activity requires a minimum of 40 to 60 IU lipase per minute in postprandial chime throughout the digestive period, corresponding to approximately 25,000 to 40,000 USP units of lipase needed for the digestion of a regular meal. Such doses should reduce steatorrhea to less than 15 g per day of fat.27,28 Unprotected immediate-release uncoated lipase is quickly rendered inactive in the low pH of the gastric environment; up to 10-fold more lipase must be given orally to reach the duodenum and correct steatorrhea.27 There are several enzyme preparations and methods of enzyme delivery designed to avoid gastric inactivation of enzymes. First, administration of a higher-dose preparation may facilitate greater active enzyme delivery to the duodenum; however, the benefits of higherdose preparations must be weighed against potential adverse effects, including bloating, diarrhea, flatulence, hyperuricosuria, and colonic strictures.27,29-32 Second, the administration of acid-suppressing agents such as histamine-2 (H2) receptor blockers or PPIs enables an increase in gastric pH (>4.0) to prevent acid-induced deactivation; however, this approach increases treatment costs, and reported studies have not demonstrated a clear benefit associated with this strategy.28,33-35 Third, the introduction of enteric-coated preparations, which dissolve in a pH greater than 5.5, allows enzyme release to be targeted to the small intestine.5 The CFF consensus-based guideline for the nutrition-related management of adults with CF and PEI was readdressed in 2008.36 The recommended doses include 500 to 2,500 units of lipase per kilogram of body weight per meal or less than 10,000 units of lipase per kilogram of body weight per day, or less than 4,000 units of lipase per gram of dietary fat per day.36 As lipase is the lead enzyme within individual preparations, it is the most important determinant of efficacy in the treatment of steatorrhea. Lipase possesses specific biochemical properties including 1) a marked decrease in synthesis compared with other enzymes in early pancreatic insufficiency fat malabsorption; 2) denaturation secondary to diminished pancreatic bicarbonate secretion; 3) minimal extra-pancreatic lipolysis; and 4) a short intraluminal survival time compared with other enzymes.27,37 In most adults with CP, a minimum

of 30,000 USP units of lipase per meal allows adequate intraluminal digestion of fat and protein.27,37 The dose may need to be titrated to as much as 60,000 to 80,000 USP units lipase per meal because not all of the lipase may reach the proximal small intestine in the active form.27,37 Many patients with CF will require numerous PERT capsules daily—doses of 15 to 25 capsules are common—but doses of lipase in excess of 75,000 units per meal are not recommended.27,37 The timing of PERT ingestion is subject to dietary and individual considerations. Enzymes may be taken before, during, or after the meal or snack. To maximize fat absorption, enzymes may be taken before and during, or during and after, the meal. A recent trial demonstrated that administration of enzymes was most effective when given during or after the meal.38 A nutritional consultation with a registered dietitian knowledgeable in CF care should be available for PEI patients and family members to assist with proper use and understanding of PERT.5 Several drinks and foods (eg, coffee/tea, lollipops, gum, jelly beans, and popsicle), that contain simple carbohydrates and minimal nutritional value, as well as fruit and select fruit juices do not require PERT.19 Usually, half of the standard PERT dosage is administered with snacks, and slightly higher than standard doses may be appropriate for fried foods, pizza, or other high-fat foods.19 The total PERT daily dose should be based on 3 meals and 2 to 3 snacks.5,15,39 Recommended enzyme dose, based on lipase units per kilogram, is decreased for older patients as they weigh more and typically ingest less fat per kilogram of body weight.39 For patients who are unable to swallow capsules, they may be opened and the contents mixed with applesauce, rice cereal, bananas, or an alternate non-alkaline food to facilitate ingestion.14 Because of the risk for micro-coating disruption, the microcapsules cannot be crushed, chewed, or mixed with food for an extended period of time.14 Instead, the capsule beads are to be sprinkled on the food immediately before ingestion. Pancreatic enzyme products are biologic extracts that contain, in addition to the active ingredients, protein and other substances that introduce the potential for enzyme activity to vary from batch to batch.10 Enzyme activity also may vary due to environmental factors and a decline in potency over time, especially with exposure to sunlight, heat, and humidity.10 Enzymes should be stored in a cool, dry environment, and checked consistently for expiration dates.

Adverse Effects of PERT PERT is generally well tolerated at typical therapeutic doses; however, high doses of PERT have

been shown to induce nausea, vomiting, and diarrhea associated with transient intestinal upset, as well as hyperuricemia.5 In the past, the use of powdered preparations of PERT has caused hypersensitivity reactions in some patients.40 Fibrosing colonopathy—a condition associated with ingestion of high doses of PERT—can progress to colonic strictures at its most advanced stage. High-strength microencapsulated products (>20,000 units of lipase) were first commercially available in 1991; 3 years later, the first colonic strictures were reported in patients with CF, suggesting a temporal relation to the introduction of high-strength pancreatic enzyme replacement products. It has been hypothesized that the protease content of the pancreatic enzyme replacement products may cause fibrosing inflammation in some predisposed patients at ultra-high doses.15 Recent studies have suggested that methacrylic acid copolymer, which is used as the acid-resistant coating on certain brands of microencapsulated enzymes, may be the cause of fibrosing colonopathy. Until the cause of fibrosing colonopathy can be ascertained further, it is prudent to avoid excessive doses of microencapsulated products and instead attempt combination therapy with an uncoated product and a PPI or H2-receptor antagonist.26,29 Fibrosing colonopathy should be considered in patients receiving PERT who have evidence of obstruction, bloody diarrhea, or chylous ascites, as well as in patients with abdominal pain and persistent diarrhea, poor weight gain, or a combination thereof. The relative risk for developing this condition in the setting of high-dose pancreatic enzymes ranges from 10 to 200, increasing in a dose-dependent manner. Patients at high-risk for developing fibrosing colonopathy include those administered enzyme doses exceeding 6,000 lipase units per kilogram per meal for more than 6 months, or patients with a history of meconium ileus, distal intestinal obstruction syndrome, recent intestinal surgery, or inflammatory bowel disease.15,26,29-31 Overall, PERT is safe, well-tolerated, and produces few adverse effects if dosed and monitored based on a specific individual’s signs and symptoms.

Vitamin Replacement Therapy Comprehensive management of patients with PEI includes assessment of potential vitamin deficiencies and the use of over-the-counter fat-soluble vitamin supplements.5 Steatorrhea often is associated with malabsorption of the fat-soluble vitamins A, D, E, and K. Vitamin deficiencies may develop as a consequence of fat maldigestion and malabsorption, for which patients with CF and CP are at risk. Nearly half of all patients diagnosed with CF are deficient in vitamins

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A, D, and/or E.41,42 In particular, vitamin D deficiency can lead to complications such as osteoporosis. The odds ratio for fracture in patients with CP is comparable to that for patients with other gastrointestinal diseases associated with a high fracture risk.43 Although all patients with severe PEI should receive a bone scan, it may be more practical to establish a baseline bone mineral density in menopausal patients with PEI, particularly if there is a family history of osteoporosis. Young adults, adolescents, and children with CF often have low levels of vitamin D despite taking daily supplements and consequently also are at high risk for metabolic bone disease.42,44 Although most vitamin deficiencies are not clinically observed, bone demineralization is commonly seen in patients with CF and also may be a reflection of general malnutrition and corticosteroid treatment. Metabolic bone disease has been described in patients with CP, but prospective studies are needed to accurately determine its incidence and prevalence. There is a clinical consensus that a multivitamin and additional dietary supplementation of fat-soluble vitamins A, D, E, and K typically results in rapid normalization of serum markers of malnutrition (albumin) and vitamin deficiency.45

Increased Caloric Requirement And High-Fat Diet Patients with PEI should consume a high-caloric diet with unrestricted fat content that is appropriate for age and clinical status.45 Patients with CF may require anywhere from 20% to 50% more calories than a healthy individual.19 Additional calories are required for catch-up growth, and nutritional assessment should accompany evaluation in all patients.45 The CFF recommends that nutritional status be appropriately managed to avoid unintentional weight loss in patients older than 20 years.36 Additionally, as PEI in CF generally does not represent a risk factor for developing hyperlipidemia, the abundance of dietary fat—the highest density source of calories—is not particularly concerning.46 Meals can be complemented with store-bought nutritional supplements and homemade milkshakes, but these additions should not serve as primary sources of nutrition.19

4.

Boreham B, Ammori BJ. A prospective evaluation of pancreatic exocrine function in patients with acute pancreatitis: correlation with extent of necrosis and pancreatic endocrine insufficiency. Pancreatology. 2003;3(4):303-308.

5.

Ferrone M, Raimondo M, Scolapio JS. Pancreatic enzyme pharmacotherapy. Pharmacotherapy. 2007;27(6):910-920.

6.

DiMagno EP, Malagelada JR, Go VL, et al. Fate of orally ingested enzymes in pancreatic insufficiency. Comparison of two dosage schedules. N Engl J Med. 1977;296(23):1318-1322.

7.

Park RW, Grand RJ. Gastrointestinal manifestations of cystic fibrosis: a review. Gastroenterology. 1981;81(6):1143-1161.

8.

Keller J, Layer P. Pancreatic enzyme supplementation therapy. Curr Treat Options Gastroenterol. 2003;6(5):369-374.

9.

FitzSimmons SC. The changing epidemiology of cystic fibrosis. J Pediatr. 1993;122(1):1-9.

10. Durie P, Kalnins D, Ellis L. Uses and abuses of enzyme therapy in cystic fibrosis. J R Soc Med. 1998;91 (suppl 34):2-13. 11.

Holtmann G, Kelly DG, Sternby B, et al. Survival of human pancreatic enzymes during small bowel transit: effect of nutrients, bile acids, and enzymes. Am J Physiol. 1997;273(2 Pt 1):G553-G558.

12.

Keller J, Runzi M, Goebell H, et al. Duodenal and ileal nutrient deliveries regulate human intestinal motor and pancreatic responses to a meal. Am J Physiol. 1997;272 (3 Pt 1):G632-G637.

13.

Layer P, von der Ohe MR, Holst JJ, et al. Altered postprandial motility in chronic pancreatitis: role of malabsorption. Gastroenterology. 1997;112(5):1624-1634.

14. Littlewood JM, Wolfe SP, Conway SP. Diagnosis and treatment of intestinal malabsorption in cystic fibrosis. Pediatr Pulmonol. 2006;41(1):35-49. 15.

FitzSimmons SC, Burkhart GA, Borowitz D, et al. Highdose pancreatic-enzyme supplements and fibrosing colonopathy in children with cystic fibrosis. N Engl J Med. 1997;336(18):1283-1289.

16.

Giuliano CA, Dehoorne-Smith ML, Kale-Pradhan PB. Pancreatic enzyme products: digesting the changes. Ann Pharmacother. 2011;45(5):658-666.

17.

Gow R, Bradbear R, Francis P, et al. Comparative study of varying regimens to improve steatorrhoea and creatorrhoea in cystic fibrosis: Effectiveness of an enteric-coated preparation with and without antacids and cimetidine. Lancet. 1981;2(8255):1071-1074.

18.

Ansaldi-Balocco N, Santini B, Sarchi C. Efficacy of pancreatic enzyme supplementation in children with cystic fibrosis: comparison of two preparations by random crossover study and a retrospective study of the same patients at two different ages. J Pediatr Gastroenterol Nutr. 1988;7(suppl 1):S40-S45.

References 1.

Schibli S, Durie PR, Tullis ED. Proper usage of pancreatic enzymes. Curr Opin Pulm Med. 2002;8(6):542-546.

2.

Strausbaugh SD, Davis PB. Cystic fibrosis: a review of epidemiology and pathobiology. Clin Chest Med. 2007;28(2):279-288.

3.

Montalto G, Soresi M, Carroccio A, et al. Lipoproteins and chronic pancreatitis. Pancreas. 1994;9(1):137-138.

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19.

Maguiness K, Casey S, Fulton J, et al. Nutrition: pancreatic enzyme replacement In people with cystic fibrosis. www.cff.org/UploadedFiles/LivingWithCF/StayingHealthy/Diet/Nutrition-Pancreatic-Enzyme-Replacement. pdf. Accessed March 12, 2014.

20. DiMagno EP, Go VL, Summerskill WH. Relations between pancreatic enzyme ouputs and malabsorption in severe pancreatic insufficiency. N Engl J Med. 1973;288(16):813-815. 21.

Dutta SK, Russell RM, Iber FL. Impaired acid neutralization in the duodenum in pancreatic insufficiency. Dig Dis Sci. 1979;24(10):775-780.

22. Konstan MW, Strausbaugh SD, Ahrens RC, et al. Pediatr Pulmonol. 2008;43(S31):425. 23. Konstan MW, et al. A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Cross-Over Study to Evaluate the Effectiveness and Safety of a Novel Pancrelipase (PANCRECARB® MS-16) in Reducing Steatorrhea in Children and Adults with Cystic Fibrosis. 2008 North American Cystic Fibrosis Conference. Abstract 618. 24. Brady MS, Garson JL, Krug SK, et al. An enteric-coated high-buffered pancrelipase reduces steatorrhea in patients with cystic fibrosis: a prospective, randomized study. J Am Diet Assoc. 2006;106(8):1181-1186. 25. Kalnins D, Ellis L, Corey M, et al. Enteric-coated pancreatic enzyme with bicarbonate is equal to standard enteric-coated enzyme in treating malabsorption in cystic fibrosis. J Pediatr Gastroenterol Nutr. 2006;42(3):256-261. 26. Layer P, Keller J, Lankisch PG. Pancreatic enzyme replacement therapy. Curr Gastroenterol Rep. 2001;3(2):101-108. 27. Layer P. [Intestinal regulation of pancreatic enzyme secretion: stimulatory and inhibitory mechanisms]. Z Gastroenterol. 1992;30(7):495-497. 28. DiMagno EP LP, Clain JE. Chronic pancreatitis. In: Go VL ed. The Pancreas: Biology, Pathobiology and Disease. 2nd ed. New York, NY: Raven Press, Ltd, 1993. 29. Lebenthal E. High strength pancreatic exocrine enzyme capsules associated with colonic strictures in patients with cystic fibrosis: “more is not necessarily better.” J Pediatr Gastroenterol Nutr. 1994;18(4):423-425. 30. Mac Sweeney EJ, Oades PJ, Buchdahl R, et al. Relation of thickening of colon wall to pancreatic-enzyme treatment in cystic fibrosis. Lancet. 1995;345(8952):752-756. 31.

Bansi DS, Price A, Russell C, et al. Fibrosing colonopathy in an adult owing to over use of pancreatic enzyme supplements. Gut. 2000;46(2):283-285.

32. Stapleton FB, Kennedy J, Nousia-Arvanitakis S, et al. Hyperuricosuria due to high-dose pancreatic extract therapy in cystic fibrosis. N Engl J Med. 1976;295(5):246-248. 33. Regan PT, Phillips SF, Dimagno EP. Pancreatic insufficiency and Menetrier’s disease. Report of a case with

clinical response to pancreatic enzyme replacement. Am J Dig Dis. 1978;23(8):759-762. 34. Carroccio A, Pardo F, Montalto G, et al. Use of famotidine in severe exocrine pancreatic insufficiency with persistent maldigestion on enzymatic replacement therapy. A long-term study in cystic fibrosis. Dig Dis Sci. 1992;37(9):1441-1446. 35. Heijerman HG, Lamers CB, Bakker W. Omeprazole enhances the efficacy of pancreatin (pancrease) in cystic fibrosis. Ann Intern Med. 1991;114(3):200-201. 36. Stallings VA, Stark LJ, Robinson KA, et al. Evidencebased practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review. J Am Diet Assoc. 2008;108(5):832-839. 37. DiMagno EP, Go VL, Summerskill HJ. Intraluminal and postabsorptive effects of amino acids on pancreatic enzyme secretion. J Lab Clin Med. 1973;82(2):241-248. 38. Domínguez-Muñoz JE, Iglesias-García J, Iglesias-Rey M, et al. Effect of the administration schedule on the therapeutic efficacy of oral pancreatic enzyme supplements in patients with exocrine pancreatic insufficiency: a randomized, three-way crossover study. Aliment Pharmacol Ther. 2005;21(8):993-1000. 39. Borowitz DS, Grand RJ, Durie PR. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. Consensus Committee. J Pediatr. 1995;127(5):681-684. 40. Whitcomb D, Lowe M. Hereditary and childhood disorders of the pancreas, including cystic fibrosis. In: Feldman M, Friedman L, Brandt L, eds. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease Pathophysiology/Diagnosis/Management. Volume 1. 9th ed. Philadelphia, PA: Saunders, 2010. 41. Layer P, Keller J. Lipase supplementation therapy: standards, alternatives, and perspectives. Pancreas. 2003;26(1):1-7. 42. Rovner AJ, Stallings VA, Schall JI, et al. Vitamin D insufficiency in children, adolescents, and young adults with cystic fibrosis despite routine oral supplementation. Am J Clin Nutr. 2007;86(6):1694-1699. 43. Tignor AS, Wu BU, Whitlock TL, et al. High prevalence of low-trauma fracture in chronic pancreatitis. Am J Gastroenterol. 2010;105(12):2680-2686. 44. Caldeira RJ, Fonseca Vde M, Gomes SC, Jr., et al. Prevalence of bone mineral disease among adolescents with cystic fibrosis. J Pediatr. (Rio J) 2008;84(1):18-25. 45. Ramsey BW, Farrell PM, Pencharz P. Nutritional assessment and management in cystic fibrosis: a consensus report. The Consensus Committee. Am J Clin Nutr. 1992;55(1):108-116. 46. Slesinski MJ, Gloninger MF, Costantino JP, et al. Lipid levels in adults with cystic fibrosis. J Am Diet Assoc. 1994;94(4):402-408.

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Optimizing the Prevention and Management of Postsurgical Adhesions To participate in this FREE CME activity, log on to

www.CMEZone.com and enter keyword “MN125” Release date: December 1, 2012

Chair

Jon Gould, MD Chief, Division of General Surgery Alonzo P. Walker Chair in Surgery Associate Professor of Surgery Medical College of Wisconsin Senior Medical Director of Clinical Affairs Froedtert Hospital Milwaukee, Wisconsin

Faculty

Michael J. Rosen, MD Associate Professor of Surgery Division Chief, General Surgery University Hospitals Case Medical Center Cleveland, Ohio

Statement of Need Adhesions are the most common complication of abdominopelvic surgery, developing postoperatively in 50% to 100% of all such interventions. They can lead to serious medical complications, substantial morbidity, high monetary costs, large surgical workloads, dangerous and difficult reoperations, and an increasing number of medicolegal claims. An official definition of the Sponsored by

Expiration date: September 1, 2014 condition has not been established, and an unequivocally effective prevention method has not been identified. A standardized classification for adhesion assessment and scoring also is lacking, as are guidelines for diagnosis and management. To close these gaps, clinician education is necessary.

Goal The goal of this educational activity is to provide surgeons with up-to-date, clinically useful information concerning the prevention and management of postoperative adhesions.

Learning Objectives 1 Review the pathophysiology and complications of postoperative adhesion formation. 2 Summarize current strategies used to prevent postoperative adhesion formation. 3 Describe the various types of barrier materials used to prevent postoperative adhesion formation.

Intended Audience The intended audience for this educational activity includes general surgeons, vascular surgeons, colon and rectal surgeons, critical care surgeons, surgical oncologists, trauma surgeons, and thoracic surgeons. Supported by an Educational Grant from

Estimated Time for Completion: 60 minutes Course Format Monograph (print and online)

Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Medical College of Wisconsin and Applied Clinical Education. The Medical College of Wisconsin is accredited by the ACCME to provide continuing medical education for physicians.

Designation of Credit Statement The Medical College of Wisconsin designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit™. t Physicians should only claim credit commensurate with the extent of their participation in the activity.

Method of Participation There are no fees for participating in or receiving credit for this activity. To receive CME credit, participants should read the preamble and the monograph and complete the post-test and evaluation. A score of at least 70% is required to complete this activity successfully. Distributed via

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