November 2013

1978 —

35th Anniversary — 2013

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The Independent Monthly Newspaper for Gastroenterologists

Volume 64, Number 11 • November 2013

DDW 2013

EXPERT ROUNDTABLE

FODMAPS for IBS Who Will Benefit?

Private Practice e vs. Hospitals in Today’s Health alth Ca Care Sys stem: Friends or Foes?

BY CAROLINE HELWICK

With Similar Goals and Challengess, Creating a Win–Win Situation

ORLANDO, FLA.—Malabsorption of dietary carbohydrates can cause irritable bowel syndrome (IBS)-like symptoms including bloating, cramps and diarrhea. But according to Robert J. Shulman, MD, these symptoms may have less to do with the inability to absorb these substances and more to see Diet, page 16

Probiotics: What’s The Evidence?

BY CAROLINE HELWICK ORLANDO, FLA.—Probiotics have caught on as a means of alleviating a variety of gastrointestinal (GI) afflictions; however, a lack of clinical evidence regarding their efficacy remains, according to a presentation at the 2013 Digestive Disease Week

BY MONICA J. SMITH BOSTON—As stakeholders at all levells speculat ate, grapple with and attempt to adjust to anticipated d dramatic changes in health care, it iss clear that relationships between payors, hospitals, physicians and patients are shifting. The Affordable Care Act (A ACA) emphasizes coordination and integrated ap pproaches to patient care, arguably to the bettermeent of all involved. New models for caare delivery, such ch as accountable care organizations (A ACOs), also requi uire tight and timely cooperation.

But ut with so much as yet undecided d or simply unknow own, angst and uncertainty abou und. Hospitals and d private practices will experien nce unique, but somew ewhat different, challenges as th hey adjust to systemwide de changes wrought by health care reform.

For example ple, the patient population n will soon see ACA, page 7

see Probiotics, page 25

I N S I D E

Guidelines Offer Alternative to Inva vasive Diagnosis of Celiac Disease in Childr dren

BY TED BOSWORTH ORLANDO, FLA.—New diagnostic criteria to reduce the need ed for endoscopy and duodenal biopsies in children with suspected celiac disease are effective, according to two studies presented at the 2013 Digestive Disease Week meeting. The results predicted a substantial see Celiac Guidelines, page 26

OPT IN

Gastrrointestinal Cancers Endosc scopic Mucosal Resection Equivalent to Esoph hagectomy for Early Esophageal Cancer .................................................................... page 28 W Weight Loss Reduces Risk for CRC Diagnosis, Mortality..................................................... page 30 Most Patients With Metastatic CRC Lack KRAS Testing............................................. page 34 Hodgkin Lymphoma Treatment Increases Stomach Cancer Risk................................ page 37

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Important Safety Information SUPREP® Bowel Prep Kit (sodium sulfate, potassium sulfate and magnesium sulfate) Oral Solution is an osmotic laxative indicated for cleansing of the colon as a preparation for colonoscopy in adults. Most common adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal pain, nausea, vomiting and headache.

Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to components of the kit. Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reflex, regurgitation or aspiration, severe active ulcerative colitis, impaired renal function or patients taking medications that may affect renal function or electrolytes.

Use can cause temporary elevations in uric acid. Uric acid fluctuations in patients with gout may precipitate an acute flare. Administration of osmotic laxative products may produce mucosal aphthous ulcerations, and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Patients with impaired water handling who experience severe vomiting should be closely monitored including measurement of electrolytes. Advise all patients to hydrate adequately before, during, and after use. Each bottle must be diluted with water to a final volume of 16 ounces and ingestion of additional water as recommended is important to patient tolerance.

Please see brief summary of Prescribing Information on adjacent page.

3

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2013

From the Literature

Molecular Sequencing off C. difficile Reveals Unexpected Routes of Infection New Data Dispel Old Theories About Infection Control

BY BEN GUARINO A study of the genetic diversity of Clostridium difficile has surprised researchers and shed new light on the way this pathogen may be transmitted between patients.

“Unexpectedly few cases appear to be acquired from direct ward-based

contact with other symptomatic cases,” said study author David Eyre, MB, ChB, a clinical researcher at the University of Oxford, England. “These have previously been thought to be the main source of infections, and the focus of prevention efforts.”

The traditional view of C. difficile transmission is that, in hospital settings, the disease spreads through

spores released from an infected patient’s diarrhea. Infection prevention efforts frequently focus on sterilization, using sporicides like sodium hypochlorite to disinfect hospital wards. But the new study by Dr. Eyre and his colleagues shows that clinicians may want to adopt a wider lens when looking for sources of C. difficile (Eyre DW et al. N Engl J Med 2013;369:1195-1205).

“The findings are striking in that we usually talk about transmission from symptomatic patients in hospitals,” said Curtis J. Donskey, MD, professor at Case Western Reserve University and an infectious disease physician at the Louis Stokes Cleveland VA Medical Center in Ohio, who was not involved with the study. “This study clearly suggests that there are additional sources of C. difficile acquisition.”

‘Unexpectedly few cases appear to be acquired from direct wardbased contact with other symptomatic cases.’

—David Eyre, MB, ChB

SUPREP Bowel Prep Kit. Because the quality of cleansing matters.

• Effective bowel cleansing2,3 in all bowel segments1

• Low volume

• ACG-recommended split-dose regimen

• No sodium phosphate

References: 1. Rex DK, DiPalma JA, Rodriguez g R, McGowan J, Cleveland M. A randomized clinical studyy comparing p g reduced-volume oral sulfate solution with standard 4-liter sulfate-free electrolyte lavage g solution as ppreparation p for colonoscopy. py Gastrointest Endosc. 2010;72:328-336. 2. DiPalma JA, Rodriguez g R, McGowan J, Cleveland MvB. A randomized clinical study evaluatingg the safety and efficacy of a new, reduced-volume, oral sulfate colon-cleansing preparation for colonoscopy. Am J Gastroenteroll. 2009;104:2275-2284. 3. SUPREP Bowel Prep Kit [package insert].

Braintree, MA: Braintree Laboratories, Inc; 2010.

BRIEF SUMMARY: Before pprescribing, g please p see full Prescribing Information and Medication Guide for SUPREP® Bowel Prepp Kit (sodium sulfate, ppotassium sulfate and magnesium g sulfate) Oral Solution. INDICATIONS AND USAGE: An osmotic laxative indicated for cleansingg of the colon as a ppreparation p for colonoscopy py in adults. CONTRAINDICATIONS: Use is contraindicated in the followingg conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, g ggastric retention, ileus, known allergies g to components p of the kit. WARNINGS AND PRECAUTIONS: SUPREP Bowel Prepp Kit is an osmotic laxative indicated for cleansingg of the colon as a ppreparation p for colonoscopy py in adults. Use is contraindicated in the followingg conditions: ggastrointestinal (GI) obstruction, bowel pperforation, toxic colitis and toxic megacolon, g ggastric retention, ileus, known allerggies to components of the kit. Use caution when pprescribingg for patients p with a historyy of seizures, arrhythmias, y impaired p ggagg reflex, regurgitation g g or aspiration p , severe active ulcerative colitis, impaired p renal function or ppatients takingg medications that mayy affect renal function or electrolytes. y Pre-dose and post-colono p scopy ECG’s should be considered in ppatients at increased risk of serious cardiac arrhythmias. y Use can cause temporary p y elevations in uric acid. Uric acid fluctuations in ppatients with ggout mayy pprecipitate p an acute flare. Administration of osmotic laxative products p mayy pproduce mucosal aphthous p ulcerations, and there have been reports of more serious cases of ischemic colitis requiring q g hospitalization. p Patients with impaired p water handlingg who experience p severe vomitingg should be closelyy monitored includingg measurement of electrolytes. y Advise all patients p to hydrate y adequately q y before, during, g and after use. Each bottle must be dilutted with water to a final volume of 16 ounces and ingestion g of additional water as recommended is important p to patient p tolerance. Pregnancy: g y Pregnancy g y Category g y C. Animal reproduction p studies have not been conducted. It is not known whether this product can cause fetal harm or can affect reproductive p capacity. p y Pediatric Use: Safetyy and effectiveness in ppediatric ppatients has not been established. Geriatric Use: Of the 375 ppatients who took SUPREP Bowel Prepp Kit in clinical trials, 94 (25%) were 65 years of age g or older, while 25 (7%) were 75 years of age g or older. No overall differences in safety or effectiveness of SUPREP Bowel Prep Kit administered as a split-dose p (2-day) y regimen g were observed between geriatric g patients p and yyounger g patients. p DRUG INTERACTIONS: Oral medication administered within one hour of the start of administration of SUPREP mayy not be absorbed completely. p y ADVERSE REACTIONS: Most common adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal ppain, nausea, vomitingg and headache. Oral Administration: Split-Dose p (Two-Day) y Regimen: g Earlyy in the eveningg pprior to the colonoscopy: ppy Pour the contents of one bottle of SUPREP Bowel Prepp Kit into the mixingg container pprovided.

Fill the container with water to the 16 ounce fill line, and drink the entire amount. Drink two additional containers filled to the 16 ounce line with water over the next hour. Consume onlyy a light g breakfast or have onlyy clear liquids q on the dayy before colonoscopy. py Dayy of Colonoscopy py (10 to 12 hours after the eveningg dose): Pour the contents of the second SUPREP Bowel Prepp Kit into the mixingg container provided. p Fill the container with water to the 16 ounce fill line, and drink the entire amount. Drink two additional containers filled to the 16 ounce line with water over the next hour. Complete all SUPREP Bowel Prep Kit and required water at least one hour prior to colonoscopy.y Consume only clear liquids until after the colonoscopy. STORAGE: Store at 20°-25°C (68°-77°F).

Excursions permitted between 15°-30°C (59°-86°F). Rx only. Distributed by Braintree Laboratories, Inc. Braintree, MA 02185 For additional information, please call 1-800-874-6756 or visit www.suprepkit.com ©2012 Braintree Laboratories, Inc.

SU-13280T

January, 2012

To determine the potential sources of C. difficile infections, Dr. Eyre and his colleagues tested samples from all inpatients with diarrhea at the four Oxford University Hospitals in the Oxfordshire region of England.

Between September 2007 and March 2011, the researchers performed whole-genome sequencing on more than 1,200 isolates, looking for singlenucleotide variants (SNVs) that indicate if the bacteria are genetically similar or distinct. By comparing sequences taken before April 2008 with later sequences, the researchers could determine which C. difficile cases were evolutionarily similar, defined as a difference of less than two SNVs. The researchers successfully sequenced 1,223 isolates of C. difficile. Comparing 957 isolates obtained between April 2008 and March 2011 with samples obtained from September 2007 onward, they found that only 13% of patients had isolates that were genetically related and also had close hospital contact with another patient, which had been thought to be the primary route of C. difficile transmission.

Overall, 333 isolates (35%) were genetically similar to earlier cases, and 428 isolates (45%) had 10 or more SNVs compared with all previous cases. see C. difficile, page 4

4

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2013

From the Literature

C. difficile continued from page 3

“Distinct subtypes of infection continued to be identified throughout the study,” the authors wrote. This diversity, Dr. Eyre said, indicates a “reservoir of disease not previously appreciated.”

‘The study really raises a lot of questions.

It would require a great deal of work to tell us if [C. difficile] was acquired in a hospital, outpatient clinic, nursing home or other source.’

Implications for Infection Control During the three years of the study, the rate of C. difficile infections in Oxfordshire fell, not only in hospitals but also in community-acquired cases.

“In England, [there is] a lot of media attention related to C. difficile outbreaks,” Dr. Donskey said. Infection control efforts described in this article go beyond what is normally seen in the United States, he noted.

At the Oxford University Hospitals, these efforts included daily sterilization with bleach in the rooms of patients with confirmed or suspected C. difficile, preemptive isolation of suspected cases and continued monitoring and feedback for noncompliance.

But Dr. Eyre doesn’t believe that improvements in infection control

—Curtis J. Donskey, MD contributed to the observed decline in C. difficile infections during the study.

“It is likely that the fall in incidence in C. difficile was due to restricting the use of antibiotics rather than an improvement in infection control,” Dr. Eyre said. The administration of quinolones and cephalosporin fell significantly in the United Kingdom over the three years of the study, he noted.

Antimicrobial stewardship remains a vital part of keeping C. difficile transmission low.

“It’s not uncommon for transmission to occur in patients who received antibiotics when not necessary,” Dr. Donskey said, for example, in patients who contracted C. difficile after being prescribed antibiotics for dental procedures or viral respiratory infections.

Earlier research has suggested that water, pets and food may harbor C. difficile (Hensgens MP et al. Clin Microbiol Infect 2012;18:635-645), but tracing infections back to those sources would be difficult.

“The study really raises a lot of questions,” Dr. Donskey said. “It would require a great deal of work to tell us if it was acquired in a hospital, outpatient clinic, nursing home or other source.”

According to the Centers for Disease Control and Prevention (CDC), C. difficile infects about 250,000 people in the United States each year.

The pathogen causes severe diarrhea, linked to 14,000 deaths annually, and the CDC recently labeled it an “urgent threat” based on a new classification system of drugresistant microbes. Although C. difficile does not yet show widespread drug resistance, it is associated with antibiotic overuse, flourishing in patients whose gut bacteria have been eradicated by broad-spectrum antimicrobials.

“One of the real messages of the study,” Dr. Donskey noted, “is that since there are a variety of potential sources [of C. difficile infection] and not just hospitals, we need to make an effort to reduce the number of susceptible patients by avoiding the ■ unnecessary use of antibiotics.”

Vol. 64, No. 11 MEDICAL ADVISORY BOARD MANOOP S. BHUTANI, MD

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Sacramento, California

PETER R. MCNALLY, DO

Cleveland, Ohio

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LETTER TO THE EDITOR

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2013

Stretta Supported by Plethora of Evidence Re: “Endoscopy Spares Some From PPIs,” By Ted Bosworth.

Gastroenterology & Endoscopy News September 2013;64:1,16.

To the Editor: I respectfully submit this letter in response to the article in the September 2013 issue of Gastroenterology & Endoscopy Newss entitled, “Endoscopy Spares Some from PPIs.” Although the main body of the article was correct, in particular the section detailing the recent 10-year, open-label Stretta prospective study, along with mention of the 32 studies “conducted to evaluate Stretta,” these facts were contradicted by inaccurate comments later in the same article. The comments in question are: • “There are lots of abstracts, but few peer-reviewed articles”; 1978 —

• “Stretta remains poorly supported by evidence”; and • “Few Stretta procedures are performed in academic centers of excellence.”

These incorrect statements merit attention and correction, and herein is a presentation of the facts.

Regarding the statement “There are lots of abstracts, but few peer-reviewed articles,” quite the opposite is true.

Although there are dozens of compelling abstracts, there are more than 80 peer-reviewed articles. Included in this significant body of peer-reviewed publications are:

35th Anniversary — 2013

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BY TED BOSWORT R H ORLANDO, FLA.—Data on two endoscopic procedures for treating gastroesophageal reflux disease (GERD) show that the procedures are capable of eliminating, or greatly reducing, dependence on proton pump inhibitor (PPI) therapy. Findings were presented at the 2013 Digestive Disease Week meeting. e 16 16 see Antireflux Procedures, page

For IBD, ‘Decade of IImmunomonitoring’ it i ’

BY DAVID WILD ORLANDO, FLA.—An increasing number of studies indicate that a triad of measurable variables—including serum drug levels, levels of antibodies to certain drugs and mucosal healing—can help clinicians optimize the safety and efficacy of biologic treatments in patients with inflammatory bowel disease (IBD). see Immunomonitoring, page 13

Patient Satisfaction and d To Maintaining Competiit

BY MONICA J. SMITH BOSTON—At this year’s annuaal ton in March, approximately 25 50 nurses and practice managers ga g health care reform and the futtu u roster included a bevy of speaakke

Antireflux An nti Procedures V Ì Õi`ÊvÀ Ê«>}iÊ£ V Ì Õ Ì

On ne of the procedures, EsophyX2, a transoral fundoplication technique, has outcome data aavailable for six months post-procedure.

The o other procedure, Stretta, a radiofrequency technique that augments the integrity of the lower esophageal sphincter (LES), has been in clinicaal use long enough to generate outcome data aat 10 years.

‘Stretta demonstrates a significant sustained improvement measured in quality of life, patient satisfaction, and reduced need for PPIs. Overall, 64% of patients either eliminated or reduced pre-Stretta PPI use.’

—Mark Noar, MD

EsophyX2 In a randomized, multicenter study for EsophyX2, the primary end point of complete elimination of GERD symptoms was achieved in 62% of patients compared with 5% of those who were placed on a maximal dose of PPIs. Of those treated with EsophyX2, 90% were completely off PPIs at six months.

The key eligibility criteria for participation in the EsophyX2 trial were persistent, troublesome, daily GERD symptoms and a regimen of PPI see Diagnosis, page 10 therapy for at least six months. Exclusion criteria included a hiatal hernia greater than 2 cm in axial I N S I D E length; esophagitis of grade C or higher; or obesity.

Patients were randomized in a 2:1 ratio to undergo EXPERTS’ PICKS EsophyX2 or to increase to a full PPI dosage.

The Best of Digestive Disease Week (DDW): Part 3 The EsophyX2 procedure involves creating a circumferential valve at the gastroesophageal page 20 junction. Physicians do require training but the procedure is not considered technically challenging. In this study, EsophyX2 was performed by both surgeons and gastroenterologists, and the average length of the procedure was 38 minutes.

All procedures were completed without significant adverse events (AEs), such as blood transfusion or hospital readmission.

Of the 196 patients screened for the study, 63 see Patient Satisfaction, page 30 were randomized and the outcomes of 60 were available for analysis after three patients were lost CLINICAL REVIEW PRODUCT ANNOUNCEMENT to follow-up, according to lead investigator, Karim see insert between pages 18 and 19 see page 49 for product information S. Trad, MD, clinical professor of surgery, George B Washington University Medical Faculty Associates, Washington, D.C. When evaluated with 48-hour pH monitoring, pH was normalized in 54% of patients who underwent the procedure and were off all PPI treatments versus 52% in the control group on maximum of doses PPIs. Healing of esophagitis was Dr. Trad also said that a study using a sham proceachieved in 90% of those patients treated with tran- dure is now under way that “will not burn any bridges,” soral fundoplication compared with 38% of those who so that other procedures, including conventional funremained on PPIs (P=0.004). According to patient doplication, can be performed in the event of an inadquestionnaires, 72% of patients in the EsophyX2 group equate response. were satisfied with the procedure compared with 5% of patients in the PPI group. EsophyX2 also was sig- Stretta nificantly favored on specific quality-of-life measures.

An open-label, prospective study of 217 patients proAccording to Dr. Trad, this procedure “avoids the vided long-term outcome data on the Stretta procedure. undesirable post-fundoplication AEs such as bloating, A single endoscopist performed all of the procedures, flatulence, or dysphagia.” Dr. Trad did acknowledge that the first of which was performed in August 2000. A sub10% of patients in that group were back on PPIs at the group of patients was followed for more than 10 years. last follow-up, but he noted, “They were now respond“Stretta demonstrates a significant sustained improveing better to therapy, so [surgery] still seems to be a use- ment measured in quality of life, patient satisfaction ful adjunct in this group.” and reduced need for PPIs,” said Mark Noar, MD, Although much longer follow-up studies are needed Heartburn and Reflux Center, Endoscopic Microsurto verify a sustained benefit of EsophyX2, Dr. Trad said gery Associates, Towson, Md. “Overall, 64% of patients that up to two years of follow-up from an earlier series either eliminated or reduced pre-Stretta PPI use.” of patients does exist and has not shown any significant Stretta emerged at a time when a variety of endodeterioration in benefit. scopic procedures were proposed to increase the barrier

function of the LES. Almost all of these have subsequently been abandoned, but Stretta, which received FDA approval in 2000, is still available.

By one count, 32 studies have been conducted to evaluate Stretta, and the procedure also is included in the guideline recommendations of the Society of American Gastrointestinal and Endoscopic Surgeons for the treatment of GERD. In the most recent study, patient satisfaction scores showed no substantial diminution at intervals of one, two, three, four and 10 years in the data presented by Dr. Noar.

Based on the long-term benefit of Stretta in a patient population with inadequate GERD control despite twice-daily PPI use, Dr. Noar called this “mature endoscopic procedure … safe, clinically effective and economically effective.”

Linx Reflux Management System Explored Asked to comment about these procedures, Joel Richter, MD, director of the Division of Digestive Diseases and Nutrition, University of South Florida, Tampa, was cautious about both studies. With regard to the EsophyX2 device, Dr. Richter said that normalization of acid occurred only in about 50% of patients, whereas in other procedures—notably the Linx Reflux Management System—normalization has been achieved in almost 70% of patients. With 10% of EsophyX2 patients back on PPIs at six months, he also suggested that long-term follow-up will be crucial to confirm that this rate remains low.

Regarding the Stretta results, Dr. Richter said that the study was a single-center experience from a private practice, and that Stretta remains poorly supported by evidence. “There are lots of abstracts, but few peer-reviewed articles.”

Dr. Richter added it was worth noting that few Stretta procedures are performed in academic centers of excellence.

Asked for a surgeon’s perspective, Reginald Bell, MD, founder of SurgOne Foregut Institute, Englewood, Colo., and principal investigator of a study with up to two years of follow-up data for EsophyX, said previous studies have typically recruited patients who have responded positively to PPIs and then randomized them to continued PPIs or surgery. He noted that poor response to PPIs often predicts poor response to surgery. In contrast, this study recruited poor responders to PPIs, which Dr. Bell said typically represent the largest pool of candidates for surgery.

The high response rate “is a very important finding because we can recommend this therapy to patients with documented GERD, even if their response to PPI therapy is poor,” he said.

He added that the most recent data on the Linx Reflux Management System (Ganz RA et al. N Engl J Medd 2013;368:719-727) showed normalization of acid in 58% of patients at year 1, which is similar to that achieved with the EsophyX system.

■ Dr. Trad is a consultant for EndoGastric Solutions.

Dr. Noar is a consultant for Mederi Therapeutics Inc. Dr. Bell has received a research grant from EndoGastric Solutions. Dr. Richter reported no conflicts of interest.

1. Four adequately powered randomized controlled trials; 2. Thirty-two prospective observational studies employing validated and standardized measurement tools; 3. One meta-analysis that examines data from 18 Stretta trials involving approximately 1,500 patients, demonstrating significant improvements in, among other measures, lower esophageal sphincter (LES) pressure and a significant reduction and/or normalization of esophageal pH; 4. Multiple studies demonstrating reduction in transient LES relaxations as a treatment effect; 5. Proof-of-concept studies demonstrating: a. reduction in LES compliance as the direct treatment effect; b. decreased acid exposure to the esophagus, resulting in significant symptomatic improvement; c. a significant increase in LES wall thickness following Stretta, thus restoring the natural barrier effect of the LES; d. improvement in gastric yield pressure; and e. resolution of gastroesophageal reflux disease (GERD)associated gastroparesis and improved gastric motility; 6. Multiple long-term studies—including three studies of at least four years—demonstrating durability in response with improved GERD– Health-Related Quality of Life and satisfaction scores, with the overwhelming majority of patients in these studies off all medications; 7. One 500-plus person registry demonstrating sustained and significant benefits of Stretta; 8. Studies that include special populations, such as patients who failed antireflux surgery, those with postbariatric surgery GERD and those with laryngopharyngeal reflux disease, just to name a few.

These 80-plus peer-reviewed publications make Stretta one of the most studied device technologies in any field of treatment, and provide 10-fold the volume of studies of any currently available GERD device, whether it be transoral or surgical.

The veracity of these facts is easily checked (e.g., PubMed search word: Stretta).

With respect to the statement, “Stretta remains poorly supported by evidence,” in the August 2013 issue of Surgical Endoscopy, the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) published a position paper on nonsurgical treatments for GERD, which included Stretta. The SAGES review committee judged the quality of the literature on Stretta merited the highest score of “++++,” with a grade analysis recommendation of “Strong.”

The statement, “Few Stretta procedures are performed in academic centers of excellence,” also is incorrect. What is correct is that the overwhelming majority of hospitals that treat patients with Stretta, in the United States and abroad, are academic centers, at a ratio of 3:1 to community centers. Included in the list of academic centers using Stretta are some of the world’s most prestigious teaching programs.

Besides the sheer volume of positive outcomes data in the peer-reviewed publications, I’d like to draw attention to the consistency of the study results across both academic and communitybased researchers. The ability to replicate clinical outcomes outside of an academic, university-based setting is a fundamental requirement of many of the technology assessment groups worldwide.

In such a challenging patient population and disease state as GERD, it certainly is a benefit to have as many treatment options as possible, particularly those with an excellent safety, efficacy and durability record, such as Stretta. We are confident that an accurate, complete and thorough analysis of the significant body of peer-reviewed studies of Stretta, such as the one recently conducted by SAGES, will provide a clear picture of the benefits of this unique, safe and effective treatment.

■ Sincerely, William Rutan Chief Executive Officer Mederi Therapeutics, Inc.

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Comments may be published in a future issue of Gastroenterology & Endoscopy News.

5

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ENDO-000000-XX September or call 1.888.272.1001. 2013

*Data on file Resolution is a registered or unregistered trademark of Boston Scientific Corporation or its affiliates. ©2013 Boston Scientific Corporation or its affiliates. All rights reserved.

ENDO-187606-AA September 2013

EXPERT ROUNDTABLE

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2013

George Brown, MD President and CEO Legacy Health Portland, Oregon

Jim Leavitt, MD President Gastro Health Miami, Florida

Klaus Mergener, MD, PhD, MBA Digestive Health Specialists MultiCare Health System Tacoma, Washington

7

Arnold G. Levy, MD President and CEO Capital Digestive Care Washington, D.C.

Irving Pike, MD Senior Vice President and Chief Medical Officer John Muir Health Walnut Creek, California

ACA continued from page 1

include a greater proportion of newly, but not necessarily adequately, insured individuals. Also, private practices, hospitals and health care systems alike will feel the pinch of increased costs, tighter budgets and decreased reimbursements to providers.

A major theme of the two-day GI Roundtable 2013 was the status of the private practice–hospital relationship. The two entities share a common goal—to maintain and improve the health of the patients they serve.

They also face similar challenges—cost containment and quality improvement. Historically, however, the prevailing attitude has been one of rivalry: Hospitals buy up practices or steal their physicians, and practices drain away patients from hospitals. Gastroenterology & Endoscopy Newss asked leaders from both sides of the table their opinions on the practice–hospital relationship, and what can be done to foster it.

What are the main challenges for your organization—hospital or private practice—in the current health care environment?

Dr. Pike: From an organizational standpoint, I think the main challenges are to maintain and continuously improve the quality of our health care delivery, which includes the health maintenance of the community we serve, while remaining affordable. We also need to stay focused on the patient experience and make sure that it is a good and pleasant one.

Dr. Brown: The challenge is living ing in the fee- care—adjective, j , not noun—so that whatever happens pp in for-service world while preparing to shift to the [value- the future, people will want us to be their gastroenterbased] environment. There are significant unknowns ologist because we’ll be providing the most value. We with the new model in terms of how reimbursements want to remain independent, but we want to be part of will take place, who will be accountable for the risk of whatever integration strategies will develop all around us managing those populations and the costs for retooling in the large geographic area that we service because we’ll your business to accommodate the changes in health care be able to deliver the best value. delivery. Another risk worth mentioning is the action Dr. Levy: In our market region—and throughCongress takes to address the debt and deficit problems, out the country, for that matter—the state of health such as the sequester, which have a downstream effect care delivery is in flux and faces great challenges. In this on health care organizauncertain setting, cooptions. These impacts caneration among hospitals, private medical practices not be planned for ‘The challenge is living in the because we have to and payors will be key as react to whatever Conwe strive to provide the fee-for-service world while gress dictates. best and the most affordpreparing to shift to the Dr. Mergener: able care as possible. Our [value-based] environment.’

In the next few years, practice goal is to remain we anticipate that our independent. Our chal—George Brown, MD reimbursement for prolenge is to successfully fessional services and position ourselves with the ancillary services we the hospitals and with the provide will go down, local health care systems whereas costs continue to go up. Another major chal- so that we will indeed have a seat at the table when varilenge is the conundrum I could call “strategic paranoia”: ous plans and health care delivery structures are being continuing to optimize practice operations in a fee- established. At the present time, part of that challenge for-service environment, while also preparing for the is the fact that many of the hospitals and health care upcoming value-based payment system. systems in our region have yet to figure out what they Dr. Leavitt: The challenge we have is are going to do. how to establish ourselves to provide accountable see ACA, page 8

EXPERT ROUNDTABLE

8

ACA continued from page 7

What do you believe gastroenterology practices need to do to make themselves an attractive partner for their local hospitals—what can they bring to the table?

Dr. Pike: What we can do as gastroenterologists is improve workflow, measure and improve quality as we move to value-based purchasing, improve resource management, improve the patient experience and improve the quality of care that we provide. For example, when we perform procedures, we should make sure that the patient flows through the system seamlessly, that the patient can come in and have his or her procedure started within 15 or 30 minutes at most and leave promptly afterward with full information about the procedure, its results and the plan.

Dr. Brown: Gastroenterologists bring an important service to the community. Although many gastroenterology practices do only a portion of their practice in the hospital, most health care systems recognize the importance of being able to offer digestive disease services to the people they care for. That said, I think gastroenterology practices need to understand the climate of change. We are shifting away from procedure-based and fee-for-activity models to a capitated method of paying providers for manag‘When gastroenterology ing the health of a population. practices help hospitals Gastroenterolowith their own situation, gists need to figit creates a win–win.’ ure out how they can adapt to this —Klaus Mergener, MD, new methodolPhD, MBA ogy and partner with health systems.

Dr. Mergener: When gastroenterology practices help hospitals with their own situation, it creates a win–win. For example, we base some providers at the hospital who do nothing but inpatient gastrointestinal care. This makes us very responsive.

Gastroenterology practices also can be strong partners for hospitals on the ambulatory care side. To facilitate coordination of care, we use patient navigators who help in the transition between inpatient and outpatient care.

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2013

This may decrease the number of readmissions and the and practices have a natural alliance. If I were in a gascost of care by avoiding unnecessary returns to the emer- troenterology practice, I would first realize that digesgency room. tive disease is an important service for health systems.

Dr. Leavitt: Make it easier and more profitable I would then consider how I could partner with health for hospitals to use you [gastroenterology practices] systems in managing the health of a population and takrather than trying to reinvent the wheel. For example, ing some of that risk as we transition to new methodolowe sold 51% of one of our endoscopy centers to a big gies of payment. hospital so that we are in a business partnership with Dr. Mergener: It’s hard to argue that the system them. Also, we are now talking to the health system we’ve had in the past is optimal. We all know it’s not. My about developing clinical service lines in gastroenterol- advice to all of us is to view the changes that have been ogy to streamline their processes and make them more accelerated by the passage of the ACA as an opportunity efficient. We think we’ll be a good partner for them, and for all stakeholders to work together—an opportunity that it will be more costly for them to hire their own rather than a threat. gastroenterologists rather than to use us.

Dr. Leavitt: In my opinion, if you go into ownerDr. Levy: Any private practice has to make itself ship by a hospital, you’re at their mercy. You need to be relevant to the hospital or health care system, and must valuable to them. If they think of you as an easily replacebe too good and too big to be ignored. This usually able commodity service, you’re in trouble. If you want to means having a large number of doctors and nonphy- be independent, the keys are to get larger, cover more sician providers, covering a large geographic area and geography and make partnerships with payors so they providing rapid access to high-quality care. You need an understand that your overall cost structure to them is infrastructure that allows rapid electronic transmission less—they’ll want to send patients to you. of patient information and can demonstrate your abilDr. Levy: The larger you are, the less likely you ity to provide quality care and to communicate within can be ignored. Two or three small practices in a given the infrastructure of hospitals or hospital systems. Such area are best served by joining forces and becoming an organization, with a large patient base, one practice under one will be an important source of patient refertax identification numrals into a hospital or hospital system, and ber. Big or small, you’ll ‘I do not feel that to other physicians, such as surgeons, on need to have a working physicians and hospitals whose work the hospital would thrive. relationship with the hospital. One needs to are adversaries. We know what the hospital What advice do you have for are both involved needs, how your pracgastroenterology practices in improving and tice can help the hospithat perceive the hospital tal achieve its goals, and maintaining the health relationship as more of a threat how your practice and of the community.’ to independence than an the hospital can actually build a win–win workalliance?

—Irving Pike, MD ing relationship. We Dr. Pike: My concern is that this is a need to not consider carry-over from an era long past. I do not the hospitals our archfeel that physicians and hospitals are adversaries. enemy. We’re going to have to learn to live and work We are both involved in improving and maintogether. If we can do that, the practices will benefit, the taining the health of the community. Hospitals have hospitals will benefit and the patients will benefit. nothing to gain by having their physician community feel that they are an adversary or an opponent. Our particular Do you involve physicians at the health system has no desire to own or control practices. governance level of your health care We would much prefer to develop relationships that system? Why or why not? improve our performance and the performance of our physicians. That’s what’s going to attract more patients Dr. Pike: Yes. We have recently increased the to receive care in our community. proportion of physicians on the board of directors in Dr. Brown: The old way of regarding one another our health system as well as on our foundation board, as a competitor or foe needs to be rethought. Hospitals see ACA, page 12

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Superior GPIERWMRK IJ½ GEG]*

*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. P<0.002 [Prepopik: n=256/304; comparator: n=221/297].1-3

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.

…with the lowest volume of active prep solution

Prepopik helps patients arrive ready with: SUPERIOR CLEANSING with ACG-recommended split-dose regimen*†1 84% of Prepopik bowel preparations were graded as “excellent” or “good” vs 74% with the comparator (2L PEG+E plus 2x 5 mg bisacodyl tablets), assessed using the validated Aronchick scale*1,2

90% of Prepopik patients had successful cleansing in the ascending colon vs 79% with the comparator, assessed using the validated Ottawa scale†1

EXCELLENT TOLERABILITY reported by patients in pivotal trials1,3 89% of patients found Prepopik easy to take vs 29% of those taking the comparator (2L PEG+E plus 2x 5 mg bisacodyl tablets); P<0.00011

99% of patients taking Prepopik completed their regimen vs 91% of those taking the comparator (2L PEG+E plus 2x 5 mg bisacodyl tablets)1

FLEXIBLE DOSING using either a split-dose or day-before regimen 4 A DUAL MECHANISM that stimulates peristalsis and produces osmotic water retention 4 †

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 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. 4. Prepopik® Prescribing Information, July 2012. Ferring Pharmaceuticals Inc. Parsippany, NJ 07054, USA.

Visit prepopik.com/tools to access a variety of helpful patient tools!

PREPOPIK® is a registered trademark of Ferring B.V. © 2013 Ferring B.V. All rights reserved.

PK/738/2013/US

12

EXPERT ROUNDTABLE

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ NOVEMBER 2013

ACA â&#x20AC;&#x2DC;Our physicians are not part of

continued from page 8

and weâ&#x20AC;&#x2122;ve created an additional physician advisory council for our network. There are no individuals better than physicians to strategize care and delivery in our system. Our 15-member system board now includes eight physicians.

Dr. Brown: Yes. We have currently a 16-member board, three of whom are physicians. We think itâ&#x20AC;&#x2122;s imperative to have input from practicing physicians, and these are not employed physicians, these are community physicians.

Dr. Mergener: Yes, but not as much we should. MultiCare Health Systems in Tacoma recognizes that and is in the discussion stages about increasing physician involvement. Itâ&#x20AC;&#x2122;s increasingly clear that physicians need to be intimately involved at all levels of hospital management. They may drive only 20% of the cost of care directly, but theyâ&#x20AC;&#x2122;re responsible for 80% to 90% of the overall cost of care to the system because they make the care decisions for patients.

Aspiration Patients with impaired gag reĂ&#x20AC;ex and patients prone to regurgitation or aspiration should Ee oEserYed during the administration of PREPOPIK. Use with caution in these patients.

Not for Direct Ingestion Each packet must Ee dissolYed in 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 undissolYed powder may increase the risk of nausea, Yomiting, dehydration, and electrolyte disturEances.

INDICATIONS AND USAGE PREPOPIKâ&#x201E;˘ (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 %ecause clinical trials are conducted under widely Yarying conditions, CONTRAINDICATIONS adYerse reaction rates oEserYed in the clinical trials of a drug cannot PREPOPIK is contraindicated in the following conditions: Ee directly compared to rates in clinical trials of another drug and may Â&#x2021; Patients with seYerely reduced renal function (creatinine clearance not reĂ&#x20AC;ect the rates oEserYed in practice. less than 30 mL/minute) which may result in accumulation of In randomized, multicenter, controlled clinical trials, nausea, headache, magnesium and Yomiting were the most common adYerse reactions (! ) Â&#x2021; *astrointestinal oEstruction or ileus following PREPOPIK administration. 7he patients were not Elinded to Â&#x2021; %owel perforation the study drug. 6ince aEdominal Eloating, distension, pain/cramping, Â&#x2021;7 7oxic colitis or toxic megacolon and watery diarrhea are known to occur in response to colon cleansing Â&#x2021; *astric retention preparations, these effects were documented as adYerse eYents in Â&#x2021; $n allergy to any of the ingredients in PREPOPIK the clinical trials only if they reTuired medical interYention (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 adYerse eYent), Serious Fluid and Serum Chemistry Abnormalities or showed clinically signiÂżcant worsening during the study that was $dYise patients to hydrate adeTuately Eefore, during, and after the not in the frame of the usual clinical course, as determined Ey the use of PREPOPIK. 8se caution in patients with congestiYe heart inYestigator. failure when replacing Ă&#x20AC;uids. If a patient deYelops signiÂżcant Yomiting PREPOPIK was compared for colon cleansing effectiYeness with or signs of dehydration including signs of orthostatic hypotension a preparation containing two liters ( L) of polyethylene glycol plus after taking PREPOPIK, consider performing post-colonoscopy electrolytes solution (PE* E) and two -mg Eisacodyl taElets, all laE tests (electrolytes, creatinine, and %81) and treat accordingly. administered the day Eefore the procedure. 7a 7 Ele displays the most $pproximately 0 of patients in Eoth arms (PREPOPIK, L of PE* common adYerse reactions in 6tudy and 6tudy for the PREPOPIK E plus two x -mg Eisacodyl taElets) of clinical trials of PREPOPIK 6plit-Dose and Day-%efore dosing regimens, respectiYely, each as had orthostatic changes (changes in Elood pressure and/or heart rate) compared to the comparator preparation. on the day of colonoscopy. In clinical trials orthostatic changes were documented out to seYen days post colonoscopy.

Table 1: Treatment-Emergent Adverse Reactions observed in at )luid and electrolyte disturEances can lead to serious adYerse eYents Least (>1%) of Patients using the Split-Dose Regimen and Dayincluding cardiac arrhythmias or seizures and renal impairment. Fluid Before Regimen** and electrolyte aEnormalities should Ee corrected Eefore treatment with PREPOPIK. In addition, use caution when prescriEing PREPOPIK Adverse Study 1: Split-Dose Regimen Study 2: Day-Before Regimen for patients who haYe conditions or who are using medications that Reaction increase the risk for Ă&#x20AC;uid and electrolyte disturEances or that may PREPOPIK 2L PEG+E* PREPOPIK 2L PEG+E* increase the risk of adYerse eYents of seizure, arrhythmia, and renal with 2 x (N=305) with 2 x 5-mg (N=296) impairment. n (% = n/N) 5-mg n (% = n/N) bisacodyl tablets (N=298) n (% = n/N)

bisacodyl tablets (N=302) n (% = n/N) 1ausea 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) L PE* E two liters polyethylene glycol plus electrolytes solution. aEdominal Eloating, distension, pain/cramping, and watery diarrhea not reTuiring an interYention were not collected

Seizures 7here haYe Eeen reports of generalized tonic-clonic seizures with the use of Eowel preparation products in patients with no prior history of seizures. 7he seizure cases were associated with electrolyte aEnormalities (e.g., hyponatremia, hypokalemia, hypocalcemia, and hypomagnesemia) and low serum osmolality. 7he neurologic aEnormalities resolYed with correction of Ă&#x20AC;uid and electrolyte aEnormalities.

8se caution when prescriEing 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 Electrolyte abnormalities In general, PREPOPIK was associated with numerically higher rates Eenzodiazepines, patients with known or suspected hyponatremia. of aEnormal electrolyte shifts on the day of colonoscopy compared to the preparation containing L of PE* E plus two x -mg Eisacodyl Use in Patients with Renal Impairment $s in other magnesium containing Eowel preparations, use caution taElets. 7hese shifts were transient in nature and numerically similar when prescriEing PREPOPIK for patients with impaired renal function Eetween treatment arms at the Day 30 Yisit. or patients taking concomitant medications that may affect renal function (such as diuretics, angiotensin conYerting enzyme inhiEitors, Postmarketing Experience angiotensin receptor Elockers, or non-steroidal anti-inĂ&#x20AC;ammatory 7he following foreign spontaneous reports haYe Eeen identiÂżed during drugs). 7hese patients may Ee at increased risk for renal inMury. $dYise use of formulations similar to PREPOPIK. %ecause these eYents are these patients of the importance of adeTuate hydration Eefore during reported Yoluntarily from a population of uncertain size, it is not always and after the use of PREPOPIK. &onsider performing Easeline and possiEle to reliaEly estimate their freTuency or estaElish a causal post-colonoscopy laEoratory tests (electrolytes, creatinine, and %81) relationship to drug exposure. in these patients. In patients with seYerely reduced renal function (creatinine clearance < 30 mL/min), accumulation of magnesium in Allergic reactions &ases of hypersensitiYity reactions including rash, urticaria, and plasma may occur. purpura haYe Eeen reported.

Cardiac Arrhythmias 7here haYe Eeen rare reports of serious arrhythmias associated with Electrolyte abnormalities the use of ionic osmotic laxatiYe products for Eowel preparation. 8se 7here haYe Eeen reports of hypokalemia, hyponatremia and caution when prescriEing PREPOPIK for patients at increased risk of hypermagnesemia with the use of PREPOPIK for colon preparation arrhythmias (e.g., patients with a history of prolonged 47, 7 uncontrolled prior to colonoscopy. arrhythmias, recent myocardial infarction, unstaEle angina, congestiYe heart failure, or cardiomyopathy). Pre-dose and post-colonoscopy Gastrointestinal E&*s should Ee considered in patients at increased risk of serious $Edominal pain, diarrhea, fecal incontinence, and proctalgia haYe Eeen reported with the use of PREPOPIK for colon preparation cardiac arrhythmias. prior to colonoscopy. 7here haYe Eeen isolated reports of reYersiEle Colonic Mucosal Ulceration, Ischemic Colitis and Ulcerative Colitis aphthoid ileal ulcers. Ischemic colitis has Eeen reported with the use Osmotic laxatiYes may produce colonic mucosal aphthous ulcerations of PREPOPIK for colon preparation prior to colonoscopy. HoweYer, a and there haYe Eeen reports of more serious cases of ischemic colitis causal relationship Eetween these ischemic colitis cases and the use reTuiring hospitalization. &oncurrent use of additional stimulant of PREPOPIK has not Eeen estaElished. laxatiYes with PREPOPIK may increase this risk. 7he potential for mucosal ulcerations should Ee considered when interpreting Neurologic colonoscopy Âżndings in patients with known or suspected inĂ&#x20AC;ammatory 7here haYe Eeen reports of generalized tonic-clonic seizures associated with and without hyponatremia in epileptic patients.

Eowel disease.

Use in Patients with SigniĂ&#x20AC;cant Gastrointestinal Disease If gastrointestinal oEstruction or perforation is suspected, perform appropriate diagnostic studies to rule out these conditions Eefore administering PREPOPIK. 8se with caution in patients with seYere actiYe ulceratiYe colitis.

DRUG INTERACTIONS

Dr. Leavitt: There are no active physicians on our health system board. But one way we serve hospitals is that weâ&#x20AC;&#x2122;re on committees, like the pharmacy, therapeutics and quality improvement committees. We do things like that to help, so thatâ&#x20AC;&#x2122;s some value that we bring.

the governance of either of our marketplaceâ&#x20AC;&#x2122;s two large health systems, although we do participate in various activities and committees and roles at the hospitals that are part of those systems or part of other independent hospitals in our region.â&#x20AC;&#x2122;

arrhythmias, and prolonged 47 in the setting of Ă&#x20AC;uid and electrolyte aEnormalities. 7his includes patients receiYing drugs which may Ee 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-inĂ&#x20AC;ammatory drugs (16$ID6) or drugs known to induce $ntidiuretic Hormone 6ecretion (6I$DH), such as tricyclic antidepressants, selectiYe serotonin re-uptake inhiEitors, antipsychotic drugs and carEamazepine, as these drugs may increase the risk of water retention and/or electrolyte imEalance. &onsider additional patient eYaluations as appropriate.

Potential for Altered Drug Absorption Oral medication administered within one hour of the start of administration of PREPOPIK solution may Ee Ă&#x20AC;ushed from the *I tract and the medication may not Ee aEsorEed. 7etracycline and Ă&#x20AC;uoroTuinolone antiEiotics, iron, digoxin, 7 chlorpromazine and penicillamine, should Ee taken at least hours Eefore and not less than hours after administration of PREPOPIK to aYoid chelation with magnesium.

Antibiotics Prior or concomitant use of antiEiotics with PREPOPIK may reduce efÂż f cacy of PREPOPIK as conYersion of sodium picosulfate to its actiYe metaEolite %HP0 is mediated Ey colonic Eacteria.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy &ategory % Reproduction studies with PREPOPIK haYe Eeen performed in pregnant rats at oral doses up to 000 mg/kg/day (aEout . times the recommended human dose Eased on the Eody surface area), and did not reYeal any eYidence of impaired fertility or harm to the fetus due to PREPOPIK. 7he reproduction study in raEEits was not adeTuate, as treatment-related mortalities were oEserYed at all doses. $ pre and postnatal deYelopment study in rats showed no eYidence of any adYerse effect on pre and postnatal deYelopment at oral doses up to 000 mg/kg twice daily (aEout . times the recommended human dose Eased on the Eody surface area). 7here are, howeYer, no adeTuate and well-controlled studies in pregnant women. %ecause animal reproduction studies are not always predictiYe of human response, PREPOPIK should Ee used during pregnancy only if clearly needed.

Nursing Mothers It is not known whether this drug is excreted in human milk. %ecause many drugs are excreted in human milk, caution should Ee exercised when PREPOPIK is administered to a nursing woman.

Pediatric Use 7he safety and effectiYeness of PREPOPIK in pediatric patients has not Eeen estaElished.

Geriatric Use In controlled clinical trials of PREPOPIK, of 0 ( ) patients were years of age or older. 7he oYerall incidence of treatmentemergent adYerse eYents was similar among patients Â&#x2022; years of age ( 3 ) and patients < years of age ( ). $mong all patients Â&#x2022; years of age, the proportion of patients with successful colon cleansing was greater in the PREPOPIK group ( . ) than in the comparator group ( 0. ).

Renal InsufĂ&#x20AC; f ciency Patients with impaired renal function or patients taking concomitant medications that may affect renal function (such as diuretics, angiotensin conYerting enzyme inhiEitors, angiotensin receptor Elockers, or non-steroidal anti-inĂ&#x20AC;ammatory drugs) may Ee at increased risk for further renal inMury. $dYise these patients of the importance of adeTuate hydration Eefore during and after the use of PREPOPIK. &onsider performing Easeline and post-colonoscopy laEoratory tests (electrolytes, creatinine, and %U1) in these patients.

In patients with seYerely reduced renal function (creatinine clearance < 30 mL/min), accumulation of magnesium in plasma may occur. 7he signs and symptoms of hypermagnesemia may include, Eut are not limited to, diminished or aEsent deep tendon reĂ&#x20AC;exes, somnolence, hypocalcemia, hypotension, Eradycardia, muscle, respiratory paralysis, complete heart Elock, and cardiac arrest.

OVERDOSAGE 7he patient who has taken an oYerdose should Ee monitored carefully, and treated symptomatically for complications.

0anufactured Ey: Ferring Pharmaceuticals (China) Co., Ltd. 1o. HuiLing Lu (Ferring Road) 1ational Health 7 7echnology Park =hongshan City, *uangdong ProYince, CHI1$ 0anufactured for: Ferring Pharmaceuticals Inc. Parsippany, 1.-. 0 0

www.ferringusa.com - -FERRI1* Drugs That May Increase Risks of Fluid and Electrolyte Abnormalities Â&#x2039; 0 Ferring Pharmaceuticals Inc. Use caution when prescriEing PREPOPIK for patients with conditions $ll rights reserYed. Printed in U6$. or who are using medications that increase the risk for Ă&#x20AC;uid and PREPB%R60B00 B0 electrolyte disturEances or may increase the risk of seizure,

â&#x20AC;&#x201D;Arnold G. Levy, MD

Dr. Levy: Our physicians are not part of the governance of either of our marketplaceâ&#x20AC;&#x2122;s two large health systems, although we do participate in various activities and committees and roles at the hospitals that are part of those systems or part of other independent hospitals in our region. Within our own group, our governance system is built on a board and a very strong committee structure, with 37 of our 57 physicians actively involved.

Process is key to how we get things done, and everyone knows that he or she can indeed have a say.

Are you planning to create/ participate in an accountable care organization? What are some of the challenges/ opportunities you see with this model?

Dr. Pike: At John Muir Health, we currently have two ACOs: one with a commercial insurer and one with the Centers for Medicare & Medicaid Services (CMS). The challenge with the CMS model is receiving data too slowly to respond to in an efficient manner. We need databases and electronic methodology to provide physicians and our health system with actionable data in a timely manner. The second challenge is organizing our physician community, who are seeing patients from the ACO, according to evidence-based standards.

Dr. Brown: We are currently participating in an ACO. In the state of Oregon, we call it a coordinated care organization, and itâ&#x20AC;&#x2122;s been in existence for about a year. We are the largest coordinated care organization in the state.

The difficulties associated with that are: â&#x20AC;˘ Many unknowns with respect to the new model of providing care. â&#x20AC;˘ What this will mean with Medicaid expansion coming along because, with one yearâ&#x20AC;&#x2122;s experience, we are just beginning to understand the dynamics of the risks weâ&#x20AC;&#x2122;re all taking.

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2013

The challenge of getting historical competitors to cooperate on a common mission.

Dr. Mergener: We are closely following developments in our own local environment but have not, at this time, made a strategic decision about whether or not to participate in an ACO. Dr. Leavitt: Clinically integrated networks are going to happen, and being accountable for the care you give is going to happen. If a group wants to be successful,

Statement of Ownership This document is a copy of the Statement of Ownership, Management and Circulation of Gastroenterology & Endoscopy News. A copy of this document must be published in Gastroenterology & Endoscopy News once per year, as required by the United States Postal Service.

EXPERT ROUNDTABLE

accountable care and great value. If you do that, then no matter what happens it needs to develop the internal in the future, we believe capabilities to show that they can that group would be … the group of choice. provide accountable care and Dr. Levy: At the great value.’ present time, there are no —Jim Leavitt, MD ACOs in existence in our region, but development of such is under active consideration, primarily by the it needs to develop the internal capa- larger health care systems. We are waiting bilities to show that they can provide and watching. I think the challenges we

‘If a group wants to be successful,

13

all face are learning how to work together in a fair and equitable way that works well for doctors, works well for hospitals, and results in better and more cost-efficient patient care. This will be a whole new world and we’re going to have to learn how to do this.

■ Further exploration of this topic and others will take place at the GI Roundtable 2014, to be held in Boston, March 20-22, 2014.

Visit http://giroundtable.com for more details.

14

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2013

Doctors Rush To Corporate Employment As Corporate America Lays off Workers He was laid off. How long would it take to find a job? What about the kids and their education? What would his wife say? That he should never have taken that job with the hospital in the first place?

BY MARK F. WEISS, JD In the economy in general, businesses are rushing to cut full-time employment. They are using temps. They are outsourcing. They are replacing workers with technology.

Yet physicians are turning to hospital and hospitalaffiliated medical group employment at a rapid rate.

From my discussions with physicians about their careers and my experience with groups considering disbandment to become hospital employees, this is an increasing trend for office-based physicians—many physicians are leaving truly private practice for jobs with large national and regional groups and other staffing companies.

So why the disconnect? Why do many physicians believe that employment in hospitals, hospital-captive medical groups or large staffing-model groups provides safety or stability when the world around them for other employees—unskilled, skilled and professional—is in turmoil?

that employers do not have to pay nearly as much for personnel-related costs such as health insurance and other benefits. If business expands, hire temps; if business contracts, fire temps.

According to a recent Associated Press article, employers are increasingly reliant on temps and parttime labor. Nearly 17 million people, or approximately 12% of everyone with a job, is either a temporary worker or a contracted worker or consultant. That represents a 50% increase in the number of temporary workers since the end of the recession.

Corporations 101 Corporations exist to make a profit.

There’s nothing wrong with that. It’s a fact of life. But because all corporations, and that includes hospitals and especially staffing service model groups, exist to make a profit, they will always seek to lower their costs. Of course, costs include employment costs, which includes salaries. ...

Welcome to the Team … but Not Really It makes little difference whether it’s the added burden of providing health insurance imposed by Obamacare, the overall uncertainty in the economy or the harsh new employment reality, employers across the country, from large corporations to smaller entities, are turning to part-time and temporary workers. Full-timers are retiring or being laid off. In the several weeks before writing this article, a small sample of announced layoffs included Merck: more than 100 employees; Heinz: 600 employees; and Cisco: 4,000 workers.

At the same time, the number of involuntary parttime employees—that is, those who would rather have full-time jobs—remains high.

Part-time workers enable employers to escape the coming Obamacare burden and, in general, many of the employee benefit expenses that employers incur in connection with full-time workers.

And, as to temporary workers, the key is that they can be terminated almost immediately. That flexibility is an advantage in the marketplace akin to that gained by the lower costs of offshore personnel and the fact

And, despite the government’s touting of the upswing in employment, only 23% of the approximately 950,000 jobs the economy added from January to July 2013 are full-time. The remaining 730,000 of those jobs are parttime positions.

Physicians Many physicians see advantages in hospital or largegroup employment. Here are a few of the usual reasons: • It’s less complicated than running a group.

• My employer will find work for me.

• There is no need to compete for the exclusive contract.

• I may earn less, but at least I’ll have stability.

Sure, running your own medical practice or group may be complicated. It is easy just working and collecting a paycheck.

But health care employers are not substitute parents. Sure, parents may kick you out of the house, but employers fire you or lay you off and never invite you back for the holidays.

The same trends affecting industry in general, leading to layoffs, part-time and temp work, also are affecting health care.

Again, in the several-week period preceding this

Mark F. Weiss, JD

writing, layoffs were reported at Crestwood Medical Center in Alabama, Baptist Memorial Health Care in Tennessee, King’s Daughters Health Systems in Kentucky, Maine Medical Center, Alameda Health System in California and Samaritan Medical Center in New York, to name just a few.

Although physicians were not included in those layoffs, the fact is that hospitals are employers, too.

Although the health care sector of the economy is more vibrant than some others, it’s not immunized against downturns or against the need to reduce costs. With more physicians employed by large organizations, it is only a matter of time before they, too, are affected by cutbacks.

The fact that many hospitals are nonprofit does not alter the equation.

Nonprofit corporations are corporations, too. And, remember that they are not really nonprofit. They are simply about not paying taxes. These organizations are under the same pressure as employers in general to cut expenses, and that means cutting employment costs.

Look at the rest of the corporate world: If robots can build cars, the number of factory workers goes down.

If robot doctors can treat your patients, you involuntarily go part-time, or are unemployed.

The urge to seek security is entirely human and virtually universal. But what appears safe in today’s health care economy, what appears less complicated in today’s health care economy and what is clearly the trend in today’s economy—employment by hospitals—is far more risky than it appears.

There is no real security in depending on a pseudoparent employer.

So why are so many physicians falling for this same story in regard to hospital employment?

Unfortunately, the answer is simple. They’re not fooling you. You’re fooling yourself.

The reality is that the only safety that exists is within you. The reality is that you are self-employed no matter whether your paycheck comes from the largest hospital chain in the nation or from your solo practice. The only difference is who can tell you when to stop working. ■ Mr. Weiss is an attorney who specializes in the business and legal issues affecting physicians and physician groups on a national basis. He holds an appointment as clinical assistant professor of anesthesiology at USC’s Keck School of Medicine and practices with Advisory Law Group (dba The Mark F. Weiss Law Firm in Texas), a firm with offices in Los Angeles, Santa Barbara and Dallas representing clients across the country. He can be reached by email at markweiss@advisorylawgroup.com.

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DDW 2013

Diet continued from page 1

do with how the individual reacts to the malabsorption.

At the 2013 Digestive Disease Week (DDW) meeting, Dr. Shulman, professor of pediatrics at Baylor College of Medicine in Houston, and director of its Center for Pediatric Abdominal Pain Research, explored the dynamics of carbohydrate malabsorption as they relate to IBS-like symptoms, and the debate over the benefit of following a diet low in fermentable oligo-, di-, and monosaccharides and polyols (FODMAPs).

‘Lactose malabsorption was not different, but the

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2013

Similarly, a recent randomized, blinded trial from China assessed lactose absorption and tolerance to dairy products in 120 patients with IBS-D versus healthy controls. Malabsorption of 40 g lactose was observed in 93% of controls and 92% of IBS-D patients, but lactose intolerance was significantly greater among IBS-D subjects; this was true for 10, 20 and 40 g of lactose.

“Lactose malabsorption was not different, but the symptom response to lactose administration was different. The IBS-D patients had significantly more

symptoms,” Dr. Shulman said. “It is the response that is different, and this speaks to the visceral hypersensitivity we not only see in adults, but in children, too.”

Fructose Malabsorption Fructose malabsorption can occur in anyone if amounts are high enough, but its frequency is similar in IBS patients and controls. IBS-like symptoms that are possibly related to fructose malabsorption again may be associated with sensitivity to the malabsorption, according to Dr. Shulman.

Furthermore, at least one study has linked fructose malabsorption to depressive mood. Among a cohort of 68 adults with IBS, women with evidence of malabsorption (although not men) scored significantly higher on the Beck Depression Inventory (Ledochowski M et al. Dig Dis Scii 2000;45:1255-1259).

“These data emphasize the connection between the brain–gut axis and diet. Also, we know that patients often complain of being tired. Could this be somatic?” Dr. Shulman said.

More rarely, individuals who are

In Active, Mild to Moderate Ulcerative Colitis (UC)1

symptom response to lactose administration was different.’

—Robert J. Shulman, MD

Lactose Malabsorption Lactase deficiency is known to induce IBS-like symptoms but its prevalence in IBS is less clear. A study of 402 individuals in India found a similar frequency of lactase non-persistence polymorphisms between individuals with IBS of all types and healthy controls (Kumar S et al. J Gastroenterol Hepatoll 2012;27:1825-1830).

However, the CC C and GG G genotypes were observed more frequently among those with diarrhea-predominant symptoms (IBS-D). In addition, IBS patients with these genotypes, compared with those without them, had significantly more abdominal pain, distension, and higher stool frequency, and reported their symptoms following ingestion of dairy products.

INDICATIONS AND USAGE UCERIS ® is a glucocorticosteroid indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis.

DOSAGE AND ADMINISTRATION The recommended dosage of UCERIS is one 9-mg tablet to be taken once daily in the morning with or without food for up to 8 weeks.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS UCERIS is contraindicated in patients with known hypersensitivity to budesonide or any of the ingredients of UCERIS. WARNINGS AND PRECAUTIONS • Hypercorticism and adrenal suppression: Since UCERIS is a glucocorticosteroid, general warnings concerning glucocorticoids should be followed.

• Transferring patients from systemic corticosteroids: Risk of impaired adrenal function when transferring from oral steroids with high systemic effects. Taper patients slowly from systemic corticosteroids if transferring to UCERIS. • Immunosuppression: Potential worsening of infections (eg, existing tuberculosis, fungal, bacterial, viral, or parasitic

infection; or ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients.

• Increased systemic glucocorticoid susceptibility: Reduced liver function affects the elimination of glucocorticosteroids.

• Other glucocorticoid effects: Caution should be taken in patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where glucocorticosteroids may have unwanted effects.

ADVERSE REACTIONS Most common adverse reactions (incidence ≥2%) are headache, nausea, decreased blood cortisol, upper abdominal pain, fatigue, flatulence, abdominal distension, acne, urinary tract infection, arthralgia, and constipation.

DRUG INTERACTIONS Avoid Cytochrome P450 3A4 inhibitors (eg, ketoconazole, grapefruit juice). May cause increased systemic corticosteroid effects.

USE IN SPECIFIC POPULATIONS Hepatic impairment: Monitor patients for signs and/or symptoms of hypercorticism.

The Important Safety Information does not include all of the information needed to use UCERIS safely and effectively.

Please see Brief Summary of Prescribing Information on the following page and Full Prescribing Information at www.UCERIS.com.

DDW 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2013

heterozygotes for sucrose-isomaltase deficiency can have intermittent IBSlike symptoms, depending on diet. In a 2012 study of children with congenital sucrose-isomaltase deficiency, the inability to digest both starch and sucrose was observed in the affected children, but not healthy controls, and a third group of children with recurrent abdominal pain was able to digest sucrose but not starch (Robayo-Torres CC et al. J Pediatr Gastroenterol Nutrr 2012;55:S32-S34). “These data are provocative and need follow-up,” said Dr. Shulman.

FODMAPs Elimination Diet ‘These data emphasize the connection between the brain–gut axis and diet. Also, we know that patients often complain of being tired. Could this be somatic?’

—Robert J. Shulman, MD

The FODMAPs elimination diet aims to quell symptoms by removing a host of possible dietary offenders, including fermentable foods, oligosaccharides, fructans/galactans, disaccharides, monosaccharides and polyols—“practically everything that’s in our diet,” said Dr. Shulman. “Being on this diet is very restrictive.”

Among the banned foods are wheat, rye, barley, onions, garlic, artichokes, legumes, honey, apples, pears, see Diet, page 18

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3 times more patients taking UCERIS achieved combined clinical remission and mucosal healing compared with placebo2‡

A SAFETY PROFILE THAT OFFERS CONFIDENCE1 • The rates of overall expected glucocorticoid-related side effects were similar for UCERIS

and placebo at 8 weeks—10.2% vs 10.5%, respectively1‡ CORE STUDY DESIGNS: Two randomized, double-blind, placebo-controlled studies were conducted in a total of 899 adult patients with active, mild to moderate UC (Ulcerative Colitis Disease Activity Index [UCDAI]: ≥4 and ≤10 at entry). The primary endpoint was induction of combined clinical remission and mucosal healing (defined as a UCDAI score of ≤1, with scores of 0 for both rectal bleeding and stool frequency, normal mucosa with no friability on endoscopy, and a ≥1-point reduction in the endoscopic index [EI] score) after 8 weeks of treatment.1 *Some restrictions apply. Please see the eVoucherRx™ and Instant Savings Card Program brochure for Terms and Conditions. Santarus reserves the right to modify or cancel these offerings at any time. † Source: RelayHealth, June 2013. ‡ In a pooled analysis of 2 Phase III clinical trials.1,2 References: 1. UCERIS Prescribing Information. Santarus, Inc. January 2013.

2. Data on file. Santarus, Inc. 3. Brunner M, Ziegler S, Di Stefano AF, et al.

Gastrointestinal transit, release and plasma pharmacokinetics of a new oral budesonide formulation. Br J Clin Pharmacol. 2005;61:31-38.

UCERIS is a registered trademark of Santarus, Inc. MMX is a registered trademark of Cosmo Technologies, Ltd. eVoucherRx™ is a trademark of RelayHealth.

© 2013 Santarus, Inc. 1-UCE13229 V1 September 2013 Printed in the USA.

17

www.UCERIS.com

18

DDW 2013

Diet continued from page 17

watermelon, mango, stone fruits, mushrooms, cauliflower, sugar-free mints and gums, and sources of lactose.

Support for the low-FODMAPs diet largely comes from observational studies suggesting that dietary fructose restriction might lead to sustained symptomatic response in patients with IBS and fructose malabsorption. In what appears to be the only randomized, placebocontrolled trial in this area, Australian

BRIEF SUMMARY Please see package insert for Full Prescribing Information available at www.uceris.com UCERIS (budesonide) extended release tablets, for oral use Rx Only INDICATIONS AND USAGE UCERIS (budesonide) extended release tablets are indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis.

CONTRAINDICATIONS UCERIS is contraindicated in patients with hypersensitivity to budesonide or any of the ingredients of UCERIS. Anaphylactic reactions have occurred with other budesonide formulations.

WARNINGS AND PRECAUTIONS Hypercorticism and Adrenal Axis Suppression When glucocorticosteroids are used chronically, systemic effects such as hypercorticism and adrenal suppression may occur.

Glucocorticosteroids can reduce the response of the hypothalamuspituitary-adrenal (HPA) axis to stress. In situations where patients are subject to surgery or other stress situations, supplementation with a systemic glucocorticosteroid is recommended. Since UCERIS is a glucocorticosteroid, general warnings concerning glucocorticoids should be followed. Transferring Patients from Systemic Glucocorticosteroid Therapy Care is needed in patients who are transferred from glucocorticosteroid treatment with higher systemic effects to glucocorticosteroids with lower systemic effects, such as UCERIS, since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of glucocorticosteroid treatment with high systemic effects should be reduced cautiously.

Immunosuppression Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible patients or patients on immunosuppressant doses of glucocorticosteroids. In patients who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route and duration of glucocorticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior glucocorticosteroid treatment to the risk is also not known. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See prescribing information for VZIG and IG.) If chicken pox develops, treatment with antiviral agents may be considered. Glucocorticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections.

Replacement of systemic glucocorticosteroids with UCERIS tablets may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug. Increased Systemic Glucocorticoid Susceptibility Reduced liver function affects the elimination of glucocorticosteroids, and increased systemic availability of oral budesonide has been demonstrated in patients with liver cirrhosis. Other Glucocorticosteroid Effects Caution should be taken in patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where glucocorticosteroids may have unwanted effects.

ADVERSE REACTIONS Systemic glucocorticosteroid use may result in the following: t )ZQFSDPSUJDJTN BOE "ESFOBM 4VQQSFTTJPO t 4ZNQUPNT PG TUFSPJE XJUIESBXBM JO UIPTF QBUJFOUT USBOTGFSSJOH from Systemic Glucocorticosteroid Therapy t *NNVOPTVQQSFTTJPO t * ODSFBTFE 4ZTUFNJD (MVDPDPSUJDPTUFSPJE 4VTDFQUJCJMJUZ t 0UIFS (MVDPDPSUJDPTUFSPJE &GGFDUT Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of UCERIS has been evaluated in controlled and open-label clinical trials which enrolled a combined total of 1105 patients with ulcerative colitis. In two 8-week, placebo-controlled studies in patients with active disease (Study 1 and Study 2), a total of 255 patients received UCERIS 9 mg, 254 patients received UCERIS 6 mg, and 258 patients received placebo.

They ranged in age from 18-77 years (mean 43), 56% were male, and 75% were Caucasian. The most common adverse reactions were headache, nausea, decreased blood cortisol, upper abdominal pain, fatigue, flatulence, abdominal distension, acne, urinary tract infection, arthralgia, and constipation. The adverse reactions occurring in 2% or more of patients on therapy with UCERIS 9 mg are summarized in Table 1.

Table 1. Summary of Adverse Reactions in Two Placebo Controlled Trials Experienced by at Least 2% of the UCERIS 9 mg Group (Studies 1 and 2)

Headache Nausea Decreased Blood Cortisol Upper Abdominal Pain Fatigue Flatulence Abdominal Distension Acne Urinary Tract Infection Arthralgia Constipation

UCERIS 9 mg (N = 255) n (%) 29 (11.4) 13 (5.1)

UCERIS 6 mg (N = 254) n (%) 37 (14.6) 12 (4.7)

Placebo (N = 258) n (%) 27 (10.5) 11 (4.3)

11 (4.3)

6 (2.4)

1 (0.4)

10 (3.9)

8 (3.1)

5 (1.9)

8 (3.1) 6 (2.4) 6 (2.4) 6 (2.4) 5 (2.0) 5 (2.0) 5 (2.0)

5 (2.0) 8 (3.1) 4 (1.6) 2 (0.8) 1 (0.4) 5 (2.0) 1 (0.4)

5 (1.9) 5 (1.9) 2 (0.8) 5 (1.9) 1 (0.4) 4 (1.6) 2 (0.8)

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ NOVEMBER 2013

researchers concluded that dietary restriction of fructose and/or fructans was likely to be responsible for symptomatic improvement. â&#x20AC;&#x153;These sugars seem to provoke symptoms in these patients,â&#x20AC;? Dr. Shulman said.

In a single-blind, crossover study that randomized patients to a low (9 g/d) or high (50 g/d) FODMAPs diet, breath hydrogen levels were highest among IBS patients on the high-FODMAPs diet, followed by healthy controls on the high diet. IBS patients had higher levels

0G 6$&3*4 NH QBUJFOUT B UPUBM PG EJTDPOUJOVFE USFBUNFOU EVF to any adverse event (including adverse reactions) compared with 17% in the placebo group. Table 2 summarizes the percentages of patients reporting glucocorticoid related effects in the 2 placebocontrolled studies.

Table 2. Summary of Glucocorticoid Related Effects in Two Placebo-Controlled Trials (Studies 1 and 2)

0WFSBMM Mood changes Sleep changes Insomnia Acne Moon face Fluid retention Hirsutism Striae rubrae Flushing

UCERIS 9 mg (N = 255) n (%) 26 (10.2) 9 (3.5) 7 (2.7) 6 (2.4) 6 (2.4) 3 (1.2) 2 (0.8) 1 (0.4) 0 0

UCERIS 6 mg (N = 254) n (%) 19 (7.5) 10 (3.9) 10 (3.9) 6 (2.4) 2 (0.8) 3 (1.2) 3 (1.2) 0 0 1 (0.4)

Placebo (N = 258) n (%) 27 (10.5) 11 (4.3) 12 (4.7) 8 (3.1) 5 (1.9) 4 (1.6) 3 (1.2) 0 2 (0.8) 3 (1.2)

No clinically significant differences were observed with respect to the overall percentages of patients with any glucocorticoid related effects between UCERIS and placebo after 8 weeks of induction therapy. Study 3 was an open-label study evaluating UCERIS 9 mg once daily for 8 weeks in 60 patients who had previously completed an 8-week induction study (Study 1), but had not achieved remission. Among patients who took UCERIS 9 mg up to 16 weeks cumulatively across Study 1 and Study 3 combined, similar rates of adverse reactions and glucocorticoid-related effects were seen compared to those who took UCERIS 9 mg for 8 weeks in Study 1.

In Study 4, the safety of long-term treatment with UCERIS 6 mg was evaluated in a placebo-controlled 12-month maintenance study of 123 patients. Patients who had previously completed 8 weeks of therapy in any induction study (Study 1, 2, or 3) and were in remission were randomized to UCERIS 6 mg or placebo once daily for 12 months. In patients who took UCERIS 6 mg for up to 12 months, similar rates of adverse reactions were seen between placebo and UCERIS 6 mg. After up to 12 months of study treatment, 77% (27/35) of the patients in the UCERIS 6 mg and 74% (29/39) of the patients in the placebo treatment groups had normal bone density scans. In Study 4, the glucocorticoid related effects were similar in patients with up to 12 months of therapy with UCERIS 6 mg and placebo. (Table 3) Table 3. Summary of Glucocorticoid Related Effects Over 12-month Treatment (Study 4)

0WFSBMM Insomnia Mood changes Moon face Sleep changes Acne Hirsutism Flushing Fluid retention

UCERIS 6 mg (N = 62) n (%) 9 (14.5) 4 (6.5) 4 (6.5) 3 (4.8) 3 (4.8) 3 (4.8) 3 (4.8) 1 (1.6) 1 (1.6)

Placebo (N = 61) n (%) 7 (11.5) 4 (6.6) 2 (3.3) 3 (4.9) 3 (4.9) 0 0 1 (1.6) 1 (1.6)

Postmarketing Experience The following adverse reactions have been identified during postapproval use of oral budesonide.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders: anaphylactic reactions Nervous System Disorders: benign intracranial hypertension Psychiatric Disorders: mood swings DRUG INTERACTIONS Interaction with CYP3A4 inhibitors Concomitant oral administration of ketoconazole (a known inhibitor of CYP3A4 activity in the liver and in the intestinal mucosa) caused an eightfold increase of the systemic exposure to oral budesonide. If treatment with inhibitors of CYP3A4 activity (such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin) is indicated, discontinuation of UCERIS should be considered. After extensive intake of grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), the systemic exposure for oral budesonide increased about two times. Ingestion of grapefruit or grapefruit juice should be avoided in connection with UCERIS administration. Inhibitors of Gastric Acid Secretion Since the dissolution of the coating of UCERIS is pH dependent, the release properties and uptake of the compound may be altered when UCERIS is used after treatment with gastric acid reducing agents (e.g., PPIs, H2 blockers and antacids).

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Pregnancy Category C Budesonide was teratogenic and embryocidal in rabbits and rats. Budesonide produced fetal loss, decreased pup weights, and skeletal abnormalities at subcutaneous doses of 25 mcg/kg in rabbits (approximately 0.05 times the maximum recommended human dose on a body surface area basis) and 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on a body surface area basis). There are no adequate and wellcontrolled studies in pregnant women. Budesonide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects:: Hypoadrenalism may occur in infants born of mothers receiving glucocorticosteroids during pregnancy. Such infants should be carefully observed.

Nursing Mothers The disposition of budesonide when delivered by inhalation from a dry powder inhaler at doses of 200 or 400 mcg twice daily for at least 3 months was studied in eight lactating women with asthma from 1 to 6 months postpartum. Systemic exposure to budesonide in these women appears to be comparable

than controls during each dietary period (Ong DK et al. J Gastroenterol Hepatol 2010;25:1366-1377). With the lowFODMAPs diet, hydrogen production was low in both groups. Gastrointestinal symptoms and lethargy were significantly greater during the high-FODMAPs diet in patients with IBS, but only increased flatus was reported by controls. Symptoms reported during the high-FODMAPs diet were reduced when patients crossed over to the low-FODMAPs diet.

In a similar open-label, randomized trial carried out by Staudacher et al, 41

to that in non-lactating women with asthma from other studies.

Breast milk obtained over eight hours post-dose revealed that the maximum budesonide concentration for the 400 and 800 mcg total daily doses was 0.39 and 0.78 nmol/L, respectively, and occurred within 45 minutes after inhalation. The estimated oral daily dose of budesonide from breast milk to the infant is approximately 0.007 and 0.014 mcg/kg/day for the two dose regimens used in this study, which represents approximately 0.3% to 1% of the dose inhaled by the mother. Budesonide plasma concentrations obtained from five infants at about 90 minutes after breast feeding (and about 140 minutes after drug administration to the mother) were below quantifiable levels (<0.02 nmol/L in four infants and <0.04 nmol/L in one infant). The recommended daily dose of UCERIS extended release tablets is higher (9 mg daily) compared with inhaled budesonide (up to 800 Îźg daily) given to mothers in the above study.

The maximum budesonide plasma concentration following a 9 mg daily dose (in both single- and repeated-dose pharmacokinetic studies) of oral budesonide is approximately 5-10 nmol/L which is up to 10 times higher than the 1-2 nmol/L for an 800 mcg daily dose of inhaled budesonide at steady state in the above inhalation study.

Since there are no data from controlled trials on the use of UCERIS by nursing mothers or their infants, and because of the potential for serious adverse reactions in nursing infants from UCERIS, a decision should be made whether to discontinue nursing or to discontinue UCERIS, taking into account the clinical importance of UCERIS to the mother. Budesonide, is secreted in human milk. Data from budesonide delivered via dry powder inhaler indicates that the total daily oral dose of budesonide available in breast milk to the infant is approximately 0.3% to 1% of the dose inhaled by the mother.

Assuming the coefficient of extrapolation between the inhaled and oral doses is constant across all dose levels, at therapeutic doses of UCERIS, budesonide exposure to the nursing child may be up to 10 times higher than that by budesonide inhalation. Pediatric Use Safety and effectiveness of UCERIS in pediatric patients have not been established. Glucocorticosteroids, such as UCERIS may cause a reduction of growth velocity in pediatric patients.

Geriatric Use Clinical studies of UCERIS did not include sufficient numbers of subjects aged 65 and over to determine whether they SFTQPOE EJGGFSFOUMZ GSPN ZPVOHFS TVCKFDUT 0UIFS SFQPSUFE DMJOJDBM experience has not identified differences in responses between the elderly and younger patients. In general, UCERIS should be used cautiously in elderly patients due to the potential for decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Hepatic Impairment Patients with moderate to severe liver disease should be monitored for increased signs and/or symptoms of hypercorticism. Discontinuing the use of UCERIS tablets should be considered in these patients.

OVERDOSAGE Reports of acute toxicity and/or death following overdosage of glucocorticosteroids are rare. Treatment consists of immediate gastric lavage or emesis followed by supportive and symptomatic therapy. If glucocorticosteroids are used at excessive doses for prolonged periods, systemic glucocorticosteroid effects such as hypercorticism and adrenal suppression may occur. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage may be reduced temporarily. Single oral budesonide doses of 200 and 400 mg/kg were lethal in female and male mice, respectively. The signs of acute toxicity were decreased motor activity, piloerection and generalized edema.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity Carcinogenicity studies with budesonide were conducted in rats and mice. In a two-year study in SpragueDawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.023 times the maximum recommended human dose on a body surface area basis) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In an additional two-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). The concurrent reference glucocorticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.1 times the maximum recommended human dose on a body surface area basis). Mutagenesiss Budesonide was not genotoxic in the Ames test, the mouse lymphoma cell forward gene mutation (TK+/â&#x20AC;&#x201C;) test, the human lymphocyte chromosome aberration test, the Drosophila melanogasterr sex-linked recessive lethality test, the rat hepatocycte UDS test and the mouse micronucleus test. Impairment of Fertilityy In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (approximately 0.07 times the maximum recommended human dose on a body surface area basis). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.02 times the maximum recommended human dose on a body surface area basis) and above. No such effects were noted at 5 mcg/kg (approximately 0.005 times the maximum recommended human dose on a body surface area basis).

UCERISâ&#x201E;˘ is a trademark of Santarus, Inc. U.S. Patent Nos: 7,410,651; 7,431,943; RE43799; 8,293,273. Š 2013 Santarus, Inc.

1-UCE13033 V1

subjects were randomized to four weeks of their habitual diet or a low-FODMAPs diet. Patients on the low-FODMAPs diet reported fewer gastrointestinal symptoms based on intention-to-treat. Based on the per-protocol population (n=35), there were no differences in fecal short-chain

Data on Diet and IBS Adrian Miranda, MD Associate Professor of Pediatrics-Gastroenterology Co-director, Center for Pediatric Neurogastroenterology, Motility and Autonomic Disorders Childrenâ&#x20AC;&#x2122;s Hospital of Wisconsin Milwaukee, Wisconsin Patients and families have been telling us for years that food perpetuates symptoms. Yet, despite the fact that nearly two-thirds of IBS patients have postprandial symptoms, very few studies have focused on the role of food in the development of IBS symptoms.

Although it is true that a diet low in fermentable oligo-, di- and monosaccharides, and polyols (FODMAPs), limiting foods high in fructose, lactose, fructans, galactans and polyols, may help reduce symptoms of gas, bloating, cramping and/or diarrhea in certain patients, a lot more data are needed to figure out exactly how this is occurring and who the patients are who will benefit. It is clearly not beneficial for all patients.

The varied clinical presentation of patients with functional disorders with no exact pathophysiology makes it very difficult to determine who are the patients who would benefit from such dietary restriction. Currently, we only have symptoms to guide our management of patients with IBS and other painful functional bowel disorders.

Studies investigating the role of carbohydrate malabsorption and/ or maldigestion in patients with IBS have yielded mixed results and likely point to the heterogeneity of this population. It is logical to believe that a high load of fermentable substrates in patients with IBS could increase gas production and exacerbate visceral hypersensitivity. However, the data are still not clear. Lactose restriction, for example, has been shown to be marginally effective in alleviating symptoms in IBS patients.

DDW 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2013

fatty acids, but the FODMAPs group demonstrated lower concentrations and proportions of Bifidobacteria, “which is counterintuitive,” according to Dr. Shulman, as these bacteria generally have been associated with improved outcomes in various conditions.

Unpublished data from our group, and others, also suggest that a high percentage of patients with low lactase, found through disaccharidase assays, also have low sucrase. This may, at least partially, help to explain why a low-lactose diet alone is not helpful in patients with suspected lactose intolerance.

Indeed, differences in gut microflora may prove to be of greater significance in generating symptoms than disaccharidase levels alone. Already, data in animals and humans suggest a potential brain– gut connection, and studies have suggested that alterations in gut microflora can influence brain biochemistry. FODMAPs could potentially serve as prebiotics for certain strains of bacteria that would not only influence gut sensitivity, but also extraintestinal manifestations, such as anxiety and depression, that are common in IBS. However, more work is needed to investigate this potential mechanism.

Fructose is particularly interesting since it is common in the Western diet and the human intestine does not have a particular enzyme to digest it or transport it. Anecdotal evidence suggests that in some children with functional abdominal pain, eliminating juices or foods high in fructose alone can alleviate symptoms. However, we have yet to identify who these patients are and how they differ from others with similar symptoms.

The data are highly intriguing, and clearly more work is needed to identify precisely the underlying pathophysiology of dietary triggers and its effects on the microbiome, as well as on gut sensory and immune function. A better understanding of the pathophysiology of dietary triggers would allow us to identify more adequately the symptomatic patients who would benefit from such dietary modification and avoid unnecessary diagnostic testing and medication trials.

During the 2013 DDW meeting, Zhou et al reported that the FODMAPs diet enhanced not only visceral hypersensitivity but also inflammation in the colon (Zhou et al. Abstract 164).

“It seems there may be more ‘badness’ to the FODMAPs diet than just enhancing fermentation in the colon,” Dr. Shulman noted.

Since the FODMAPs diet appears to be beneficial in some, but not all, patients, it would be helpful to have a means of identifying the best candidates for this rather challenging intervention,

he said. A pilot study from his research team has taken a step in this direction.

They presented data at the DDW meeting showing that among children with IBS, response to a low-FODMAPs diet was related to baseline microbiome composition and fecal metabolites (Chumpitazi BP et al. Abstract 946).

“Perhaps we can begin to identify which children might respond to these diets,” said Dr. Shulman.

Carbohydrate malabsorption in the small bowel is believed to induce adverse symptoms by increasing the osmotic load

DO WE NEED MORE

FOCUS IN

19

with resultant increased luminal fluid and distension leading to diarrhea, bloating and pain. Additionally, if carbohydrates are fermentable, gas production occurs, which also may be associated with bloating and/or pain.

The newest data are showing that there may be other mechanisms, not yet well understood, by which these diets produce symptoms.

■ Dr. Shulman disclosed relationships with Gerson Lehrman Group Inc., Mead Johnson & Co., and QOL Medical.

IBD?

Understanding the pathophysiology can help bring further clarity to IBD. Learn more at IBDInsights.com.

Dr. Miranda reported no conflicts of interest. © 2013 Takeda Pharmaceuticals U.S.A., Inc. All rights reserved. Printed in U.S.A./September 2013 87404

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DDW 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2013

Multidisciplinary Intervention Reaps ‘Striking’ Benefits ‘With our intervention, the results were striking. It’s amazing what we In Children With IBS

BY CAROLINE HELWICK ORLANDO, FLA.—An — interventional program that targets adolescents recently diagnosed with irritable bowel syndrome (IBS) effectively reduced subsequent use of health care resources at the Kaiser Permanente Sacramento and Walnut Creek (California) health care system.

“With our intervention, the results were striking.

It’s amazing what we could achieve. We were able to reduce the frequency of visits to the ER [emergency room], and subsequently the number of imaging procedures,” said Michael Lawson, MD, PhD, senior investigator in the study.

“What’s been clear to me is that most adult patients I see have had IBS since adolescence. What’s happening is that around age 12, adolescents are asking for help, not just for gastrointestinal symptoms but for other health reasons. At the same time, parents are beside themselves,” said Dr. Lawson.

Abdominal pain is common among school-aged children, with about three-fourths of them reporting an episode in a single year. Approximately 8% of all high school and middle school students have seen physicians for this complaint. IBS is the suggested cause of abdominal pain for about 6% of middle school and 14% of high school students, and these students have increased school absenteeism, anxiety, depression, headache and social isolation, and a reduced quality of life.

“Children with IBS have significantly higher outpatient health care costs, since they have increased ambulatory care visits. And children with IBS may become adults with IBS,” said study author Amir Kalani, MD, PhD, who presented the findings at the 2013 Digestive Disease Week meeting.

“We have recognized that a ‘crisis year’ [exists] in IBS, which is the year after the IBS diagnosis is made, [when] patients increasingly seek medical attention [that leads to] significant health care utilization through visits and imaging,” said Dr. Kalani. He pointed out that many of these visits were for non–gastrointestinal (GI)-related complaints such as headache, back pain and anxiety.

Now an intern at Drexel University, in Philadelphia, Dr. Kalani conducted the research while he was a graduate student at University of California, Davis.

Multidisciplinary Approach The comprehensive behavioral program that Drs. Kalani and Lawson developed significantly reduced GIrelated visits, all health care visits and all imaging during the crisis year, and the benefits of the program persisted through a four-year period, they said.

The program took a multidisciplinary approach that involved a gastroenterologist, a psychologist, a registered dietitian, a health educator and a physical trainer. The goal was to reduce symptoms of IBS, improve quality of life and reduce future use of health care resources. The behavioral intervention aimed to reassure and educate both the patients and their parents during two 90-minute sessions (patients and parents met in separate groups).

The patients were taught exercises using stability balls and cable tubing, relaxation techniques using guided imagery, and yoga. All sessions included time for discussion.

The average age of the children and adolescents with

could achieve. We were able to reduce the frequency of visits to the ER [emergency room], and subsequently the number of imaging procedures.’

—Michael Lawson, MD, PhD

IBS who participated in the program was 13.5 years. The groups included 97 children and adolescents (aged 7-17) recently diagnosed with IBS; the control group comprised 86 children and adolescents recently diagnosed with IBS who enrolled but did not attend the classes and who were matched for age, gender and previous health care utilization. The researchers compared medical records three years prior to the intervention and one year post-intervention (plus four years of follow-up). The current analysis was based on data from the first two years of the program, which is now in its seventh year.

Compared with controls during the “crisis year,” intervention participants had less GI-related imaging, less imaging for any reason and fewer GI-related visits.

Even at four years, most of these differences persisted.

The reduction in imaging was clinically and economically meaningful, with GI-related imaging reduced by 33% and all imaging reduced by 27%.

In the “costly” year after diagnosis, GI-related visits, all visits and overall imaging (but not GI-related imaging) were reduced significantly. At four years, GI-related visits, overall imaging and GI-related imaging were reduced significantly, but overall visits did not differ significantly between the two groups, Dr. Kalani said.

In the year after diagnosis, GI-related and overall visits increased by 44% among controls but decreased significantly, by up to 24% (P<0.05), among intervention participants. Regarding overall visits, although both

groups had an increase in the year following diagnosis, intervention participants had significantly fewer visits than controls (46% increase over baseline vs. 97%, respectively). Intervention participants also utilized significantly less overall imaging; however, there was no significant difference in GI-related imaging between the two groups during the year after diagnosis. At four years, GI-related visits were 59% less in participants (P<0.05), but total number of visits was similar. GI-related imaging was 33% less (P<0.05) and overall imaging was 27% less among the participants at four years (P<0.05), compared with controls.

“In the year afterr diagnosis, only 20% of overall visits were GI-related, which emphasizes the complexity of the condition,” Dr. Kalani said.

‘Information Overload’ Dr. Lawson pointed out that these changes were the result of decreasing the “information overload” experienced by IBS patients.

“By intervening, working to reduce stress, teaching diet and exercise, and helping with socialization, we are helping the pain gate in the mid-brain to properly filter out unnecessary information,” he said. “We hypothesize that this has to do with neuroplasticity. We are reducing the information overload that IBS patients develop over time.” see Childhood IBS, page 24

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COLORECTAL CANCER:

The “Right” Perspective

Adenocarcinoma Detection and Prevalence in the Proximal Colon

Diagnoses of colorectal cancer (CRC) in the proximal (right) colon are recognized to be of increasing importance 1-3 • In a review of 9 population-based cancer registries of patients with CRC (N=243,861)1: — There was a relative increase of 18% in the proportion of right colon CRC cases from 1978 to 1998, while diagnoses in the left (distal) colon decreased1 • Right colon CRC is more common in the elderly,1,4,5 which is a growing percentage of the population6

Adenomas present special challenges in the right colon • “Endoscopically subtle” lesions* (Figure 17) are harder to detect and more common in the right colon8 • Cancers developing from serrated lesions are usually in the proximal region8 — Serrated adenocarcinoma represents up to 17.5% of most proximal CRCs (vs ≈7.5% of all CRCs)9 • Split-dose bowel preparations that improve cleansing may improve adenoma detection in the right colon8 — Ingestion of the second dose close to the time of colonoscopy clears mucus/chyme that tends to stick to the cecum/right colon8

Figure 1. Types of colorectal lesions* that are more difficult to detect7,8

*These include nonpolypoid (flat, depressed) lesions and serrated lesions.8 Photographs shown to the left are from the cecum and were taken during a colonoscopy in a patient who had used a split-dose bowel preparation.7

Flat lesion

Serrated lesion

Importance of thorough adenoma detection during colonoscopy Adenoma detection rates (ADRs) ≥20% are significantly associated with lower risk of interval colorectal cancer (Figure 2)10 Figure 2. Interval Colorectal Cancers Reported in a Colonoscopy-based Screening Program10*

Number of interval cancers†

35 33.6

30 25

*Results encompass the findings of 186 endoscopists in 45,026 patients. Each endoscopist had performed at least 30 screening examinations within the study period (October 2000– December 2004).

25.5 22.1

20

†Number of interval cancers/ 100,000 person-years of follow-up. A person-year represents one person at risk of development of CRC during a 1-year period.

15 10

‡ Proportion

2.4

5 0

<11%

11%-14.9% 15%-19.9% Adenoma detection rates‡

of subjects in whom at least one polyp was identified.

≥20%

Tracking ADR as a quality measure in colonoscopy will soon be required by law 11 Table. ACS/MSTF§ Colorectal Cancer Surveillance Guidelines12

§

Screening colonoscopy: adenoma findings

1-2 <1 cm tubular adenomas with low-grade dysplasia

3-10 adenomas; adenomas ≥1 cm; adenoma with villous features; high-grade dysplasia

>10 adenomas

Sessile adenomas removed piecemeal

Recommended timing of follow-up

5-10 years

3 years

<3 years; consider possibility of familial syndrome

2-6 months to verify complete removal

ACS, American Cancer Society; MSTF, Multi-Society Task Force on Colorectal Cancer.

References: 1. Rabeneck L, Davila JA, El-Serag HB. Is there a true “shift” to the right colon in the incidence of colorectal cancer? Am J Gastroenterol. 2003;98:14001409. 2. Kee F, Wilson RH, Gilliland R, et al. Changing site distribution of colorectal cancer. BMJ. 1992;305:158. 3. Cucino C, Buchner AM, Sonnenberg A. Continued rightward shift of colorectal cancer. Dis Colon Rectum. 2002;45:1035-1040. 4. Benedix F, Kube R, Meyer F, et al. Comparison of 17,641 patients with right- and left-sided colon cancer: differences in epidemiology, perioperative course, histology, and survival. Dis Colon Rectum. 2010;53:57-64. 5. Strul H, Kariv R, Leshno M, et al. The prevalence rate and anatomic location of colorectal adenoma and cancer detected by colonoscopy in average-risk individuals aged 40-80 years. Am J Gastroenterol.

2006;101:255-262. 6. US Census Bureau. Unprecedented global aging examined in new Census Bureau report commissioned by the National Institute on Aging. http://www.census.gov/newsroom/releases/archives/aging_population/cb09-108.html. Published July 20, 2009. Accessed November 14, 2012. 7. Data on file.

Braintree, MA; Braintree Laboratories, Inc.; 2012. 8. Lasisi F, Rex DK. Improving protection against proximal colon cancer by colonoscopy. Expert Rev Gastroenterol Hepatol. 2011;5:745-754. 9. Mäkinen MJ. Colorectal serrated adenocarcinoma. Histopathology. 2007;50:131-150. 10. Kaminski MF, Regula J, Kraszewska E, et al. Quality indicators for colonoscopy and the risk of interval cancer. N Engl J Med. 2010;362:1795-1803. 11. GIQulC colonoscopy quality registry surpasses 100,000 cases: milestone underscores value of clinical benchmarking tool for gastroenterology practices [press release]. Bethesda, MD: American Society for Gastrointestinal Endoscopy. October 11, 2012. 12. Kaiser Family Foundation, American Cancer Society, National Colorectal Cancer Roundtable. Coverage of colonoscopies under the Affordable Care Act’s prevention benefit. http://www.kff.org/healthreform/upload/8351.pdf. Published September 2012. Accessed November 12, 2012.

©2013 Braintree Laboratories, Inc.

SU-13899

May, 2013

Brought to you as an educational service by

24

DDW 2013

Childhood IBS continued from page 20

Dr. Lawson also said parents are especially grateful for the educational aspect of the intervention.

“We have moms in tears, saying our program is the best thing that has happened to them. Children say that they don’t feel like freaks anymore,” he said.

‘Up to 60% of children with IBS will have similar symptoms as adults, according to numerous studies, and the treatment of IBS in adults costs the United States $6 billion to $12 billion per year. It’s critical, therefore, that we develop interventions that prevent this.’

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2013

“First, Dr. Kalani and [his] colleagues combined methodologies that have previously been shown to be effective in the treatment of children with IBS (i.e., relaxation, guided imagery, etc). Importantly, their intervention only involved two sessions, whereas other interventions often are more time-intensive and therefore more costly and less acceptable to families,” Dr. Shulman said.

He applauded the researchers for “wisely choosing to target parents as well as children,” based on studies by Lynn Walker, PhD, professor

of pediatrics at Vanderbilt University School of Medicine, Nashville, Tenn., that have emphasized the importance of involving parents.

“Secondly, and perhaps most importantly, the investigators showed that these interventions, done early in the presentation of IBS, have an impact on reducing health care utilization and hence, likely health care–related costs. Furthermore, the benefit lasted for at least four years,” Dr. Shulman said.

The fact that IBS symptoms can be treated and use of health care resources

reduced early in the course of IBS is of great value, Dr. Schulman said.

“Up to 60% of children with IBS will have similar symptoms as adults, according to numerous studies, and the treatment of IBS in adults costs the United States $6 billion to $12 billion per year. It’s critical, therefore, that we develop interventions that prevent this.”

■ Drs. Kalani and Lawson reported no relevant conflicts of interest. Dr. Shulman has worked with Gerson-Lehrman, Mead Johnson & Co., and QOL Medical, LLC.

—Robert Shulman, MD

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Because of these meaningful benefits to the patients and their parents, Dr. Lawson said this research has “dwarfed any other research I do.”

Long-term follow-up is planned as the intervention participants reach adulthood. The program is further described in Dr. Lawson’s book, The Gut Solution (www.thegutsolution.com).

Robert Shulman, MD, professor of pediatrics and director of the Center for Pediatric Abdominal Pain Research at Baylor College of Medicine, Houston, said the study is important for several reasons.

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Probiotics continued from page 1

(DDW) meeting.

Stefano Guandalini, MD, professor of pediatrics and section chief of Pediatric Gastroenterology, Hepatology and Nutrition at the University of Chicago Medicine, led a discussion on the topic at the DDW meeting.

“We have patients rushing out to buy probiotics, but the majority of the products have shown no evidence of benefit,” Dr. Guandalini said. “Patients do express a desire for more information, and they need this from their physicians.”

For example, data from a multicenter, focus group–based study found that patients with inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) were interested in using probiotics to improve their digestive health but remained somewhat skeptical due to a lack of endorsement by their physicians, lax governmental regulations and limited empirical evidence supporting their efficacy (Mercer M et al. J Clin Gastroenterol 2012;46:138-144).

“Patients are interested in probiotics but have many unanswered questions about their use,” the authors of that study concluded.

Although publications concerning probiotics are increasing, clinical research is still scarce. A search of the 2012 literature on probiotics revealed only 10 original research papers but nearly 60 editorials, coming primarily from outside the United States. But despite a lack of research, a trend toward increased acceptance of probiotics among physicians was documented in a 2011 survey of 220 doctors in the United Kingdom. Among this group, 81% of gastroenterologists and 53% of surgeons reported recommending or prescribing probiotic supplements to their patients (Cordina C et al. J Dig Dis 2011;12:489-496).

“At least in the [United Kingdom], physicians are inclined to think seriously about probiotics,” Dr. Guandalini said, noting that most of the recommendations were for patients with IBS. Importantly, evidence supports the use of some but not all strains of probiotics.

“Not all probiotics are created equal, and it’s a mistake to think that one can use any of them,” Dr. Guandalini noted.

Strain-Specific Evidence There is some clinical evidence to support the use of probiotics in some patients with some GI disorders, and it is important to distinguish among different probiotic strains.

Lactobacillus rhamnosuss GG (LGG) is one of the most extensively investigated probiotics, and its overall benefit in children with abdominal pain–related

functional GI disorders was confirmed in a 2011 meta-analysis (Horvath A et al.

Aliment Pharmacol Therr 2011;33:13021310). Compared with placebo, LGG was associated with a significantly higher proportion of treatment responders in the overall population with functional abdominal pain and in a subgroup of children with IBS. However, treatment response did not differ between children with functional abdominal pain or functional dyspepsia who received LGG and those receiving placebo. Intensity of pain was significantly reduced both in the overall and IBS populations, whereas frequency of pain was reduced only in patients with IBS.

fasting antral area (Indrio F et al. J Pediatrr 2008;152:801-806). Authors of the study concluded that L. reuterii improves feeding tolerance and gut function in formula-fed preterm newborns. In another double-blind, randomized, placebo-controlled study involving 44 infants with chronic constipation, L. reuteri DSM 17938 supplementation was associated with a significantly higher frequency of defecation compared with placebo at weeks 2, 3 and 8; however, there was no improvement in stool consistency or crying episodes.

In another study, lower pain intensity, although not lower frequency of pain, was observed in 60 children with functional

25

the VSL#3 group at six weeks (P<0.05).

“There was some improvement with placebo, but the change from baseline was much greater with the probiotic,” Dr. Guandalini noted.

Dr. Guandalini concluded that probiotic supplementation with Lactobacilli, Bifidobacteria and Streptococcuss is “promising,” as these strains offer statistically significant—albeit modest—benefits in children with functional GI disorders.

“They may well represent an attractive therapeutic option; however, we need to better define the strain, optimal dosage, mode of action, safety, and especially long-term efficacy and tolerability. We have established evidence of benefit, but we need to build on the data,” he said.

Evidence Strong Enough?

‘Not all probiotics are created equal, and it’s a mistake to think that one can use any of them.’

—Stefano Guandalini, MD

Bifidobacterium lactiss strain DN-173 010 has been shown to increase stool frequency in women with constipation; however, in a prospective randomized, double-blind controlled trial of 159 children with constipation, the strain showed no benefit over placebo when delivered as a fermented dairy product containing B. lactiss (Tabbers MM et al.

Pediatrics 2011;127:e1392-e1399). Stool frequency after three weeks increased in both groups; therefore, clinical evidence is insufficient to recommend this product for these patients, the authors maintained.

Some evidence has backed dietary supplements containing Lactobacillus reuteri. In a 30-day randomized, double-blind, placebo-controlled trial of 30 preterm infants, newborns who received L. reuterii ATCC 55730 had significant decreases in regurgitation and in mean daily crying time, and had more frequent stools, as well as an increase in gastric emptying rate and a reduction in

abdominal pain who received L. reuteri DSM 17938 (Romano C et al. J Paediatr Child Health 2010 Jul 8. [Epub ahead of print]).

Streptococcus thermophilus VSL#3 is a combination of eight different strains, in high concentrations, and its use is supported by a study from a team of researchers led by Dr. Guandalini. In a crossover study of 59 children with IBS, VSL#3 provided significantly greater relief of symptoms, including abdominal pain/discomfort and bloating/gas, compared with placebo, and was associated with less “life disruption” (Guandalini S et al. J Pediatr Gastroenterol Nutrr 2010;51:24-30). However, stool pattern in this population was not improved compared with placebo.

For the primary end point of improvement in global assessment of symptom relief, the average score of 4 at baseline dropped to approximately 3.5 in the placebo group and to less than 2.5 in

“I agree with virtually every aspect of this review by Dr. Guandalini,” said J. Marc Rhoads, MD, professor in the Department of Pediatrics at the University of Texas Medical School in Houston. “Probiotics are taking their niche in pediatric gastroenterology practice, as well they should. In fact, there is more evidence at the meta-analysis level for the use of probiotics than there is for many of the other things that are done in practice, including the use of stool softeners over laxatives, the treatment of gastroesophageal reflux in infants and the treatment of infants with hematochezia with hypoallergenic formula. All of these are examples of standard practice with limited evidence,” he noted.

“There is strong evidence from metaanalyses for the use of probiotics to reduce the severity of acute gastroenteritis, to prevent necrotizing enterocolitis [and] antibiotic-associated diarrhea, and to reduce the severity of IBS,” he said.

“There is also very promising evidence that probiotics are efficacious in babies with colic, as mentioned for children with ulcerative colitis, infants with atopic eczema and children with constipation.”

But despite the firm evidence of some effect, the magnitude of that effect is unclear, Dr. Rhoads noted.

“For example, it seems that probiotics have a major impact in preventing necrotizing enterocolitis but only modifying effects on IBS. It is not at all clear if one probiotic is better than another, or one combination better than an individual probiotic for any of the above-mentioned conditions. I personally believe that dose is not as important, and most of the commercially available probiotics do have at least 108 CFUs [colony-forming units] per unit dose,” he said.

In addition to efficacy and dosing, there may be issues of product homogeneity, product quality and safety, Dr. Rhoads noted. see Probiotics, page 26

26

DDW 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2013

Celiac Guidelines continued from page 1

reduction in the need for biopsies to diagnose celiac disease in children. However, the retrospective studies, which were undertaken at centers in North America, identified potential limitations.

The studies evaluated criteria set forth in the 2012 guidelines developed by the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). The aim of the ESPGHAN guidelines was to “achieve a high diagnostic accuracy and to reduce the burden for patients and their families” (Husby S et al. J Pediatr Gastroenterol Nutr 2012;54:136-160).

“Almost half of the pediatric patients diagnosed with celiac disease in our multicenter retrospective analysis would have met the ESPGHAN criteria and avoided biopsy,” said the author of one of the studies, Catherine D. Newland, MD, of the Department of Pediatrics, University of Chicago. In addition to reducing the burden of the invasive procedure on children and their families, Dr. Newland predicted there would be a large cost savings.

However, in reviewing patient records that were gathered from three institutions, researchers noted that omitting endoscopy would have meant missing a substantial number of unexpected other gastrointestinal diagnoses, including chronic gastritis, reflux esophagitis and eosinophilic esophagitis. Therefore, forgoing endoscopy does have consequences, Dr. Newland noted.

A similar assessment was made by Canadian researchers. They performed a retrospective review of 352 children with an antiserum tissue transglutaminase (tTG) greater than 10 times the upper limit of normal (ULN), which is the ESPGHAN cutoff for considering celiac disease without biopsy in symptomatic children. In evaluating the laboratory results of this population, it was determined that the positive predictive value (PPV) was 100% in symptomatic patients when anti-tTG was greater than 10 times the ULN and a positive anti-endomysial antibody (EMA) was greater than 1:80.

“Adoption of the ESPGHAN criteria for the non-biopsy diagnosis of celiac

Probiotics continued from page 25

“The [FDA] and the National Institutes of Health’s National Center for Complementary and Alternative Medicine are concerned about safety in the vulnerable infant population, which is reasonable,” he said. However, to date, studies have not reported more than a fraction of a percentage who develop serious adverse events, he noted (see “Safety

‘Adoption of the ESPGHAN criteria for the non-biopsy diagnosis of celiac disease will relieve the stress of an invasive procedure in children and families, as well as reduce costs.’

—Dominica Gidrewicz, MD

disease will relieve the stress of an invasive procedure in children and families, as well as reduce costs,” said Dominica Gidrewicz, MD, from the Department of Pediatrics, University of Calgary, Alberta, Canada. However, Dr. Gidrewicz said if all symptomatic children with positive EMAs of any titer were diagnosed with a “no-biopsy” protocol as recommended in the ESPGHAN guidelines, 2% would be misdiagnosed with celiac disease.

Furthermore, if an anti-tTG greater than 10 times the ULN was used as the sole criterion for a “no-biopsy” protocol, the Calgary data suggest another 2% of patients would be misdiagnosed. Testing for HLA-DQ2/DQ8—a 8 gene commonly associated with celiac disease—which is recommended by the ESPGHAN guidelines to confirm a diagnosis, was not helpful because all false-positive patients were HLA-DQ2/DQ8–positive.

8 Decker Butzner, MD, senior author of the Canadian study, also from the Department of Pediatrics at the University of Calgary, said, “Any unit that plans to institute a ‘no-biopsy’ protocol needs

to know how their celiac antibody tests perform, so children with ‘false-positive’ tests will not be diagnosed with celiac disease. In North America, standardization does not exist to ensure uniform results of the many celiac antibody tests on the market. Thus, we evaluated our antibody test results to ensure a 100% PPV of the ‘no-biopsy’ protocol to be instituted in Calgary.”

The ESPGHAN guidelines describe two algorithms for diagnosis. In children with symptoms of celiac disease, the initial approach is to test for anti-tTG immunoglobulin (Ig) A antibodies. If the antibody test is negative and IgA levels are normal for age, then celiac disease is considered unlikely. The same is true if an IgG anti-deamidated gliadin peptide (DGP) assay—which can be substituted for antitTG IgA antibodies in the ESPGHAN guidelines—is negative. If anti-tTG antibodies were greater than 10 times the ULN, the guidelines suggest discussing the option of non-biopsy testing.

In such patients, according to the ESPGHAN guidelines, “if the patient

of Probiotics to Reduce Risk and Prevent or Treat Disease,” available at www.ncbi. nlm.nih.gov/books/NBK56091).

“Finally,” Dr. Rhoads said, “duration of effect and of colonization is a very interesting question. In adults, within two weeks, virtually all the probiotic is gone.

This may not be true in infants, although the colonization may be limited to three to six months. What I think is fascinating,” he added, “is the profound [effect]

that some probiotics have on the neonatal immune system. We have found that administration of L. reuterii to newborn rat or mouse pups produces a significant increase in regulatory T-cell numbers [Liu Y et al. PLoS Onee 2013;8:e56547] and dramatically reduces the severity of necrotizing enterocolitis, at least in part by reducing NF [nuclear factor]-κB signaling and the inflammatory cascade [Liu Y et al. Am J Physiol Gastrointest

tests positive for EMA antibodies and positive for HLA-DQ2 or HLA-DQ8, then a diagnosis of celiac disease is confirmed. A gluten-free diet is started and the patient is studied for improvement in symptoms and a decline in antibodies.”

Although these steps are considered sufficient to rule in a diagnosis of celiac disease, they may not be sufficient to rule out the diagnosis, according to the guidelines. A long list of caveats regarding the potential for false-negative results and the need for additional diagnostic workup, including biopsy, in the rare cases when EMA and HLA findings are negative in a symptomatic child with anti-tTG greater than 10 times the ULN are included in the guidelines.

Furthermore, the guidelines state that in the diagnostic algorithm for asymptomatic children, “histological proof is needed to accept the diagnosis” of celiac disease. However, reflecting on the difficulty of a definitive diagnosis in some individuals, the guidelines also caution that celiac disease cannot be confirmed uniformly even after biopsy in asymptomatic seropositive individuals. In such cases, the guidelines recommend periodic reevaluation while maintaining such individuals on a gluten-free diet.

The independent retrospective analyses conducted by Drs. Newland and Gidrewicz support the potential advantages of a non-biopsy diagnosis of celiac disease in symptomatic children, but also underscore the limitations. In addition to the false-positives identified in the Canadian evaluation, a substantial proportion of symptomatic children with celiac disease will not meet the criteria. In the analysis conducted by Dr. Newland, only 46% of patients for whom there were data for both anti-tTG and EMA, were positive for both. Of those who underwent biopsy, 31.3% had a Marsh score of 2 or less.

However, in those who meet the criteria, the test would avoid both the inconvenience of biopsy and its cost.

“Avoiding biopsy would eliminate risk to the patient and drastically reduce health care costs by as much as $10,000 per patient,” Dr. Newland said.

■ Drs. Newland, Gidrewicz and Buznar reported no conflicts of interest.

Liver Physioll 2012;302:G608-G617].

This effect was not shared by all strains of the probiotics we studied, pointing to the importance of preclinical trials and carefully selected biomarkers for human trials, for example, cytokine levels and regulatory T-cell percentages.”

■ Dr. Guandalini reported no relevant conflicts of interest. Dr. Rhoads has received a research grant from BioGaia, Inc.

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DDW 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2013

Endoscopic Mucosal Resection Equivalent to Esophagectomy For Patients With Early Esophageal Cancer ‘Complete Paradigm Shift’ in the Management of Esophageal Adenocarcinoma

BY TED BOSWORTH

endoscopic therapy group and 89.6% in the surgical resection group (P=0.12).

P At five years, when followup data were available for 49% of the patients, survival rates also were similar (69.3% vs. 75.8%, respectively; P=0.23). In a Cox proportional hazard model, signifiP cant predictors of esophageal cancer–specific mortality included older age at diagnosis (P<0.001), stage T1a disease (P=0.001 P vs. stage T0), year of diagnosis (P=0.02) P and radiation therapy (P<0.001).

It is notable that the proportion of esophageal cancers treated with endoscopic eradication therapies relative to surgical resection has been increasing over the past several years, according to a time-trend analysis of the SEER data. Although the relative increase in endoscopic treatment was greater in the T0 group than in the T1a group, this trend appears to reflect a growing acceptance of endoscopic procedures.

Although Dr. Wani acknowledged the limitations of an observational, population-based study and called for longer-term follow-up to ‘Patients undergoing endoscopic therapies confirm that these approaches provide equivalent outcomes, these data “really were more likely to die of non–esophagealincrease the degree of confidence” in the related causes, predominantly ability of endoscopic ablation to treat early esophageal cancer effectively. In the cardiovascular disease.’ absence of a randomized trial, the large —Sachin Wani, MB SEER database may provide the best evidence so far that endoscopic ablation is a viable treatment alternative.

ORLANDO, FLA.—On the basis of long-term outcomes, endoscopic mucosal resection (EMR) appears to be as effective as surgical esophagectomy for early esophageal adenocarcinoma. This conclusion was drawn from an analysis of more than 1,000 patients from the Surveillance, Epidemiology, and End Results (SEER) database.

No significant differences in mortality related to esophageal cancer were found at either two or five years after the procedure.

“There was a significantly higher non– cancer-related mortality in the group receiving endoscopic treatment, but this appears to reflect a selection bias,” reported Sachin Wani, MB, assistant professor of medicine-gastroenterology at the University of Colorado School of Medicine in Aurora. In a late-breaking study presented at the 2013 Digestive Disease Limitations of Therapeutic Week meeting, Dr. Wani explained that Endoscopy patients treated with endoscopy tended to be older and to have more comorbidities, Asked to comment on these data, suggesting a preference for this treatment Steven R. DeMeester, MD, assistant over surgery in this population. professor of surgery, Department of Surgical resection is widely regarded as Cardiothoracic Surgery, Keck School of the gold standard in the treatment of early Medicine, University of Southern Caliesophageal adenocarcinoma, defined in this fornia, Los Angeles, called the use of study as carcinoma in situ (T0) or invasive endoscopic surgery “a complete paradigm tumor confined to the mucosa, lamina proshift in the management of Barrett’s pria and muscularis mucosae (T1a). Interhigh-grade dysplasia and intramucoest in endoscopic eradication therapies for sal adenocarcinoma in the last decade.” this early esophageal adenocarcinoma is He believes that endoscopic therapy ‘Although repeated sessions of endotherapy usually are growing due to the substantial morbidity with resection or ablation can be curasuccessful, some patients have recalcitrant or progressive and mortality associated with esophagective while reducing morbidity relative to disease that is best treated with an esophagectomy. tomy. Although this study was observaesophagectomy, but he cautioned that it tional, it provided long-term follow-up in cannot always be performed in a single Furthermore, after successful endoscopic therapy, a relatively large patient cohort. procedure. surveillance continues indefinitely.’

An analysis of the SEER database “Endoscopic therapy requires that all —Steven R. DeMeester, MD revealed that 1,098 patients meeting the of the intestinal metaplasia, not just the definition of early esophageal adenocardysplasia or cancer, is removed or patients cinoma were treated between 1998 and are at significant risk for the development “Patients undergoing endoscopic therapies were more of metachronous cancers. Although repeated sessions of 2009. Of these, 283 (26%) underwent endoscopic therapy, usually in the form of EMR, as their first procedure. likely to die of non–esophageal-related causes, predomi- endotherapy usually are successful, some patients have The remainder of the patients initially were treated with nantly cardiovascular disease,” Dr. Wani said. “However, recalcitrant or progressive disease that is best treated surgical resection. Most of these patients received total the treatment arm that a patient belonged to was not a with an esophagectomy. Furthermore, after successful esophagectomy with partial gastrectomy. predictor of overall survival.” endoscopic therapy, surveillance continues indefinitely,” The two groups differed markedly in baseline characThe SEER database does not capture information on Dr. DeMeester said. Due to the fact that even small teristics. Although patients treated with endoscopy were comorbidities, but Dr. Wani suggested that it is reason- lesions may be malignant and must be excised, he recsignificantly older (mean age, 70 vs. 63 years; P<0.001), able to infer, based on the age of the patients and greater ommended “an exhaustive” evaluation of the tissue. they also were more likely to have T0 (32.5% vs. 23.1%) non-cancer mortality, that those receiving endoscopic “Pathologic evaluation of an endoscopic resection rather than T1a disease (67.5% vs. 76.9%; P P=0.002 for treatment had a greater comorbidity index. specimen is complicated, and should be done by an both). Patients who underwent endoscopy also had more Retrospective analysis of SEER data has some limita- expert in gastrointestinal pathology because invasion favorable tumor characteristics. In particular, histologic tions, including that only the first treatment is recorded. into the submucosa must be differentiated from invasion grade was more likely to be well differentiated (33% vs. As a result, the rate of recurrence and the need for sub- limited to the mucosa,” Dr. DeMeester said.

24.1%; P<0.001). Endoscopic patients also were less sequent therapies cannot be compared. However, there Although Dr. DeMeester believes “there is no queslikely to receive radiation therapy than those undergo- also are some advantages relative to studies with fewer tion that endotherapy is a major advance,” he said it ing surgical resection. patients or fewer participating centers: As patients’ data requires a significant commitment “to achieve the oncoIn the 79% of patients for whom outcomes were avail- are captured across diverse treatment centers, it is reason- logic success of an esophagectomy.”

■ able at the end of two years, esophageal cancer–free sur- able to assume that SEER data are more representative vival was similar for both treatments, at 93.5% in the of real-world results with both endoscopy and surgery.

Drs. Wani and DeMeester reported no conflicts of interest.

motility monitoring

30

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2013

Weight Loss Reduces Risk for CRC Diagnosis, Mortality

BY CHRISTINA FRANGOU SAN FRANCISCO—Individuals can lower their risk for colorectal cancer (CRC)—particularly cancers of the colon and especially among men—by increasing recreational physical activity, according to new research.

Doing so will also significantly reduce the risk for death in patients who have been diagnosed with the disease.

Excess body weight also negatively affects diagnosis and prognosis. Obese individuals are more likely to be diagnosed with, and more likely to die of, CRC. Moreover, the effect of obesity is independent of treatment complications, meaning that obesity does not appear to negatively affect treatment, but does cause disruptions at a systemic level that treatment cannot overcome.

“Counseling patients to achieve a normal body weight or a more healthy body weight is probably indicated,” said Peter T. Campbell, PhD, a cancer epidemiologist and director of the tumor repository at the American Cancer Society, adding that patients should never lose more than two pounds per week and weight loss in cancer survivors should be achieved through exercise and proper diet.

In his presentation on the topic at the 2013 Gastrointestinal Cancers Symposium, Dr. Campbell said that the take-home message is that people can mitigate their risk for CRC by losing weight and engaging in physical activity even while undergoing treatment.

In 2010, a large meta-analysis demonstrated that every five-unit increase in body mass index (BMI) is associated with an 18% rise in risk for CRC (Ning Y et al. Obes Rev v 2010;11:19-30). In other words, an individual with an obese BMI (≥30) has about a 40% higher risk for CRC compared with a person with a BMI in the lower range of normal (18.5-25), Dr. Campbell said, adding that the studies leave no question that “obesity is convincingly associated with colorectal cancer incidence.”

However, the relationship between weight and CRC is not entirely straightforward. Results from the same study showed that the association is stronger in men than in women, and stronger for cancers that occur in the colon than the rectum. Furthermore, a high BMI appears to correlate only with a higher risk for tumors that display the more common microsatellite-stable phenotype, Dr. Campbell said.

In a study of 1,794 case participants and 2,684 unaffected sex-matched siblings, each increase in BMI, modeled in 5 kg/m2 increments, was associated with an increased risk for microsatellite-stable tumors (odds ratio [OR], 1.38; 95% confidence interval [CI], 1.241.54) and microsatellite instability (MSI)-low tumors (OR, 1.33; 95% CI, 1.04-1.72). No relationship was found for MSI-high tumors (OR, 1.05; 95% CI, 0.841.31), according to the study published by Dr. Campbell and his colleagues in 2010 in the Journal of the National Cancer Institutee (102:391-400).

More recently, the same research team confirmed that BMI is not only linked to risk for CRC but also to prognosis. In the Cancer Prevention Study II Nutrition Cohort—an ongoing, prospective study that includes regularly updated lifestyle and outcome data from more than 2,200 CRC survivors—patients who reported having an obese BMI several years before their cancer diagnosis had a higher risk for death (approximately 30%) from all causes, over the study period. They also

The take-home message is that people can mitigate their risk for CRC by losing weight and engaging in physical activity, even while undergoing treatment.

had a 35% increased risk for death from CRC and a 68% increased risk for death from cardiovascular disease (Campbell PT et al. J Clin Oncol 2012;30:42-52).

The study also showed that an individual’s BMI after diagnosis of cancer had no bearing on their long-term mortality risk, possibly due to the effects of both the disease and its treatment on a person’s weight.

These findings were reinforced in April with the publication of a study that examined the effects of BMI in more than 25,000 patients with stage II and III colon carcinoma in the Adjuvant Colon Cancer Endpoints (ACCENT) database. Obesity—as well as underweight status—was independently associated with inferior outcomes in patients with colon cancer who received treatment in adjuvant chemotherapy trials (Sinicrope FA et al. Cancer 2013;119:1528-1536).

Dr. Campbell said several factors could explain the relationship between obesity and poorer survival rates, including fatty acid synthase expressed in colon tumor tissue and the systemic effects of obesity. He noted that treatment did not appear to play a role. “We think, based on the evidence from our clinical colleagues, that it is not related to suboptimal treatment or surgery-related complications.”

Physical activity levels also play a major role in CRC development. Many studies in the United States have consistently found that adults with higher levels of physical activity—in intensity, duration or frequency—can reduce their risk for developing colon cancer by 30% to 40% relative to those who are sedentary, regardless of BMI. A meta-analysis published in 2009 examined 14 prospective studies, and found that the most physically active men experienced a 20% reduction in the incidence of colon cancer compared with those who were least active. In women, the effect was similar at about 14% (Harriss DJ et al. Colorectal Dis 2009;11:689-701).

In a study published in the March edition of the Journal of Clinical Oncology, Dr. Campbell and his colleagues found that people who met the public health recommendation of at least 150 minutes of physical activity per week had a lower risk for all-cause and cardiovascular mortality (Campbell PT et al. 2013;31:876-885).

All 2,293 patients in the study were diagnosed with invasive, nonmetastatic CRC between 1993 and 2007.

Analysis showed that those who completed at least 150 minutes of moderate-intensity activity per week had a 28% reduced risk for mortality compared with those who performed less than 60 minutes per week of moderate physical activity.

Clinicians who treat cancer patients said they are emphasizing the importance of maintaining a healthy body weight and increasing physical activity to help patients manage their risk for recurrence.

Frank Sinicrope, MD, professor of medicine and oncology at Mayo Clinic, Rochester, Minn., and the lead author of many studies looking at cancer and obesity, said he counsels patients with a BMI of 30 kg/m2 or higher to consume nutrient-rich foods such as fruits, vegetables and whole grains; to reduce their red meat consumption; and to increase physical activity.

“Obesity appears to be a source of chronic inflammation that can adversely affect multiple organ systems and, as such, contributes to cardiovascular disease and cancer, among others,” he said.

James C. Cusack Jr., MD, associate professor of surgery at Harvard Medical School, Boston, said he and his colleagues are increasingly working with their patients to help them achieve and maintain a healthy weight before and after surgery. He said that patients rarely have time to make significant changes in the period between diagnosis and surgery, but he does encourage them to participate in a programmatic weight loss and exercise program during neoadjuvant therapy to improve their surgical outcomes and their overall likelihood of surviving the disease.

Surgeons also work more closely with patients to help them modify diet and lifestyle in the long term, he said.

Recent data suggest that increased activity levels and weight loss after surgery may improve the likelihood of surviving CRC, providing “a strong rationale for the surgeon to initiate the discussion of modifying diet and lifestyle for the long-term benefit of the patient.”

Dr. Cusack and his colleagues are expanding their hospital’s weight loss program for preoperative bariatric surgery patients to include patients recently diagnosed with colon or rectal cancer.

Cancer patients should not lose more than two pounds per week and any weight loss should be achieved through exercise and proper diet.

■

31

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2013

Malnutrition Often Overlooked in Cancer Patients

BY DAVID WILD WASHINGTON—When it comes to providing enteral or parenteral nutrition to patients with cancer, the evidence shows the sooner an intervention is implemented, the better the outcomes. However, malnutrition remains all too common.

“A significant number of cancer patients have already experienced weight loss by the time they are diagnosed,” said Noreen Luszcz, RD, MBA, CNSC, national home nutrition support program director, Walgreens Infusion Services, Deerfield, Ill.

‘There are still those physicians who believe that if you feed the patient, you feed the tumor.’

—Randy Fasnacht, RPh In a poster she presented at the 2013 Oncology Nursing Society’s annual congress (abstract 363), Ms. Luszcz noted that the American Society of Parenteral and Enteral Nutrition recommends screening cancer patients for nutritional status frequently and intervening early if necessary (August DA et al. JPEN J Parenter Enteral Nutr 2009;33:472-500). Nutritional support is more beneficial to patients when they are undernourished, with only minor weight loss, than when they are severely malnourished after significant weight loss, she said (Bozzetti F et al.

Clin Nut2009;28:445-454).

“Every new patient admitted to Walgreens home infusion services ... undergoes a complete nutrition evaluation, which includes a review of the patient’s diet, appetite, [and] weight and a comprehensive gastrointestinal system review. If a patient is identified as being at risk for malnutrition, the nurse and a dietitian make recommendations to the treating physician to improve the patient’s nutritional status,” she said.

“The clinician may provide guidance to the patient as to how to increase calories and protein, as well as recommending use of oral supplements,” she added. “If the patient continues to deteriorate nutritionally, enteral or parenteral nutrition may be indicated.”

One way to improve detection and intervention could be to educate clinicians on the benefits of adequate nutrition, including the lower mortality risk associated with intervention (Pacelli F et al. JPEN J Parenter Enteral Nutr 2007;31:451-455), said Randy Fasnacht, RPh, director of

pharmacy at Advanced Infusion Services in Akron, Ohio.

“There are still those physicians who believe that if you feed the patient, you feed the tumor,” said Mr. Fasnacht, who was not involved in the study by Ms. Luszcz.

Mr. Fasnacht added that even clinicians who know about the risks for malnutrition and use screening tools—such as the Patient-Generated Subjective Global Assessment

NEW

or the Malnutrition Screening Tool— face administrative barriers to timely intervention.

“Insurance companies and Medicare and Medicaid are the thorn in everybody’s side,” he noted. “You need to make sure you have reams and reams of documentation showing enteral or parenteral nutrition are justified if you want to go ahead with it.”

The need to overcome these educational and administrative barriers, as

well as any others that prevent timely screening and nutritional intervention, is imperative, noted Mr. Fasnacht.

“The fact is we need to think about ensuring adequate nutrition from day one.”

■ Ms. Luszcz and Mr. Fasnacht reported no relevant financial conflicts of interest. Mr. Fasnacht requested that his colleague, Talon Schroyer, a 2014 PharmD candidate, be cited as a contributor to the research that informed Mr. Fasnacht’s comments.

In bowel preparation

The NEW Combination Makes the Difference Introducing Suclear Provides the flexibility and convenience of two dosing regimens (same-day, split-dose), with success* achieved in 90% of patients1,2 Significantly more “excellent” preps* with Suclear vs HalfLytely (47.7% vs 35.6%, respectively; P=0.01†) in same-day dosing comparison1 – Prep time was 33% less with Suclear compared to HalfLytely (3.7 hours vs 5.5 hours, respectively; P<0.001†)1 Equivalent rates of excellent cleansing* between Suclear and MoviPrep®‡ (51.9% vs 51.4%, respectively) in split-dose comparison1 Cecum reached in almost all patients using Suclear (split-dosing: 100%; same-day dosing: 99%)1 * *Based on investigator grading. † Statistically significant difference. ‡ MoviPrep [PEG-3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate and ascorbic acid for oral solution] is a trademark of the Norgine group of companies.

IMPORTANT SAFETY INFORMATION Suclear™ (sodium sulfate, potassium sulfate and magnesium sulfate oral solution; and PEG-3350, sodium chloride, sodium bicarbonate and potassium chloride for oral solution) is a combination of osmotic laxatives indicated for cleansing of the colon as a preparation for colonoscopy in adults. Most common adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal pain, nausea, vomiting and headache. Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to components of Suclear. Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reflex, regurgitation or aspiration, impaired renal function or patients taking medications that may affect renal function or electrolytes. Patients with severe active ulcerative colitis may be at increased risk of exacerbation of their disease. Administration of osmotic laxative products may produce mucosal aphthous ulcerations, and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Patients with impaired water handling who experience severe vomiting should be closely monitored including measurement of electrolytes. Advise all patients to hydrate adequately before, during, and after use. Each bottle must be diluted with water to the recommended (sodium sulfate, potassium sulfate, and magnesium sulfate final volume.

NEW

Please see brief summary of Full Prescribing Information on adjacent page.

oral solution; and PEG-3350, sodium chloride, sodium bicarbonate and potassium chloride for oral solution)

32

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2013

Debating Treatment of Colorectal Liver Metastases: Yes or No on Chemotherapy?

BY KATE O’ROURKE Should adjuvant chemotherapy be given to all patients undergoing hepatic resection for colorectal liver metastases? At the 2013 annual meeting of the Society of Surgical Oncology, a spirited pro– con debate was devoted to this topic.

(The debaters, it should be noted, were assigned their positions.)

Chemotherapy Does Not Improve Overall Survival “Surgery alone for colorectal hepatic metastases is enough,” said Nicholas Petrelli, MD, medical director of the Helen F. Graham Cancer Center, Newark, Del.

“We do not need chemotherapy.

Hepatic resection is the only potentially curable treatment for colorectal liver metastases.”

He argued that overall survival (OS) is “the end point that matters,” and because available drugs don’t improve OS in this patient population, individuals should not be exposed to the agents’ toxicities.

‘We do not need chemotherapy.

Hepatic resection is the only potentially curable treatment for colorectal liver

NEW (sodium sulfate, potassium sulfate, and magnesium sulfate oral solution; and PEG-3350, sodium chloride, sodium bicarbonate and potassium chloride for oral solution)

Introducing Suclear The NEW combination for dosing flexibility High success rates in same-day and split-dose regimens1,2 Cecum reached in nearly 100% of patients1 Significantly less prep time compared to HalfLytely1 References: 1. Data on file. Braintree Laboratories, Inc., Braintree, MA. 2. Suclear [package insert]. Braintree, MA: Braintree Laboratories, Inc; 2013.

BRIEF SUMMARY: Before prescribing, please see Full Prescribing Information and Medication Guide for Suclear™ (sodium sulfate, potassium sulfate and magnesium sulfate oral solution; and PEG-3350, sodium chloride, sodium bicarbonate and potassium chloride for oral solution). INDICATIONS AND USAGE: A combination of osmotic laxatives indicated for cleansing of the colon as a preparation for colonoscopy in adults. CONTRAINDICATIONS: Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to components of the kit. WARNINGS AND PRECAUTIONS: Suclear is a combination of osmotic laxatives indicated for cleansing of the colon as a preparation for colonoscopy in adults. Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to Suclear. Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reflex, regurgitation or aspiration, impaired renal function or patients taking medications that may affect renal function or electrolytes. Patients with severe active ulcerative colitis may be at increased risk of exacerbation of their disease. Pre-dose and post-colonoscopy ECG’s should be considered in patients at increased risk of serious cardiac arrhythmias. Administration of osmotic laxative products may produce mucosal aphthous ulcerations, and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Patients with impaired water handling who experience severe vomiting should be closely monitored including measurement of electrolytes. Advise all patients to hydrate adequately before, during, and after use. Each bottle must be diluted with water to the recommended final volume. Pregnancy: Pregnancy Category C. Animal reproduction studies have not been conducted. It is not known whether this product can cause fetal harm or can affect reproductive capacity. Pediatric Use: Safety and effectiveness in pediatric patients has not been established. Geriatric Use: Of the 362 patients who took Suclear in clinical trials, 90 (25%) were 65 years of age or older, while 29 (8%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between geriatric patients and younger subjects.

DRUG INTERACTIONS: Oral medication administered within one hour of the start of administration of each Suclear dose may not be absorbed completely.y Concurrent use of stimulant laxatives and Suclear may increase the risk of mucosal ulcerations or ischemic colitis. ADVERSE REACTIONS: Most common adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal pain, nausea, vomiting and headache. Oral Administration: Consume only clear liquids (no solid food or milk) and avoid alcohol on the day before colonoscopy until after completion of the colonoscopy. Split-Dose (2-Day) Regimen (Preferred Method): Dose 1 – Evening before the colonoscopy (10 to 12 hours prior to Dose 2): Dilute the 6 oz. oral solution by pouring the entire contents of the bottle into the 16 oz. mixing container and then filling the container with cool water to the fill line and mix. Drink the entire solution in the container. It is best to complete drinking the solution within 20 minutes. Refill the container and drink another 16 oz. of water over the next 2 hours, and another before going to bed. Dose 2 – Next morning on the day of colonoscopy (start at least 3 ½ hours prior to colonoscopy): Dissolve the powder of Dose 2 by adding water to the fill line on the jug. Shake jug until powder is dissolved. The solution can be used with or without the addition of a flavor pack. Using the 16 oz. container provided, drink all the solution in the jug at a rate of one 16 oz. container every 20 minutes. Complete drinking the solution at least 2 hours before the colonoscopy. Consume only clear liquids until 2 hours prior to colonoscopy. Day-Before (1-Day) Regimen (Alternative Method): On the evening before the colonoscopy: Dose 1 (begin at least 3 ½ hours prior to bedtime): Dilute the 6 oz. oral solution by pouring the entire contents of the bottle into the 16 oz. mixing container and then filling the container with cool water to the fill line and mix. Drink the entire solution in the container. It is best to complete drinking the solution within 20 minutes. Drink another 16 oz. of water over the next 2 hours. Dose 2 (approximately 2 hours after starting Dose 1): Dissolve the powder of Dose 2 by adding water to the fill line on the jug. Shake jug until powder is dissolved. The solution can be used with or without the addition of a flavor pack. Using the 16 oz. container provided, drink all the solution in the jug at a rate of one 16 oz. container every 20 minutes. Refill the container and drink another 16 oz. of water before going to bed. Consume only clear liquids until 2 hours prior to colonoscopy.

STORAGE: Store at 20-25°C (68-77°F). Excursions permitted between 15-30°C (59-86°F). Rx only. Distributed by Braintree Laboratories, Inc. Braintree, MA 02185 For additional information, please call 1-800-874-6756 or visit www.braintreelabs.com ©2013 Braintree Laboratories, Inc.

SU-14168

March, 2013

metastases.’

—Nicholas Petrelli, MD

Chemotherapeutics and biologics can cause side effects from skin rash to myocardial infarction, neurotoxicity, steatohepatitis, cerebral hemorrhage, tracheal stenosis and bowel perforation, all of which negatively affect quality of life. For example, irinotecan causes steatohepatitis; 5-fluorouracil (5-FU) and irinotecan cause steatosis; oxaliplatin causes sinusoidal dilatation; and bevacizumab (Avastin, Genentech) is associated with liver degeneration and hemorrhage.

“These side effects can [cause] surgical mortality, especially with prolonged chemotherapy, in general six cycles or more,” said Dr. Petrelli, pointing to a study in Annals of Surgery (Karoui M et al. 2006;243:1-7). A study in the Journal of Clinical Oncology also concluded that chemotherapy had a detrimental effect on 90-day mortality (Vauthey JN et al.

2006;24:2065-2072).

Three prospective randomized trials demonstrate that chemotherapy doesn’t improve OS, said Dr. Petrelli.

In a pooled analysis of two randomized trials evaluating complete resection of colorectal liver metastases, investigators did not identify any statistically significant difference in OS or progression-free survival (PFS) in patients who received adjuvant 5-FU-leucovorin chemotherapy postsurgery and those who received surgery alone (Mitry E et al. J Clin Oncoll 2008;26:4906-4911).

In the EORTC (European Organisation for Research and Treatment of Cancer) 40983 trial, 364 patients with colorectal cancer and one to four resectable hepatic metastases were randomized to surgery alone or six cycles of FOLFOX4 (oxaliplatin, 5-FU and leucovorin) followed by surgery and six cycles of postoperative FOLFOX4 (Nordlinger B et al. Lancett 2008;371: 1007-1016). At three years, patients

33

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2013

who received chemotherapy had higher PFS rates (42.4% vs. 33.2%), but this did not translate into improved OS at 8.5 years, according to a study presented at the 2012 American Society of Clinical Oncology annual meeting (abstract 3503).

Furthermore, said Dr. Petrelli, patients in the chemotherapy arm had higher rates of postoperative complications, including biliary fistula (8% vs. 4%), hepatic failure (7% vs. 5%), intraabdominal infection (7% vs. 2%) and the need for reoperation (3% vs. 2%; P=0.04).

P “How good are the agents that we use today? They are not good at all,” said Dr. Petrelli.

Even when patients receiving chemotherapy for colorectal liver metastases have a complete response on computed tomography (CT), this does not mean they are cured. In a recent study, 66 lesions disappeared on CT, but macroscopic cancer was seen in 20 of these patients at surgery (Benoist S et al. J Clin Oncoll 2006;24:3939-3945). Sites of 15 initial liver metastases invisible at surgery were resected and 12 had viable tumors. The sites of 31 other initial liver metastases, invisible at surgery, were left in place during surgery, and at one year of follow-up, 23 of the 31 liver metastases considered in complete response had recurred in situ.

The last nail in the coffin, said Dr. Petrelli, is a study evaluating the effect of bevacizumab on future liver remnant hypertrophy after portal vein occlusion before major hepatectomy for colorectal liver metastases (Aussilhou B et al.

Ann Surg Oncoll 2008;16:1553-1559).

Patients with a portal vein occlusion had a smaller increase in volume hypertrophy if they received bevacizumab (15% vs. 40%; P<0.05).

With no improvement in OS, said Dr. Petrelli, these agents are hard to justify, especially when cost is considered. Eight-week courses of FOLFOX (oxaliplatin plus 5-FU; $11,889), FOLFOX plus bevacizumab ($21,033), and FOLFIRI (irinotecan, 5-FU and leucovorin) plus cetuximab ($30,790) are pricey (Schrag D. N Engl J Med 2004;351:317-319).

“Value is cost and quality of care.

Chemotherapy increases patient cost and health care costs. It increases hepatic toxicity, systemic toxicity and poor quality of life, said Dr. Petrelli. “There is no improvement in overall survival, leading to no value.”

Chemotherapy Does Improve Outcomes Mitchell Posner, MD, Thomas D. Jones Professor and chief of general surgery and surgical oncology, University of Chicago, argued the pro-chemotherapy position. With a five-year

‘When you take patients who are initially unresectable (R1), treat them with chemotherapy and then resect them, you see the [survival] curve closely approaches those patients who are initially resectable (R0).’

—Mitchell Posner, MD

survival of 38% after resection of hepatic metastases (Kanas GP et al. Clin Epidemioll 2012;4:283-301), patients with colorectal cancer have a substantial risk

for recurrence, and chemotherapy can improve outcomes.

“When you take patients who are initially unresectable (R1), treat them with

chemotherapy and then resect them, you see the [survival] curve closely approaches those patients who are initially resectable (R0),” said Dr. Posner, pointing to a study in Annals of Surgery (de Haas RJ et al. 2008;248:626-637).

This, he said, demonstrates the efficacy of chemotherapy in stage IV disease.

He then pointed out that in the previously mentioned pooled analysis of randomized trials of adjuvant chemotherapy after hepatic resection, a multivariate analysis revealed a statistically see Chemotherapy, page 34

Coming in 2014…

IRA M. JACOBSON, MD Vincent Astor Distinguished Professor of Medicine Chief, Division of Gastroenterology and Hepatology Medical Director, Center for the Study of Hepatitis C NewYork-Presbyterian Hospital/Weill Cornell Medical College New York, New York

R

ecent research has demonstrated the eagerly awaited proof of concept that hepatitis C virus (HCV) infection can be cured without interferon. Trials involving directacting antiviral agents of several classes, as well as drugs with other mechanisms of action, either with or without interferon and ribavirin are proceeding at a remarkable pace. These exciting developments mandate the education of all physicians who treat patients with HCV infection in the proper use of the new agents, including management of side effects. Individualization of treatment decisions, both in treatment-naive and treatment-experienced patients, remains of paramount importance. The latest data will be summarized in this comprehensive review, scheduled for publication in 2014.

34

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2013

Most Patients With Metastatic CRC Lack KRAS S Testing

BY CHRISTINA FRANGOU SAN FRANCISCO—The majority of patients newly diagnosed with metastatic colorectal cancer (CRC) in the United States have not undergone KRAS testing, despite recommendations to the contrary.

Only 47.5% of patients with metastatic CRC who were diagnosed between Jan. 1 2008 and Dec. 31, 2011, underwent KRAS testing, according to a recent study.

“This is extremely surprising,” said Sanjay Goel, MD, associate professor of medicine (oncology), Albert Einstein College of Medicine and Jack D. Weiler Hospital, New York City, who was not affiliated with the study. “A small fraction of patients are being tested. This is not standard-of-care practice.”

The findings, which were presented at the 2013 Gastrointestinal Cancers Symposium, showed there was a boost in KRAS testing following the 2008 recommendations from the National Comprehensive Cancer Network (NCCN), calling for universal testing for the gene in patients with metastatic CRC. Testing rates rose from 5.8% before 2008 to 15.9% in 2008.

They peaked at 29.1% of eligible patients in 2009, and have remained relatively unchanged ever since. Of eligible patients, 27% and 28%

Chemotherapy continued from page 33

significant improvement in PFS (hazard ratio [HR], 1.39; P=0.026) and OS (HR, 1.39; P=0.046) with chemotherapy. Additionally, overall, there was a trend for improved median PFS (27.9 vs. 18.8 months; P=0.058) and median OS (62.2 vs. 47.3 months; P=0.095).

OS is not the only end point that should matter, argued Dr. Posner. Patients who received chemotherapy in the EORTC 40983 trial had improved PFS (HR, 0.73; P=0.025), an end point that many clinicians value. A clinical trial of 173 patients in France showed that adding chemotherapy after hepatic resection resulted in improved disease-free survival (DFS) rates (33.5% vs. 26.7%; P=0.028) and a trend for improved OS (51.1% vs. 41.9%; P=0.13; Portier G et al. J Clin Oncol 2006;24:4976-4982). In another French study of 1,471 patients with solitary, metachronous colorectal liver metastases, postoperative chemotherapy improved DFS and OS at five years (65% vs. 55%; P<0.01; Adam R et al. Ann Surgg 2010;252:774-787).

According to Dr. Posner, clinicians are capable of managing treatment toxicities, and these do not increase mortality and cause only mild morbidity when chemotherapy is limited to a reasonable number of cycles. In patients with colorectal liver metastases who received preoperative chemotherapy before major hepatectomy, morbidity

were tested for the KRAS gene in 2010 and 2011, respectively.

“While KRAS testing increased during the 2008-2009 period—corresponding to changes in treatment guidelines and anti-EGFR [epidermal growth factor receptor] product labels—the majority of patients were not tested,” concluded study author Gebra Cuyun Carter, PhD, and her colleagues from Eli Lilly and Company, Indianapolis.

In an email interview, Dr. Carter said it is important to increase the proportion of patients who are tested for KRAS so that clinicians and patients can better understand all available treatment options.

The NCCN guidelines stipulate that cetuximab and panitumumab are only indicated for patients with tumors that express the wild-type KRAS gene.

The current study was based on an analysis of data from the Accelerated Community Oncology Research Network’s (ACORN) Oncology Data Warehouse. The warehouse integrates patient-reported outcomes, electronic medical records, claims data and laboratory information systems garnered from community oncology practices across the United States, representing 85% of cancer care. The study revealed that the majority of testing is done at diagnosis. Of patients tested, 27.4% were

was roughly 10% in patients who received no chemotherapy, 20% in patients who received five cycles of chemotherapy or less, 50% in patients who received six to nine cycles, and more than 60% in those who received 10 cycles or more (Adam R et al. Ann Surgg 2006;244:897-907; Nakano H et al. Ann Surgg 2008;247:118-124).

Rebuttals In rebuttal remarks, Dr. Petrelli said he completely agreed that using chemotherapy to make unresectable patients resectable was a good idea, but this was not the group of patients they were debating.

“We are talking about patients who present initially with resectable disease, and in those patients, the toxicity is sky high and there really is no benefit in terms of overall survival,” he said.

Dr. Posner, in his rebuttal, called Dr. Petrelli a “flip-flopper.”

If OS is actually the only important end point, Dr. Posner wondered, then why is Dr. Petrelli, currently chair of the NSABP Gastrointestinal Committee, involved in designing trials with primary end points other than OS? The NSABP C09 trial tested the addition of chemotherapy for hepatic resection using a PFS end point and the NSABP C11 trial, which examined perioperative versus postoperative chemotherapy for resectable hepatic metastases, also used recurrence-free survival as the primary end point, said Dr. Posner.

■

tested at diagnosis in 2008, 65.4% in 2009, 73.2% in 2010 and 78.4% in 2011.

Patients with greater comorbidities and poorer performance status were more likely to undergo KRAS testing than healthier patients.

KRAS-tested patients were younger (58.5% vs. 51.5% age <65 years; P=0.004); had more baseline comorbid conditions (3.7±4.0 vs.

2.7±3.4; P<0.001); had poorer performance status; and were more likely to have metastases.

Investigators did not know why healthier patients were less likely to undergo testing for the KRAS gene. Dr. Goel said there might be multiple reasons why patients fail to undergo testing, including lack of insurance, reluctance to undergo core needle biopsy, or lack of tumor blocks or unstained slides. But physicians need to find ways to overcome these problems, he said.

All physicians who treat CRC patients should be aware of the need for universal [KRAS] testing, he said.

“There may be practitioners who are not aware of this, but that’s a very sad scene if it’s true.”

Dr. Carter is employed by Eli Lilly.

The other authors of the study are employed by Truven Health Analytics and the Seattle Cancer Care Alliance/Fred Hutchinson Cancer Research Center.

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35

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2013

Ras Mutations Predict Lung Recurrence in Patients With Colorectal Liver Metastases

BY CHRISTINA FRANGOU A new study shows that Ras gene mutations in patients with colorectal liver metastases predict a lung-specific recurrence pattern, as well as worse survival. This is the first study of surgical patients to link Ras status to lung recurrence.

Patients with a Ras mutation experienced a worse pathologic response to chemotherapy and had a twofold risk for a lung recurrence after liver resection, according to an analysis of 193 patients treated with single-regimen modern chemotherapy before hepatic resection. Their three-year overall survival (OS) rates were about 60% of that of patients with wild-type Ras. Lead author Jean-Nicolas Vauthey,

MD, professor of surgery, the University of Texas MD Anderson Cancer Center, Houston, said the findings indicate Ras status is as important as, and possibly more important than the widely accepted prognostic factors such as the size and number of liver metastases and the presence of affected lymph nodes.

“Before, we used an aggregate of clinical and pathologic findings for prognosis, but now we are getting to the real biological factor that’s driving the prognosis,” said Dr. Vauthey.

He presented the findings at the 2013 annual meeting of the American Surgical Association.

The study was based on a series of

patients who underwent preoperative chemotherapy and curative resection of colorectal liver metastases between 1997 and 2011. All patients underwent an extensive analysis of gene mutations using Sequenom technology. The method, which is not approved for use by the FDA, tests

Think of Enterography as a GPS for Crohn’s disease.

Image shows not only thickening of the bowel wall, but also the increased attenuation of the mucosa compatible with active Crohn’s disease.*

‘Before, we used an aggregate of clinical and pathologic findings for prognosis, but now we are getting to the real biological factor that’s driving the prognosis.’

—Jean-Nicolas Vauthey, MD

Enterography gives you a highly effective diagnostic tool for evaluating and managing treatment of small bowel disorders like Crohn’s disease.1 By producing abdominal images that provide clear visualization of the small bowel wall and lumen,2 enterography shows the degree, extent and location of Crohn’s disease3 and is quickly becoming a first-line exam in leading IBD Centers for the evaluation of small bowel disorders.2 For more information about the benefits of enterography for small bowel diagnostics, please contact Bracco Professional Services at 1-800-257-5181, option 1. * Representational image, individual results may vary. Image courtesy of Alec Megibow, MD, NYU

Ribbon diagram of H-ras.

Image courtesy of Elaine Meng

REFERENCES: 1. Bruining DH, Siddiki HA, Fletcher JG, et al. Benefit of computed tomography enterography in Crohn’s disease: Effects on patient management and physician level of confidence. Inflamm Bowel Dis. 2012;18(2):219-225. 2. Fletcher JG. CT enterography technique: theme and variations. Abdom Imaging. 2009;34(3):283-288. 3. MDCT and 3D imaging of the small bowel and mesentery.

Mahmoud M. Al-Hawary, MD, Ravi K. Kaza, MD, and Joel F. Platt, MD, University of Michigan Health System, Ann Arbor, MI. Applied Radiology. 2011 Nov;40(11). ©2012 Bracco Diagnostics Inc. All Rights Reserved.

see Ras, page 36

36

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2013

Ras continued from page 35

for 159 cancer mutations in 33 genes including all K-ras and N-ras mutations known to be associated with aggressive colorectal cancer biology.

Analysis identified 34 patients (17.6%) with Ras mutations. These patients had a 13.5% three-year recurrence-free survival compared with 34% among patients with wildtype Ras (P=0.001). OS was 52.2% in Ras-mutant patients and 81% in

patients with wild-type Ras ((P=0.002).

In multivariate analysis, wild-type Ras was the most important predictor of OS with a hazard ratio (HR) of 2.26 (95% confidence interval [CI], 1.134.50; P=0.002). Pathologic response to chemotherapy was the only other significant predictor of OS (HR, 2.1; 95% CI, 1.11-3.96; P=0.022).

Ras-mutant patients also had a higher risk for early lung recurrence

after liver resection. Three-year recurrence for lung metastases reached 59.3% among patients with Ras mutations compared with 34.6% among patients with wild-type Ras. Liver recurrence rates did not appear to be influenced by Ras status (43.8% for wild-type Ras vs. 50.2% for Ras mutation; P=0.181).

Experts in the field said the study could change how surgeons select

WE’RE

ORM

FOR PATIENTS WITH CROHN’S DISEASE After Crohn’s surgery, it is common for the disease to return within a few months despite anti-inflammatory medicine. At UPMC, our multidisciplinary team developed a new post-op treatment approach that has reduced the recurrence of Crohn’s disease by nearly two thirds. And now many other hospitals are adopting this novel approach.

patients for surgery or follow patients after treatment.

The study identifies patients who are at higher risk for recurrence and “may, therefore, require closer monitoring and improving the selection of chemotherapy or biological therapy,” said Anton Bilchik, MD, assistant director of surgical oncology and director of gastrointestinal research at the John Wayne Cancer Institute in Santa Monica, Calif.

He said prospective studies are needed before physicians change practice patterns. Still, it’s one more step toward individualizing cancer care for patients.

“The future of cancer care is in individualized targeted treatment and this study provides further evidence that perhaps ‘one size does not fit all.’”

Dr. Vauthey said the study findings might encourage some surgeons to be more aggressive in patients who are considered borderline resectable but have no Ras mutation.

“The decision to be aggressive or not in these patients is sometimes difficult,” said Dr. Vauthey.

He added that he would not use Ras status to deny surgery to patients with colorectal metastases because resections have become safer. However, “we now have to decide if we can expand our resection criteria and propose more complex sequential resections in some patients.”

He recommends that patients with Ras mutations be considered for computed tomography of the chest before and after resection to fully evaluate ■ the extent of metastatic disease.

Because when you make patients feel better, it’s normal to want them to stay that way. Learn more at UPMCPhysicianResources.com/Crohns.

ACT NOW! Renew your free subscription to

today at GastroEndoNews.com/ Renew UPMC is affiliated with the University of Pittsburgh School of Medicine.

37

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2013

From the Literature

Hodgkin Lymphoma Treatment Increases Stomach Cancer Risk

BY GEORGE OCHOA Treatment of Hodgkin lymphoma (HL) with certain radiation and chemotherapy regimens may put patients at increased risk for stomach cancer, according to a new study by scientists at the National Cancer Institute (NCI).

In the case–control study (Morton LM et al. J Clin Oncol 2013;31:33693377), investigators analyzed data from 19,882 individuals who had survived for at least five years after a diagnosis of HL. The cohort included patients from the United States, Canada, Denmark, Finland, the Netherlands, Norway and Sweden. The researchers identified 89 patients who developed stomach cancer and 190 matched controls. Among the cases, the median age at diagnosis of HL was 30 years, and the median age at diagnosis of stomach cancer was 50 years.

Among patients who received procarbazine less than 5,600 mg/ m2 and radiation to the stomach of 25 Gy or higher, radiation-related risk for stomach cancer increased 2.8-fold (95% CI, 1.3-6.4; 23 cases, 41 controls). Additionally, dacarbazine was associated with a 5.4-fold increased risk for stomach cancer among patients who received radiation to the stomach less than 25 Gy

(95% CI, 1.1-30.2; seven cases, eight controls).

“Our study adds strong support to the growing concern that stomach cancer is a rare but important adverse late effect of treatment for Hodgkin lymphoma,” said lead author Lindsay M. Morton, PhD, an investigator at the Radiation Epidemiology Branch, NCI Division of Cancer Epidemiology and Genetics, Bethesda, Md.

“Because Hodgkin lymphoma patients commonly receive treatment in their 20s and 30s, many of the stomach cancers arise before age 50, nearly 20 years earlier than is typical for newly diagnosed patients who have never had cancer,” Dr. Morton noted. “Clinicians who follow these survivors should be alert to patient complaints related to the gastrointestinal tract.”

■

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stomach cancer is a rare but important adverse late effect of treatment for Hodgkin lymphoma.’

—Lindsay M. Morton, PhD

For patients with stomach cancer, overall survival was poor: 88% of patients died, with a median survival of six months among them. The risk for stomach cancer increased with increasing radiation dose to the stomach, as well as with increasing number of chemotherapy cycles containing the alkylating agents procarbazine and dacarbazine.

“The association between procarbazine and stomach cancer risk was strikingly dependent on the radiation dose to the stomach,” the authors wrote.

Based on data from 25 cases and two controls, patients who received radiation to the stomach of 25 Gy or higher and procarbazine (≥5,600 mg/ m2) had a 77.5-fold increased risk for stomach cancer (95% confidence interval [CI], 14.7-1,452). Conversely, no risk was evident among patients in any procarbazine dose category who received radiation to the stomach of less than 25 Gy.

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2013

Steris Updates Educational Portal on Device Sterilization and Infection Prevention Control

In September, Steris Corporation announced improvements to its learning management system, “Steris University,” an educational resource designed for health care industry professionals.

The Steris University education portal focuses on

device reprocessing, infection prevention and perioperative support.

The online portal helps learners to meet Centers for Medicare & Medicaid Services or credentialing documentation requirements and offers a number of new features, capabilities and benefits, according to Steris. These include the ability for learners to track relevant continuing education credits, print out a history and document progress toward recertification. Learners also can store, access and print all certificates of completion at any time.

Once learners arrive on the landing page of

Optimizing the Prevention and Management of Postsurgical Adhesions

Steris University, they can register and set up their own “My Learning Page,” allowing them to create a unique account profile and to build a personal archive of completed and in-progress courses.

Furthermore, they also can create a “wish list” of additional courses they would like to take at a future date.

Courses are accredited by several bodies including the International Association of Healthcare Central Service Material Management (IAHCSMM); the California Board of Nursing; the Certification Board for Sterile Processing and Distribution, Inc.; and the American Board of Certification for Gastroenterology.

From the landing page, users also can find out about the Sterissponsored IAHCSMM scholarship, or browse the DeMeo Legacy Series page to view educational videos and written guidelines on sterile reprocessing.

Further information is available at http://university.steris.com/ sterisu.

—Based on a press release from Steris Corporation

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: December 1, 2013 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

BroadcastMed Launches Digital Medical Broadcasting Network for Gastroenterology

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

BroadcastMed Inc., a developer and distributor of digital medical broadcasting content from world-renowned physicians and health care organizations, has announced the launch of the BroadcastMed Network, consisting of more than 40 affiliated institutional channels and 17 specialty channels, including ORLive.com.

The network provides physicians and health care professionals with see BroadcastMed, page 39

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2013

39

ASP Launches Added Feature to Sterrad 100NX System for Sterile Reprocessing Advanced Sterilization Products (ASP) recently announced the availability of the DUO Cycle, available for all new Sterrad 100NX Systems and as an upgrade to existing systems.

The Sterrad 100NX System from ASP Photo courtesy of ASP

The 60-minute DUO Cycle joins the Express, Flex and Standard cycles on the Sterrad 100NX System platform, creating one of the widest ranges of low-temperature sterilization options currently available, according to ASP. The DUO Cycle offers improved efficiency in sterilizing most single-channel, flexible endoscopes, cameras and accessory light cords

1978

—

(including those from Olympus). It has been validated to sterilize flexible endoscopes with a single-channel polyethylene or Teflon lumen with an inside diameter of 1 mm or larger and a length of 875 mm or shorter, according to the manufacturer.

Engineered using hydrogen peroxide gas plasma technology that is proprietary to ASP, the Sterrad 100NX System platform sterilizes medical

devices safely and effectively, without the limitations or risks associated with peracetic acid, steam and ethylene oxide gas systems.

Customers can purchase the DUO Cycle for new or existing Sterrad 100NX Systems. For further information, call (888) 783-7723 or visit www.aspjj.com/us.

—Based on a press release from ASP

35th Anniversary — 2013

BroadcastMed continued from page 38

an extensive digital library. Specialty-specific clinical content and learning channels are available for a variety of disciplines, including gastroenterology.

“The BroadcastMed Network aims to aggregate the finest clinical content from the best institutions and top experts,” said Ross Joel, CEO and cofounder of BroadcastMed. “Physicians know that they are coming to find the most dependable and relevant clinical information so that they can better treat their patients, in what is an incredibly fast-moving health care environment.”

According to a press release from the company, the network is powered by digital content from top hospitals and leading organizations in the health care industry. Affiliates include Brigham and Women’s Hospital in Boston, The University of Alabama at Birmingham, and the University of Miami Health, among others. Participating organizations include Medtronic, Stryker and Covidien.

BroadcastMed Network’s dedicated gastroenterology channel is available at http:// gi.broadcastmed.com.

—Based on a press release from BroadcastMed Inc.

The Independ Independent Monthly Newspaper for Gastroenterologists

For more than three 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.

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Volume 64, Number 1 • January 2013

ACG 2012

IBS No Longer Only Functional Disorder

Experienced Physicians Offer Tips To Trainees on Landing a Job It’s Never Too Early To Start the Search

BY DAVID WILD

BY CHRISTINA FRANGOU LAS VEGAS—For the first time, investigators have documented structural abnormalities in the small bowel of patients with irritable bowel syndrome (IBS). These findings “will fundamentally change our thinking on the disease,” researchers told attendees of the 2012 see IBS, page 8

Mesalamine Elicits Response in IBS

BY MONICA J. SMITH LAS VEGAS—Mesalamine, a 5-aminosalicyte acid that is effective for maintenance of remission in patients with ulcerative colitis, also may be effective in relieving and controlling symptoms in irritable bowel syndrome see Mesalamine, page 9

If they haven’t already, fellows and residents should add one more resolution to their New Year’s list: Start the job search.

The earlier that trainees begin the search, the better, experts say. Many recommend that residents and fellows start the process 18 months before they are due to finish training.

With recruiting season kicking into high gear over the next few months, Gastroenterology & Endoscopy Newss summarized some practical tips for finding a job in academic medicine or private practice, as outlined by two gastroenterologists with experience in each area. see Job Search, page 25

Experts’ Picks

I N S I D E

Best of the American College e Of Gastroenterology: Part 2

MDs and DOs Plan Unified Accreditation System For Graduate Medical Education ............... page 5

EXPERT REVIEW: Sexual Misconduct by Professionals: A New Model of Understanding

COMPILED AND WRITTEN BY DAVID WILD Gastroenterology & Endoscopy Newss asked several experts to select their favvorite abstracts from the 2012 American College of Gastroenterology (ACG) Annual Scien ntific Meeting.

Inside is a collection of their selections and comments that reflect the varied interests of the experts who we interviewed. (Part 1 of this series appeared in the Decemberr 2012 issue of Gastroenterology & Endoscopy News.) see Best of ACG, page 14

BY GREGORY E. SKIPPER, MD, STEPHEN SCHENTHAL, MD ..................... page 29 AND

EXPERT REVIEW: Safeguarding Yourself Against Allegations Of Sexual Abuse or Patient Impropriety

BY HARVEY TETTLEBAUM, JD, AND KEVIN MEYERS, JD .................................................................. page 33

PRODUCT ANNOUNCEMENT Clinical Applications of Probiotics in Gastroenterology: Questions and Answers, An Issue of Gastroenterology Clinics see page 37

The Gastric Cancers: Targeted for Personalized Medicine see pages 10-11

We are proud to be the best-read gastroenterology publication in the marketplace, and we look forward to continuing to be your #1 source for gastroenterology news in decades to come.

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2013

First Generic Capecitabine Approved For Colorectal Cancer In September, the FDA approved the first generic form of the oral chemotherapy drug capecitabine, a treatment for metastatic colorectal and breast cancer. Currently, the Swiss company Roche offers capecitabine under the brand name Xeloda. With the FDA’s ruling, Teva Pharmaceuticals USA now can market 150 and

500 mg generic tablets.

“This medication is widely used by people living with cancer, so it is important to have access to affordable treatment options,” said Kathleen Uhl, MD, acting director of the Office of Generic Drugs at the FDA Center for Drug Evaluation and Research, in a press statement.

Originally approved by the FDA in 1998, capecitabine is a firstline treatment for metastatic colorectal carcinoma. In a randomized Phase III clinical trial of 602 patients with metastatic colorectal Photo courtesy of Teva Pharmaceuticals

RESEARCH Advancing the knowledge of gastric cancers.

Creating more precise and effective treatments.

Targeted for Personalized Medicine nyp.org 877 NYP-WELL (877-697-9355)

cancer, oral capecitabine did not lead to a significant increase in overall survival (OS) compared with IV fluorouracil-leucovorin (12.9 vs. 12.8 months, respectively), but capecitabine showed better tolerability compared with the IV chemotherapy regimen (Twelves C et al. Eur J Cancer 2001;37:597-604). Following failure of anthracycline chemotherapy, capecitabine in combination with docetaxel also is available for patients with metastatic breast cancer. Capecitabine plus docetaxel (n=255) compared with docetaxel alone (n=256) improved average OS in a trial of patients with metastatic breast cancer (14.5 vs. 11.5 months, respectively; P=0.013; Verma S. Cancerr 2005;103:2455-2465).

Capecitabine is a prodrug of the antimetabolite fluorouracil. During clinical trials, the most common adverse reactions to capecitabine included diarrhea, vomiting, nausea, pain, swelling, stomatitis, hand–foot syndrome, fever and infection. According to its FDA warning label, capecitabine also may increase the effects of anticoagulants, such as warfarin. A study of 77 patients receiving capecitabine found that the incidence of bleeding at 130 days was significantly higher among those on warfarin (n=21) compared with those who did not receive the anticoagulant (18% vs.

2%, respectively; P<0.0001; Shah HR et al. Clin Colorectal Cancer 2006;5:354-358).

The National Cancer Institute estimates there will be 142,820 diagnoses of colorectal cancer and 232,340 diagnoses of breast cancer in the United States in 2013.

“Generic drugs are important options,” Dr. Uhl said, “that allow greater access to health care for all Americans.”

—Based on a press release from the FDA

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2013

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

41

FDA Approves Abraxane for Metastatic Pancreatic Cancer For the first time in nearly eight years, a new treatment for metastatic pancreatic cancer has met FDA approval, Celgene announced in a press release on Sept. 6. The FDA approved the company’s drug, Abraxane (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) as a first-line treatment for patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine.

Clinical Oncology. Investigators randomized 861 treatment-naive patients with metastatic pancreatic adenocarcinoma into two groups: Abraxane in combination with gemcitabine (n=431) and gemcitabine alone (n=430). After treatment, patients in the Abraxane plus gemcitabine group had a statistically significant higher median overall survival compared with patients in the group that received gemcitabine alone (8.5 vs. 6.7 months, respectively;

P<0.0001). Additionally, median progression-free survival of patients in the Abraxane plus gemcitabine group was significantly longer compared with patients in the gemcitabine-only group (5.5 vs. 3.7 months, respectively; P<0.0001).

Abraxane is a form of the mitotic inhibitor paclitaxel bound to albumin particles. In MPACT, the most common adverse reactions of treatment with Abraxane and gemcitabine

were neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash and dehydration.

According to The New York Times (Sept. 6, 2013), Celgene said the cost of Abraxane for patients with pancreatic cancer will be $6,000 to $8,000 per month.

—Based on press releases from Celgene Corporation and the FDA

The #1 best-read gastroenterology publication in the USA. Anytime. Anywhere.

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at

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The Independent Monthly Newspaper for Gastroenterologists

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

Guidance Equivocal On HCV Screening Of Baby Boomers

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 see NAFLD, page 14

see Income, page 28

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

Photo courtesy of Celgene NAFLD Threatening Public Health

BY KATE O’ROURKE

“For more than 15 years, treatment with gemcitabine has been the standard of care in this disease,” said Jean-Pierre Bizzari, MD, executive vice president of hematology and oncology for Celgene Corporation.

“The addition of Abraxane to gemcitabine demonstrated meaningful improvements across key efficacy outcomes, including overall survival, with a well-characterized safety profile.”

The FDA had previously approved Abraxane to treat metastatic breast cancer and non-small cell lung cancer.

“Historically, patients with pancreatic cancer have not experienced benefit with many of the drugs so useful in other malignancies,” said Margaret A. Tempero, MD, director of the Pancreas Center at the University of California, San Francisco, in a press release. “The combination of Abraxane and gemcitabine represents an important new therapeutic option for patients with pancreatic cancer.”

The results of the open-label, multicenter randomized Phase III trial, MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial), that established Abraxane’s safety and efficacy were presented at the 2013 annual meeting of the American Society of

Despite Above Average Income, Gastros Report Job Dissatisfaction 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.

BY CHRISTINA FRANGOU

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 Strategies 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

ARUN SWAMINATH, MD Assistant Attending Physiciana Assistant Professor of Clinical Medicinec

BRIAN BOSWORTH, MD

T

see page 63 for product information

he e greatest ch hallenge for cllinicians who

treat pattients with inflamma atory bowel disease (IBD) is to move from symptomoriented d (step-u -up) strategies toward preventio on-orie ented (early intervention) strategies aimed at tight inflammation control and alteration of the natural history of IBD. This review focuses on a personalized approach to the treatment of IBD using 5-aminosalicylic acid (5-ASA) agents.

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

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS •

2013

1

FibroScan® Cleared by the FDA For Sale in the United States

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2013

FDA Investigating Case of PML in Patient Taking Fingolimod In August, the FDA issued an alert to the public that a European patient diagnosed with possible multiple sclerosis (MS) developed progressive multifocal leukoencephalopathy (PML) after taking fingolimod (Gilenya, Novartis). This is the first case of PML reported following the administration of fingolimod, a drug used to treat relapsing forms of MS, to a patient who had not previously received natalizumab (Tysabri, Biogen Idec), an MS drug that also is indicated for the treatment of moderately to severely active Crohn’s disease and is associated with a higher risk for PML. PML is a rare and serious brain infection caused by the John Cunningham (JC) virus that damages the myelin of the brain and usually causes death or severe disability. The FDA has recommended that patients should not stop taking fingolimod without first consulting their health care professionals.

Novartis reported that approximately 71,000 patients worldwide have been treated with fingolimod. The FDA is continuing to investigate the reported case of PML and is working with Novartis to obtain and review all available information about the case.

“Having reviewed all available information to date, Novartis considers that several features of this case of PML make it unlikely to be attributable to Gilenya,” Novartis said in a statement.

The FDA is continuing to evaluate the risk for PML associated with natalizumab, which has been approved for the treatment of relapsing forms of MS since November 2004 and for the treatment of Crohn’s disease since January 2008. In a 2012 FDA Drug Safety Communication, the agency stated that 201 cases of PML had been reported among approximately 96,582 patients treated with natalizumab worldwide through Jan. 4, 2012. The FDA has published three risk factors associated with an elevated risk for PML in patients taking natalizumab: • the presence of anti–JC virus antibodies; • longer duration of treatment with natalizumab, especially beyond two years; and • prior treatment with an immunosuppressant (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate mofetil).

The patient who developed PML while taking fingolimod had received nearly eight months of treatment with the drug before being diagnosed with PML. The patient had received multiple courses of IV corticosteroids for several months before and during treatment with fingolimod, and one month of treatment with interferon beta-1a and azathioprine before treatment with fingolimod. According to Novartis, expert reviewers

Fingolimod (Gilenya, Novartis) was recently associated with a case of PML. Photo courtesy of Novartis

found atypical lesions present in this patient on magnetic resonance imaging prior to initiation of fingolimod and could not rule out PML. Patients and health care professionals are encouraged to report adverse events or side effects related to the use of fingolimod or natalizumab to the FDA’s MedWatch Safety Information and Adverse Events Reporting Program at www. accessdata.fda.gov/scripts/medwatch.

—Based on press releases from the FDA and Novartis

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43

Olympus Announces Launch of Forward-Viewing Curvilinear Ultrasound Gastrovideoscope In October, Olympus announced the launch of its TGF-UC180J forwardviewing curvilinear ultrasound gastrovideoscope that has received FDA 510(k) clearance.

The scope’s enhanced maneuverability and handling may improve visualization of fundus diseases, which can be challenging to view and diagnose, according to Olympus. Furthermore, the auxiliary water jet may provide better acoustic coupling as well as reduce costs by avoiding the need for a balloon.

“The forward-viewing therapeutic echoendoscope is a major advance for interventional endoscopy,” said Kenneth Binmoeller, MD, medical director of the Interventional Endoscopy Service at California Pacific Medical Center, San Francisco. “It is the first true ‘hybrid’ ultrasound endoscope, enabling both ultrasound- and endoscopy-guided interventions with the same instrument.

This will facilitate existing EUS [endoscopic ultrasound]-guided therapies such as pseudocyst drainage, as well as enable new EUS-guided treatments,” Dr. Binmoeller said in a press statement by Olympus.

The design of the scope provides a reduced distal tip length compared with its oblique-viewing counterparts. The combination of a shorter tip with wider angulation capabilities of 180 degrees or greater, which allows for enhanced maneuverability and handling, and the scope’s straight channel enable therapeutic devices to directly reach the target site.

The TGF-UC180J is powered by the next-generation ProSound F75 Ultrasound Imaging

FDA Update & Product News column is compiled by the editors based on press releases from manufacturers and the U.S. Food and Drug Administration.

Please send product news to: cgordon@ mcmahonmed.com

Platform that was developed in partnership with Hitachi Aloka Medical Ltd. The scope also is backward compatible with older-generation processors, including the Olympus EU-ME1 and Hitachi Aloka SSD-α10.

—Based on a press release from Olympus

The TGF-UC180J forward-viewing curvilinear ultrasound gastrovideoscope Photo courtesy of Olympus

Aspiration Patients with impaired gag reflex and patients prone to regurgitation or aspiration should be observed during the administration of MoviPrep. Use with caution in these patients.

MOVIPREP® (PEG-3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate and ascorbic acid for oral solution, 100g/7.5g/ 2.691g/1.015g/5.9g/4.7g) The following is a brief summary only. See complete prescribing information on www.moviprep.com or request complete prescribing information by calling 1-800-508-0024.

INDICATION AND USAGE MoviPrep is an osmotic laxative indicated for cleansing of the colon as a preparation for colonoscopy in adults 18 years of age or older.

CONTRAINDICATIONS MoviPrep is contraindicated in the following conditions: • • • • • •

Gastrointestinal (GI) obstruction Bowel perforation Gastric retention Ileus Toxic colitis or toxic megacolon Hypersensitivity to any components of MoviPrep

WARNINGS AND PRECAUTIONS Serious Fluid and Electrolyte Abnormalities Advise patients to hydrate adequately before, during, and after the use of MoviPrep. If a patient develops significant vomiting or signs of dehydration after taking MoviPrep consider performing postcolonoscopy lab tests (electrolytes, creatinine, and BUN). Fluid and electrolyte disturbances can lead to serious adverse events including cardiac arrhythmias, seizures and renal impairment.

Patients with electrolyte abnormalities should have them corrected before treatment with MoviPrep. MoviPrep should be used with caution in patients using concomitant medications that increase the risk of electrolyte abnormalities [such as diuretics, angiotensin converting enzyme (ACE)-inhibitors or angiotensin receptor blockers (ARBs)] or in patients with known or suspected hyponatremia. Consider performing pre-dose and postcolonoscopy laboratory tests (sodium, potassium, calcium, creatinine, and BUN) in these patients. [See DRUG INTERACTIONS] 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 MoviPrep 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 ECGs should be considered in patients at increased risk of serious cardiac arrhythmias.

Seizures There have been rare reports of generalized tonic-clonic seizures and/or loss of consciousness associated with 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 fluid and electrolyte abnormalities.

Use caution when prescribing MoviPrep for patients with a history of seizures and in patients at increased risk of seizure, such as patients taking medications that lower the seizure threshold (e.g., tricyclic antidepressants), patients withdrawing from alcohol or benzodiazepines, or patients with known or suspected hyponatremia.

Renal Impairment Use with caution in patients with impaired renal function or patients taking concomitant medications that affect renal function (such as diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, or nonsteroidal anti-inflammatory drugs). Advise these patients of the importance of adequate hydration, and consider performing pre-dose and postcolonoscopy laboratory tests (electrolytes, creatinine, and BUN) in these patients.

(Colonic) Mucosal Ulceration, Ischemic Colitis and Ulcerative Colitis 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 stimulant laxatives and MoviPrep may increase the risk and is not recommended. The potential for mucosal ulcerations resulting from the bowel preparation should be considered when interpreting colonoscopy findings in patients with known or suspected inflammatory bowel disease.

Use in Patients with Significant Gastrointestinal Disease If gastrointestinal obstruction or perforation is suspected, perform appropriate diagnostic studies to rule out these conditions before administering MoviPrep. If a patient experiences severe bloating, abdominal distension, or abdominal pain, administration should be slowed or temporarily discontinued until symptoms abate.

Use with caution in patients with severe ulcerative colitis.

Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency Since MoviPrep contains sodium ascorbate and ascorbic acid, MoviPrep should be used with caution in patients with glucose6-phosphate dehydrogenase (G-6-PD) deficiency, especially G-6-PD deficiency patients with an active infection, with a history of hemolysis, or taking concomitant medications known to precipitate hemolytic reactions.

Contains Phenylalanine Phenylketonurics: Contains aspartame 233 mg per treatment which corresponds to 131 mg of phenylalanine per treatment (after hydrolysis of the aspartame molecule in-vivo to aspartic acid and phenylalanine).

ADVERSE REACTIONS Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

In the MoviPrep trials, abdominal distension, anal discomfort, thirst, nausea, and abdominal pain were some of the most common adverse reactions to MoviPrep administration. Since diarrhea was considered as a part of the efficacy of MoviPrep, diarrhea was not defined as an adverse reaction in the clinical studies. Tables 1 and 2 display the most common drug-related adverse reactions of MoviPrep and its comparator in the controlled MoviPrep trials.

Table 1: The Most Common Drug-Related Adverse Reactions1 ( 2%) in the Study of MoviPrep vs. 4 Liter Polyethylene Glycol plus Electrolytes Solution

Malaise Nausea Abdominal pain Vomiting Upper abdominal pain Dyspepsia 1

2

General: Hypersensitivity reactions including anaphylaxis (some of which were severe, including shock), rash, urticaria, pruritus, lip, tongue and facial swelling, dyspnea, chest tightness and throat tightness. Fever, chills and dehydration.

Nervous system: Syncope, tremor, seizure.

Renal: Renal impairment and/or failure.

DRUG INTERACTIONS Drugs That May Increase Risks Due to Fluid and Electrolyte Abnormalities Use caution when prescribing MoviPrep for patients with conditions, or who are using medications that increase the risk for fluid and electrolyte disturbances or may increase the risk of adverse events of seizure, arrhythmias, and prolonged QT in the setting of fluid and electrolyte abnormalities. Consider additional patient evaluations as appropriate. [See WARNINGS] Potential for Altered Drug Absorption Oral medication administered within 1 hour of the start of administration of MoviPrep may be flushed from the gastrointestinal tract and the medication may not be absorbed.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. Animal reproduction studies have not been performed with MoviPrep. It is also not known if MoviPrep can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. MoviPrep should be given to a pregnant woman 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 MoviPrep is administered to a nursing woman.

MoviPrep® (split dose) N=180 n (% = n/N)

4L PEG + E2 N=179

Pediatric Use The safety and effectiveness of MoviPrep in pediatric patients has not been established.

n (% = n/N)

35 (19.4) 26 (14.4) 24 (13.3) 14 (7.8) 10 (5.6) 5 (2.8)

32 (17.9) 36 (20.1) 27 (15.1) 23 (12.8) 11 (6.1) 2 (1.1)

Geriatric Use Of the 413 patients in clinical studies receiving MoviPrep, 91 (22%) patients were aged 65 or older, while 25 (6%) patients were over 75 years of age. No overall differences in safety or effectiveness were observed between geriatric patients and younger patients, and other reported clinical experience has not identified differences in responses between geriatric patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Drug-related adverse reactions were adverse events that were possibly, probably, or definitely related to the study drug.

4L PEG+E is 4 liter Polyethylene Glycol plus Electrolytes Solution

Table 2: The Most Common Drug-Related Adverse Reactions1 ( 5%) in the Study of MoviPrep vs. 90 mL Oral Sodium Phosphate Solution

Abdominal distension Anal discomfort Thirst Nausea Abdominal pain Sleep disorder Rigors Hunger Malaise Vomiting Dizziness Headache Hypokalemia Hyperphosphatemia

Cardiovascular: Tachycardia, palpitations, hypertension, arrhythmia, atrial fibrillation, peripheral edema.

MoviPrep® (evening only) y (full dose) ( dose) N=169 n (% = n/N)

90 mL OSPS2 N=171

101 (59.8) 87 (51.5) 80 (47.3) 80 (47.3) 66 (39.1) 59 (34.9) 57 (33.7) 51 (30.2) 45 (26.6) 12 (7.1) 11 (6.5) 3 (1.8) 0 (0) 0 (0)

70 (40.9) 89 (52.0) 112 (65.5) 80 (46.8) 55 (32.2) 49 (28.7) 51 (29.8) 121 (70.8) 90 (52.6) 14 (8.2) 31 (18.1) 9 (5.3) 10 (5.8) 10 (5.8)

n (% = n/N)

1

Drug-related adverse reactions were adverse events that were possibly, probably, or definitely related to the study drug. In addition to the recording of spontaneous adverse events, patients were also specifically asked about the occurence of the following symptoms: shivering, anal irritations, abdominal bloating or fullness, sleep loss, nausea, vomiting, weakness, hunger sensation, abdominal cramps or pain, thirst sensation, and dizziness.

2 OSPS is Oral Sodium Phosphate Solution

Isolated cases of urticaria, rhinorrhea, dermatitis, and anaphylactic reaction have been reported with PEG-based products and may represent allergic reactions.

Published literature contains isolated reports of serious adverse events following the administration of PEG-based products in patients over 60 years of age. These adverse events included upper gastrointestinal bleeding from a Mallory-Weiss tear, esophageal perforation, asystole, and acute pulmonary edema after aspirating PEG-based preparation.

Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse events have been identified during postapproval use of MoviPrep. Because they 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. These events have been chosen for inclusion due to either their seriousness, frequency of reporting or causal connection to MoviPrep, or a combination of these factors.

PATIENT COUNSELING INFORMATION • Advise patients who require a diet low in phenylalanine that MoviPrep contains aspartame – a maximum of 233 mg per treatment. This sweetener, after hydrolysis in the body, provides 131 mg of phenylalanine to the patient.

• Ask patients to inform you if they have trouble swallowing or are prone to regurgitation or aspiration.

• Instruct patients that each pouch needs to be diluted in water before ingestion and that they need to drink additional clear liquids. Examples of clear liquids are: water; clear fruit juices without pulp including apple, white grape, or white cranberry; strained limeade or lemonade; coffee or tea (Do not use any dairy or non-dairy creamer); clear broth; clear soda; gelatin (without added fruit or topping); popsicles (without pieces of fruit or fruit pulp).

• Inform patients that oral medications may not be absorbed properly if they are taken within one hour of starting each dose of MoviPrep.

• Tell patients not to take other laxatives while they are taking MoviPrep.

• Tell patients that MoviPrep produces a watery stool (diarrhea) which cleanses the colon before colonoscopy.

Advise patients receiving MoviPrep to adequately hydrate before, during, and after the use of MoviPrep. Patients may have clear soup and/or plain yogurt for dinner, finishing the evening meal at least one hour prior to the start of MoviPrep treatment. No solid food should be taken from the start of MoviPrep treatment until after the colonoscopy.

• Tell patients that the first bowel movement may occur approximately 1 hour after the start of MoviPrep administration. Abdominal bloating and distention may occur before the first bowel movement. If severe abdominal discomfort or distention occurs, stop drinking MoviPrep temporarily or drink each portion at longer intervals until these symptoms diminish. If severe symptoms persist, notify your health provider.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

For additional information, call: 1-866-SLXP(7597) To report adverse events, call: 1-800-508-0024 Manufactured for: Salix Pharmaceuticals, Inc. 8510 Colonnade Center Drive Raleigh, NC 27615 www.salix.com © 2013 Salix Pharmaceuticals, Inc. All rights reserved.

MOV-RALAB7-092013

Seeing is believing

patient approved 9 OUT OF 10

MoviPrep® has proven 89% excellent or good cleansing when used as a split dose1

patients would take 2 MoviPrep again

° Low-volume PEG-3350 provides consistent, clear visibility of the entire colon ° Comprehensive patient support, including a live nurse help line (1-855-4MOVIRX), a downloadable prep kit, and educational materials ° In clinical trials, no differences in safety and tolerability between younger and geriatric patients

physician trusted

-Most common adverse reactions for split dosing (incidence 5%) are malaise, nausea, abdominal pain, vomiting, and upper abdominal pain. The most common adverse reactions for evening only dosing (incidence 5%) are abdominal distension, anal discomfort, thirst, nausea, abdominal pain, sleep disorder, rigors, hunger, malaise, vomiting, and dizziness

NEARLY 8 MILLION MoviPrep prescriptions 3 written in the US since 2006

www.MoviPrep.com CONTRAINDICATIONS MOVIPREP® is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, gastric retention, ileus, toxic colitis or toxic megacolon, or hypersensitivity to any components of MoviPrep.

Please see Brief Summary of complete Prescribing Information for MoviPrep on reverse.

References: 1. MoviPrep [prescribing information]. Raleigh, NC: Salix Pharmaceuticals, Inc.; 2012. 2. Ponchon T, Boustière C, Heresbach D, et al. A low-volume polyethylene glycol plus ascorbate solution for bowel cleansing prior to colonoscopy: the NORMO randomised clinical trial [published online ahead of print June 14, 2013]. Dig Liver Dis. doi: 10.1016/j.dld.2013.04.009. 3. Symphony Health Solutions, Pharmaceutical Audit Suite (PHAST), September 2006 through June 2013.

Website: www.MoviPrep.com 8510 Colonnade Center Drive, Raleigh, NC 27615 Tel·866.669.SLXP (7597). MoviPrep® is a registered trademark and PM| AM Split Dosing™ is a trademark of Salix Pharmaceuticals, Inc. © 2013 Salix Pharmaceuticals, Inc. All rights reserved. MOV 13/11-2