The March 2013 Digital Edition of Gastroenterology and Endoscopy News

1978 —

35th Anniversary — 2013

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The Independent Monthly Newspaper for Gastroenterologists

Volume 64, Number 3 • March 2013

NATIONAL COLORECTAL CANCER AWARENESS MONTH

Heritable Colorectal Cancer: What Every Gastro Should Know

What’s New in Colon Cancer Screening?

The Latest in Imaging, Colonoscopes and Other Gadgets

BY MONICA J. SMITH

BY MONICA J. SMITH NEW YORK K—Although most colorectal cancers (CRC) are sporadic, CRC also can be heritable, especially in patients with genetic syndromes that increase their risk for cancer and the chance that they will develop cancer see Heritable CRC, page 24

Molecular Subtyping ‘Symbolic of New Age of Cancer Care’

BY CAROLINE HELWICK SAN FRANCISCO—Two studies presented at the 2013 American Society of Clinical Oncology Gastrointestinal Cancers Symposium demonstrated a role for molecular classification of tumor cells in the prognosis and treatment see Molecular Subtyping, page 28

NEW YORK K—In the classic idiom, it’s a poor craftsman who blames his tools. But try telling that to the cabinetmaker whose chisel won’t hold an edge.

Colonoscopy prevents colorectal cancer (CRC) and saves lives, but the procedure isn’t perfect and there’s always hope that better technology will result in better screening.

“We know that when we do this procedure we can miss things, and we do. Every endoscopist does. So the question is how can we do it better?” said Mark B. Pochapin, MD, MD who h posed d this h question to attendees of the annual meeting of the New York Society for Gastrointestinal Endoscopy (NYSGE), held in December.

Quality, of course, is essential, and endoscopists should make sure they are meeting proposed quality

CMS Set To Require Proof of Adherence to Quality Benchmarks Some Doctors Unaware of Impending Requirements

b h benchmarks, k such h as adequate d colonoscope l withh drawal time, good to excellent bowel preparation, a cecal intubation rate of 95% and an adenoma detection rate (ADR) of 15% in women and 25% in men.

But some advances in capsule endoscopy, computed see CRC Screening, page 10

I N S I D E

Spread the word!

March Is National Colorectal Cancer Awareness Month Experimental Colon Cancer Vaccine Elicits Immune Response— Will It Be Able To Prevent Polyps, Cancer? ..........................page 3

BY MONICA J. SMITH

When Colonoscopy Misses: Who or What Is To Blame?

Making Colonoscopy the Best It Can Be .............................page 6

LAS VEGAS—Regulations set out by the Affordable Care Act will require physicians to be responsible for documenting the quality of the care they provide and will enforce penalties to hold them responsible if that quality of care does not measure up to established benchmarks.

Newly FDA-Approved, Low-Volume Bowel Prep Shows High Patient Acceptance in Latest Trials ............................page 12 Study Shows Elevated CRC Risk in FDRs of Those Diagnosed With CRC Even After Age 60 Years ....................................page 23

see Quality Benchmarks, page 14 PRODUCT ANNOUNCEMENT

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Clinical Challenges and Complications of IBD

Uceris Approved For Induction of Remission In Ulcerative Colitis

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Effective cleansing in all bowel segments, including the right colon Percent of patients with NO RESIDUAL STOOL by colon segment1* Colon Segment

Cecum Ascending Descending Transverse Sigmoid/Rectum

SUPREP Bowel Prep Kit split-dose regimen (n=63) 91%† 91%† 92% 92% 94%

4-Liter Prep same-day regimen‡ (n=66)§ 67% 69% 84% 82% 81%

*This clinical trial was not included in the product labeling. †P≤0.02 vs 4-Liter Prep. Statistically significant difference. ‡ Standard 4-Liter Prep (sulfate-free PEG electrolyte lavage solution). § One patient was excluded who took the preparation but refused colonoscopy. Three patients had one or more segments that could not be evaluated because the procedure was stopped for poor preparation before cecal intubation.

SUPREP Bowel Prep Kit achieved “excellent” bowel cleansing in patients based on investigator grading1,2 • Split-dose regimens of SUPREP Bowel Prep Kit and MoviPrep®|| were equivalent in colon cleansing2 • Significantly more patients had “excellent” preps with SUPREP Bowel Prep Kit compared to MoviPrep (63% vs 53%, respectively; P=0.043¶)2 MoviPrep (PEG-3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate and ascorbic acid for oral solution) is a registered trademark of Salix Pharmaceuticals, Inc. ¶ Statistically significant difference. ||

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.

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2013

NATIONAL COLORECTAL CANCER AWARENESS MONTH

3

From the Literature

Experimental Colon Cancer Vaccine Elicits Immune Response— Will It Be Able To Prevent Polyps, Cancer?

BY CHRISTINA FRANGOU For the first time, researchers have successfully used a vaccine to prompt an immune response to early indications of colon cancer in people at high risk for the disease.

“This prophylactic colon cancer vaccine boosts the patient’s natural

immune surveillance, which potentially could lead to the elimination of premalignant lesions before their progression to cancer,” co-author Olivera Finn, PhD, distinguished professor and chair of immunology, University of Pittsburgh Cancer Institute, said in a statement. “This might spare patients the risk and inconvenience of repeated invasive surveillance

tests, such as colonoscopy, that currently are used to spot and remove precancerous polyps.”

The vaccine is directed against an abnormal variant of the cellular protein MUC1—which is expressed in a larger amount and in a modified form—in adenomatous polyps and colorectal cancer cells. The changes in MUC1 are thought to be part of the process

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 study comparingg 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 studyy 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 pplease 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 ppatients 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 ppost-colonoscopy 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 pproducts 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 ppatient 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 ggeriatric ppatients and yyounger g ppatients. 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 provided.

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 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. 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

of progression from adenomas to cancer. The goal of the vaccine is to help the immune system to identify the changes in the MUC1 protein that signal the progression to cancer, and to eliminate specifically the cells that make abnormal MUC1 (Kimura T et al.

Cancer Prev Res 2013;6:18-26).

In this first-ever trial in human patients, the vaccine was tested in 39 patients, between the ages of 40 and 70 years, who were at increased risk for colorectal cancer due to a history of advanced adenoma. In 17 (43.6%) of the vaccinated individuals, the vaccine elicited high levels of anti-MUC1 immunoglobulin G and long-lasting immune memory.

Researchers said that the lack of response in the other 22 patients was likely due to already high levels of cells that suppress the immune system’s ability to fight cancer.

“This suggests that it might be better to vaccinate people against colon cancer at an even earlier stage, or vaccinate people who do not already have suppressed immune systems,” said Dr. Finn.

The patients received an initial dose of the vaccine, followed by additional shots, at weeks 2 and 10. Once the medication was injected, blood samples were drawn to measure the participants’ immune response and samples were drawn again at 12, 28 and 52 weeks. A booster injection was given at one year.

The vaccine was well tolerated.

Side effects included red skin color, discomfort at the injection site and flu-like symptoms after the first injection.

Specialists not affiliated with the study said that it provides strong proof of principle on two points: the vaccine can be safely administered to a human population, and the vaccine can elicit an immunologic response as a potential way of controlling the development of cancer.

“This is a very exciting first step in understanding the potential role of vaccines for cancer prevention,” said Andrew T. Chan, MD, MPH, assistant professor in the Department of Medicine at Harvard Medical School, Boston.

“The next step will be demonstrating whether that antibody response has any sort of clinical consequences. For example, does it actually protect someone against developing a colorectal polyp or a colorectal cancer?” Dr. Chan said.

Investigators are planning a larger randomized trial that will examine the vaccine’s efficacy in polyp prevention.

■

4

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2013

Vol. 64, No. 3 MEDICAL ADVISORY BOARD MANOOP S. BHUTANI, MD

GARY R. LICHTENSTEIN, MD

Houston, Texas

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ALAN F. CUTLER, MD

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

Farmington Hills, Michigan

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Sacramento, California

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PETER R. MCNALLY, DO

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Fort Carson, Colorado

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JOEL E. RICHTER, MD Tampa, Florida

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PRATEEK SHARMA, MD

Gainesville, Florida

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Memphis, Tennessee

New York, New York

March 2013

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2013

an ACG Visit dA us ASLboot at D boh #1 oth 614 #1 13

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Correction

40th AN N IVERSARY 1 972– 2012

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

By Christina Frangou San Diego—One of the most widely used diabetes drugs in the world appears to have an unexpected secondary benefit: reducing the risk for hepatocellular carcinoma (HCC) by more than 50%, according to two new studies. Results from an American case–control study and a see Metformin, page 26

First Guideline on NAFLD Published

By Christina Frangou

Re: “Linzess, New Drug for IBS and Chronic Constipation, Now Available in Pharmacies.” Gastroenterology & Endoscopy News January 2013;64:38 In the two aforementioned articles, Gastroenterology & Endoscopy News incorrectly stated that Linzess (linaclotide), which received FDA approval last August to treat chronic idiopathic constipation and to treat irritable bowel syndrome with constipation, is indicated for individuals “who do not respond to standard treatments.” This phrase is inconsistent with the FDAapproved indication for Linzess, which does not contain this stipulation.

AGA Says…

“After discontinuing medications that can cause constipation and performing blood and other tests as guided by clinical features, a therapeutic trial (i.e., fiber supplementation and/or osmotic or stimulant laxatives) is recommended before anorectal testing (strong recommendation, moderate-quality evidence). … When bowel symptoms are refractory to simple laxatives, newer agents should be considered.”

Studies Attempt To Define Patient Preferences for CRC Screening

“It is not necessary to fail another therapy before beginning treatment with Linzess,” noted Douglas S. Levine, MD, vice president of Medical Scientific Affairs, Ironwood Pharmaceuticals, which co-markets Linzess with Forest Pharmaceuticals.

The Prescribing Information for Linzess states: Linzess is a guanylate cyclase-C agonist indicated in adults for treatment of: • Irritable bowel syndrome with constipation (IBS-C) • Chronic idiopathic constipation For more detailed information about Linzess, see the FDA press release at www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm317505.htm, or see the Prescribing Information at www.frx.com/pi/linzess_pi.pdf.

‘Astonishing’ Data on Metformin for HCC

Re: “FDA Approves Linzess To Treat IBS and Chronic Constipation,” by Maureen Sullivan. Gastroenterology & Endoscopy News October 2012;63:64

It may not be correct according to the language the FDA approved, but it is right on with the American Gastroenterological Association’s recommendations. The “American Gastroenterological Association Medical Position Statement on Constipation” states:

gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

Three leading American gastroenterology societies have published a new guideline on the diagnosis and management of non-alcoholic fatty liver disease (NAFLD).

Prompted by the fact that physicians are seeing a growing number of patients with the disease, this is the first time that any of these professional societies have developed

By Caroline Helwick

Despite its clear benefits, colorectal cancer (CRC) screening rates in the United States have stalled at around 50% of those eligible for screening.

Acceptance of screening recommendations might be enhanced if certain barriers could be overcome. Some believe that computed tomographic colonography (CTC) might be one way to improve adherence to screening recommendations.

This topic has been the aim of several recent clinical research surveys. What do these surveys reveal?

Are they accurate reflections of what patients truly desire? And why bother asking: Does patient preference really matter?

“The patient’s input and preferences have to be regarded as an absolutely central component of highquality care,” said David Weinberg, MD, MSc, chairman and professor of medicine at Fox Chase Cancer Center in Philadelphia, who spoke on the subject at

the 2012 Digestive Disease Week meeting in a lecture entitled, “What Will Be Competing with Colonoscopy in 5 years?”

“Clearly, patients who are well versed at an appropriate level, understand their treatment options and see Patient Preferences, page 7

see NAFLD Guideline, page 28

GI Rou Roundtable und 2012

Gasttroent oe enterologists e Discuss Challenges, Chan nges, Fu Future of GI Health Care Compiled and written by Monica J. Smith

Knoxville, Tenn.—The GI Roundtable conference evolved as a collaboration between Bergein Overholt, MD, of Gastrointestinal Associates in Knoxville, Tenn., and Klaus Mergener, MD, PhD, MBA, of Digestive Health Specialists in Tacoma,

I N S I D E

EXPERT’S PICKS Best of Digestive Disease Week (DDW): Inflammatory Bowel Disease (IBD) Ellen J. Scherl, MD, provides an overview of IBD research presented at the DDW meeting Ellen J. Scherl, ............................................ page 10 MD Complications of Biologic Therapy for IBD

Four IBD experts discuss common risks and complications associated with anti-TNF therapy for IBD ............................................ page 14

see GI Roundtable, page 50

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[Gastroenterologyy 2013;144:211217; available at http://download.jour nals.elsevierhealth. com/pdfs/journals/0016-5085/ PIIS0016508512015454.pdf.] ekhin Via website on Jan. 30, 2013

Correction Re: “Best of the American College of Gastroenterology: Part 2,” by David Wild. Gastroenterology & Endoscopy News January 2013;64:1,14,15,18-21 Gastroenterology & Endoscopy News published an outdated affiliation for David T. Rubin, MD, who contributed to the aforementioned article.

Dr. Rubin is professor of medicine, co-director of the Inflammatory Bowel Disease Center, and associate section chief for educational programs, Section of Gastroenterology, Hepatology and Nutrition at The University of Chicago Medicine.

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NATIONAL COLORECTAL CANCER AWARENESS MONTH

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2013

When Colonoscopy Misses: Who or What Is To Blame?

Making Colonoscopy the Best It Can Be Interval Cancers—Biology or Missed Lesions?

BY MONICA J. SMITH LAS VEGAS—Researchers at last year’s American College of Gastroenterology Annual Scientific Meeting discussed the effectiveness of colonoscopy, specifically in the detection of colorectal cancers (CRC) in the proximal colon, and the issue of missed or incompletely resected lesions. Speakers attempted to discern if differences in CRC detection were based predominantly on biological factors or endoscopist-related issues.

Right- vs. Left-Sided CRCs The symposium began with a discussion of comparative advantage regarding colonoscopy and flexible sigmoidoscopy, as described by Douglas J. Robertson, MD, MPH, associate professor of medicine, Geisel School of Medicine at Dartmouth and the Dartmouth Institute for Health Policy & Clinical Practice, Hanover, N.H., and chief, Section of Gastroenterology, White River Junction VA Medical Center, in Vermont.

“A person has a comparative advantage if he can produce something at lower cost than anyone else,” Dr. Robertson explained.

For example, sigmoidoscopy has some advantages over colonoscopy—it is less invasive, it requires no bowel preparation and nurses can perform it. However, its protection against CRC is limited to the left side of the colon.

A randomized controlled trial that examined the effectiveness of sigmoidoscopy found that the procedure was associated with a reduction in CRC mortality of 26%, and a reduction in the incidence of CRC of 21%; however, there was little difference between the screened group and the usual care group regarding proximal cancers (Schoen RE et al. N Engl J Med 2012;366:2345-2357). Dr. Robertson pointed out that, with regard to comparative effectiveness, the results of this trial could be interpreted in a couple of different ways.

“If you are a colonoscopy enthusiast, you could correctly point out that flexible sigmoidoscopy had no benefit in the right colon,” he said. “That being said, many in the sigmoidoscopy arm didd go on to get a full colonoscopy because of the findings of polyps on flexible sigmoidoscopy; therefore, the lack of any benefit to the right side of the colon also may be partly attributed to a colonoscopy’s lack of effectiveness there.”

Studies have come to different conclusions regarding the effectiveness of colonoscopy for detecting rightsided colon cancers. One such study showed no protective benefit of colonoscopy in the right colon (Baxter NN et al. Ann Intern Med. 2009;150:1-8), whereas another study found a 42% reduction in right-sided cancers for colonoscopy (Baxter NN et al. J Clin Oncol 2012;30:2664-2669).

Dr. Robertson asked whether biology or technology is paramount in the difference in right- and left-sided CRC detection.

“If it’s biology, it’s really an issue of fast growth—that some lesions grow so quickly that in the short time after a colonoscopy you develop another cancer or new cancer that wasn’t there at the time of your exam,” Dr. Robertson noted.

“Biology is certainly part of this, but to what degree?”

Given that the right side of the colon differs from the left in terms of pH level, bacterial composition and apoptotic index, it is plausible that it could be a host to different types of lesions. Aasma Shaukat MD, associate professor, University of Minnesota, Minneapolis, explained the three predominant mechanisms through which CRC develops and progresses: chromosomal instability (CIN), microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP).

CIN is understood as the traditional adenoma-carcinoma pathway—a slow-growing process that takes anywhere from eight to 20 years.

‘We know from studies with large numbers of patients and endoscopists that endoscopists don’t perform equally well in preventing interval cancers. …

There are really only two explanations for this: One possibility is that some endoscopists are just unlucky and happen to inherit all the patients with biologically fast-growing lesions. The other is that there is something different about how we apply our technology.’

—Douglas J. Robertson, MD, MPH

“We used to think that about 95% of cancers follow this pathway, but it might be closer to 50% to 70%,” Dr. Shaukat noted.

The MSI pathway is seen in about 15% of interval cancers.

“Microsatellites are short, repetitive sequences of DNA that are essentially the housekeeping genes that perform DNA checks and repairs,” Dr. Shaukat explained. Loss of DNA mismatch repair activity leads to cancers that have a specific phenotype. The mismatch repair defect is “associated with hypermethylation of the mismatch repair gene promoter, which results in inactivation of the gene, an overlap with the CIMP pathway.”

Another factor in this pathway is the BRAF F gene, which is involved in the RAS/RAF pathway of cell proliferation.

“BRAF F mutations are strongly associated with CIMP and MSI in sporadic cancers,” she said.

Researchers at the University of Minnesota extracted DNA from interval cancers and noninterval cancers and performed molecular marker testing.

“Interval cancers were three times more likely to be MSI-positive, two-and-a-half times more likely to have a CIMP-positive phenotype, and MSI cancers were seven times more likely to be associated with BRAF mutations,” Dr. Shaukat said.

Interval cancers also were more likely to be located in

the proximal colon colon, were smaller in size than noninterval cancers and tended to have a mucinous histology.

Biology is not the only factor at play in the development of interval cancers.

“We also looked at the question: Is there a contribution of missed or incompletely resected lesions?” Dr. Shaukat said. She and her team compared the locations of interval and noninterval cancers and found that about 30% of the interval cancers occurred in previous polypectomy segments.

“This was more than we would expect than if it were happening just by chance,” she said. “Interval cancers were three times more likely to be located in the right colon, and tumor size was smaller for interval cancers, suggesting that these may have been lesions that were not detected or were incompletely resected.”

Dr. Robertson and his colleagues also have tried to gauge how often endoscopists miss cancers or adenomas.

“We know how often adenomas are found in people who come in for screening; we have good evidence about how often we find polyps of different sizes; we know from tandem colonoscopy studies how often we miss polyps of various sizes; and finally, pathology studies tell us how often we find cancers in polyps of different sizes,” he said.

Based on these factors, Dr. Robertson and his colleagues calculated that 1.8 per 1,000 people who undergo screening colonoscopy had a missed adenoma harboring cancer or transitioning to cancer during a short interval after the examination.

“I think missed lesions probably account for about 80% of the missed cancers, and biology [accounts for] probably about 20% of these lesions,” he said.

Furthermore, evidence suggests that technology and technique play a larger role than biology based on variation observed in an endoscopist’s skill and performance.

“We know from studies with large numbers of patients and endoscopists that endoscopists don’t perform equally well in preventing interval cancers,” Dr. Robertson said.

“There are really only two explanations for this: One possibility is that some endoscopists are just unlucky

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increased detection of these subtle, sessile-serrated polyps and other difficult lesions in the right colon. But we do have some evidence that there is a tight correlation between adenoma detection and advanced adenoma detection, as well as sessile polyp adenoma detection.”

Multiple studies have established core principals for high-quality colonoscopy that include allowing enough inspection time to wash and visualize the entire colon; looking behind folds and flexures where polyps may be hidden; the ability to recognize subtle flat lesions; and the use of a split-dose bowel preparation.

But the problem in the United States, and indeed worldwide, is the dramatic variation in the quality of a colonoscopy procedure from one endoscopist to another.

“In the original trial from Barclay, there was a 10-fold variance in adenoma detection,” Dr. Wallace noted (Barclay RL et al. N Engl J Medd 2006;355:2533-2541). “I would guess there is still significant variation.”

‘We’ve been a little stunned over the last four or five years that we’re less effective than we thought we were. But and happen to inherit all the patients with biologicall biologically fast-growing lesions; the other is that there is something different about how we apply our technology.”

Highlighting this disparity, a study of 186 endoscopists including more than 45,000 patients showed that patients whose endoscopists had the highest adenoma detection rates (ADRs) had almost no interval cancers compared with patients whose endoscopists had an ADR below 11% (Kaminski MF et al. N Engl J Med 2010;362:1795-1803).

But difficulty in detecting right-side lesions is only part of the problem—those lesions also tend to be more difficult to remove. Dr. Robertson’s group biopsied the margins of complete polypectomies performed by 11 gastroenterologists in 271 patients to see how often adenomatous tissue was left behind.

“Low and behold, about 10% of neoplastic polyps … were incompletely resected,” Dr. Robertson said (Pohl H et al. Gastroenterologyy 2013;144:74-80).

Of 42 sessile-serrated polyps, 31% were incompletely resected, and of the large serrated adenomas, 50% were incompletely resected.

“So maybe part of the reason these things are not going away is because we don’t see them, and when we do, maybe we’re not resecting them as effectively as we should,” Dr. Robertson said.

Improving Outcomes If preventing right-sided CRCs is the comparative advantage of colonoscopy, it is critical for patients, and will be increasingly important to payers, that gastroenterologists demonstrate colonoscopy’s effectiveness in that segment of the colon.

“We’ve been a little stunned over the last four or five years that we’re less effective than we thought we were,” noted Michael B. Wallace, MD, MPH, professor of medicine and chief, Division of Gastroenterology and Hepatology at Mayo Clinic, Jacksonville, Fla. “But also very encouraged by new data that show we can improve our ability to detect advanced—and all—adenomas,” he added.

“We’re just beginning to see data emerge on the

also very encouraged by new data that show we can improve our ability to detect advanced—and all—adenomas.’

—Michael B. Wallace, MD, MPH

Barclay et al found that endoscopists with a colonoscope withdrawal time of less than six or seven minutes had lower ADRs. However, a study that specifically examined the effect of enforcing a seven-minute endoscope withdrawal time found that the mandate did little to improve ADRs (Sawhney MS et al. Gastroenterology 2008;135:1892-1898).

“Simply telling people to spend more time in the colon does not translate to improved quality,” Dr. Wallace said.

Dr. Wallace’s team recently published results of an Endoscopic Quality Improvement Program (EQUIP) in which half of the 15 staff endoscopists were randomly assigned to undergo EQUIP training (Coe SG et al. Am J Gastroenterol 2013;108:219-226). Endoscopists received training on how to distinguish adenomas and hyperplastic polyps, as well as how to recognize subtle polyps.

Endoscopists in the trial were given monthly feedback on ADRs and withdrawal times, and the de-identified results were posted publicly. Doctors were labeled with generic identifiers for confidentiality “but this inspired some competitiveness within our group to achieve a higher level of quality,” Dr. Wallace noted.

To evaluate the effect of training, the investigators measured ADR for all endoscopists (trained and untrained) at baseline and after the intervention in a total of 1,200 procedures.

“To our pleasure, we saw that our baseline ADR was relatively good. All of our endoscopists were above 20%—but the lowest one was at 26% and the highest at 70%,” Dr. Wallace noted.

The endoscopists who were randomly assigned to receive EQUIP training had a significant increase in

7

ADR, from an average of 36% to 47%. There was no change in ADR in the control group.

“The main effects we saw were in the lowest adenoma detectors who achieved the greatest benefits,” Dr. Wallace said, noting that the endoscopist with the highest ADR actually came down, slightly.

Advances in technology, such as more sophisticated imaging techniques, do not appear to have much of an effect, Dr. Wallace noted.

“The 10% increase in ADR we saw was achieved with a simple education intervention. It’s not going to be reproduced with technology,” he said.

“High-definition helps a little bit, but very slightly,” he added. “If you’re at 18% and you want to get to 21.5%, this might help, but it is a modest effect,” (Subramanian V et al. Endoscopyy 2011;43:499-505). Narrow-band imaging shows a similar, but even weaker, correlation with improvements in ADR (Dinesen L et al. Gastrointest Endoscc 2012;75:604-611).

Most of the newer instruments include a high-definition endoscope with some type of optical enhancement, which may be of greater benefit than any one technology alone (Gross SA et al. Endoscopyy 2011;43:10451051), Dr. Wallace noted, and clear colonoscope caps can improve cecal intubation time to a degree, but offer little benefit in terms of ADR (Ng SC et al. Am J Gastroenteroll 2012;107:1165-1173).

One improvement in colonoscopy—split-dose bowel preparation—does seem to make a difference and seems to have become the standard in bowel preparation over the past year or so. Patients tolerate the preparation better, and it also results in a cleaner bowel (Kilgore TW et al. Gastrointest Endoscc 2011;73:1240-1245).

Managing Expectations Despite the strictest adherence to quality parameters, interval cancers will still occur in the patients of even the most meticulous endoscopists. Therefore, endoscopists should be sure to discuss the possibility of missed lesions with patients during the informed consent process. Endoscopists should document that the discussion occurred, that the optimal technique was used and that an optimal examination was performed. Documenting these three things, as well as outcomes, will be important for protecting the endoscopist, and in the future, will be tied to reimbursements, Dr. Shaukat noted.

Getting a detailed family history, too, is important.

“We work in open access endoscopy settings, so we don’t know these patients that well,” Dr. Shaukat said.

“But take a few minutes … and follow what’s in the guidelines. Then, if polyps are removed during colonoscopy, it’s really important that you follow appropriate surveillance guidelines.”

For interval cancers that occur despite the implementation of best practices, endoscopists might want to consider tumor testing for MSI. A local pathologist or hospital can conduct immunohistochemistry testing quite inexpensively or DNA testing of the tumor tissue itself.

“If MSI is positive, you can think about BRAF F testing of the tumor, which will tell you whether this was a sporadic, microsatellite unstable cancer, or maybe a hereditary cancer,” Dr. Shaukat said.

“Communicate with your patients, all the way from consent to getting the pathology report, and discuss indications for their family members if findings merit that discussion,” she said.

■

References: 1. Jensen RT, Doherty GM. Carcinoid tumors and the carcinoid syndrome. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.

Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:1559-1574. 2. Caplin ME, Buscombe JR, Hilson AJ, Jones AL, Watkinson AF, Burroughs AK. Carcinoid tumour. Lancet. 1998;352(9130):799-805.

What’s behind the symptoms?

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CRC Screening continued from page 1

tomography colonography (CTC), enhanced visualization of colonic mucosa and improved colonoscopes might make it easier to find what endoscopists are missing.

Dr. Pochapin, who is director of the Division of Gastroenterology, professor of medicine and Sholtz/Leeds Professor of Gastroenterology at New York University Langone Medical Center, New York City, reviewed some of the latest developments in CRC screening at the NYSGE meeting.

Capsule Colonoscopy The PillCam COLON 2, which is approved for use in Europe but is not yet cleared for marketing or distribution in the United States, is basically the same tool approved for visualization of the small bowel but modified for use in the colon. It works in fluid rather than air, and yields spectacular images.

“There has been some good data published on the sensitivity and specificity,” Dr. Pochapin noted.

For polyps at least 10 mm diameter, the PillCam has a sensitivity of 88% and a specificity of 95%. Sensitivity for polyps 6 mm or larger is still fairly good, at 84%, but the specificity for those polyps falls to 64%.

“This is mainly due to size mismatch,” Dr. Pochapin explained. “If the PillCam calls it 6 mm but it’s actually 12 mm on colonoscopy, that would be considered a false-positive because the size is different.”

So, the PillCam allows visualization of polyps, but it has some significant drawbacks. Like any nontherapeutic approach, it would have to be followed by standard colonoscopy in the event of positive findings. It also requires a bowel preparation that can be even more burdensome than the regimen recommended for patients undergoing standard colonoscopy.

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2013

“Patients need to take 2 L of polyethylene glycol in the evening, 2 L in the morning, and upon reaching the first component of the small bowel, the capsule sends a signal to the device the patient is wearing telling them to take yet another component of prep—30 mL of sodium phosphate. And, if necessary, there’s a second boost, and even a third, with a suppository,” Dr. Pochapin said.

“You need a lot of fluid and forward motion to get that capsule through the colon and visualize it so beautifully in the liquid. But what the typical American patient wants is to just swallow a pill and be done with it,” he noted.

CT Colonography CTC also provides spectacular images when bowel preparation is excellent, and it does quite well at revealing adenomas.

“When we look at meta-analyses, there is 83% sensitivity for smaller adenomas and 88% for larger, with a specificity in the high 90th percentile,” Dr. Pochapin said.

But, despite the media-driven general public perception of CTC as a gentler alternative to colonoscopy, it still requires significant preparation, and it’s not entirely noninvasive—it requires the placement of a small tube in the rectum to provide insufflation, and that insufflation can be uncomfortable for patients not under sedation. Again, colonoscopy is required for patients with positive CTC results.

“We need to recognize where CTC

Full Spectrum Endoscope Shows More of the Colon Than Seen Before

BY MONICA J. SMITH A new colonoscope is aiming to make inspection of the sinuous anatomy of the colon easier by providing a more comprehensive view.

Ian Gralnek, MD, of The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel, and his colleagues have conducted two studies investigating the Full Spectrum Endoscope, which aims to improve ADRs by giving endoscopists side views of the colonic mucosa, in addition to the standard front view.

“The [Full Spectrum Endoscope] maintains all of the standard colonoscope techniques and technologies we are familiar with,” said Dr.

Gralnek, who is chief of the Department of Hospital-Wide Ambulatory Care Services and senior physician in the Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel. “But it has three lenses, on the front and sides of the colonoscope tip, and the video images are presented on three monitors—a center monitor that shows you the forward view, and right and left monitors, which show the right and left lenses on the scope tip.”

The instrument, developed by PeerMedical, Ltd., Caesarea, Israel, now owned by EndoChoice, Atlanta, is a flexible, reusable colonoscope, 168 cm in length and 12.8 mm in diameter, with a full deflection tip, standard working channel, water jet irrigation, full suction and air

insufflation—all features that are standard to the colonoscopes endoscopists use in everyday practice. The difference is that Full Spectrum Endoscope operates in two modes of view: a forward view that provides 160 degrees of visualization, and a full-spectrum mode that allows up to 330 degrees of visualization.

In one study, Dr. Gralnek and his colleagues evaluated the detection of embedded metal beads in a colon model by 37 gastroenterologists using the standard view or the full spectrum view of the Full Spectrum Endoscope.

“We found it highly statistically significant that many more of the metallic beads were found with the wide view than with the standard viewing mode,” Dr. Gralnek

noted. Furthermore, the gastroenterologists detected 85% of beads purposely hidden on the proximal sides of folds using the full-spectrum mode compared with about 35% in the standard view. The full study will be published in Gastrointestinal Endoscopy.

In another study, an institutional review board–approved pilot study to establish the feasibility and usability of the Full Spectrum Endoscope, the researchers looked at cecal intubation rates, time to reach the cecum, total procedure time, success of therapeutic interventions, adverse events and subjective endoscopist evaluation in procedures for screening, surveillance or diagnostic evaluation in 50 patients, all of whom underwent standard bowel preparation,

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sits in our role as gastroenterologists,” Dr. Pochapin said. “It may be great for a patient on anticoagulation or a patient with an incomplete colonoscopy. I don’t think we need to be afraid of it, but I think we have to recognize it as an alternative that needs further study.”

Advances in Imaging Technology ‘We know that when we do this procedure we can miss things, and we do. Every endoscopist does. So the question is, how can we do it better?’

—Mark B. Pochapin, MD

It stands to reason that technologies that can help the endoscopist more easily see and define differences in the colonic mucosa would lead to better ADRs, but so far narrow band imaging (NBI) and trimodal technologies (NBI, high definition and autofluorescence) have yet to prove their mettle.

“A lot of us use NBI, a technology in which the 415- and 540-mm wavelengths of light that are highly absorbed by hemoglobin are preferentially filtered in the RGB [red-green-blue] signal in our scope,” Dr. Pochapin explained.

“This image processing makes hemoglobin stand out, and consequently the vascularity of a polyp will stand out from the background. But does it really make a difference? Will we find more polyps—and more significant polyps?”

A recent meta-analysis revealed little difference between high-definition, white-light endoscopy and high-definition NBI in the detection of polyps, adenomas and flat adenomas; furthermore, high-definition NBI was not associated with a lower miss rate for polyps or adenomas (Pasha SF et al. Am J Gastroenterol 2012;107:363-370).

The Full Spectrum Endoscope from EndoChoice (not available for sale) Photo courtesy of EndoChoice

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Conversely, a small study published in 2008 showed an advantage for NBI in patients with hereditary nonpolyposis CRC, allowing the detection of more adenomas and a higher percentage of flat adenomas (East JE et al. Gut 2008;57:65-70).

“Patients at higher risk might benefit from some of this advanced technology, but for conventional screening, it might not make much of a difference,” Dr. Pochapin concluded.

Trimodal technology, which combines high definition, autofluorescence and NBI, also failed to improve miss rates in a study comparing the technique with standard colonoscopy (Kuiper T et al. Gastroenterology 2011;140:1887-1894).

“It really didn’t make much of a difference,” Dr. Pochapin noted. “In this study, as in almost every other study, it’s the tandem colonoscopy that tends to pick up these polyps.”

Better Colonoscopes?

Advances in colonoscope technology aim to make procedures easier for endoscopists and more comfortable for patients, potentially improving ADRs and patient compliance with screening recommendations.

The Third Eye Retroscope (Avantis Medical Systems, Inc.), for example, was developed to help endoscopists find polyps hidden behind folds in the colon, and it does appear to allow the detection of more polyps and adenomas compared with standard colonoscopy. The benefits, however, do not extend as much to screening examinations for average-risk patients; the technology appears to be more compelling for higher-risk patients. For example, in the TERRACE (Third Eye Retroscope Randomized Clinical Evaluation) study, endoscopists using the Third Eye Retroscope found 4.4% more adenomas in averagerisk patients undergoing screening colonoscopy compared with 35.7% and 55.4% more adenomas for higher-risk

conscious sedation and a follow-up phone call.

The endoscopists achieved 100% cecal intubation, with a mean time to cecum of 3.1 minutes. Mean withdrawal time and mean total procedure time were 12.7 minutes and 15.3 minutes, respectively.

Subjective assessment of ease of use, ease of scope advancement, quality of images, ability to perform polypectomy and other aspects was consistently “excellent” or “good.” The endoscopists also were not technically challenged by any aspect of the modified colonoscope or its multiple monitors.

“Your eyes end up picking up images on the sides very quickly,” Dr. Gralnek said. “You don’t have to look from screen to screen—your

see CRC Screening, page 18

brain actually picks up when polyps show up on the sides.”

A randomized controlled trial is currently under way comparing the Full Spectrum Endoscope with a standard colonoscope for the incremental detection of adenomas.

“I truly believe this technology has the ability to change the way we do colonoscopy,” Dr. Gralnek said. “My opinion is that this is a tool that will improve our ability to perform high-quality colonoscopy and improve our ADR, and I also think it will allow people who may not be doing perfect colonoscopy to perform better.”

Dr. Gralnek is a paid consultant for PeerMedical, Ltd., which funded the pilot and feasibility study.

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Newly FDA-Approved, Low-Volume Bowel Prep Shows High Patient Acceptance in Latest Trials

BY TED BOSWORTH LAS VEGAS—The efficacy of a newly licensed, low-volume bowel preparation for colonoscopy was found to be similar to that of conventional preparations, with a notably higher rate of patient tolerability, according to recent studies.

The new bowel preparation, marketed under the brand name Prepopik (Ferring Pharmaceuticals) and approved by the FDA last year, consists of 10 g of sodium picosulfate, 3.5 g of magnesium oxide and 12 g of citric acid (P/MC). It is consumed in two five-ounce glasses, followed by clear liquids, to reach a volume of 2 L.

“The key question that was asked was how easy or difficult was it to consume the prescribed bowel preparation,” explained Philip O. Katz, MD, Albert Einstein Healthcare Network, Philadelphia, who presented data on the preparation at the 2012 annual meeting of the American College of Gastroenterology.

CO2 instead of room air for GI endoscopy?

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Researchers presented data from two randomized Phase III trials that compared a “day-before” and a “same-day” split-dose regimen of Prepopik with a 2-L polyethylene glycol (PEG) solution with two 5-mg bisacodyl tablets (HalfLytely and Bisacodyl Tablets Bowel Prep Kit [Braintree Laboratories]). Both trials were structured as non-inferiority tests using the Aronchick Scale as the primary method of judging the quality of the preparation. The Ottawa Scale was used as a secondary outcome tool.

The difference in patient perception between the two bowel preparations was striking. Among patients using the P/ MC regimen, 58.4% of patients rated it very easy and 29% rated it easy to take, compared with 16.1% and 21.1%, respectively, of patients consuming the 2-L PEG plus bisacodyl preparation.

When responses for very easy and easy were combined, the difference in patient satisfaction between the two preparations was significant (87.4% vs. 37.2%; P<0.001).

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‘The key question that was asked was how easy or

Better for your patients Better for you s CO2 insufflation during ERCP may “significantly reduce[] postprocedural abdominal pain.” 1 s #/2 is absorbed 150 times faster than the nitrogen in air, and is promptly eliminated via the lungs.2 s CO2 insufflation “reduces pain and is safe to use in colonoscopy in sedated patients”. 3 Indications for Use: The CO2EFFICIENT Endoscopic Insufflator is designed to use CO2 as a distention media in the gastrointestinal tract when used in conjunction with a gastrointestinal endoscope.

For additional product information please visit www.bdigastro.com

Contraindications for Use: The CO2EFFICIENT ENDOSCOPIC INSUFFLATOR™ should be used only for an endoscopic procedure when insufflation of the gastrointestinal tract is necessary to support navigation of the endoscope and perform any evaluation procedures through the endoscope, and should therefore not be used for any other treatments. It should only be used under the direct guidance of a physician experienced in Gastrointestinal Endoscopy procedures. This device is contraindicated for hysteroscopic or laparoscopic insufflation, i.e., it must not be used for intrauterine distension. This device is contraindicated for CT Colonography.

For questions or instructions for use, please contact Bracco Diagnostics Professional Services Department at 800-257-5181, option 2.

References: 107 College Road East P.O. Box 5225 Princeton, NJ 08540 Ph: 609-514-2200 Toll Free: 1-800-631-5245 Fax: 609-514-2446

1. Bretthauer M, Seip B, et al. Carbon dioxide insufflation for more comfortable endoscopic retrograde cholangiopancreatography: a randomized, controlled, double-blind trial. Endoscopy 2007; 39:58-64.

2. Grant DS, Bartram CI, Heron CW, A preliminary study of the possible benefits of using carbon dioxide insufflation during double-contrast barium enema. The British Journal of Radiology 1986; 59:190-191.

3. Bretthauer M, Lynge AB, et al. Carbon dioxide insufflation in colonoscopy: Safe and effective in sedated patients.

Endoscopy 2005; 37:706-709.

© 2012 Bracco Diagnostics Inc. All rights reserved.

difficult was it to consume the prescribed bowel preparation.’

—Philip O. Katz, MD

In the day-before trial, researchers randomized 594 participants to receive either P/MC or PEG/bisacodyl. The P/MC group dissolved the first packet of the active ingredient in five ounces of liquid and ingested the solution between 4 p.m. and 6 p.m. This was followed by 1.2 L of clear liquids taken in eight-ounce glasses over a period of four hours. A second five-ounce solution of P/MC was taken between 10 p.m. and midnight, followed by 0.7 L of liquid.

The comparison group took two bisacodyl tablets with water, followed by 2 L of PEG in eight-ounce doses every 10 minutes after the first bowel movement or within six hours.

On the Aronchick Scale, the numerically (but not significantly) greater efficacy of P/MC versus the comparator fulfilled the non-inferiority criteria (83% vs. 79.7%, respectively). On the Ottawa Scale, P/MC was numerically

superior on two of the three scales evaluated, but the differences were not statistically significant. In contrast, differences in ease of use between preparations were substantial. For example, although 17.4% of those taking PEG/ bisacodyl found this preparation difficult or very difficultt to consume, only 1% of patients who used the P/MC regimen rated it as difficult or very difficultt (P<0.001). When questioned about taste, 73.7% of participants found P/MC to be excellent or goodd versus 27.8% of those taking PEG/bisacodyl (P<0.001).

The results of the split-dose trial were similar, although the efficacy of P/MC was consistently higher. In this trial of 603 patients, the second dose of P/MC was taken on the day of the colonoscopy. This regimen was compared with the standard day-before protocol of PEG/bisacodyl. According to Douglas K. Rex, MD, director of endoscopy, Indiana University School of Medicine, in Indianapolis, who presented these results, significantly more patients achieved successful bowel cleansing with P/MC (84.2%) compared with PEG/bisacodyl (74.4%), based on the Aronchick Scale (P<0.05). On the Ottawa Scale, all three measured outcomes favored P/MC. The split-dose P/MC was characterized as “superior” for bowel cleansing compared with the day-before PEG/bisacodyl regimen.

Additionally, more patients in the splitdose trial preferred P/MC compared with PEG/bisacodyl.

According to Dr. Rex, the incidence of adverse events (AEs) was low in both groups. The most common AEs associated with P/MC and PEG/bisacodyl, respectively, were nausea (2.6% vs. 3.7%), vomiting (1% vs. 3.4%), headache (1.6% vs. 1.7%) and chills (0% vs. 1%).

Based on data from both studies, Dr. Katz indicated that P/MC could improve patient satisfaction—an advantage that might have implications for compliance outside of a clinical trial.

Asked to comment on the results, Brintha K. Enestvedt, MD, of the Division of Gastroenterology, Temple University, Philadelphia, said that a split-dose 4-L PEG preparation might have provided a more appropriate comparison, given evidence that this regimen is more effective.

“A recent meta-analysis we did with randomized controlled trials clearly demonstrates that split-dose 4-L PEG is superior in bowel cleansing efficacy versus all its comparators, including some 2-L preparations,” said Dr. Enestvedt, referring to a study that was published last year (Enestvedt et al. Clin Gastroenterol Hepatoll 2012;10:1225-1231).

However, “the meta-analysis did not

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GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2013

show any difference in patient tolerance” between the 4-L preparations relative to lower-volume comparators, according to Dr. Enestvedt.

Bowel preparation regimens remain “a significant deterrent to screening colonoscopy,” Dr. Enestvedt said, and palatability is important, “especially since it influences compliance with and quality of screening exams.

“There is a need for rigorous comparisons in which patient satisfaction is identified as the key end point,” Dr. Enestvedt said. “We need to be

“

committed to continuing to search for solutions that provide equal cleansing efficacy to what is the most effective regimen: 4-L, split-dose PEG, which is the closest thing we have to a current gold standard.”

■ The CLEAR trials were initiated, sponsored and analyzed by Ferring Pharmaceuticals.

Philip O. Katz, MD, has served as an advisor, consultant or a member of the speaker’s bureau for AstraZeneca Pharmaceuticals, Eisai Inc., Intec Pharma, Ironwood Pharmaceuticals, Inc., Novartis Pharmaceuticals

Corporation, Sunovion Pharmaceuticals Inc., and Takeda Pharmaceuticals.

Douglas K. Rex, MD, has served as an advisor, consultant or member of the speaker’s bureau, or has received research grants from American BioOptics LLC, Boston Scientific, Braintree Laboratories, Inc., Check-Cap, Ltd., Epigenomics AG, Exact Sciences Corporation, Given Imaging Ltd. and Olympus Corporation.

Brintha K. Enestvedt, MD, reported no conflicts of interest.

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Quality Benchmarks continued from page 1

At an American College of Gastroenterology (ACG) symposium on quality improvement for CRC screening with colonoscopy, Philip S. Schoenfeld, MD, MSEd, MSc, professor of medicine at the University of Michigan, Ann Arbor, and director of the university’s Gastrointestinal and Epidemiology Training Program, discussed the measures that the Centers for Medicare & Medicaid Services (CMS) might use to gauge the quality of colonoscopy screening for colorectal cancer (CRC).

“CMS will probably require endoscopists to report cecal intubation rate based on photo documentation of the ileocecal valve and appendiceal orifice; adenoma detection rate [ADR]; withdrawal time; per-procedure complication rate; and adherence to recommended guidelines on the frequency of repeat colonoscopy,” Dr. Schoenfeld told attendees of the 2012 ACG Annual Scientific Meeting.

Measuring Quality Achieving a cecal intubation rate greater than 95% is considered a standard measure of quality.

“I think that’s intuitive, but [the rate] is documented in the Baxter et al study [Gastroenterologyy 2011:140:65-72],” Dr. Schoenfeld said. In this study, researchers reviewed a database of the Ontario Cancer Registry to identify people with interval cancers, identified as CRC occurring six to 36 months after a colonoscopy, and then stratified the data based on cecal intubation rates.

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2013

an interval cancer than those patients whose doctors were more likely to fail to reach the cecum.

ADR is also a straightforward measure of quality. In their position statement on quality indicators for colonoscopy, the ACG and the American Society for Gastrointestinal Endoscopy (ASGE) support a colonoscopy screening ADR of 15% and 25% in average-risk women

“At this time, however, a lot of endoscopists don’t even calculate … the ADR,” Dr. Schoenfeld said. “It’s easier to crawl before you walk, and easier to walk before you run, so we’re just trying to encourage gastroenterologists to calculate and report a basic ADR.” Complication rates are another measure of quality. In prospective colonoscopy studies, the pooled rate of colon perfora-

‘Some endoscopists are quite aware of the change and are beginning to develop databases that will allow them to easily transmit data on quality indicators for CMS, and there are others who seem to be really unaware of these potential changes.’

—Philip S. Schoenfeld, MD, MSEd, MSc “Not surprisingly, the doctors who achieved a cecal intubation rate of 95% or higher were significantly less likely to have patients develop interval colon cancer in the proximal colon compared with patients whose physicians achieved cecal intubation rates of 80% or less,” Dr. Schoenfeld said. Patients whose doctors achieved a high cecal intubation rate were 28% less likely to have

and men, respectively. Endoscopists with ADRs greater than 20% are less likely to report interval colon cancer in their patients than their peers with ADRs less than 10% (Kaminski et al. N Engl J Med 2010;362:1795-1803).

More complex formulas to calculate ADR may evolve to take into account factors such as patient age and size and location of the polyp.

tion is much less than one in 1,000. Less clear, however, is how long gastroenterologists should monitor patients after a colonoscopy.

“We usually know if a perforation has occurred at the time of colonoscopy or within 24 hours, but most colonoscopy complications, like post-polypectomy bleeding, may not occur for seven to 14 days after the procedure,” Dr.

Recent Studies Focus on Quality of Bowel Preparation

BY MONICA J. SMITH Critical to the quality of a colonoscopy for colorectal cancer (CRC) screening is effective bowel preparation. Several papers and posters, presented at the 2012 American College of Gastroenterology annual scientific meeting, examined approaches that may enhance this process. Gastroenterology & Endoscopy News invited Lawrence B. Cohen, MD, clinical professor of medicine, Mount Sinai School of Medicine and consultant, New York Gastroenterology Associates, both in New York City, to comment on some of these papers.

Bowel Prep Palatability The regimens recommended for ensuring a quality bowel preparation require patients to ingest large volumes of an isosmotic polyethylene glycol electrolyte solution (PEG-ES), a task that many patients find distasteful. Mustapha M. El-Halabi, MD, of the American University of Beirut Medical Center in Lebanon, and colleagues randomized patients scheduled for colonoscopy to receive 4-L split-dose PEG-ES, with or without the addition of sugar-free mentho-lyptus drops, to assess the effect of the drops on tolerability and palatability of the preparation, which was assessed on a fivepoint scale (1 = disgusting; 5 = tasty). y Of the 99 patients who completed the study, the 49 patients in the mentho-lyptus group registered

significantly higher palatability scores than those who did not receive the drops; they also were more likely to have good or excellent bowel preparations than the control group (92% vs. 82%, respectively). Researchers concluded that the addition of sugar-free mentho-lyptus to PEG-ES is safe and effective, and improves tolerability and bowel cleansing.

‘The authors demonstrated that a simple and inexpensive flavor additive—sugar-free mentho-lyptus—combined with 4-L PEG-ES, improves both bowel preparation quality and patient tolerability.’

—Lawrence B. Cohen, MD

Dr. Cohen: The authors demonstrated that a simple and inexpensive flavor additive—sugar-free mentholyptus—combined with 4-L PEG-ES, improves both bowel preparation quality and patient tolerability. Similar studies in other cultures and geographic regions are necessary to determine whether these findings are generalizable. Evaluation also is required to establish that the additive

is safe and produces no clinically important changes in fluid and electrolyte balance.

Combining PEG With Sports Drinks Gastroenterologists worry about the risks for hyponatremia associated with the combination of PEG and non–FDA-approved purgative–sports drinks (SD), popular among some patients.

Rebecca Matro, MD, and her colleagues at the Thomas Jefferson University Hospital in Philadelphia, conducted a randomized prospective trial to compare serum electrolytes in 180 patients taking PEG-ES and 184 patients taking PEG with an SD before undergoing a colonoscopy.

Seven patients in the PEG-SD group and four in the PEG-ES group developed hyponatremia, with changes in electrolyte baseline being small but slightly significant in the PEG-SD group. The researchers concluded that PEG-SD did not significantly increase the risk for hyponatremia, which was rare in any case, and that preparation completion, quality and side effects were similar in both groups (paper 21; financial support provided by Salix Pharmaceuticals).

Dr. Cohen: Dr. Matro and her colleagues designed this study to answer the clinical question: “Does the absence of electrolytes in a PEG-based bowel preparation increase the risk for hyponatremia compared with a conventional PEG-ES preparation?” Although the study failed to show meaningful differences in serum electrolytes among

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2013

Schoenfeld said. “Proper tracking of the colonoscopy complication rates may ultimately require that we follow-up with patients seven to 14 days after the procedure.”

Indications for colonoscopy and adherence to guidelines for screening and surveillance also will factor into whether an endoscopist meets quality standards.

NATIONAL COLORECTAL CANCER AWARENESS MONTH

guidelines, especially if they suspect they have missed a polyp.

“Gastroenterologists know that polyps are missed during colonoscopy, even among excellent endoscopists,” Dr. Schoenfeld said. “Also, in the current fee-for-service health care system, insurers will usually pay for a colonoscopy even when the procedure is performed more frequently than recommended, so endoscopists hope that they

“When we do colonoscopy more often, we’re exposing patients to the risks of colonoscopy, which are not zero, as well as [a patient] having to go through the preparation, miss a day of work and have someone drive them home. Those are not minor inconveniences. Those are a pretty big deal.”

Notably, the level of awareness that exists among endoscopists varies with

‘Quality indicators continue to evolve and will be instrumental in defining not only physician quality, but physician payment.’

—David A. Johnson, MD

“There are good data to support that colonoscopy should be repeated at 10-year intervals in patients with normal colonoscopy results, and repeated after five years for patients who have one to two small adenomas,” said Dr. Schoenfeld. “And yet there is a lot of data [to indicate] that colonoscopy is overused in that population.”

At present, there is no incentive for gastroenterologists to follow colonoscopy

will find a ‘missed’ polyp from a previous exam if they repeat the colonoscopy sooner.

Gastroenterologists know that the most common reason they get sued is for interval cancers, so that is another factor that may drive recommendations to overuse colonoscopy,” Dr. Schoenfeld said.

But the cost-effectiveness of colonoscopy screening vanishes when the exam is overused.

patients using PEG-SD compared with those taking an FDA-approved preparation of PEG-ES plus ascorbic acid (MoviPrep, Salix Pharmaceuticals), the study population (N=364) was insufficient in size to exclude a small but important risk for hyponatremia.

Video Education of Patients Ideally, all endoscopists would have the time to thoroughly explain to their patients how to take their bowel preparation and why it’s important, but in a time-crushed office, other educational tools may be useful to ensure that patients have the information they need. To investigate the effect of an instructional video on the quality of bowel preparation for colonoscopy, Sateesh R. Prakash, MD, of Southern Gastroenterology Specialists Research and Educational Institute, LLC, Locust Grove, Ga., and his colleagues randomized 127 patients undergoing colonoscopy to watch a video about bowel preparation, or to undergo the procedure without the video.

The researchers found a significant difference in bowel preparation quality between the patients who watched the video and those who received only written instructions. The video group had superior bowel preparation scores in the right, left and transverse colon; in fluid content; and in their aggregate score. There was no difference, however, in patient satisfaction. The researchers concluded that the addition of the instructional video significantly improved the quality of bowel preparation.

regard to the potential requirements for measuring and documenting quality standards.

“Some endoscopists are quite aware of the change and are beginning to develop databases that will allow them to easily transmit data on quality indicators for CMS, and there are others who seem to be really unaware of these potential changes,” Dr. Schoenfeld said.

15

Economic Effects Disregarding these potential changes could have economic consequences down the road, according to David A. Johnson, MD, professor of medicine and chief of gastroenterology, Eastern Virginia Medical School, Norfolk.

“Quality indicators continue to evolve and will be instrumental in defining not only physician quality, but physician payment,” he said. “The emphasis on valuebased purchasing as we move forward in a new health care reform era will demand that [physicians] show that their performance is not only adequate, but of quality.”

Currently, endoscopists receive a 2% bonus for reporting quality indicators, but by 2014 those who do not report quality indicators will be penalized 1.5% of the reimbursement fee from insurers, and it is likely that a quality index will be established by 2015.

“The impact is that in 2014, as long as I report quality indicators, I avoid the penalty, even if I do a bad job at colonoscopy,” Dr. Schoenfeld explained. “But by 2015, a formula is supposed to be implemented that will measure how well you do on quality indicators, and that will see Quality Benchmarks, page 16

Dr. Cohen: Fairfax, Va., and his colleagues trained endosUp to 25% of colonoscopies in the United copists in water immersion and water exchange States are reported to have an inadequate bowel in two coaching sessions, six months apart, preparation. Methand evaluated 348 ods for improving consecutive patients the quality of bowel ‘The study by Dr. Prakash and his colleagues receiving a stanpreparation include dard split-dose and patient prescreen- confirms previous work that video patient undergoing the water ing designed to education improves the outcome of exchange method of identify individuals colonoscopy. bowel preparation in ambulatory patients with an increased They found that risk for poor-quality undergoing colonoscopy.’ structured coaching preparation, with a —Lawrence B. Cohen, MD helped endoscopists split-dose bowel acquire satisfactory regimen. The study salvage cleansing

by Dr. Prakash and his colleagues confirms maneuvers with a high final cecal intubation previous work that video patient education rate and little prolongation of insertion times. improves the outcome of bowel preparation in ambulatory patients undergoing colonoscopy. Dr. Cohen: Similar findings have been observed using a Poor bowel preparation results in an high-quality patient brochure (Spiegel B et al. increased risk for missed lesions in colonosAm J Gastroenterol 2011;106:875-883). It seems copy. Consequently, updated guidelines on that a little effort up front pays big dividends on CRC screening recommend that colonoscopy the back end when it comes to the quality of be repeated within one year when the bowel bowel preparation for colonoscopy. preparation is rated poor (Lieberman DA et al. Gastroenterologyy 2012;143:844-857). Dr. Water Exchange Colonoscopy Fischer and his colleagues report that water Split-dose bowel preparations may be more exchange may be useful for salvaging an inadtolerable for patients and result in a more thor- equate bowel preparation. It remains unproven, ough bowel preparation, but they are not fool- however, whether aggressive water lavage and proof. To evaluate the role of the water exchange exchange improves the quality of preparation method of colonoscopy in salvage cleansing and enough to eliminate the need for repeat examiimproving bowel preparation, Leonard Fischer, nation within a short interval. More data on this MD, of Gastrointestinal Medicine Associates, important topic are awaited.

16

NATIONAL COLORECTAL CANCER AWARENESS MONTH

Quality Benchmarks continued from page 15

affect how much you get reimbursed per colonoscopy,” he said.

Some reporting demands already have been established by the CMS. As of Oct. 1, 2012, physicians are required to report on the presence or absence of events occurring in ambulatory surgery centers such as burns or falls, transfer to a hospital and whether or not the patient received prophylactic antibiotics.

“This has nothing to do with assuring

quality, but you’re required to report these measures to CMS,” Dr. Johnson said. As of 2013, physicians will be subject to a 3% reduction in Medicare reimbursements if they don’t report such incidents.

At present, the most well-validated quality measures pertaining to the areas of gastroenterology and endoscopy are cecal intubation, ADR and adherence to guidelines for post-polypectomy surveillance—the last of which is likely to receive a lot of attention.

“Payers are all over this,” Dr. Johnson

said. “There will be much scrutiny of adherence to national guidelines.”

He predicted a number of quality benchmarks that may arise in the future such as serrated polyp detection rate, presence of interval cancers, early surgical referral for polyps, incomplete polypectomy, and poor bowel preparation. He predicted that insurance companies also will examine the routine use of monitored anesthesia care and the overutilization of in-house pathology.

“So, it’s important to measure these things, but to react is critical,” Dr.

Save when you register by April 10

PHOTO © VISIT ORLANDO

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2013

‘Payers are all over this.

There will be much scrutiny of adherence to national guidelines. …

It’s important to measure these things, but to react is critical. Quality measurement is nothing in the absence of responding to deficiencies in a way that is nonconfrontational and collaborative.’

—David A. Johnson, MD

Johnson said. “Quality measurement is nothing in the absence of responding to deficiencies in a way that is nonconfrontational and collaborative.”

Addressing Deficiencies ORANGE COUNTY CONVENTION CENTER ORLANDO, FLORIDA

2 0 1 3 A S G E A N N U A L P O S T G R A D U AT E C O U R S E

May 20, 2013 Orange County Convention Center Orlando, Florida Held in conjunction with DDW®

Back to the popular one-day format!

Course Directors

Todd H. Baron, MD, FASGE Mayo Clinic Rochester, MN

An International and Multidisciplinary Approach to Gastrointestinal Diseases: Patient Care at its Best In today’s healthcare environment, understanding the role endoscopy plays in the multidisciplinary, team-based setting is essential. This course will demonstrate how gastrointestinal endoscopy integrates with specialists in various fields to provide excellent, state-of-the-art care for gastrointestinal diseases.

The 2013 ASGE Annual Postgraduate course will feature: lectures and expert * Evidence-based opinion about common issues in daily practice from internationally renowned endoscopic experts and leaders in surgery, oncology and radiology. fic panel discussions and * Topic-specifi breakout sessions for individualized, practice-specifi fic learning.

Vanessa M. Shami, MD, FASGE University of Virginia Health System Charlottesville, VA

If endoscopy is your practice, this is your course!

symposia on a variety of * Thematic gastrointestinal problems, including Barrett’s esophagus, treatment of gastrointestinal bleeding, endoscopic screening, surveillance and treatment of upper and lower luminal neoplasia as well as pancreaticobiliary diseases.

Course Objectives

*

Identify current and emerging technologies in gastrointestinal endoscopy and their applicability to practice.

how respected experts integrate * Describe scientific fi evidence with experience to diagnose and treat gastrointestinal disorders most effectively. the state-of the-art management * Discuss of important gastrointestinal issues in a multidisciplinary manner. current trends in quality assurance * Integrate with effective and costeffective endoscopic interventions. current controversies in the * Characterize utilization of novel endoscopic techniques to screen, detect and treat gastrointestinal luminal and pancreaticobiliary neoplasia.

* Plus much more!

For additional information, visit www.ddw.org

In February 2012, results of the longterm National Polyp Study (O’Brien MJ et al. Gastroenterology 1990;98:371-379) confirmed that having a colonoscopy not only protects against CRC, but also reduces CRC-related mortality. In recent years, however, it has become increasingly clear that this protective effect is highly operator-dependent.

For a practice leader or endoscopy director, dealing with endoscopists who underperform can be a sensitive situation.

“I think one has to approach it from the perspective that our primary responsibility is to our patients,” said Douglas K. Rex, MD, Chancellor’s Professor and distinguished professor of medicine at Indiana University School of Medicine and director of endoscopy at Indiana University Hospital, both in Indianapolis. “If you keep that in mind, you generally can find a way to approach it in a fashion that is constructive and can lead to improvements and uses some sort of penalty only as a last resort.”

Studies that examine the retraining of underperformers have been conducted, but their conclusions do not point to a standard approach for addressing this issue.

One such study examined the effect of supervising the work of endoscopists who had a record of low polyp detection rates (PDRs) and interviewing those whose PDRs did not improve as a result (Imperiali G et al. Endoscopyy 2007;39:314-318).

In this study, the approach did not increase the average PDR of the group; however, a different study showed that endoscopists appear to conduct a better quality colonoscopy when they know they are being recorded on video compared with when

NATIONAL COLORECTAL CANCER AWARENESS MONTH

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2013

they are unaware of it (Rex DK et al. Am J Gastroenteroll 2010;105:2312-2317).

The Endoscopic Quality Improvement Program, a study conducted by Mayo Clinic, combines education and training in optimal techniques to help improve performance. Endoscopists who underwent the study’s intensive training session on the spectrum of disease and optimal detection techniques experienced an increase in ADRs from 36% to 47%; those who did not receive training saw no improvement.

“This needs to be studied further, but it’s just a couple of hours of training and looks like a really practical and useful way that [physicians with low PDRs] could improve,” Dr. Rex said.

Another study, presented at last year’s ACG annual meeting, examined the effect of a software system that provides real-time feedback during a colonoscopy procedure. Study participants were third-year fellows who could see a mark on a monitor every time they completed a rotary movement. A blinded review of the videos of 194 endoscopists who received real-time feedback and 289 who did not showed that the feedback group improved in the percentage of mucosa viewed, degree of removal score, distension score and withdrawal time.

‘If [an endoscopist], after multiple measures is not able to improve, then you have to consider taking serious steps. But the key to keep in mind is that your first obligation is to provide effective care for patients, and you have to be able to take that as far as it needs to go. That’s the constant, No. 1, overriding issue.’

—Douglas K. Rex, MD “Real-time feedback is very attractive as a concept, and this is a promising story that we’ll need to watch,” Dr. Rex said.

The ability to recognize serrated lesions as well as conventional ones is critical to improving performance and reducing the risk for interval cancers.

There are a number of websites on which

an endoscopist can view images of serrated lesions to better identify them. But serrated lesions are not only harder to see, they are about five times more likely than conventional lesions of equal size to be incompletely resected.

“My own recommendation is that we use cold techniques for many diminutive and small lesions,” Dr. Rex said. “I believe this is the single most powerful thing for reducing your complication rate and your delayed post-polypectomy bleed rate, because all of those bleeds are related to the use of electrocautery.”

Dr. Rex offered a few tips for the resection of larger serrated lesions. First, he said, leave the mucus cap on all the way through the resection.

“If you wash it off, it’s very hard to see the edges, and that’s most often where we’re unsuccessful,” he said. Use a highdefinition scope, inject a contrast agent beneath the lesion and consistently resect a margin of normal tissue.

“The problem is, when serrated lesions are big and you resect them piecemeal, edema develops during the resection and you lose track of the edges. An injection

of a color contrast agent—indigo carmine or methylene blue—defines the border and you can more clearly resect a normal margin,” Dr. Rex said.

“If somebody, after multiple [intervention] measures is not able to improve [the level of performance], then you have to consider taking serious steps,” he said. “But the key to keep in mind is that your first obligation is to provide effective care for patients, and you have to be able to take that as far as it needs to go. That’s the constant, No. 1, overriding issue.”

■

MoviPrep®

USE IN SPECIFIC POPULATIONS

(PEG-3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate, and ascorbic acid for oral solution) The following is a brief summary only; see full Prescribing Information for complete product information.

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.

INDICATIONS 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 patients with the following conditions: gastrointestinal (GI) obstruction, bowel perforation, gastric retention, ileus, toxic colitis or toxic megacolon, or hypersensitivity to any components of MoviPrep.

WARNINGS AND PRECAUTIONS Use 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), patients with known or suspected hyponatremia), patients at increased risk of cardiac arrhythmias, patients with a history of seizures or at increased risk of seizures such as patients taking medications that lower the seizure threshold (e.g., tricyclic antidepressants), patients withdrawing from alcohol or benzodiazepines, patients with impaired renal function or patients taking concomitant medications that affect renal function (such as diuretics, ACE inhibitors, ARBs, or non-steroidal anti-inflammatory drugs), patients with severe ulcerative colitis or inflammatory bowel disease, patients with impaired gag reflex or patients prone to regurgitation or aspiration, patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.

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.

If gastrointestinal obstruction or perforation is suspected, appropriate diagnostic studies should be performed 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.

Patients with electrolyte abnormalities should have them corrected before treatment with MoviPrep. Patients should be advised to hydrate adequately before, during, and after the use of MoviPrep. If a patient develops significant vomiting or signs of dehydration after taking MoviPrep post-colonoscopy lab tests (electrolytes, creatinine, and BUN) should be considered. Fluid and electrolyte disturbances can lead to serious adverse events including cardiac arrhythmias, seizures and renal impairment.

MoviPrep contains phenylalanine (233 mg per treatment).

ADVERSE REACTIONS

In clinical trials, the most common adverse reactions for split dosing regimen (incidence 5%) were malaise, nausea, abdominal pain, vomiting, and upper abdominal pain. The most common adverse reactions for evening only dosing regimen (incidence 5%) were abdominal distension, anal discomfort, thirst, nausea, abdominal pain, sleep disorder, rigors, hunger, malaise, vomiting, and dizziness.

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 MalloryWeis tear, esophageal perforation, asystole, and acute pulmonary edema after aspirating PEG-based preparation.

In addition to adverse reactions reported from clinical trials, the following adverse events have been identified during post-approval use of MoviPrep: hypersensitivity reactions including anaphylaxis (some of which were severe, including shock), rash, urticaria, pruritis, lip, tongue and facial swelling, dyspnea, chest tightness and throat tightness. Fever, chills and dehydration.

DRUG INTERACTIONS 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.

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.

17

Nursing Mothers: Because many drugs are excreted in human milk, caution should be exercised when MoviPrep is administered to a nursing woman.

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

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.

OVERDOSAGE There have been no reported cases of overdose with MoviPrep. Purposeful or gross accidental ingestion of more than the recommended dose of MoviPrep might be expected to lead to severe electrolyte disturbances, including hyponatremia and/or hypokalemia, as well as dehydration and hypovolemia, with signs and symptoms of these disturbances. The patient who has taken an overdose should be monitored carefully, and treated symptomatically for complications.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY Long-term studies in animals to evaluate the carcinogenic potential have not been performed with MoviPrep. Studies to evaluate potential for impairment of fertility or mutagenic potential have not been performed with MoviPrep.

STORAGE Store carton/container at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).

When reconstituted, store upright and keep solution refrigerated. Use within 24 hours.

PATIENT COUNSELING INFORMATION s Advise patients to read the Medication Guide included in the full prescribing information. s Advise patients who require a diet low in phenylalanine that MoviPrep contains phenylalanine. s Ask patients to inform you if they have trouble swallowing or are prone to regurgitation or aspiration. s Instruct patients that each pouch needs to be diluted in water before ingestion and that they need to drink additional clear liquid (e.g., water, clear soup, fruit juice without pulp, soft drinks, tea and/or coffee without milk) according to instructions. s Inform patients that oral medications may not be absorbed properly if they are taken within one hour of starting each dose of MoviPrep. s Tell patients not to take other laxatives while they are taking MoviPrep. s 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. s 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.

Rx only

Manufactured by: Norgine B.V. Hogehilweg 7 1101 CA Amsterdam Zuidoost Netherlands For: Salix Pharmaceuticals, Inc. Raleigh, NC 27615 © 2012 Salix Pharmaceuticals Inc. Feb 12

Web site: www.salix.com E-mail: customer.service@salix.com 8510 Colonnade Center Drive Raleigh, NC 27615 Tel. 866-669-SLXP (7597) All rights reserved.

18

NATIONAL COLORECTAL CANCER AWARENESS MONTH

CRC Screening continued from page 11

patients undergoing surveillance and diagnostic colonoscopy, respectively (Siersema PD et al. World J Gastroenterol 2012;18:3400-3408).

Another new colonoscope, the Invendoscope (Invendo Medical), is a robotic colonoscope that recently was approved by the FDA. There is not yet much data on the Invendoscope, but it may reduce patient discomfort.

“The scope elongates from the tip

instead of being pushed from the rectum up, so there’s no pressure on the colonic wall by the scope,” Dr. Pochapin explained. “I’ve used this scope, and patients do seem comfortable.”

The NaviAid G-EYE (Smart Medical Systems Ltd.), which is just being developed, is a standard colonoscope with a balloon on the tip that can be inflated to distend and elongate colonic folds. Theoretically, upon withdrawal of the colonoscope, the endoscopist will be able to detect polyps previously hidden behind the folds.

‘Years ago, when endoscopy was first coming out, it was really difficult not to be excited about new technologies, the latest “I think this is a wonderful idea and a way of making regular colonoscopy a little bit better,” Dr. Pochapin said.

“Something again to look forward to study.”

Another new colonoscope, the Full Spectrum Endoscope (EndoChoice),

MoviPrep®

#1 prescribed

branded purgative in the United States1

Seeing is believing MoviPrep has proven 89% excellent or good cleansing when used as a split dose2 ° Low-volume PEG-3350 provides consistent, clear visibility of the entire colon ° FDA approved for PM| AM Split Dosing™ ° Osmotic laxative with electrolytes ° Most common adverse reactions for split dosing (incidence ⱖ5%) are malaise, nausea, abdominal pain, vomiting, and upper abdominal pain. The most common adverse reactions for evening only dosing (incidence ⱖ5%) are abdominal distension, anal discomfort, thirst, nausea, abdominal pain, sleep disorder, rigors, hunger, malaise, vomiting, and dizziness.

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

References: 1. Medi-Span® Price Rx® [database online]. Indianapolis, IN: Wolters Kluwer Health. http://www.medispan.com/drug-pricing-analysis-pricerx.aspx. Accessed July 13, 2012.

2. MoviPrep [prescribing information]. Raleigh, NC: Salix Pharmaceuticals, Inc.; 2012.

Web site: www.salix.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. MOV11/41-4

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2013

endoscopes. But with all these new things we see, we’re always doing reality checks.’

—Anthony Starpoli, MD

holds promise for improving ADRs by giving endoscopists a 330-degree view of the colon (see sidebar, “Full Spectrum Endoscope Shows More of the Colon Than Seen Before,” page 10).

Reality Check As enticing as this new technology may be, however, enthusiasm is tempered by the economic reality. With reimbursements for CRC screening continuing to decline, any new technology that adds cost—or time—to the procedure will need to prove its value by significantly improving ADRs and making screening examinations more enticing to patients.

“It’s one thing to make the clinically correct decision, and then there’s the one that’s financially sensible,” said Anthony Starpoli, MD, clinical assistant professor of medicine at New York University School of Medicine, New York City, and president of the NYSGE. “I think we’re really in a conundrum, and that hasn’t always been the case.

Years ago, when endoscopy was first coming out, it was really difficult not to be excited about new technologies, the latest endoscopes. But with all these new things we see, we’re always doing reality checks,” Dr. Starpoli said.

In the bigger picture, today’s modifications and improvements may predicate a changing role for gastroenterologists and for colonoscopy.

“If you look at MRI [magnetic resonance imaging] colonography, there’s talk that eventually patients won’t even need preparation—it will just be a scan,” Dr. Starpoli said.

“It’s not there yet, and colonoscopy remains the gold standard, but you could envision a paradigm shift in not too many years where its utility will be reshaped for sure. It may turn into more of a therapeutic tool than a diagnostic tool—not completely, and not tomorrow, but I think current generations of people in training need to put their thinking caps on.”

■ Drs. Pochapin and Starpoli reported no conflicts of interest.

www.MoviPrep.com

NATIONAL COLORECTAL CANCER AWARENESS MONTH

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2013

19

ACS Tracking System Improves Care for Cancer Patients

BY CHRISTINA FRANGOU Cancer centers that participated in a performance tracking system significantly improved their adherence to key quality measures in oncologic care, according to a new study. Developed by the Commission on Cancer of the American College of Surgeons (ACS), the system also helps hospitals to track their patients’ information, which prevents medical records from getting lost, the researchers said.

“Cancer care is unique in that it requires extensive coordination with providers across disciplines to ensure patients receive all of their treatments. Patients are not only getting surgical treatment but also chemotherapy, radiation and possibly hormone therapy,” said Erica McNamara, MPH, lead study author and quality improvement analyst at the ACS. “Our system is built to provide an extra layer of support in the coordination of that care.”

Ms. McNamara presented the findings at the American Society of Clinical

Oncology’s inaugural Quality Care Symposium, held in December (abstract 286).

Participants in the program said The ACS’ Rapid Quality that they regularly ‘catch’ Reporting System (RQRS) provides feedback to cancer patients who otherwise centers on individual patient would have been missed, care while the patient is still when the system issues undergoing oncologic treatment. Accredited cancer cenan alert that the patient ters submit data about their should have received current breast or colorectal cancer cases on a monthly or adjuvant therapy. quarterly basis. The RQRS system tracks the data for adherence to five quality measures for colon and breast cancer that are endorsed by the National Quality Forum, a not-for-profit organization whose mission is to “improve the quality of American health care.”

These measures, which are considered the standard of care, include 12 regional lymph nodes for resected adjuvant therapy for lymph node–posi- cancer, as well as radiation therapy foltive colon cancer patients, the removal lowing breast-conserving surgery, muland pathologic examination of at least tiadjuvant chemotherapy for hormone

by the

receptor–negative breast cancer patients, and hormone therapy for hormone receptor–positive breast cancer patients. see Tracking System, page 22

According to a 2012 study by Pharmaceutical Research and Manufacturers of America (PhRMA), 981 medicines and vaccines to fight cancer were in testing by U.S. companies.

Drugs designed to target colorectal cancer ranked among the top ten.

numbers

Number of Drugs in Clinical Development for Different Tumor Types Lung cancer

Drug Development

121

Leukemia

120

Lymphoma

The U.S. has perhaps the most rigorous and expensive drug development process in the world.

117

Breast

111

Other cancers

102

Prostate

94

Unspecified cancer

It takes 10 to 15 years, on average, for an experimental drug to travel from the lab to patients

72

Skin cancer

67

Colorectal cancer

66

Ovarian cancer

63

Brain cancer

It costs a company $1.2 billion, including the cost of failures, to get one new medicine from the laboratory to patients

62

Pancreatic cancer

58

Multiple myeloma

57

Liver cancer

Only five in 5,000 compounds that enter preclinical testing make it to human testing

36

Kidney cancer

35

Head/Neck cancer

25

Stomach cancer

Only one of those five is approved for use

23

Sarcoma

21

Bladder cancer

9

Cervical cancer

Applications for FDA approval typically run 100,000 pages or more

8

0

30

60

90

120

150 Sources: Pharmaceutical Research and Manufacturers of America, 2012, Medicine in Development for Cancer; Tufts Center for the Study of Drug Development

BE PREPARED FOR CRC AWARENESS MONTH

Indication and Important Safety Information Prepopikâ&#x201E;¢ for oral solution is indicated for cleansing of the colon as a preparation for colonoscopy in adults. r 1SFQPQJL JT DPOUSBJOEJDBUFE JO UIF GPMMPXJOH DPOEJUJPOT QBUJFOUT XJUI TFWFSFMZ SFEVDFE SFOBM GVODUJPO HBTUSPJOUFTUJOBM PCTUSVDUJPO PS JMFVT CPXFM perforation, toxic colitis or toxic megacolon, gastric retention, or in patients with a known allergy to any of the ingredients in Prepopik. Patients should CF BEWJTFE PO UIF JNQPSUBODF PG BEFRVBUF IZESBUJPO BOE QPTU DPMPOPTDPQZ MBC UFTUT TIPVME CF DPOTJEFSFE JG B QBUJFOU EFWFMPQT TJHOJGJDBOU WPNJUJOH or signs of dehydration after taking Prepopik r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r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r 1SFQPQJL TIPVME OPU CF VTFE JG HBTUSPJOUFTUJOBM PCTUSVDUJPO PS QFSGPSBUJPO JT TVTQFDUFE 1SFQPQJL JT OPU GPS EJSFDU JOHFTUJPO &BDI QBDLFU NVTU CF EJTTPMWFE JO PVODFT PG DPME XBUFS BOE BENJOJTUFSFE BU TFQBSBUF UJNFT JO BEEJUJPO UP BEEJUJPOBM DMFBS GMVJET BDDPSEJOH UP UIF EPTJOH SFHJNFO *O SBOEPNJ[FE NVMUJDFOUFS DPOUSPMMFE DMJOJDBM USJBMT OBVTFB IFBEBDIF BOE WPNJUJOH XFSF UIF NPTU DPNNPO USFBUNFOU FNFSHFOU BEWFSTF SFBDUJPOT (>1%) following Prepopik administration 1MFBTF TFF CSJFG TVNNBSZ PG 1SFTDSJCJOH *OGPSNBUJPO GPMMPXJOH UIJT BEWFSUJTFNFOU

Prepopik helps patients arrive ready with: t Lowest volume of active prep solution and a flexible hydration schedule1 t Demonstrated non-inferiority, with both split-dose and day-before regimen1 t Superior cleansing efficacy with ACG-recommended split-dose vs day-before regimen comparator*1 – 84% vs 74%, respectively, achieving “excellent or good” visualization, validated per the Aronchick scale* t A dual mechanism that stimulates peristalsis and produces osmotic water retention1 *Evaluated in a randomized trial. 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.1

To learn more, scan this code with your smartphone, or go to www.prepopik.com.

Reference: 1. Prepopik™ Prescribing Information, July 2012.

Ferring Pharmaceuticals Inc. Parsippany, NJ 07054, USA.

© 2013 Ferring B.V. PREPOPIKTM is a trademark of Ferring B.V. PK/047/2013/US

22

NATIONAL COLORECTAL CANCER AWARENESS MONTH

Tracking System continued from page 19

The RQRS system will send an alert to the cancer center when patients are scheduled to enter the next stage of treatment. Physicians, cancer registrars and cancer program administrators have access to the feedback. For example, a hospital will receive a color-coded alert to indicate that staff should check on a patientâ&#x20AC;&#x2122;s treatment status when the RQRS does not receive a timely report confirming that a treatment decision or

adjuvant therapy has been completed.

Furthermore, the RQRS system provides performance rates and comparisons with other centers, based on current patients and clinical practice.

Study researchers examined data from 64,129 colorectal and breast cancer patients treated between 2006 and 2010 at 64 RQRS-participating cancer programs nationally. The investigators assessed how well the cancer programs adhered to the five quality measures before and after participation in the program.

Aspiration 3DWLHQWV ZLWK LPSDLUHG JDJ UHĂ&#x20AC;H[ DQG SDWLHQWV SURQH WR UHJXUJLWDWLRQ RU DVSLUDWLRQ VKRXOG EH REVHUYHG GXULQJ WKH DGPLQLVWUDWLRQ RI PREPOPIK. Use with caution in these patients.

Not for Direct Ingestion (DFK SDFNHW PXVW EH GLVVROYHG LQ RXQFHV RI FROG ZDWHU DQG 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.

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Analysis of the data showed that all five compliance rates rose considerably after hospitals joined RQRS. The greatest increase was in the number of patients who received hormone therapy for breast cancer, which grew from 47% in 2006 to 85% to 2010. Delivery of adjuvant chemotherapy for colon cancer increased 18%, from 68% to 86%, and the percentage of patients from whom 12 or more lymph nodes were retrieved rose from 70% to 90%. â&#x20AC;&#x153;This study is really noteworthy in that the development of this database

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significantly improved cancer care within a very short period of time,â&#x20AC;? said Jyoti Patel, MD, an oncologist and associate professor of medicine at Feinberg School of Medicine of Northwestern University, Chicago. â&#x20AC;&#x153;This sort of innovative feedback can provide realtime improvement in care, so itâ&#x20AC;&#x2122;s very exciting.â&#x20AC;?

Investigators also reported that performance rates differed by patient age, race and payer status (private insurance versus Medicare), but the relative number and size of the disparities were reduced in participating programs two years after implementing the RQRS system. â&#x20AC;&#x153;The results from this analysis suggest that those differences may actually have been more of a reflection of incomplete data and information in the registries than a reflection of differences in care delivery to subpopulations of patients,â&#x20AC;? said Andrew Stewart, MA, study coauthor and National Cancer Database senior manager at the ACS. These measures have been the focus of significant public awareness campaigns, led by professional organizations and the National Quality Forum, and they frequently are discussed at surgical and oncologic meetings.

Officials familiar with RQRS said that the system boosts compliance with quality measures because it improves the coordination of evidence-based care among different disciplines, and it requires more complete reporting of adjuvant therapy data.

Participants in the program said that they regularly â&#x20AC;&#x153;catchâ&#x20AC;? patients who otherwise would have been missed, when the system issues an alert that the patient should have received adjuvant therapy. â&#x20AC;&#x153;We find that after about six to nine months of using RQRS, one-third of program participants report that they have prevented RQRS patients from slipping through the cracks or not receiving timely adjuvant care,â&#x20AC;? Ms. McNamara said.

An anonymous RQRS participant said, â&#x20AC;&#x153;We have prevented at least two patients from slipping through the cracks. The oncology providers now ask for the reports to be given to them monthly so that they can review the yellow and orange alert cases and prevent any red alerts.â&#x20AC;?

The RQRS system is the only known disease-specific treatment monitoring system in the country. The program was launched nationally in September 2011, in 66 test sites that are accredited by the Commission on Cancer. Currently, there are about 400 centers using the system.

The researchers are developing additional clinical measures to expand the use of RQRS to encompass adherence to quality measures for lung, stomach and esophageal cancers. â&#x2013;

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2013

NATIONAL COLORECTAL CANCER AWARENESS MONTH

23

Of Those Diagnosed With CRC Even After Age 60 Years But Experts Disagree on Implications for Screening Guidelines Researchers also looked at the relative risk for adenomas in the relatives of patients with CRC. “Very similar to our CRC data, FDRs, SDRs and LAS VEGAS—The American College of GastroenterTDRs are at an elevated risk for having adenomatous ology (ACG) recommends screening colonoscopy for polyps,” Dr. Samadder said. FDRs, SDRs and TDRs people aged 50 years or younger, if they have a firsthad elevated risks of 1.82-fold, 1.2-fold and 1.1-fold, degree relative (FDR) who was diagnosed with colorecrespectively, “all of which were statistically significant,” tal cancer (CRC) before the age of 60 years. New Dr. Samadder said.

‘Importantly, however, we showed that research now suggests extending this recommendation In summary, relatives of patients with CRC had an even in CRC cases diagnosed over the to include people whose FDR was diagnosed after the elevated risk for CRC—up to 80% more than in the age of 60 years. control group, and the all-time elevated risk for adenoage of 60, FDRs have a more than The ACG guidelines are based on studies that show matous polyps was up to 82% higher than in the control 1.5-fold elevated risk.’ an increased risk for CRC in people with FDRs who group. Risk was highest in patients whose relatives were were diagnosed with CRC—but those studies have limidiagnosed with CRC before the age of 60 years, and in —N. Jewel Samadder, MD, MSc tations, such as patient recall bias and self-reporting of those with the closest degree of kinship (i.e., FDRs). family history that may not be accurate. To quantify the “Our data support current CRC screening guidelines, risk for CRC or adenomas in FDRs, second-degree and also a consideration to expanding [screening at age relatives (SDR) and third-degree relatives (TDR), 40 and every five years] to FDRs of those diagnosed N. Jewel Samadder, MD, MSc, assistant professor over the age of 60,” Dr. Samadder said. in the Department of Medicine and an investigaCarol A. Burke, MD, director of the Center for tor at the Huntsman Cancer Colon Polyp and Cancer PreInstitute, both at the Univention, Cleveland Clinic versity of Utah School Foundation, Ohio, said of Medicine in Salt the research supports Lake City, and his other studies that concolleagues conducted firm the familial tena retrospective, popudency for the development lation-based study of of adenomas and CRC Utah residents aged in patients with a fambetween 50 and 80 ily history of CRC, but years, who underwent questions whether it cara colonoscopy between ries enough weight to 1995 and 2009. merit revisiting current screening The researchers merged the recommendation guidelines. group’s de-identified medical “The data do not support earinformation with family history lier or more frequent screendata and cancer diagnoses, coning in relatives,” Dr. Burke said. firmed through the Utah Popula“Although the study shows an tion Database and Utah Cancer increased risk for adenomas and Registry. They also performed a cancer out to third-degree relaCox regression analysis to calcutives, it does not provide any late the relative risk for CRC or data on the age of onset of those adenomas in relatives of CRC lesions. Data from previous studpatients, and randomly selected ‘Our data ies found that the colorectal canage- and gender-matched con- support current cer “risk advancement periods” for trols in a 5:1 ratio. tthose with a family history were ‘The data do not support earlier consistently found to be between They identified 126,936 CRC screening patients who underwent colo- guidelines, and or more frequent screening in nine and 11 years for both sexes noscopy, of whom 3,804 had [Brenner H et al. Am J Gastroenrelatives. Although also a consideration confirmed CRC. teroll 2008;103:2326-2331].” the study shows “We were able to show thatt to expanding “Additionally, a major limitarelatives of CRC cases and [screening at age 40 tion t is that the investigators were an increased risk controls have similar numbers not able to discern whether there for adenomas and w of colonoscopies performed,”” and every five years] was a genetic syndrome leading to Dr. Samadder noted. cancer out to third-degree cancer and adenomas in relatives to FDRs of those diagnosed FDRs, SDRs and even TDRs of patients with CRC. We know relatives, it does not provide tthat Lynch syndrome accounts for of patients with CRC had an over the age of 60.’

—N. Jewel Samadder, MD, MSc elevated risk for CRC of 1.8-, any data on the age of onset about one in 35 CRCs,” Dr. Burke 1.3- and 1.15-fold, respectively. noted.

■

BY MONICA J. SMITH

The greatest risk for CRC was in those patients with a relative who was diagnosed before the age of 60 years.

“Importantly, however, we showed that even in CRC cases diagnosed over the age of 60, FDRs have a more than 1.5-fold elevated risk,” Dr. Samadder said.

of those lesions.’

—Carol A. Burke, MD

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NATIONAL COLORECTAL CANCER AWARENESS MONTH

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2013

Heritable CRC continued from page 1

at a young age. Gastroenterologists need to identify these patients so they can tailor screening and surveillance strategies to best protect them and their families, said Steven Itzkowitz, MD, professor of medicine and director of the gastroenterology fellowship program at Mount Sinai School of Medicine, in New York City.

“If you tell people in these families to start coming in at age 50 for their colonoscopies, you’ve missed the boat,” Dr. Itzkowitz told attendees of the annual meeting of the New York Society for Gastrointestinal Endoscopy, held last December.

CRC syndromes fall into two categories: 1) polyposis syndromes, the most typical of which is familial adenomatous polyposis (FAP), and 2) nonpolyposis familial CRC syndromes, such as Lynch syndrome, which are more common. Although genetic syndromes are present in only 2% to 3% of all CRC, all gastroenterologists should know how to identify them.

“Every practicing gastroenterologist will encounter patients with syndromes,” said Mark Schattner, MD, associate professor of medicine, Weill Cornell Medical College, and associate member, Memorial Sloan-Kettering Cancer Center, both in New York City. “They are not so rare that you’ll only encounter them once or twice in your career; these are people you will encounter every year.”

‘If you tell people in these families to start coming in at age 50 for their colonoscopies, you’ve missed the boat.’

—Steven Itzkowitz, MD

‘Not 100% of gastroenterologists will ask for a family history. … Especially for Lynch, you need to ask for a family history of endometrial cancer and other nongastrointestinal cancers.’

—Mark Schattner, MD

Polyposis Syndromes When should you suspect your patient has a syndrome?

“Very often it’s two things,” Dr. Itzkowitz said. “It’s what you might see at the time of endoscopy, or after taking a good personal and family history, not only for CRC but also for polyps, and importantly, for other types of cancers.”

For example, a 50-year-old, asymptomatic man comes in for a screening colonoscopy, and the endoscopist finds a few small bumps that are revealed to be adenomas.

“Is it just bad luck, or is it a genetic syndrome?” Dr. Itzkowitz said.

In this particular patient, it turned out to be FAP (an attenuated version, with a later onset and fewer adenomas than seen in classic FAP), which originates from a mutation in the adenomatous polyposis coli ((APC C) gene. People with FAP have a 50% chance of passing the mutation to their children, and unless the colon is surgically removed, CRC is inevitable in the classic form of this syndrome.

“In the colon [of FAP patients], you see scores to hundreds of adenomas. Importantly, because the APC C gene is in every cell of your body, mutations of APC C can cause polyps and other lesions elsewhere in the body,” Dr. Itzkowitz explained. Patients may get fundic gland polyps in the stomach or adenomas in the small intestine.

“There are extraintestinal manifestations of FAP that you should also be aware of, and remember to think backward,” Dr. Itzkowitz said. The extraintestinal malignancies associated with FAP are rare and include medulloblastoma in the brain, hepatoblastoma in the liver and thyroid cancer. Among the benign conditions that may indicate FAP are epidermoid cysts of the skin, desmoid tumors, congenital hypertrophy of the retinal pigment epithelium (a lesion of the retinal pigment), osteomas and extra teeth.

“Ask your patients about these things,” Dr. Itzkowitz recommended.

Sometimes a patient presents with something that looks like FAP but isn’t: for example, a patient on longterm proton pump inhibitor (PPI) therapy who presents with numerous fundic gland polyps.

“The key here is that if these fundic gland polyps are due to PPIs, there shouldn’t be dysplasia, so look at your pathology report,” Dr. Itzkowitz explained.

If the patient does have FAP, 30% of the fundic gland polyps will have low-grade dysplasia. Fortunately, the incidence of gastric cancers in FAP patients is low. Nevertheless, gastroenterologists should be on the lookout for ampullary and duodenal adenomas and be aware of how these adenomas appear.

The bottom line for FAP: Consider it when a patient has multiple adenomatous polyps, extraintestinal manifestations of FAP and a family history of CRC. But also be aware that FAP is a de novo manifestation in 30% of people.

“So take a good family history, but don’t be too shocked if you find nothing,” Dr. Itzkowitz said.

Nonpolyposis Syndromes The third case Dr. Itzkowitz described was a 38-yearold man diagnosed with cancer of the ascending colon.

His mother had uterine cancer at age 54 years, but there were no other cancers reported in the family.

“Is this Lynch syndrome?” he asked.

People with Lynch syndrome, which is caused by a germline mutation in one of the DNA mismatch repair genes, have an 80% lifetime risk for CRC and tend to get cancers at a much younger age than the general population.

“The important thing here is that when adenomas develop in these patients, they’re on the fast track to cancer,” Dr. Itzkowitz said.

Additionally, unlike the general population, among whom about 3% will develop a new primary colon cancer within 10 years, 30% of patients with Lynch syndrome

will develop a new primary CRC within 10 years, and 50% will do so within 15 years.

Furthermore, the extraintestinal manifestations in patients with Lynch syndrome tend to be malignant; the most common are cancers of the uterus, ovaries, stomach, small bowel, hepatobiliary region, pancreas, upper genitourinary tract and brain.

“The main thing is to keep Lynch syndrome in mind when you see a new patient, and get a family history,” Dr. Schattner suggested.

“I think gastroenterologists are good at being aware that family history plays a role, and at assigning a risk and dictating a need for more intensive screening and surveillance.

But still, not 100% of gastroenterologists will ask for a family history. And it’s not just for colon cancer. Especially for Lynch, you need to ask for a family history of endometrial cancer and other non-gastrointestinal cancers.”

Lynch syndrome is classically defined by the Amsterdam criteria: three or more Lynch cancers in two or more generations with at least one person affected before the age of 50 years.

“It’s pretty uncommon to find a family that fulfills all three rules,” noted Dr. Itzkowitz. “To see if someone with CRC has Lynch syndrome, we will often [do an immunohistochemical stain of ] the tumor for the expression of one of the DNA mismatch repair genes.”

Another nonpolyposis syndrome, familial CRC syndrome type X, can be mistaken for Lynch: Family members with it tend to experience multiple CRCs but there are no extracolonic cancers associated with familial CRC type X, and it is not caused by a genetic mutation, so it does not reveal itself with genetic testing.

“It looks like Lynch, but you can’t call it Lynch, so just be aware of that in your practice,” Dr. Itzkowitz said. ■ Dr. Itzkowitz is a member of the scientific advisory board of Exact Sciences Corporation, from which he receives research support.

READY FOR A

POWER IN UC?

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

INDICATIONS AND USAGE UCERISâ&#x201E;˘ is a glucocorticosteroid indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis.

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. t *ODSFBTFE TZTUFNJD HMVDPDPSUJDPJE TVTDFQUJCJMJUZ 3FEVDFE MJWFS DOSAGE AND ADMINISTRATION function affects the elimination of glucocorticosteroids.

The recommended dosage for UCERIS is one 9-mg tablet to be taken t 0UIFS HMVDPDPSUJDPJE FGGFDUT $BVUJPO TIPVME CF UBLFO JO QBUJFOUT once daily in the morning with or without food for up to 8 weeks. with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or IMPORTANT SAFETY INFORMATION glaucoma, or with any other condition where glucocorticosteroids CONTRAINDICATIONS may have unwanted effects.

UCERIS is contraindicated in patients with known hypersensitivity ADVERSE REACTIONS to budesonide or any of the ingredients of UCERIS. Most common adverse reactions (incidence â&#x2030;Ľ2%) are headache, WARNINGS AND PRECAUTIONS nausea, decreased blood cortisol, upper abdominal pain, fatigue, t )ZQFSDPSUJDJTN BOE BESFOBM TVQQSFTTJPO 4JODF 6$&3*4 JT B flatulence, abdominal distension, acne, urinary tract infection, glucocorticosteroid, general warnings concerning glucocorticoids arthralgia, and constipation. should be followed.

DRUG INTERACTIONS t 5SBOTGFSSJOH QBUJFOUT GSPN TZTUFNJD DPSUJDPTUFSPJET Avoid Cytochrome P450 3A4 inhibitors (eg, ketoconazole, grapefruit Risk of impaired adrenal function when transferring from oral steroids with high systemic effects. Taper patients slowly from juice). May cause increased systemic corticosteroid effects. systemic corticosteroids if transferring to UCERIS. USE IN SPECIFIC POPULATIONS t *NNVOPTVQQSFTTJPO 1PUFOUJBM XPSTFOJOH PG JOGFDUJPOT FH )FQBUJD JNQBJSNFOU .POJUPS QBUJFOUT GPS TJHOT BOE PS TZNQUPNT existing tuberculosis, fungal, bacterial, viral, or parasitic of hypercorticism.

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]: â&#x2030;Ľ4 and â&#x2030;¤10 at entry). The primary endpoint was induction of combined clinical remission and mucosal healing (defined as a UCDAI score of â&#x2030;¤1, with scores of 0 for both rectal bleeding and stool frequency, normal mucosa with no friability on endoscopy, and a â&#x2030;Ľ1-point reduction in the endoscopic index score) after 8 weeks of treatment.1

UCERIS™:

A POWERFUL, LOCALLY ACTING STEROID1-3 t MMX® technology targets delivery of budesonide throughout the full length of the colon1,2 t 3 times more patients taking UCERIS achieved combined clinical remission and mucosal healing compared with placebo3*

A SAFETY PROFILE THAT OFFERS CONFIDENCE1 t The rates of overall expected glucocorticoid-related side effects were similar for UCERIS and placebo at 8 weeks— 10.2% vs 10.5%, respectively1*

www.UCERIS.com 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. *In a pooled analysis of 2 Phase III clinical trials.1,3 References: 1. UCERIS Prescribing Information. Santarus, Inc. January 2013. 2. 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. 3. Data on file. Santarus, Inc. UCERIS is a trademark of Santarus, Inc. MMX is a registered trademark of Cosmo Technologies, Ltd.

© 2013 Santarus, Inc. 1-UCE13089 January 2013 Printed in the USA.

28

NATIONAL COLORECTAL CANCER AWARENESS MONTH

Molecular Subtyping continued from page 1

of patients with colorectal cancer (CRC). â&#x20AC;&#x153;We have developed a diagnostic, single-sample predictor that allows the classification of CRC tumors of different intrinsic molecular subtypes,â&#x20AC;? said Josep Tabernero, MD, PhD, director of Vall dâ&#x20AC;&#x2122;Hebron Institute of Oncology in Barcelona, Spain, and lead investigator of one of the studies. â&#x20AC;&#x153;These subtypes could be clinically relevant as they differ in their underlying biology and clinical outcomes, 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)

and consequently require different treatment strategies.â&#x20AC;?

Molecular classification systems could be most helpful in managing patients with stage II CRC who have a variable risk for relapse that is hard to predict with current clinical and pathological methods. The goal of subtyping is not only to identify patients who need aggressive treatment, but also to pair the right patient with the right drug.

Patterns of Gene Expression Dr. Tabernero and his team used gene

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

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

expression data taken from 188 patients with CRC (stages I-IV) to develop the classification system, which they subsequently validated in 543 patients with CRC (stages II-III).

Three distinct molecular patterns were identified: 21.5% of samples were categorized as subtype A (32 genes), 62% as subtype B (53 genes) and 16.5% as subtype C (102 genes). These subtypes differed according to three biological hallmarks of colorectal tumors: epithelial-to-mesenchymal transition (associated with aggressive tumors); deficiency 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

â&#x20AC;&#x2DC;The subtypes were significantly associated with prognosis and significantly correlated with benefit from adjuvant 5-FU-based treatment.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Josep Tabernero, MD, PhD

in mismatch repair genes (associated with genetic alterations); and the rate of cellular proliferationâ&#x20AC;&#x201D;features that are known to independently affect outcomes, said Dr. Tabernero. â&#x20AC;&#x153;The subtypes were significantly associated with prognosis and significantly correlated with benefit from adjuvant 5-FU-based treatment,â&#x20AC;? Dr. Tabernero said.

Patients with subtype A had a good prognosis, regardless of whether chemotherapy was given: 10-year survival rates were approximately 65% without chemotherapy and 80% with chemotherapy (P=0.183).

P Patients with subtype B had a pronounced benefit from chemotherapy, with 10-year survival rates of approximately 55% without chemotherapy versus 80% with chemotherapy (P=0.014).

P Patients with subtype C, in contrast, derived no benefit from adjuvant chemotherapy, with 10-year survival rates of approximately 65% without chemotherapy and 50% with chemotherapy (P=0.542).

P The five-year overall survival difference between types A and B, versus type C, was statistically significant (P=0.0166).

P The findings suggest that patients with subtypes A and B would be treated differently: Subtype A patients would probably

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2013

NATIONAL COLORECTAL CANCER AWARENESS MONTH

‘We observed that molecular subgroups of CRC demonstrated differential sensitivity to specific targeted agents, such as … inhibition of HER2 by lapatinib, and inhibition of the epidermal growth factor receptor by erlotinib.’

—Joshua M. Uronis, PhD the subgroups exhibited differences in recurrence-free survival rates (P=0.046), according to Dr. Uronis.

Additionally, researchers translated the unique patterns of pathway deregulation

1978 not require chemotherapy; subtype B patients would receive chemotherapy; and subtype C patients would require a more aggressive and perhaps novel treatment. The study researchers plan to evaluate these subtypes in patients who have received more current regimens, especially oxaliplatin.

Oncogenic Signaling Pathway Deregulation Another study, presented by Joshua M. Uronis, PhD, found that deregulation of oncogenic signaling pathways can be used as a powerful tool in the classification of patients with CRC into molecular subgroups. The researchers, including David Hsu, MD, PhD, of the Duke Institute for Genome Sciences and Policy, Durham, N.C., have developed a preliminary set of biomarkers that are prognostic, predictive of treatment response and applicable to patients who have undergone resection for primary or metastatic tumors.

Dr. Uronis and his colleagues examined microarray data, based on the activity of 19 oncogenic pathways, from 850 patients with primary CRC and generated patterns of pathway deregulation for each patient’s tumor. A molecular profile of CRC was created that identified six molecular subgroups of CRC and showed that patients in each subgroup differed significantly in their risk for CRC recurrence. For example, although recurrence-free survival approached 100% for subgroup 4, it fell to about 40% for subgroup 3 (P=0.0004).

P The model was then applied to a data set of 133 tumor samples, of which 94 patients presented with metastatic disease and 34 with primary lesions. Again,

—

into gene expression signatures that were used to measure the probability of pathway activation in a panel of cell lines.

With this approach, the model also was predictive of response to various drugs.

29

“We observed that molecular subgroups of CRC demonstrated differential sensitivity to specific targeted agents, such as molecular subgroup of CRC 1, 2 and 3 to inhibition of HER2 by lapatinib, and inhibition of the epidermal growth factor receptor by erlotinib [P<0.05],” Dr. Uronis said. “From this we gather that we can make basic predictions using pathway signatures.”

The study was validated using a murine model of drug sensitivity that used patient-derived CRC explants see Molecular Subtyping, page 30

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ACG 2012

IBS No Longer Only Functional Disorder

BY DAVID WILD

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

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 .................................................................. «>}iÊÎÎ

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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GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2013

Oncotype DX Colon Cancer Assay Plays Influential Role In Treatment Recommendations, Medical Costs Prospective Data on Outcomes of Disease Recurrence, Mortality Still Needed

BY GEORGE OCHOA The Oncotype DX Colon Cancer Assay (Genomic Health) alters treatment recommendations and may reduce medical costs and improve patient well-being, according to posters presented at the 2013 American Society for Clinical Oncology Gastrointestinal Cancers Symposium, held in San Francisco.

“This test is a useful tool for medical oncologists for risk assessment for their stage II patients beyond [how] the clinicopathologic factors alone can help us,” said Saima Sharif, MD, MS, assistant director of medical affairs for the National Surgical Adjuvant Breast and Bowel Project, and assistant professor of medicine at Temple University School of Medicine in Philadelphia.

Dr. Sharif was not involved in the studies presented at the meeting.

One of the studies (abstract 453) involved 141 stage II, T3 mismatch repair (MMR)–proficient colon cancer patients from 17 centers in the Mayo Clinic Cancer Research Consortium. In this prospective study, researchers analyzed treatment decisions for these patients and found that the use of the Oncotype DX Colon Cancer Assay changed treatment decisions 45% of the time, with treatment intensity decreasing for 33% of patients and increasing for 11%. Recommendations for chemotherapy fell from 52% pre-assay to 30% post-assay.

In a second study (abstract 391), researchers used the same data to evaluate cost and quality of life. Given the decrease in actual adjuvant chemotherapy recommendations (a 22% decline, from 52% pre-assay to 30% post-assay), average total direct medical costs were calculated to decrease by $4,203. The net effect on average patient well-being was a gain of 0.083 quality-adjusted life-years.

Molecular Subtyping continued from page 29

implanted into mice. This model showed that subgroups with high mammalian target of rapamycin (mTOR) activity were highly sensitive to mTOR inhibitors and those with low mTOR expression were found to be resistant to these drugs. Researchers deduced that the combination of a genomic-based molecular profile of CRC and their preclinical murine model using patient-derived CRC explants can be used to develop a clinically relevant prognostic and predictive biomarker of CRC.

Taking Staging One Step Further “There has been considerable interest in determining whether molecular alterations in primary CRC are more accurate prognostic indicators than a tumor’s pathologic stage, which is what is currently used,” noted William M. Grady, MD, associate professor of medicine and chief of the gastroenterology section at the University of Washington Medical Center, Seattle.

Oncotype DX Colon Cancer Assay at a Glance • •

•

•

•

Cost: $3,640.00 Availability: Launched in January 2010; availability extended to stage III patients in June 2012.

What It Can Do: The Oncotype DX Colon Cancer Assay is the first multigene expression test developed for the assessment of risk for recurrence in patients with stage II or III colon cancer.

What It Cannot Do: Oncotype DX is only intended for use in patients with stage II or III colon cancer following surgery.

Required Sample: The test is performed using formalin-fixed, paraffin-embedded colon tumor tissue obtained by surgical resection or biopsy.

Source: Genomic Health

In a third study (abstract 349), 30 community-based and 20 university-based oncologists were surveyed to assess the agreement among physicians regarding their recurrence risk assessments of patients with stage II colon cancer. Each physician made an assessment in 10 cases using only clinicopathologic factors, and in 10 separate cases using clinicopathologic factors plus the Oncotype DX Colon Cancer Assay recurrence score and MMR tests. Addition of the Oncotype DX Colon Cancer Assay significantly increased agreement among physicians in their recurrence risk assessments, in both university and community settings.

“I have used [the Oncotype DX Colon Cancer Assay] for selected cases, particularly those with pT3N0 pathologic stage or when there are conflicting traditional clinicopathologic features that, in some cases, are not supported by a consistently high level of evidence,” said Robin Katie Kelley, MD, assistant professor of medicine at the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, and lead author of the study.

Dr. Kelley noted that the assay could be helpful “in cases with average-risk, stage II colon cancer, without distinct high- or low-risk features.” “[The test] has been analytically validated for its accuracy, and … has clinical validity from two large randomized data sets,” she said.

Dr. Sharif said the Oncotype DX Colon Cancer Assay is a reliable assay based on retrospective data available for clinical use; however, it is yet to be evaluated prospectively in a randomized clinical trial to make treatment decisions and to look at outcomes of disease recurrence and death in patients.

“It is a useful tool for risk assessment of patients with stage II colon cancer but does not predict benefit from chemotherapy. … Based on each patient’s risk for recurrence, chemotherapy can be offered with the ‘hope,’ but no definitive evidence, that it will improve outcome of disease recurrence or death from cancer,” she said.

According to Genomic Health, the Journal of Clinical Oncologyy has accepted results from the second large clinical validation study of the Oncotype DX Colon Cancer Assay for publication.

■ Dr. Kelley reported receiving research funding from Genomic Health for research on the clinical utility of the Oncotype DX Colon Cancer Assay. Dr. Sharif reported involvement with clinical trials from which samples of tumor tissue were used to develop the assay, but he was not directly involved with its development.

“[The researchers] have professor at Harvard used a unique approach to ‘These molecular alteration patterns Medical School, both in identify molecular alteraBoston. “For example, we tions that are predictive of have the potential to be used as as surgeons can surgically recurrent cancer, not only markers to identify which patients remove tumors to the best for non-metastatic disease of our oncologic ability, should receive aggressive care … and but also for metastatic disand enable our partners, ease,” Dr. Grady said of the to direct the specific chemotherapeutic the pathologists, to stage study by Dr. Uronis and his agents they should receive.’ the tumors and help detercolleagues. “If these results mine the best treatment; —William M. Grady, MD however, currently, there are can be validated, these molecular alteration patserious limitations. terns have the potential to be used as markers to identify “At the extremes, there is less controversy,” she conwhich patients should receive aggressive care after surgi- tinued. “There, there is no question that chemotherapy cal resection of both primary and metastatic colorectal does not (for stage I) or does (for stage III or IV) help cancer and to direct the specific chemotherapeutic agents the patient, overall. But the vast majority of patients they should receive,” he said. fall into those shades of gray, stage II especially, where “The work by Uronis et al is critical for CRC care we are weighing potentially toxic chemotherapy risks advancement, and symbolic of the new age of cancer and benefits versus disease recurrence risks and bencare in general,” said Jennifer Tseng, MD, chief of sur- efits. This type of study helps point us to personalizing gical oncology and co-clinical director for surgery at cancer care for the individual tumor, and thus the indiBeth Israel Deaconess Medical Center, and associate vidual patient,” Dr. Tseng concluded.

■

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2013

31

NEW PRODUCT ANNOUNCEMENT

New Budesonide Formulation Approved For Induction of Remission in UC On Jan. 14, Santarus, Inc., announced that the FDA had approved budesonide (Uceris) extended-release tablets for the induction of remission in patients with active, mild to moderate ulcerative colitis. At press time, the company planned to commence the commercial launch of the drug in March 2013.

Uceris comprises budesonide in a novel oral tablet formulation that uses the MMX multimatrix system delivery technology. The approved dosing regimen for adult patients is one, 9-mg tablet taken orally, once daily in the morning for up to eight weeks.

“The FDA approval of Uceris provides an important new therapeutic option to patients and physicians for the treatment of active, mild to moderate ulcerative colitis,” said William J. Sandborn, MD, chief, Division

of Gastroenterology, professor of clinical medicine, University of California, San Diego (UCSD) Health System and director, UCSD Inflammatory Bowel Disease Center.

According to Santarus, budesonide demonstrated a safety profile similar to placebo in both long- and short-term studies: For the five most common steroid-related side effects, occurrence rates were similar in both the budesonide and placebo groups. Additionally, in the long-term study (12 weeks), the majority of patients in both the budesonide and placebo groups had normal bone density scans. (A 6-mg maintenance dose was used in the 12-week budesonide safety study, which is not currently approved by the FDA.) For more information about Uceris, visit www.uceris.com.

—Based on a press release from Santarus, Inc.

Photo courtesy of Santarus, Inc.

US Endoscopy Announces Release of AquaShield Water Bottle for Use With CO2 Insufflation On Jan. 29, US Endoscopy announced the release of the AquaShield water bottle for CO2 delivery systems. This new tool is an addition to the existing disposable AquaShield product family, which is used in conjunction with the endoscope’s air/water function to clean the lens.

“The new CO2 system accommodates our customers using CO2 insufflation and offers the same benefits of reducing the risk for contamination, with a disposable option,” said Gulam Khan, president, US Endoscopy.

According to US Endoscopy, the Society of Gastroenterology Nurses and Associates recently issued a position statement clarifying the reprocessing of water bottles used during endoscopy. If water bottles are not reprocessed appropriately, they carry a risk for cross contamination. The disposable AquaShield water bottle system is a 24-hour use system that saves time associated with reprocessing and promotes patient safety, the company said.

The AquaShield water bottle for CO2 delivery systems Photo courtesy of US Endoscopy

—Based on a press release from US Endoscopy

New Indication for Avastin With Chemotherapy for Metastatic Colon Cancer Approved The FDA has approved a new use for Avastin (Genentech; bevacizumab) in combination with fluoropyrimidinebased irinotecan or oxaliplatin chemotherapy for use in patients with metastatic colorectal cancer (mCRC). The new indication will allow people who received Avastin plus an irinotecan- or oxaliplatin-containing chemotherapy as an initial treatment (first-line) for mCRC to continue to receive Avastin plus a different irinotecan- or oxaliplatin-containing chemotherapy after their cancer worsens (second-line treatment).

The approval is based on positive results from the Phase III ML18147 study, which showed that people who continued to receive an Avastin-based treatment regimen after their cancer worsened lived longer than people who switched to chemotherapy alone.

“The majority of people diagnosed with metastatic colorectal cancer receive Avastin plus chemotherapy as their initial treatment,” said Hal Barron, MD, chief medical officer and head of global product development at Genentech, in a press release. “These people now have the option to continue with Avastin plus a new chemotherapy after their cancer worsens, which may help them live longer than changing to the new chemotherapy alone.”

The ML18147 study was a randomized, open-label, multicenter, multinational trial evaluating the efficacy and safety profile of Avastin plus standard second-line chemotherapy in 820 patients with mCRC whose disease had progressed following Avastin plus standard first-line chemotherapy (irinotecan- or oxaliplatin-based). The primary end point of the trial was overall survival measured from the time patients were randomized to receive the second-line treatment.

Results showed that the risk for death was reduced by 19% in patients who received Avastin in combination with standard chemotherapy in both first- and secondline, compared with those who received chemotherapy alone (hazard ratio, 0.81; P=0.0057). The median overall survival was 11.2 months in the Avastin group compared with 9.8 months in the chemotherapy-alone group.

Adverse effects in the trial were consistent with those seen in previous pivotal trials of Avastin in mCRC. Avastin contains several boxed warnings: In clinical trials, some people treated with Avastin experienced serious and sometimes fatal side effects, including gastrointestinal perforation, surgery and wound-healing problems, and severe bleeding.

For more information about Avastin, visit www.avastin.com.

—Based on a press release from Genentech

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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 • MARCH 2013

FDA Approves Single Test To Detect 11 Causes of Gastroenteritis The FDA has allowed the marketing of a first-in-kind test that can simultaneously detect 11 viral, bacterial and parasitic causes of infectious gastroenteritis from a single patient sample.

The xTAG Gastrointestinal Pathogen Panel (GPP) is a multiplexed nucleic acid test that can detect the following bacteria that cause gastroenteritis: Campylobacter, Clostridium difficile (C. difficile) toxin A/B, Escherichia coli (E. coli) O157, enterotoxigenic E. coli (ETEC) LT/ST, Salmonella, Shigella and Shiga-like toxin-producing E. colii (STEC) stx 1/ stx 2. The test also can detect norovirus and rotavirus A, and the parasites Cryptosporidium and Giardia.

“Tests such as the xTag GPP that can detect viruses, bacteria and parasites from one sample at the same time can help clinicians more quickly identify and treat what’s causing gastroenteritis,” said Alberto Gutierrez, PhD, director of the Office of In Vitro Diagnostics and Radiology at the FDA’s Center for Devices and Radiological Health, in a statement.

“The test could also allow clinicians and public health professionals to more quickly identify and investigate the source of potential gastroenteritis outbreaks.”

Luminex Corporation, the manufacturer of xTAG GPP, evaluated the test using samples from 1,407

patients with suspected infectious gastroenteritis and comparing the results obtained with xTAG GPP testing with those obtained with the individual tests that are known to separately and reliably detect the 11 bacteria, viruses or parasites detected by xTAG GPP. The company

also ran xTAG GPP on 203 samples from patients with previously confirmed infectious gastroenteritis, and on 313 specimens from pediatric patients with suspected infectious gastroenteritis. Results from the xTAG GPP test were comparable to those from the individual tests.

Because of the possibility of falsepositive results, all positive results obtained with xTAG GPP should be confirmed by additional testing.

The FDA reviewed the data for xTAG GPP through the de novo classification process, a regulatory pathway for medical devices that are generally low- to moderate-risk but are not comparable to an already legally marketed device.

According to the Centers for Disease Control and Prevention, between 1999 and 2007, gastroenteritis-associated deaths in the United States increased from nearly 7,000 to more than 17,000 per year; norovirus and C. difficile accounted for two-thirds of the deaths.

—Based on a press release from the FDA

The xTAG Gastrointestinal Pathogen Panel from Luminex Corporation

Crofelemer Is First FDA-Approved Antidiarrheal Drug for Patients With HIV/AIDS On the last day of 2012, the FDA approved crofelemer (Fulyzaq, Salix Pharmaceuticals) for the symptomatic relief of noninfectious diarrhea in patients with HIV/AIDS who are receiving antiretroviral therapy, according to an FDA press release. Diarrhea is common in patients with HIV/AIDS and is a frequent reason for discontinuing or switching antiretroviral therapies. Crofelemer is the first FDA-approved antidiarrheal drug for these patients.

“Currently, there are no FDA-approved therapies for HIV-associated diarrhea,” Julie Beitz, MD, director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research, said in a statement.

“Fulyzaq may be helpful to HIV/AIDS patients with this troublesome condition.”

A botanical prescription drug derived from the Croton lechleri plant, crofelemer is believed to act by blocking chloride secretion, thereby reducing the high-volume water loss that occurs in patients with HIV-associated diarrhea, according to Salix. The recommended dosage is one, 125mg delayed-release tablet taken orally, twice daily.

The FDA approval of crofelemer is based on a randomized, multicenter, double-blind, placebo-controlled (one-month) and placebo-free

(five-month) study of 374 HIV-positive patients on stable antiretroviral therapy with a history of diarrhea lasting one month or longer. The primary end point of the study was defined as the proportion of patients having no more than two watery bowel movements per week. Investigators found that significantly more patients taking crofelemer experienced a clinical response compared with those taking placebo (17.6% vs. 8%, respectively).

Some patients had a persistent antidiarrheal effect for 20 weeks.

Statistically significant reductions from baseline to the end of the double-blind period also

were observed for the number of watery bowel movements per day and daily stool consistency score among patients taking crofelemer compared with placebo. Furthermore, crofelemer showed significantly greater efficacy compared with placebo in subgroup analyses based on duration of diarrhea, baseline number of daily watery bowel movements, use of HIV protease inhibitors and CD4 cell count.

“In addition, the Phase III study showed that Fulyzaq did not influence the efficacy or safety of the patients’ HIV medications,” said Bill Forbes, PharmD, executive vice president of medical research and development, and chief development officer at Salix.

The most common adverse reactions in patients taking crofelemer were upper respiratory tract infection, bronchitis, cough, flatulence and elevated bilirubin concentration.

Crofelemer is not intended for the treatment of infectious diarrhea; infectious etiologies of diarrhea should be ruled out before starting a patient on crofelemer.

At press time, Salix had announced plans to make crofelemer available in early 2013.

—Based on press releases from the FDA and Salix Pharmaceuticals

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Acing the GI Board Exam: The Ultimate Crunch-Time Resource

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Benign and Neoplastic Conditions of the Esophagus, An Issue of Gastroenterology Clinics

Nicholas J. Shaheen, MD April 11, 2013 Esophageal diseases are among the most common gastrointestinal illnesses encountered by both the gastroenterologist as well as the primary care physician. Gastroesophageal reflux symptoms affect 20% of adult Americans on a weekly or more frequent basis, and Barrett’s esophagus, a precancerous lesion of the distal esophagus associated with chronic GERD, is prevalent in 2% ti 6% of the adult population.

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Clinical Challenges and Complications of IBD

Miguel D. Regueiro; Jason M. Swoger October 15, 2012 Clinical Challenges and Complications of IBD D is an invaluable guide for gastroenterologists, nurse practitioners, physician assistants and gastroenterology trainees as it is a one-of-a-kind resource for recognizing and dealing with the challenges and complications in patients with IBD.

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ERCP: Expert Consult—Online and Print: Second Edition

Todd H. Baron February 27, 2013 ERCP, P now in its second edition, is dedicated to simplifying and explaining everything that you need to know to effectively and safely practice endoscopic retrograde cholangiopancreatography. High-quality images, illustrative diagrams and coverage of the latest techniques guide you t oug this through t s complex co p e topic top c and a d help e p you achieve ac e e optimal opt a outcomes. outco es

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Handbook of Gastrointestinal Cancer

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Morson and Dawson’s Gastrointestinal Pathology

Neil A. Shepherd; Bryan F. Warren; Geraint T. Williams; Joel K. Greenson; Gregory Y. Lauwers; Marco R. Novelli February 15, 2013 Emphasizing the important role the gastrointestinal pathologist plays in patient management, this book is a comprehensive resource for both training and practice. This textbook reflects current practice, where the abundance of surgical specimens and the revolution in endoscopy has made virtually the entire gastrointestinal tract accessible to biopsy.

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Marcelo F. Vela; Joel E. Richter; John E. Pandolfino February 15, 2013 Highly practical, expertly written and packed with useful tools like case histories, pitfall boxes and management algorithms, this convenient and user-friendly manual provides you with complete clinical guidance to gastroesophageal reflux disease, one of the most common conditions that gastroenterologists g g face every y day. y GEN0313

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Teduglutide Approved for Short Bowel Syndrome First Major Long-Term Treatment Advance for Short Bowel Syndrome in Nearly 40 Years On Dec. 21, the FDA approved teduglutide (Gattex [rDNA origin] for injection, NPS Pharmaceuticals, Inc.) to treat adults with short bowel syndrome who are dependent on parenteral support, according to an FDA press release. An injection administered once daily, teduglutide helps to improve intestinal absorption of fluids and nutrients, reducing frequency and volume of parenteral nutrition.

“Today’s approval expands the available treatment options for patients with this life-threatening condition,” said Victoria Kusiak, MD, deputy director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research.

“In addition to serious medical complications, patients with short bowel syndrome can have socially restricted lives,” said Ken Fujioka, MD, of the Nutrition and Metabolic Research Center at Scripps Clinic, Del Mar, Calif., in a press statement.

“Long infusion periods often disrupt sleep for patients. This is coupled with constant concern about using restrooms, as many patients will need to use the bathroom up to 25 times a day, or having an accident with unpredictable diarrhea. Other patients that have an ostomy bag have a fear of an ostomy bag leakage.

These factors leave many patients unable to socialize or work. Considering Gattex has been shown to significantly reduce, or in some cases even eliminate, the requirement for parenteral support, it may become a cornerstone therapy in the management of short bowel syndrome.”

The safety, efficacy and tolerability of teduglutide were evaluated in two randomized, placebo-controlled, clinical trials and two extension studies. Designed to quantify the number of patients who achieved at least a 20% reduction in the volume of weekly parenteral nutrition after 20 and 24 weeks of treatment (clinical response), the clinical trials showed that 46% and 63% of patients, respectively, treated with teduglutide achieved a clinical response compared with 6% and 30% of patients treated with placebo, respectively.

The most common side effects of teduglutide identified in clinical trials were abdominal pain, injection site reactions, nausea, headaches, abdominal distension and upper respiratory tract infection. A postmarketing study is required to evaluate

teduglutide’s potential increased risk for colorectal cancer and other conditions.

In an NPS press release, Francois Nader, MD, president and chief executive officer of NPS Pharmaceuticals, stated: “Gattex is a ground-breaking therapy that has been evaluated in the largest clinical program to date in

The following is a brief summary; see complete Prescribing Information at www.Xifaxan550.com.

INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of XIFAXAN and other antibacterial drugs, XIFAXAN when used to treat infection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

short bowel syndrome. We are very excited about the opportunity to help [short bowel syndrome] patients by offering this first-in-class therapy.”

The NPS press release added that teduglutide—a novel, recombinant analog of human glucagon-like peptide 2, a protein involved in rehabilitation of the intestinal lining—is the first major long-term treatment advance

21-82) years; approximately 20% of the patients were ≥ 65 years old, 61% were male, 86% were White, and 4% were Black. Ninety-one percent of patients in the trial were taking lactulose concomitantly. All adverse reactions that occurred at an incidence ≥ 5% and at a higher incidence in XIFAXAN 550 mg-treated subjects than in the placebo group in the 6-month trial are provided in Table 2. (These include adverse events that may be attributable to the underlying disease).

Table 1: Adverse Reactions Occurring in ≥ 5% of Patients Receiving XIFAXAN and at a Higher Incidence Than Placebo

Hepatic Encephalopathy XIFAXAN 550 mg is indicated for reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients ≥ 18 years of age.

In the trials of XIFAXAN for HE, 91% of the patients were using lactulose concomitantly. Differences in the treatment effect of those patients not using lactulose concomitantly could not be assessed.

XIFAXAN has not been studied in patients with MELD (Model for End-Stage Liver Disease) scores > 25, and only 8.6% of patients in the controlled trial had MELD scores over 19. There is increased systemic exposure in patients with more severe hepatic dysfunction [see Warnings and Precautions (5.4), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

CONTRAINDICATIONS Hypersensitivity XIFAXAN is contraindicated in patients with a hypersensitivity to rifaximin, any of the rifamycin antimicrobial agents, or any of the components in XIFAXAN. Hypersensitivity reactions have included exfoliative dermatitis, angioneurotic edema, and anaphylaxis [see Adverse Reactions (6.2)].

WARNINGS AND PRECAUTIONS Travelers’ Diarrhea Not Caused by Escherichia coli XIFAXAN was not found to be effective in patients with diarrhea complicated by fever and/or blood in the stool or diarrhea due to pathogens other than Escherichia coli. Discontinue XIFAXAN if diarrhea symptoms get worse or persist more than 24-48 hours and alternative antibiotic therapy should be considered.

XIFAXAN is not effective in cases of travelers’ diarrhea due to Campylobacter jejuni. The effectiveness of XIFAXAN in travelers’ diarrhea caused by Shigella spp. and Salmonella spp. has not been proven. XIFAXAN should not be used in patients where Campylobacter jejuni, Shigella spp., or Salmonella spp. may be suspected as causative pathogens.

Clostridium difficile-Associated Diarrhea Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XIFAXAN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon which may lead to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.

CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Development of Drug Resistant Bacteria Prescribing XIFAXAN for travelers’ diarrhea in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Severe (Child-Pugh C) Hepatic Impairment There is increased systemic exposure in patients with severe hepatic impairment. Animal toxicity studies did not achieve systemic exposures that were seen in patients with severe hepatic impairment.

The clinical trials were limited to patients with MELD scores <25.

Therefore, caution should be exercised when administering XIFAXAN to patients with severe hepatic impairment (Child-Pugh C) [see Use in Specific Populations (8.7), Nonclinical Toxicology (13.2) and Clinical Studies (14.2)].

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 practice.

Hepatic Encephalopathy The data described below reflect exposure to XIFAXAN 550 mg in 348 patients, including 265 exposed for 6 months and 202 exposed for more than a year (mean exposure was 364 days). The safety of XIFAXAN 550 mg taken two times a day for reducing the risk of overt hepatic encephalopathy recurrence in adult patients was evaluated in a 6-month placebo-controlled clinical trial (n = 140) and in a long term follow-up study (n = 280). The population studied had a mean age of 56.26 (range:

for short bowel syndrome in nearly 40 years.

NPS plans to make Gattex available in the first quarter of 2013. For more information, visit www.gattex. com.

Number (%) of Patients

MedDRA Preferred Term Edema peripheral Nausea Dizziness Fatigue Ascites Muscle spasms Pruritus Abdominal pain Abdominal distension Anemia Cough Depression Insomnia Nasopharyngitis Abdominal pain upper Arthralgia Back pain Constipation Dyspnea Pyrexia Rash

XIFAXAN Tablets 550 mg TWICE DAILY N = 140

Placebo N = 159

21 (15%) 20 (14%) 18 (13%) 17 (12%) 16 (11%) 13 (9%) 13 (9%) 12 (9%) 11 (8%) 11 (8%) 10 (7%) 10 (7%) 10 (7%) 10 (7%) 9 (6%) 9 (6%) 9 (6%) 9 (6%) 9 (6%) 9 (6%) 7 (5%)

13 (8%) 21 (13%) 13 (8%) 18 (11%) 15 (9%) 11 (7%) 10 (6%) 13 (8%) 12 (8%) 6 (4%) 11 (7%) 8 (5%) 11 (7%) 10 (6%) 8 (5%) 4 (3%) 10 (6%) 10 (6%) 7 (4%) 5 (3%) 6 (4%)

The following adverse reactions, presented by body system, have also been reported in the placebo-controlled clinical trial in greater than 2% but less than 5% of patients taking XIFAXAN 550 mg taken orally two times a day for hepatic encephalopathy. The following includes adverse events occurring at a greater incidence than placebo, regardless of causal relationship to drug exposure.

Ear and Labyrinth Disorders: Vertigo Gastrointestinal Disorders: Abdominal pain lower, abdominal tenderness, dry mouth, esophageal variceal bleed, stomach discomfort General Disorders and Administration Site Conditions: Chest pain, generalized edema, influenza like illness, pain NOS Infections and Infestations: Cellulitis, pneumonia, rhinitis, upper respiratory tract infection NOS Injury, Poisoning and Procedural Complications: Contusion, fall, procedural pain Investigations: Weight increased Metabolic and Nutritional Disorders: Anorexia, dehydration, hyperglycemia, hyperkalemia, hypoglycemia, hyponatremia Musculoskeletal, Connective Tissue, and Bone Disorders: Myalgia, pain in extremity Nervous System Disorders: Amnesia, disturbance in attention, hypoesthesia, memory impairment, tremor Psychiatric Disorders: Confusional state Respiratory, Thoracic, and Mediastinal Disorders: Epistaxis Vascular Disorders: Hypotension

Postmarketing Experience The following adverse reactions have been identified during post approval use of XIFAXAN. Because these reactions are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to either their seriousness, frequency of reporting or causal connection to XIFAXAN. Infections and Infestations Cases of C. difficile-associated colitis have been reported [see Warnings and Precautions (5.2)].

General Hypersensitivity reactions, including exfoliative dermatitis, rash, angioneurotic edema (swelling of face and tongue and difficulty swallowing), urticaria, flushing, pruritus and anaphylaxis have been reported. These events occurred as early as within 15 minutes of drug administration.

—Based on press releases from the FDA and NPS Pharmaceuticals, Inc.

An in vitro study has suggested that rifaximin induces CYP3A4 [see Clinical Pharmacology (12.3)]. However, in patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations.

An in vitro study suggested that rifaximin is a substrate of P-glycoprotein. It is unknown whether concomitant drugs that inhibit P-glycoprotein can increase the systemic exposure of rifaximin [see Clinical Pharmacology (12.3)].

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy g y Category g yC There are no adequate and well controlled studies in pregnant women. Rifaximin has been shown to be teratogenic in rats and rabbits at doses that caused maternal toxicity. XIFAXAN tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Administration of rifaximin to pregnant rats and rabbits at dose levels that caused reduced body weight gain resulted in eye malformations in both rat and rabbit fetuses. Additional malformations were observed in fetal rabbits that included cleft palate, lumbar scoliosis, brachygnathia, interventricular septal defect, and large atrium.

The fetal rat malformations were observed in a study of pregnant rats administered a high dose that resulted in 16 times the therapeutic dose to diarrheic patients or 1 times the therapeutic dose to patients with hepatic encephalopathy (based upon plasma AUC comparisons). Fetal rabbit malformations were observed from pregnant rabbits administered mid and high doses that resulted in 1 or 2 times the therapeutic dose to diarrheic patients, based upon plasma AUC comparisons.

Post-natal developmental effects were not observed in rat pups from pregnant/lactating female rats dosed during the period from gestation to Day 20 post-partum at the highest dose which resulted in approximately 16 times the human therapeutic dose for travelers’ diarrhea (based upon AUCs) or approximately 1 times the AUCs derived from therapeutic doses to patients with hepatic encephalopathy.

Nursing Mothers It is not known whether rifaximin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from XIFAXAN, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use The safety and effectiveness of XIFAXAN 200 mg in pediatric patients with travelers’ diarrhea less than 12 years of age have not been established. The safety and effectiveness of XIFAXAN 550 mg for HE have not been established in patients < 18 years of age.

Geriatric Use Clinical studies with rifaximin 200 mg for travelers’ diarrhea did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger subjects. In the controlled trial with XIFAXAN 550 mg for hepatic encephalopathy, 19.4% were 65 and over, while 2.3% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Renal Impairment The pharmacokinetics of rifaximin in patients with impaired renal function has not been studied.

Hepatic Impairment Following administration of XIFAXAN 550 mg twice daily to patients with a history of hepatic encephalopathy, the systemic exposure (i.e., AUC␶) ␶ of rifaximin was about 10-, 13-, and 20-fold higher in those patients with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, respectively, compared to that in healthy volunteers.

No dosage adjustment is recommended because rifaximin is presumably acting locally. Nonetheless, caution should be exercised when XIFAXAN is administered to patients with severe hepatic impairment [see Warnings and Precautions (5.4), Clinical Pharmacology (12.3), Nonclinical Toxicology (13.2), and Clinical Studies (14.2)].

Manufactured for Salix Pharmaceuticals, Inc., Raleigh, NC 27615, under license from Alfa Wassermann S.p.A. XIFAXAN® is a trademark of Salix Pharmaceuticals, Inc., under license from Alfa Wassermann S.p.A. Copyright © Salix Pharmaceuticals, Inc.

DRUG INTERACTIONS In vitro studies have shown that rifaximin did not inhibit cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and CYP3A4 at concentrations ranging from 2 to 200 ng/mL [see Clinical Pharmacology (12.3)]. Rifaximin is not expected to inhibit these enzymes in clinical use.

Web site: www.salix.com E-mail: customer.service@salix.com 8510 Colonnade Center Drive, Raleigh, NC 27615 Tel. 866-669-SLXP (7597) ©2012 Salix Pharmaceuticals, Inc. All rights reserved. Printed in USA. RIFHE 13/11

For overt HE* patients

OUT OF THE HOSPITAL DOESN’T MEAN OUT OF THE WOODS “After an episode of [overt HE], prophylactic therapy with lactulose or rifaximin is recommended for an indefinite period of time or until liver transplantation.”

—Clinics in Liver Disease, February 20121 73% of recurrences among lactulose patients result in hospitalization2 Xifaxan 550 mg reduces the risk of HE-related hospitalizations by 50%3†‡ The most common adverse reactions (≥12% incidence) in clinical trials with Xifaxan 550 mg were peripheral edema, nausea, dizziness, and fatigue.

Prescribe. Protect. Repeat.

*HE=hepatic encephalopathy. † Over a 6-month period; P=0.0129 vs placebo.3 ‡ HE-related hospitalization defined as hospitalization directly caused by HE or a hospitalization during which an HE event occurred.3

Important Safety Information About XIFAXAN 550 mg XIFAXAN® (rifaximin) 550 mg tablets are contraindicated in patients with a hypersensitivity to rifaximin, any of the rifamycin antimicrobial agents, or any of the components in XIFAXAN. Hypersensitivity reactions have included exfoliative dermatitis, angioneurotic edema, and anaphylaxis.

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XIFAXAN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon which may lead to overgrowth of C. difficile. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued.

There is increased systemic exposure in patients with more severe hepatic dysfunction. The clinical trials were limited to patients with MELD scores <25. Therefore, caution should be exercised when administering XIFAXAN to patients with severe hepatic impairment (Child-Pugh C).

Based on animal data, XIFAXAN may cause fetal harm. Discontinue in nursing mothers after taking into account the importance of the drug to the mother.

The most common adverse reactions occurring in ≥10% of patients and at a higher incidence than placebo in the clinical study were edema peripheral (15%), nausea (14%), dizziness (13%), fatigue (12%), and ascites (11%).

Xifaxan 550 mg is not available for sale outside the U.S. Xifaxan 550 mg is licensed by Alfa Wassermann S.p.A. to Salix Pharmaceuticals, Inc. Please see Brief Summary on reverse.

References: 1. Khungar V, Poordad F. Management of overt hepatic encephalopathy. Clin Liver Dis. 2012;16(1):73-89. 2. Bajaj JS, Sanyal AJ, Bell D, Gilles H, Heuman DM. Predictors of the recurrence of hepatic encephalopathy in lactulose-treated patients. Aliment Pharmacol Ther. 2010;31(9): 1012-1017. 3. Xifaxan [prescribing information]. Raleigh, NC: Salix Pharmaceuticals, Inc; 2011.

Web site: www.salix.com 8510 Colonnade Center Drive, Raleigh, NC 27615 Tel. 866-669-SLXP (7597) ©2013 Salix Pharmaceuticals, Inc. All rights reserved. Printed in USA. RIFHE 12/74-1

www.Xifaxan550.com

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Bowel Preparation For Colonoscopy Maximizing Efficacy, Minimizing Risk

LAWRENCE B. COHEN, MD Clinical Professor of Medicine The Mount Sinai School of Medicine New York City

T

he success of colonoscopy as a screening modality for colorectal cancer is highly dependent on the

ability to purge the colon of fecal material in order to provide an unobstructed view of the bowel wall. Inadequate cleansing of the colon, reported to occur in about 27% of all examinations, results in missed adenomas.1 Suboptimal bowel preparation leads to prolonged procedure times, lower rates of cecal intubation, reduced screening intervals, higher screening costs, and possibly an increased risk for procedure-related complications. Furthermore, recent studies demonstrate that colonoscopy is more effective in the prevention of left-sided than right-sided cancers.2-5 Possible reasons for this include suboptimal cleansing of the right side of the colon and increased difficulty in detecting right-sided lesions because they often are flat or sessile. The adoption of more effective methods

of bowel cleansing and a greater emphasis on patient compliance with preparation instructions will improve the effectiveness and efficiency of colonoscopy, as well as minimize the risk for procedural complications.

Bowel Preparations The available purgatives for colonoscopy can be divided into 3 categories: osmotic agents, polyethylene glycol (PEG)–based solutions, and stimulants.

Osmotic laxatives increase intraluminal water by promoting the passage of extracellular fluid across the bowel wall. Examples of osmotic preparations include sodium phosphate (NaP), magnesium citrate, and sodium sulphate. The PEG-based solutions consist of a high-molecular-weight nonabsorbable polymer in a dilute electrolyte solution. PEG solutions are designed to be osmotically balanced, limiting the exchange of fluid and electrolytes across the colonic membrane. Stimulant laxatives work by increasing smooth muscle activity within the wall of the colon.

Examples of stimulant purgatives include senna, bisacodyl, and sodium picosulfate. Bisacodyl’s laxative effect is based on 2 mechanisms of action: stimulation of small intestinal secretion and increased motor activity within the colon. Dietary modification, consisting of a clear liquid or a low-fiber diet for 24 hours before the procedure, usually is combined with a purgative regimen.

G A ST R O E N T E R O LO GY & E N D O S CO P Y N E WS •

MARCH 2013

1

This section provides a brief overview of the available purgatives for bowel preparation (Table 1). Several comprehensive reviews on the comparative efficacy, safety, and tolerability of these agents recently have been published, and readers who want a more in-depth analysis of this subject are referred to these sources.6-8

POLYETHYLENE GLYCOL A variety of PEG-based lavage regimens currently are available for bowel cleansing before colonoscopy.

These preparations differ with respect to volume of lavage solution, electrolyte content, molecular weight of the polymer, requirement for an adjunctive laxative, and the presence of artificial sweeteners. FDAapproved PEG lavage solutions include the traditional 4-L preparations (GoLYTELY, Braintree; Colyte, Schwarz Pharma; NuLYTELY, Braintree; TriLyte, Schwarz Pharma), and low-volume 2-L regimens (HalfLytely, Braintree; MoviPrep, Salix). The recommended dosing of most PEG solutions is 240 mL (8 oz) every 10 minutes. A “splitdose” regimen—in which part of the laxative is taken the evening before and the remainder is taken the morning of the procedure—has been demonstrated to be more effective and better tolerated than a single dose taken the evening before the procedure.9 It is estimated that 5% to 38% of patients are unable to complete the 4-L PEG preparation because of volume-related symptoms of abdominal fullness, nausea, and vomiting.8 Lowvolume PEG preparations were developed in an effort to improve patient tolerance for the lavage regimen.

Two reduced-volume PEG preparations are approved by the FDA for pre-colonoscopy bowel preparation.

MoviPrep combines PEG-3350 with sodium sulfate and ascorbic acid, the latter 2 ingredients serving to enhance the bowel cleansing activity of PEG. At least 4 randomized controlled trials have demonstrated comparable, if not superior, bowel cleansing activity with MoviPrep compared with 4-L PEG.10-13 Furthermore, patient tolerability is generally reported to be better with MoviPrep than the conventional 4-L PEG preparations. HalfLytely, the other FDA-approved, low-volume PEG preparation, consists of oral bisacodyl (5 or 10 mg) to be ingested at noon the day before the procedure, followed by 2-L of PEG solution no more than 6 hours later. A study comparing MoviPrep with HalfLytely demonstrated improved bowel cleansing and higher rates of adenoma detection with MoviPrep.14 MiraLax (PEG-3350) is available as an over-thecounter (OTC) product for the treatment of mild constipation. It also has been used as a pre-colonoscopy bowel cleansing regimen. One often recommended regimen for MiraLax is for patients to consume 4 bisacodyl delayed-release tablets at approximately 1 PM the day before the procedure, followed by the ingestion of 238 mg of MiraLax (8.3-oz bottle) mixed with 64 oz of Gatorade. In some cases, 10 oz of magnesium citrate also is recommended. Unlike the FDA-approved 2- and 4-L PEG products that contain additional electrolytes in order to produce an osmotically balanced solution,

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thereby minimizing net absorption or secretion of fluid or electrolytes into the intestinal lumen, the MiraLax/ Gatorade preparation is hypotonic. The safety and efficacy of MiraLax recently has been evaluated in several randomized, investigator-blinded single-site studies.

Enestvedt14 and Hjelkrem15 independently observed that 4-L PEG solution with electrolytes was more effective than a solution of MiraLax in 64 oz of Gatorade.

Split-dose preparations were used in both trials. However, Samarasena et al16 observed that MiraLax (238 g PEG)/64 oz Gatorade had comparable efficacy to 4-L PEG under conditions of either 1- or 2-day dose-splitting, and Gerard et al17 reported that a modified protocol of MiraLax (306 g PEG)/64 oz Gatorade taken at noon and between 5 and 9 PM the day before colonoscopy achieved efficacy and safety comparable to 4-L PEG. Anecdotal reports of severe hyponatremia resulting from MiraLax/Gatorade have been published, although the prevalence of this problem remains uncertain.

Overall, the safety record with PEG-based preparations has been excellent. During the 6-year period ending in 2002, the FDA received 100 reports of adverse events (AEs) with PEG solutions, including 30 serious and 6 fatal events.8 Complications of PEG preparations include hypothermia, hyponatremia, intestinal perforation, aspiration, and Mallory-Weiss tear.18 The use of PEGbased bowel cleansing is contraindicated in patients with gastric outlet obstruction, high-grade small bowel obstruction, and suspected bowel perforation.

ORAL SODIUM PHOSPHATE For many endoscopists, a new era in bowel cleansing for colonoscopy was ushered in on Dec. 11, 2008, when the FDA issued an alert about the safe use of oral sodium phosphate (OSP) products.19 The agency expressed its concern about the risks associated with the use of OSP at the higher doses typically used for bowel cleansing before colonoscopy, and it recommended that consumers not use the OTC OSP products designed specifically for bowel cleansing. The FDA said, however, that the available data continue to indicate the safety of OSP at the lower dose used for the laxative.

In response to the FDA warning, CB Fleet immediately announced a voluntary recall of its OTC products, Fleet Phospho-soda and Fleet Phospho-soda EZ-Prep. The future of these products, either in the OTC or prescription market, is uncertain at this time.

The FDA alert also indicated that the manufacturer of prescription NaP tablets (Osmoprep, Salix) would be required to put a black box warning on its product labels. The warning highlights several key concepts related to the use of NaP laxatives for bowel cleansing, including the following: 1) acute phosphate nephropathy, sometimes resulting in permanent renal impairment, has been observed rarely following ingestion of OSP; 2) identifiable patient risk factors for acute phosphate nephropathy include increased age, hypovolemia, increased bowel transit time (such as bowel obstruction), active colitis, and baseline kidney

Table 1. Commonly Used Purgatives for Colonoscopy Preparation Class Polyethylene glycol

Product

Recommended Usea

4-L PEG-ELS

GoLYTELY (Braintree)

240 mL (8 oz) every 10 min beginning at 5 to 6 PM the evening before colonoscopy (total, 3 L); remaining 1 L 10 to 12 h later (at least 3 h before procedure)

Colyte (Schwarz Pharma)

Same as above

NuLYTELY (Braintree)

Same as above

TriLyte (Schwarz Pharma)

Same as above

2-L PEG-ELS and bisacodyl delayed-release tablets

HalfLytely (Braintree)

2 bisacodyl delayed-release tablets at noon the day before colonoscopy; 240 mL (8 oz) every 10 min beginning at 5 to 6 PM (total, 1 L); repeat 240 mL (8 oz) every 10 min beginning 3 to 4 h before procedure (total, 1 L)

2-L PEG and bisacodyl delayed-release tablets

MiraLax (Schering-Plough)

Same as above

2-L PEG with ascorbate

MoviPrep (Salix)

240 mL (8 oz) every 15 min beginning at 5 to 6 PM the evening before colonoscopy (total, 1 L), followed by at least 16 oz of fluid; 240 mL (8 oz) every 15 min at least 3 to 4 h before procedure (total, 1 L), followed by 16 oz of fluid

OsmoPrep (Salix)

20 tablets (4 tablets every 15 min) at 5 to 6 PM the evening before colonoscopy; repeat with 12 tablets 10 to 12 h later (at least 3 h before procedure)

4-L SF-PEG

Sodium phosphate Tablet

Sodium picosulfate/magnesium citrate Prepopik (Ferring Pharmaceuticals, Inc.)

Step 1: Dissolve 1 packet in 5 oz of liquid and consume, followed by 5, 8-oz glasses of clear liquid at 4 to 6 PM Step 2: Repeat step 1, followed by 3, 8-oz glasses of clear liquid (later the same evening, or 4 to 6 h before the procedure)

Sodium sulfate Suprep (Braintree)

6-oz bottle diluted with 16 oz of water followed by 32 oz water over the next hour; take the evening before colonoscopy and repeat the morning of examination

ELS, electrolyte lavage solution; PEG, polyethylene glycol; SF, sulfate-free a In some cases, these recommendations do not correspond with the FDA-approved dosage.

disease; and 3) use of certain medications, including diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and possibly nonsteroidal anti-inflammatory drugs, may increase the risk for kidney damage. Physicians, nurses, and other health care professionals who are involved in the process of advising patients about bowel cleansing for colonoscopy or other procedures should be thoroughly familiar with these cautions.

The tablet formulation of NaP (Visicol, Salix) was approved by the FDA in 2000. The recommended dose of the initial formulation of Visicol was 48 to 60 g, or 32 to 40 tablets taken in 2 doses. Because of the presence of insoluble microcrystalline cellulose—an insoluble excipient within the NaP tablet that obscured visualization of colonic mucosa in some instances—a residue-free NaP tablet (OsmoPrep, Salix) was developed. OsmoPrep is smaller and has a smooth waxy surface that facilitates swallowing. The recommended dosage is 32 tablets—20 tablets the evening before and 12 tablets 3 to 5 hours before the examination.

Compared with Visicol, OsmoPrep induced smaller changes in electrolyte levels and fewer AEs, including abdominal distention, nausea, pain, and vomiting.20 At least 16 studies have compared the efficacy and tolerability of PEG with that of NaP.8 Overall, the trials demonstrated that NaP is as effective as either the 2- or 4-L PEG-based preparations. In most of the studies, patient tolerance and compliance with bowel preparation was improved with NaP compared with the PEG formulations. These conclusions are supported by the findings of 2 meta-analyses and an evidencebased position statement prepared by the Canadian Association of Gastroenterology.6-8 The use of NaP often is associated with abnormalities in serum electrolytes, including hypernatremia, hypokalemia, hypocalcemia, and hyperphosphatemia.

Although these electrolyte alterations usually are transient and patients are clinically asymptomatic, the FDA received 34 reports of AEs between 1997 and 2002, including 18 serious AEs and 8 fatalities related to the use of NaP preparations.8 A 2005 study reported 21 cases of

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acute phosphate nephropathy, all occurring in patients who recently had taken a NaP bowel preparation.21 Seventeen patients (81%) were female, the mean age of the patients was 64 years, 16 (76%) of the 21 patients had a history of hypertension, and 14 (67%) were taking an ACE inhibitor or an ARB. Although the exact incidence of this complication cannot be quantified accurately, the risk appears to be quite low considering the relatively small number of cases reported and the extraordinarily large number of exposures to NaP (estimated to be in excess of 5 million per year).22 On the basis of its overall safety and efficacy, NaP is an appropriate option for bowel preparation in healthy individuals without any of the contraindications previously discussed. One study suggests that in low-risk patients, hyperphosphatemia following standard NaP doses is related to body weight.23 Accordingly, it may be advisable to recommend a reduced dosage of NaP in low-weight individuals.

a non-inferiority study.28 A total of 603 patients were randomized to receive either picosulfate/magnesium citrate or 2 L of PEG and two 5-mg bisacodyl tablets.

Patients in both study groups completed bowel preparation on the day before colonoscopy. Based on the Ottawa scale, a validated instrument for assessing quality of bowel cleansing, overall bowel cleansing was comparable in the 2 groups, with successful preparation in 78.9% and 78% of patients receiving picosulfate/ magensium citrate and HalfLytely, respectively. Similarly, cleansing within the ascending colon was successful in 83% and 79.7% in the picosulfate/magnesium citrate and HalfLytely arms, respectively. Patient tolerability differed between the 2 study arms, however, more patients in the picosulfate/magnesium citrate group were willing to repeat the bowel preparation than were patients in the HalfLytely group.

Clinical Considerations OTHER BOWEL PREPARATIONS Oral sodium sulfate (Suprep, Braintree) is a newly developed bowel cleansing preparation that contains sodium sulfate, magnesium sulfate, and potassium sulfate, plus flavoring agents in an aqueous form supplied in two 6-oz bottles. Each 6-oz bottle is diluted with water to 16 oz. Sulfate salts have long been used as osmotic laxatives, dating back to the 17th century.

The traditional 4-L PEG preparation (GoLytely) includes sodium sulfate in order to improve bowel cleansing and to minimize fluid shifts and changes in serum electrolytes. Unlike OSP, sulfate salts do not produce renal tubular injury in animal models.26 The efficacy of oral sodium sulfate as a bowel cleansing preparation for colonoscopy has been established in 2 multicenter, randomized, single-blind studies.27,28 The sulfate preparation administered as a split-dose regimen produced better bowel cleansing than standard 4-L PEG and was comparable with MoviPrep. Patient tolerability and the safety profile were comparable for oral sodium sulfate and MoviPrep. The new drug application for Braintreeâ&#x20AC;&#x2122;s oral sodium sulfate was approved by the FDA in 2010.

A dual-action bowel cleansing preparation, which exerts both stimulant and osmotic laxative effect, was recently approved in the United States for bowel preparation before colonoscopy. Prepopik (Ferring Pharmaceuticals, Inc.) contains sodium picosulfate and magnesium citrate. Magnesium citrate, which is formed during the dissolution of citric acid and magnesium oxide, acts as an osmotic agent to draw water into the lumen of the colon and flush it of debris. Sodium picosulfate undergoes bacterial cleavage in the colon, producing the laxative compound bis-(P-hydroxyphenyl)-pyridyl-2-methane, the active ingredient in bisacodyl, which stimulates peristalsis within the large bowel.27 Sodium picosulfate has gained significant popularity in Canada, Europe, and Australia as a bowel cleansing agent. A Phase III, randomized, multicenter, assessorblinded study compared Prepopik and HalfLytely in

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An effective preparation for colonoscopy should consistently produce a high-quality bowel cleansing that is adequate for the detection of all adenomatous polyps. It also must be safe and, ideally, work quickly without producing gastrointestinal (GI) distress. None of the products currently marketed for colonoscopy preparation meet all of these criteria. Although most are effective when properly administered, they require 12 to 24 hours for adequate bowel cleansing, and a significant proportion of patients experience disturbing GI side effects. Consequently, the choice of purgative(s) and the regimen of administration vary considerably among endoscopists.

This section examines strategies for colon cleansing and provides suggestions for improving the quality and safety of bowel preparation. Recommendations for colonoscopy preparation within special patient populations also are presented.

BOWEL PREPARATION: ONE SIZE DOES NOT FIT ALL Some endoscopists prefer to offer all patients a single method of bowel preparation. The benefits of such an approach include simplicity and economy of time, eliminating the need to discuss with the patient more than 1 regimen of bowel cleansing. Among the disadvantages, however, is an inability to adjust for differences between patients. For example, individuals vary in their tolerance and reaction to purgatives.29 The same cathartic may be well tolerated by 1 patient but cause nausea, vomiting, and abdominal cramps in another.

Individuals with chronic constipation may require a more rigorous regimen for adequate bowel cleansing. Differences such as these are best accommodated by offering several bowel preparations, so that each patient can be matched with the preparation that is most likely to be effective, safe, and well tolerated.

When endoscopy is performed in an open-access setting, it is necessary to prescreen patients before selecting a purgative regimen. In our practice, a receptionist or medical assistant completes a brief

medical questionnaire for each patient at the time of scheduling. Information obtained that pertains to the choice of purgative regimen includes the following: a list of current medications and drug/food allergies; a history of heart failure, kidney disease, ascites, or fluid/electrolyte abnormalities; and a history of chronic constipation or incomplete colonoscopy. Based on the responses, a bowel cleansing regimen (NaP vs PEG) is then suggested. When a PEG-based regimen is used, the 2-L PEG preparation is chosen, except for patients with chronic constipation. In this way, the method of bowel cleansing for colonoscopy is selected individually to maximize safety, efficacy, and patient satisfaction.

PATIENT EDUCATION Some endoscopy centers use a patient education program when preparing patients for GI endoscopy.

The topics to be covered include a description of the procedure, possible AEs and complications, and preparation instruction. The effect of bowel preparation on the success of colonoscopy and the importance of compliance with instructions should be emphasized.

This message may be communicated through oneon-one sessions, group meetings, or self-instruction with either a videotape or a computer-based program.

Communicating this information effectively to the patient helps to alleviate fear and anxiety related to the procedure. In a prospective study, an education program reduced the rate of failed preparations among ambulatory patients from 26% to 5%.30 A role for educational intervention in hospitalized patients has not yet been established.31

THE ROLE

OF

HYDRATION

Colon cleansing produces significant volume loss through the GI tract that can result in intravascular volume depletion. The fluid loss during bowel preparation may exceed 2 to 3 L, based on an assessment of hemodynamic parameters and indirect measures such as body weight, serum osmolality, and hematocrit.32 Significant differences in fluid loss between NaP and PEG formulations have been reported in some studies.33-36 Decreases in systolic blood pressure (>10 mm Hg from baseline) and/or postural tachycardia (≥10 beats per minute from baseline) have been described in 10% to 35% of patients who completed a bowel cleansing regimen.33 Additionally, the use of NaP preparations often is associated with changes in serum electrolytes, including transient increases in phosphate and sodium and reductions in calcium and potassium. Despite these changes, serum electrolytes generally remain within the normal range, and patients are clinically asymptomatic. Serious electrolyte disturbances, however, have been reported with both NaP37 and PEG.38 Inadequate hydration is widely believed to play an important role in such complications. Therefore, adequate hydration during bowel preparation should be emphasized, particularly in high-risk individuals, such as the elderly, patients on diuretics or other medications that alter electrolyte

levels, and patients with preexisting electrolyte abnormalities. Patients should be advised to consume at least 64 oz (approximately 2 L) of clear fluid the day before colonoscopy. The use of a carbohydrate-electrolyte solution (eg, Gatorade) has been reported to improve hydration, tolerance for the preparation, and the quality of bowel preparation.39 Patients also should be reminded to continue hydration after colonoscopy; we advise that they consume at least 32 oz (four 8-oz glasses) of clear fluid during the 8 hours following completion of the procedure.40

TIMING IS EVERYTHING The quality of colon preparation—especially in the ascending colon—is closely related to the length of time between completion of preparation and the examination.35,41 Despite diet restriction for 24 hours, optimal cleansing of the colon requires that at least part of the preparation be ingested within 4 to 6 hours of the examination. When more than 6 hours has elapsed, ileal contents begin to fill the right colon, coating the ascending colon with a thin film of chyme that obscures mucosal detail. The American College of Gastroenterology (ACG) supports the concept of split-dosing as a method for enhancing the efficacy of commercial bowel cleansing preparations.42 Split-dose regimens improve the efficacy of both NaP and PEG preparations.9 In a study of 3-L PEG plus bisacodyl, a split-dose regimen (including 1 L on the day of the procedure) increased the proportion of satisfactory preparations (75% vs 66%) and patient compliance, with lower rates of discontinuation.43 Another study sought to determine whether the quality of bowel preparation was better with a 2-L PEG solution administered on the day of (6-8 hours before) versus the evening before (13-16 hours before) the procedure.44 Colon preparation was better (93% vs 72%) and more lesions were detected (2.8 vs 1.9) in the patients who received same-day bowel cleansing than in the patients who received cleansing the evening before the examination.

A randomized trial compared 2 dosing regimens of NaP, one consisting of two, 45-mL doses taken the evening before (3 and 8 PM) the procedure and the other consisting of the same 2 doses with the second dose taken the morning of the procedure (8 PM and 6 AM).45 Patients who received part of their preparation on the same day had better scores for quality of cleansing compared with those who underwent preparation on the previous day (global rating of good/excellent, 80% vs 68%). These and other studies provide convincing evidence that a split-dose regimen, including a single dose of laxative within 6 to 8 hours before the examination, improves cleansing of the mucosa, especially within the right side of the colon, where flat polyps are encountered more often.

When patients are prepared for colonoscopy, it is helpful to distinguish those scheduled for morning procedures from those scheduled for afternoon procedures. Patients undergoing a morning procedure should

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ingest the first dose of cathartic between 4 and 6 PM the night before and the remainder between 3 and 5 AM on the day of the procedure (depending on the time of the procedure and the laxative selected). Patients scheduled for afternoon procedures should take their first dose at 6 to 7 PM the night before and the second dose at 6 to 7 AM the day of the procedure. Some endoscopy units have modified their schedule, booking all colonoscopy procedures beginning at noon. This affords patients the convenience of taking the second dose of laxative at 6 to 7 AM, rather than at 3 to 5 AM. However, a study comparing the outcomes of morning versus afternoon colonoscopy reported significantly higher rates of incomplete procedures and lower rates of adequate bowel preparation in the afternoon.46 In our experience, many patients prefer to undergo colonoscopy in the morning, and most do not object to waking during the night to complete the cleansing regimen.

In Japan, the concept of split-dosing has been taken a step further, with colon cleansing performed entirely on the morning of examination.47 Little or no diet modification is required the day before colonoscopy. Patients are instructed to begin the preparation at approximately 6 AM with 2 to 3 L of PEG. The preparation is complete when the rectal effluent is clear.

A recent study from the United States compared the efficacy and tolerability of a 4-L PEG preparation administered either the evening before or the morning of the procedure in 136 patients undergoing afternoon colonoscopy. The overall quality of bowel cleansing was better in the morning group compared with the evening group (4.73 vs 7.10, respectively; P<0.01), based on the validated Ottawa scale (range 0-14, 0=best). However, there were no differences in polyp detection rates between the 2 treatment groups. Tolerability was better with the morning-only dosing regimen.48 In some instances, the timing of bowel preparation may require alteration in order to accommodate the fasting requirements related to procedural sedation.

There are no universally accepted guidelines on preprocedural fasting, and consequently the literature contains a variety of recommendations on this subject. Guidelines published by the American Society of Anesthesiology state that patients should fast for a minimum of 2 hours for clear liquids and 6 hours for light meals before sedation.49 On the other hand, an evidence-based review by the American College of Emergency Physicians50 states that “recent food intake is not a contraindication for administering procedural sedation and analgesia, but should be considered in choosing the timing and target level of sedation.”

A position statement from the American Gastroenterological Association51 concluded that “there is inadequate evidence to permit the development of absolute requirements for pre-procedural fasting, and the clinician should be guided by the practice parameters provided by various professional societies.”

A prospective study comparing residual gastric volume in patients receiving split-dose versus

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evening-before bowel preparation showed no significant difference between the 2 regimens (19.7 vs 20.2 mL, respectively; P=0.85). Based on the current available data, it is reasonable to recommend that patients undergoing colonoscopy with sedation fast for a minimum of 2 hours before the procedure.52

SPECIAL PATIENT SUBPOPULATIONS Elderly Patients. Individuals aged 65 years and older comprise at least 20% of the patient population undergoing routine colonoscopy and are more likely to have an incomplete preparation.1,53 The reasons for this are multifactorial and include an increased likelihood of constipation, reduced mobility, and difficulty completing the preparation. Elderly patients using NaP also are more likely to manifest hyperphosphatemia as a result of impaired renal function, comorbid illness, and concomitant medications.36 The efficacy, safety, and tolerability of various purgatives in older individuals have been evaluated in several studies. A randomized controlled trial with octogenarians compared NaP with a 4-L PEG preparation.53 The quality of preparation was similar in the 2 groups, with a good or excellent rating in 77% to 81% of patients receiving NaP or PEG, respectively. As anticipated, PEG produced less change than NaP in the clinical parameters of dehydration and laboratory values.

Fewer patients were unable to complete the NaP preparation than the PEG preparation, although the difference did not reach statistical significance. Overall, patients preferred NaP to PEG and were more willing to repeat this preparation in the future. A second study comparing NaP with PEG in elderly patients reported that the overall quality of colon cleansing was comparable for the 2 preparations.54 Furthermore, patients who received NaP tolerated the preparation better than those who received PEG, although the difference was not statistically significant.

Patients With Inflammatory Bowel Disease. In general, patients with inflammatory bowel disease can prepare for colonoscopy with any of the standard bowel purgatives.

An exception is the patient with moderate to severe diarrhea (>6-8 bowel movements per day); for this patient, the dose of cathartic may be reduced or eliminated altogether. NaP preparations can produce aphthoid lesions in the colon, most prominently within the rectum and sigmoid. This endoscopic appearance is distinct and can be readily distinguished from the endoscopic appearances of Crohn’s disease and ulcerative colitis.

Pediatric Patients. In children 12 years or older, an oral NaP solution at a dosage of 45 mL taken twice was probably the most widely used preparation.10 For children 6 to 11 years, the dosage often is reduced to 30 mL taken twice. NaP is not recommended for children aged 5 years and younger. A second method of preparation for children is a PEG-based formulation (MiraLax) administered at a dose of 1.25 to 1.5 g/kg daily for 4 days. In some instances, a laxative, such as bisacodyl, may be added to the regimen 1 day before colonoscopy.

The least commonly used preparation is either a saline or a phosphate enema in combination with a senna laxative.10 In the pediatric population, there are inadequate data assessing efficacy and safety to recommend a particular regimen over another. The PEG-based preparations generally are effective but often are accompanied by abdominal bloating and vomiting.55 A modified PEG preparation that is administered over 4 days appears to be better tolerated but has the potential for disrupting a child’s ability to attend school and participate in other activities.56 Generally, children tolerate oral NaP better than PEG, although hyperphosphatemia often is observed. Practice recommendations for bowel preparation in children undergoing colonoscopy vary. A recent consensus statement prepared by a joint task force within the United States10 concluded that NaP, PEG, and phosphate enema/senna preparations all are “safe and will adequately prepare the child’s colon for colonoscopy.” The authors caution, however, that “in certain circumstances, such as bowel preparation in children, … it may be advisable to adhere to PEG-based solutions because of the risks for occult physiologic disturbances that may potentially contraindicate the use of NaP-based regimens.” Regardless of the regimen selected, it is important to provide children with adequate hydration during the process of bowel preparation. A carbohydrate-electrolyte solution designed specifically for children often is helpful for this purpose.

Patients With Lower Gastrointestinal Bleeding. In most circumstances, patients undergoing colonoscopy for hematochezia must be prepared quickly.57 Colon transit is hastened by the presence of blood, and in most cases, bowel cleansing can be completed within 2 to 3 hours by using 0.5 to 2 L of PEG solution. Patients who are unresponsive or mechanically ventilated may receive the PEG solution through a nasogastric tube.

Patients With a History of Inadequate Preparation or Chronic Constipation. There are no studies to provide the clinician with guidance for preparation of the patient with chronic constipation or a history of inadequate bowel cleansing during a previous colonoscopy. Measures that have been recommended include the following: extending the period of diet modification from 24 to 48 hours; adding oral bisacodyl or senna to a PEG or a NaP regimen; and increasing the total volume of PEG from 4 to 6 L, with administration split over 48 hours (usually 1-2 L on day 1, and 3-4 L on day 2). Additionally, adequate hydration will help to improve the adequacy of cleansing.

Reporting the Quality of Bowel Preparation. The American Society for Gastrointestinal Endoscopy (ASGE)/ACG Task Force on Quality in Endoscopy has recommended that the quality of bowel cleansing be documented for every colonoscopy.58 The terms excellent, good, fair, and poor often are used in clinical practice to characterize the quality of bowel cleansing, without reference to a standardized definition of these qualifiers. Preferably, clinicians should become familiar with one of the validated bowel preparation assessment

Key Points 1. The choice of bowel cleansing regimen for colonoscopy should be based on the patient’s age, health status, comorbid diseases, and personal preference.

2. A split-dose bowel cleansing regimen that includes one dose of laxative within 6 to 8 hours before the examination improves the quality of bowel cleansing, especially within the ascending colon.

3. NaP regimens have demonstrated better efficacy and tolerability than PEG-based preparations for colonoscopy preparation. NaP should be avoided in patients with impaired renal function, congestive heart failure, advanced liver disease, or hypercalcemia.

4. All purgatives have been associated with serious AEs. The risk for complications can be minimized by selecting the most appropriate bowel cleansing regimen for each patient and highlighting the importance of adherence to preparation instructions.

5. The importance of adequate hydration during and after bowel preparation should be emphasized for all patients undergoing colonoscopy.

scales and incorporate it into a structured endoscopy reporting system.59,60 The task force recommends that an examination be considered complete if it enables the detection of colon polyps 5 mm or larger. An incomplete examination that results from poor bowel preparation will often necessitate repeat examination.

Conclusion A substantial number of colonoscopy procedures are suboptimal because of inadequate bowel preparation.

This figure ranges from 17% to 30% in randomized trials and is probably higher in clinical practice. Several patient characteristics have been associated with poor bowel preparation, including a history of constipation, in-patient status, use of antidepressants, and noncompliance with bowel preparation instructions.61,62 An awareness of these factors, combined with strategies designed to optimize the results of purgative regimens and an emphasis on patient education and compliance, will maximize the efficiency of colonoscopy and minimize its risks (Key Points).

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18. Gerard DP, Holden JL, Foster DB, Raiser MW. Clin Translational Gastroenterol. 2012;3:e16. [Epub ahead of print June 21] 19. US Food and Drug Administration. Oral sodium phosphate (OSP) products for bowel cleansing (marketed as Visicol and OsmoPrep, and OSP products available without a prescription). www.fda.gov/ Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm103354.htm.

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AUTHOR DISCLOSURE—Dr. Cohen has served on the advisory board and speakers’ bureau of Salix Pharmaceuticals.