the march 2013 digital edition of gastroenterology and endoscopy news

Heritable ColorectalCancer: What Every Gastro Should Know

BY MONICA J. SMITH

NEW YORK—Although most colorectal cancers (CRC) KK

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

CMS Set To Require Proof ofAdherence to Quality BenchmarksSome Doctors Unaware of Impending Requirements

BY MONICA J. SMITH

LAS VEGAS—Regulations set out by the Affordable Care Act will require phy-sicians 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.

What’s New in Colon Cancer Screening?The Latest in Imaging, Colonoscopes and Other Gadgets

BY MONICA J. SMITH

NEW YORK—In the classic KK

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 colo-rectal 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 ques-tion is how can we do it bet-ter?” said Mark B. Pochapin, MD, who posed thisquestion to attendees of the annual meeting of theNew York Society for Gastrointestinal Endoscopy (NYSGE), held in December.

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

benchmarks, such as adequate colonoscope with-drawal time, good to excellent bowel preparation, a cecal intubation rate of 95% and an adenoma detec-tion rate (ADR) of 15% in women and 25% in men. But some advances in capsule endoscopy, computed

Molecular Subtyping‘Symbolic of NewAge 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

I N S I D E

The Independent Monthly Newspaper for Gastroenterologists gastroendonews.com

Volume 64, Number 3 • March 2013

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

When Colonoscopy Misses: Who or What Is To Blame? Making Colonoscopy the Best It Can Be .............................page 6

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 Heritable CRC, page 24

see Molecular Subtyping, page 28

see Quality Benchmarks, page 14

see CRC Screening, page 10

NEW PRODUCT ANNOUNCEMENTsee page 31 for product information

Uceris Approved For Induction of RemissionIn Ulcerative Colitis

PRODUCT ANNOUNCEMENTsee page 33 for product information

Clinical Challenges and Complications of IBDNow for sale atwww.McMahonMedicalBooks.com

1978 — 35th Anniversary — 2013

NATIONAL COLORECTAL CANCER AWARENESS MONTH

MD h d h b h k h d l h

Colon Segment SUPREP Bowel Prep Kit split-dose

regimen (n=63)

4-Liter Prepsame-day regimen‡

(n=66)§

Cecum 91%† 67%

Ascending 91%† 69%

Descending 92% 84%

Transverse 92% 82%

Sigmoid/Rectum 94% 81%

Clean Freak

Percent of patients with NO RESIDUAL STOOL by colon segment1*

*This clinical trial was not included in the product labeling. †P≤0.02 vs 4-Liter Prep. Statistically signifi cant 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 Kitand MoviPrep®|| were equivalent in colon cleansing2

• Signifi cantly 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 signifi cant difference.

Effective cleansing in all bowel segments, including the right colon

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 preparationfor 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 refl ex, 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 fl uctuations in patients with gout may precipitate an acute fl are. 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 fi nal 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.

MCGEN1722.indd 1 3/2/12 4:01 PM

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

BY CHRISTINA FRANGOU

For the first time, researchers havesuccessfully used a vaccine toprompt an immune response to earlyindications of colon cancer in people at high risk for the disease.

“This prophylactic colon cancervaccine boosts the patient’s natural

immune surveillance, which poten-tially could lead to the elimination of premalignant lesions before their progression to cancer,” co-author Olivera Finn, PhD, distinguished pro-fessor and chair of immunology, Uni-versity 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 cur-rently 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

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 thatmake 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 in39 patients, between the ages of 40and 70 years, who were at increasedrisk for colorectal cancer due to ahistory of advanced adenoma. In 17(43.6%) of the vaccinated individu-als, the vaccine elicited high levelsof anti-MUC1 immunoglobulin G andlong-lasting immune memory.

Researchers said that the lack of response in the other 22 patients waslikely due to already high levels of cells that suppress the immune sys-tem’s ability to fight cancer.

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

The patients received an initial dose of the vaccine, followed by addi-tional shots, at weeks 2 and 10. Once the medication was injected, bloodsamples were drawn to measure the participants’ immune response andsamples were drawn again at 12, 28and 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 andflu-like symptoms after the first injection.

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

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

“The next step will be demon-strating whether that antibody response has any sort of clinicalconsequences. For example, doesit actually protect someone againstdeveloping a colorectal polyp or acolorectal cancer?” Dr. Chan said.

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2013 3NATIONAL COLORECTAL CANCER AWARENESS MONTH

From the Literature

References: 1. Rex DK, DiPalma JA, Rodriguez R, McGowan J, Cleveland M. A randomized clinical study comparing reduced-volume oral sulfate solution with standard 4-liter sulfate-free electrolyte lavage solution as preparation for colonoscopy.

gGastrointest Endosc. 2010;72:328-336. 2. DiPalma JA, Rodriguez R, McGowan J, Cleveland MvB. A randomized clinical study evaluating the

gg

safety and effi cacy of a new, gg p p

reduced-volume, oral sulfate colon-cleansing preparation for colonoscopy. py

Am J Gastroenterolg

. 2009;104:2275-2284. ll 3. SUPREP Bowel Prep Kit [package insert].gy

Braintree, MA: Braintree Laboratories, Inc; 2010.

BRIEF SUMMARY: Before prescribing, please see full Prescribing Information and Medication Guide for SUPREP® Bowel Prep Kit (sodium sulfate, potassium sulfate and magnesium sulfate) Oral Solution.

p g pp gINDICATIONS AND USAGE: An osmotic laxative indicated for cleansing of the colon as a preparation for

p pp

colonoscopy in adults.gg

CONTRAINDICATIONS: Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic g p pg p

colitis and toxic megacolon, gastric retention, ileus, known allergies to components of the kit. py gg

WARNINGS AND PRECAUTIONS: SUPREP Bowel Prep Kit is an osmotic laxative indicated for cleansing of the colon as a preparation for colonoscopy in adults. Use is contraindicated

g g g pg g g pin the following conditions:

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gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergg p p pyg p p py

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, severe active ulcerative colitis, impaired renal function or patients taking medications that may affect renal function or electrolytes. Pre-dose and post-colono

p g p y y p g g g g pp g p y y p g g g g pscopy ECG’s should be considered

in patients at increased risk of serious cardiac arrhythmias. Use can cause temporary elevations in uric acid. Uric acid fl uctup p g y y pp g y y p

ations in patients with gout mayprecipitate an acute fl are. Administration of osmotic laxative products may produce mucosal aphthous ulcerations, and there hav

p y p yy p ye been reports of more serious

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cases of ischemic colitis requiring hospitalization. Patients with impaired water handling who experience severe vomiting shoulp p p y p pp y p p

d be closely monitored including measurement of electrolytes. Advise all patients to hydrate adequately before, during, and after use. Each bottle must be dilut

q g p p g p gq g p p g p ged with water to a fi nal volume of

y gy gtt

16 ounces and ingestion of additional water as recommended is important to patient tolerance.y p y q y gy p y q y g

Pregnancy: Pregnancy Category C. Animal reproduction studieshave not been conducted. It is not known whether this product can cause fetal harm or can affect reproductive capacity.

g p pg p p g y g y gPediatric Use:

y p Safety and

effectiveness in pediatric patients has not been established. Geriatric Use: Of the 375 patients who took SUPREP Bowel Prep Kit in clinical trials, 94 (25%) p p y y

were 65 years of age or older, while 25 (7%) were 75 years of age or older. No overall differences in safety or effectiveness op p p p

f SUPREP Bowel Prep Kit administered as a split-dose (2-day) regimen were observed between geriatric patients and younger patients.

g gg gDRUG INTERACTIONS: Oral medication

administered within one hour of the start of administration of SUPREP may not be absorbed completely. p y g g p y g pp y g g p y g

ADVERSE REACTIONS: Most common adversereactions (>2%) are overall discomfort, abdominal distention, abdominal pain, nausea, vomiting and headache.

y p yOral Administration: Split-Dose (Two-Day)

Regimen: Early in the evening prior to the colonoscopy: Pour the contents of one bottle of SUPREP Bowel Prep Kit into the mixing container provided.p gp g p y

Fill the container with water to the 16 ounce fi ll line, and drink the entire amount. Drink two additional containers fi lled togg y g p pyg p p p

the 16 ounce line with water over thegg

next hour. Consume only a light breakfast or have only clear liquids on the day before colonoscopy. Day of Colonoscopy (10 to 12 hours after the evening dose): Pour the contents of the second SUPREP Bowel Prep Kit into the mixing container provided. Fill the container with water to the

y g y q y pyg y q y y pypy 16 ounce fi ll

line, and drink the entire amount. Drink two additional containers fi lled to the 16 ounce line with water over the next hour. Cgg p g pp g p

omplete all SUPREP Bowel Prep Kit and required water at least one hour prior to colonoscopy. 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

y. Distributed by Braintree Laboratories, Inc. Braintree, MA 02185

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

©2012 Braintree Laboratories, Inc. SU-13280T January, 2012

For additional information, please call 1-800-874-6756 or visit www.suprepkit.com

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 20134

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Vol. 64, No. 3 March 2013

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

Re: “Linzess, New Drug for IBS and Chronic Constipation, Now Available in Pharmacies.” Gastroenterology & Endoscopy News January 2013;64:38In 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 constipa-tion, is indicated for individuals “who do not respond to standard treatments.” This

phrase is inconsistent with the FDA-approved indication for Linzess, whichdoes not contain this stipulation.

“It is not necessary to fail another therapy before begin-ning treatment with Linzess,” noted Douglas S. Levine,MD, vice president of Medical Scientific Affairs, IronwoodPharmaceuticals, 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.

CorrectionRe: “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 contrib-uted to the aforementioned article.Dr. Rubin is professor of medicine,co-director of the Inflammatory Bowel Disease Center, and associatesection chief for educational pro-grams, Section of Gastroenterology,Hepatology and Nutrition at The University of Chicago Medicine.

AGA Says…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 “Ameri-can Gastroenterological Associa-tion Medical Position Statement on Constipation” states:

“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.”

[Gastroenterology 2013;144:211-y217; available at http://down-load. journals.elsevierhealth.com/pdfs/journals/0016-5085/PIIS0016508512015454.pdf.]

ekhinVia website on Jan. 30, 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2013 5

‘Astonishing’ Data onMetformin for HCCBy 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 stud-

ies. Results from an American case–control study and a

GI Roundtable 2012GI Rouundenterologists Discuss Challenges,GasttroentGast oe e

Future of GI Health CareChannges, Fu

Studies Attempt To Defi ne PatientPreferences for CRC Screening

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 recommen-

dations might be enhanced if certain

barriers could be overcome. Some

believe that computed tomographic

colonography (CTC) might be one

way to improve adherence to screen-

ing recommendations.

This topic has been the aim of

several recent clinical research sur-

veys. 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 high-

quality care,” said David Weinberg, MD, MSc, chair-

man 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 Colonos-

copy in 5 years?”

“Clearly, patients who are well versed at an appro-

priate level, understand their treatment options and

First Guideline onNAFLD PublishedBy Christina Frangou

Three leading American gastroenterology societies have

published a new guideline on the diagnosis and man-

agement 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

I N S I D E

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,


see Metformin, page 26

see NAFLD Guideline, page 28

see GI Roundtable, page 50

see Patient Preferences, page 7


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EXPERT’S PICKS Best of Digestive Disease Week (DDW): Infl ammatory Bowel Disease (IBD)

Ellen J. Scherl, MD, provides an overview of IBD research presented at the DDW meeting............................................page 10

Complications of Biologic Therapy for IBD

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

40th ANNIVERSARY1972–2012

HEPATOLOGY I N F O C U S

Ellen J. Scherl, MD

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When Colonoscopy Misses: Who or What Is To Blame?Making Colonoscopy the Best It Can Be

BY MONICA J. SMITH

LAS VEGAS—Researchers at last year’s American Col-lege 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 differ-ences in CRC detection were based predominantly on biological factors or endoscopist-related issues.

Right- vs. Left-Sided CRCsThe symposium began with a discussion of compara-

tive advantage regarding colonoscopy and flexible sig-moidoscopy, 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 pro-duce 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 prep-aration 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 proce-dure was associated with a reduction in CRC mortal-ity of 26%, and a reduction in the incidence of CRCof 21%; however, there was little difference betweenthe screened group and the usual care group regard-ing proximal cancers (Schoen RE et al. N Engl J Med2012;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 cor-rectly point out that flexible sigmoidoscopy had no benefit in the right colon,” he said. “That being said, many in the sigmoidoscopy arm did go on to get a fulldcolonoscopy because of the findings of polyps on flexible sigmoidoscopy; therefore, the lack of any benefit to theright 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 right-sided colon cancers. One such study showed no protec-tive 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 Oncol2012;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. Robert-son noted.

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

Interval Cancers—Biology or Missed Lesions?Given that the right side of the colon differs from

the left in terms of pH level, bacterial composition andapoptotic index, it is plausible that it could be a host to different types of lesions. Aasma Shaukat MD, asso-ciate professor, University of Minnesota, Minneapolis,explained the three predominant mechanisms throughwhich CRC develops and progresses: chromosomalinstability (CIN), microsatellite instability (MSI) andthe CpG island methylator phenotype (CIMP).

CIN is understood as the traditional adenoma-car-cinoma pathway—a slow-growing process that takesanywhere from eight to 20 years.

“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 intervalcancers.

“Microsatellites are short, repetitive sequences of DNA that are essentially the housekeeping genesthat perform DNA checks and repairs,” Dr. Shaukat explained. Loss of DNA mismatch repair activity leadsto cancers that have a specific phenotype. The mis-match repair defect is “associated with hypermethyl-ation of the mismatch repair gene promoter, whichresults in inactivation of the gene, an overlap with theCIMP pathway.”

Another factor in this pathway is the BRAF gene,Fwhich is involved in the RAS/RAF pathway of cellproliferation.

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

Researchers at the University of Minnesota extractedDNA from interval cancers and noninterval cancers andperformed molecular marker testing.

“Interval cancers were three times more likely to beMSI-positive, two-and-a-half times more likely to havea CIMP-positive phenotype, and MSI cancers wereseven times more likely to be associated with BRAFmutations,” Dr. Shaukat said.

Interval cancers also were more likely to be located in

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

Biology is not the only factor at play in the develop-ment of interval cancers.

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

“This was more than we would expect than if it werehappening just by chance,” she said. “Interval cancerswere 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 werenot detected or were incompletely resected.”

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

“We know how often adenomas are found in peoplewho come in for screening; we have good evidenceabout how often we find polyps of different sizes; weknow from tandem colonoscopy studies how often wemiss polyps of various sizes; and finally, pathology stud-ies tell us how often we find cancers in polyps of differ-ent sizes,” he said.

Based on these factors, Dr. Robertson and his col-leagues calculated that 1.8 per 1,000 people who undergoscreening colonoscopy had a missed adenoma harboring cancer or transitioning to cancer during a short intervalafter 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 andtechnique play a larger role than biology based on varia-tion observed in an endoscopist’s skill and performance.

“We know from studies with large numbers of patientsand endoscopists that endoscopists don’t perform equally well in preventing interval cancers,” Dr. Robertson said.“There are really only two explanations for this: Onepossibility is that some endoscopists are just unlucky

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 20136 NATIONAL COLORECTAL CANCER AWARENESS MONTH

‘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

and happen to inherit all the patients with biologically and happen to inherit all the patients with biologicallfast-growing lesions; the other is that there is something different about how we apply our technology.”

Highlighting this disparity, a study of 186 endosco-pists 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 Med2010;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. Gastroenterology 2013;144:74-80).y

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 OutcomesIf preventing right-sided CRCs is the comparative

advantage of colonoscopy, it is critical for patients, and will be increasingly important to payers, that gastroen-terologists 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 medi-cine and chief, Division of Gastroenterology and Hepa-tology 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

increased detection of these subtle, sessile-serrated pol-yps and other difficult lesions in the right colon. But we do have some evidence that there is a tight correla-tion 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 (Bar-clay RL et al. N Engl J Med 2006;355:2533-2541). “I dwould guess there is still significant variation.”

Barclay et al found that endoscopists with a colono-scope 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 endo-scope withdrawal time found that the mandate did little to improve ADRs (Sawhney MS et al. Gastroenterology2008;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 ran-domly assigned to undergo EQUIP training (Coe SG et al. Am J Gastroenterol 2013;108:219-226). Endosco-pists 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 un-trained) 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

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. Wal-lace 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,” (Subrama-nian V et al. Endoscopy 2011;43:499-505). Narrow-band yimaging shows a similar, but even weaker, correlation with improvements in ADR (Dinesen L et al. Gastroin-test Endosc 2012;75:604-611).c

Most of the newer instruments include a high-defini-tion endoscope with some type of optical enhancement,which may be of greater benefit than any one technol-ogy alone (Gross SA et al. Endoscopy 2011;43:1045-y1051), Dr. Wallace noted, and clear colonoscope capscan improve cecal intubation time to a degree, but offer little benefit in terms of ADR (Ng SC et al. Am J Gas-troenterol 2012;107:1165-1173).l

One improvement in colonoscopy—split-dose bowelpreparation—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 bet-ter, and it also results in a cleaner bowel (Kilgore TW et al. Gastrointest Endosc 2011;73:1240-1245).c

Managing ExpectationsDespite the strictest adherence to quality param-

eters, interval cancers will still occur in the patientsof even the most meticulous endoscopists. Therefore,endoscopists should be sure to discuss the possibility of missed lesions with patients during the informedconsent process. Endoscopists should document that the discussion occurred, that the optimal techniquewas used and that an optimal examination was per-formed. Documenting these three things, as well asoutcomes, will be important for protecting the endos-copist, and in the future, will be tied to reimburse-ments, 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 theguidelines. Then, if polyps are removed during colonos-copy, it’s really important that you follow appropriatesurveillance guidelines.”

For interval cancers that occur despite the imple-mentation of best practices, endoscopists might want toconsider tumor testing for MSI. A local pathologist or hospital can conduct immunohistochemistry testing quiteinexpensively or DNA testing of the tumor tissue itself.

“If MSI is positive, you can think about BRAF test-Fing of the tumor, which will tell you whether this wasa sporadic, microsatellite unstable cancer, or maybe ahereditary cancer,” Dr. Shaukat said.

“Communicate with your patients, all the way fromconsent to getting the pathology report, and discussindications for their family members if findings merit that discussion,” she said. ■


‘We’ve been a little stunned over the

last four or fi ve years that we’re less

effective than we thought we were. But

also very encouraged by new data that

show we can improve our ability to detect

advanced—and all—adenomas.’—Michael B. Wallace, MD, MPH

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.

123218_Nov_Sando_GI_Awrnss_KING.v1.indd 1 10/18/12 10:34 AM

MCGEN1849.indd 1 10/22/12 8:46 PM

What’s behind the symptoms?

Carcinoid Syndrome Can Be Deceptive

Early diagnosis of carcinoid syndrome is essential.

The most common symptoms of carcinoid syndrome are severe diarrhea, fl ushing,

abdominal pain, cardiac disease, wheezing, and telangiectasia.1,2

To learn more, visit www.carcinoidfacts.com.

Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936-1080 ©2012 Novartis 9/12 CAR-1052009

123218_Nov_Sando_GI_Awrnss_KING.v1.indd 1 10/18/12 10:34 AM

MCGEN1849.indd 1 10/22/12 8:46 PM

tomography colonography (CTC), enhanced visual-ization of colonic mucosa and improved colonoscopesmight make it easier to find what endoscopists aremissing.

Dr. Pochapin, who is director of the Division of Gas-troenterology, 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 ColonoscopyThe PillCam COLON 2, which is approved for use

in Europe but is not yet cleared for marketing or distri-bution in the United States, is basically the same tool approved for visualization of the small bowel but modi-fied 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 hasa 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. Pochapinexplained. “If the PillCam calls it 6 mm but it’s actu-ally 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 nontherapeu-tic 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 bur-densome than the regimen recommended for patients undergoing standard colonoscopy.

“Patients need to take 2 L of poly-ethylene glycol in the evening, 2 L inthe morning, and upon reaching thefirst component of the small bowel, thecapsule sends a signal to the device thepatient is wearing telling them to takeyet another component of prep—30 mLof 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 forwardmotion to get that capsule through thecolon and visualize it so beautifully inthe liquid. But what the typical Ameri-can patient wants is to just swallow a pilland be done with it,” he noted.

CT ColonographyCTC also provides spectacular images

when bowel preparation is excellent, andit does quite well at revealing adenomas.

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

But, despite the media-driven gen-eral public perception of CTC as a gen-tler alternative to colonoscopy, it stillrequires significant preparation, and it’snot entirely noninvasive—it requires theplacement of a small tube in the rectumto provide insufflation, and that insuffla-tion can be uncomfortable for patientsnot under sedation. Again, colonoscopy is required for patients with positiveCTC results.

“We need to recognize where CTC


CRC Screeningcontinued from page 1

Full Spectrum Endoscope Shows More of the Colon Than Seen Before

BY MONICA J. SMITH

A new colonoscope is aiming tomake inspection of the sinuousanatomy of the colon easier by pro-viding a more comprehensive view.

Ian Gralnek, MD, of The Ruthand Bruce Rappaport Faculty ofMedicine, Technion-Israel Institute of Technology, Haifa, Israel, and his colleagues have conducted two studies investigating the FullSpectrum Endoscope, which aimsto improve ADRs by giving endos-copists side views of the colonic mucosa, in addition to the standard front view.

“The [Full Spectrum Endoscope]maintains all of the standard colo-noscope techniques and technolo-gies we are familiar with,” said Dr.

Gralnek, who is chief of the Depart-ment of Hospital-Wide AmbulatoryCare Services and senior physi-cian in the Department of Gas-troenterology, Rambam HealthCare Campus, Haifa, Israel. “But it has three lenses, on the front andsides 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, whichshow the right and left lenses on the scope tip.”

The instrument, developed byPeerMedical, 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 arestandard to the colonoscopesendoscopists use in everydaypractice. The difference is that FullSpectrum Endoscope operates intwo modes of view: a forward viewthat provides 160 degrees of visu-alization, and a full-spectrum modethat allows up to 330 degrees ofvisualization.

In one study, Dr. Gralnek and hiscolleagues evaluated the detec-tion of embedded metal beads in acolon model by 37 gastroenterolo-gists using the standard view or thefull spectrum view of the Full Spec-trum Endoscope.

“We found it highly statisticallysignificant that many more of themetallic beads were found withthe wide view than with the stan-dard viewing mode,” Dr. Gralnek

noted. Furthermore, the gastroen-terologists detected 85% of beadspurposely hidden on the proximalsides of folds using the full-spec-trum mode compared with about35% in the standard view. The fullstudy will be published in Gastroin-testinal Endoscopy.

In another study, an institu-tional review board–approved pilotstudy to establish the feasibilityand usability of the Full SpectrumEndoscope, the researchers looked at cecal intubation rates, time toreach the cecum, total proceduretime, success of therapeutic inter-ventions, adverse events and sub-jective endoscopist evaluation in procedures for screening, surveil-lance or diagnostic evaluation in 50 patients, all of whom under-went standard bowel preparation,

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 alter-native that needs further study.”

Advances in Imaging TechnologyIt 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 defi-nition and autofluorescence) have yet to prove their mettle.

“A lot of us use NBI, a technology in which the 415- and 540-mm wave-lengths 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 hemo-globin 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 pol-yps—and more significant polyps?”

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

Conversely, a small study published in 2008 showed an advantage for NBI in patients with hereditary non-polyposis CRC, allowing the detection of more adeno-mas 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 screen-ing, it might not make much of a difference,” Dr. Pochapin concluded.

Trimodal technology, which combines high defini-tion, 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 adeno-mas compared with standard colonoscopy. The benefits, however, do not extend as much to screening examina-tions 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 average-risk patients undergoing screening colonoscopy compared with 35.7% and 55.4% more adenomas for higher-risk


conscious sedation and a follow-upphone call.

The endoscopists achieved100% cecal intubation, with a meantime to cecum of 3.1 minutes. Meanwithdrawal time and mean totalprocedure time were 12.7 minutesand 15.3 minutes, respectively.Subjective assessment of ease ofuse, ease of scope advancement,quality of images, ability to performpolypectomy and other aspects was consistently “excellent” or “good.” The endoscopists alsowere not technically challenged byany aspect of the modified colono-scope or its multiple monitors.

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

brain actually picks up when polypsshow up on the sides.”

A randomized controlled trial iscurrently under way comparing theFull Spectrum Endoscope with astandard colonoscope for the incre-mental detection of adenomas.

“I truly believe this technologyhas the ability to change the waywe do colonoscopy,” Dr. Gralneksaid. “My opinion is that this is atool that will improve our ability toperform high-quality colonoscopyand improve our ADR, and I alsothink it will allow people who maynot be doing perfect colonoscopyto perform better.”

Dr. Gralnek is a paid consultant forPeerMedical, Ltd., which funded the pilot

and feasibility study.The Full Spectrum Endoscope from EndoChoice (not available for sale)Photo courtesy of EndoChoice

see CRC Screening, page 18

‘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

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

BY TED BOSWORTH

LAS VEGAS—The efficacy of a newly licensed, low-volume bowel preparationfor colonoscopy was found to be similar to that of conventional preparations, witha notably higher rate of patient tolerabil-ity, according to recent studies.

The new bowel preparation, marketed under the brand name Prepopik (Fer-ring 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 vol-ume of 2 L.

“The key question that was asked was how easy or difficult was it to con-sume the prescribed bowel prepara-tion,” 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.

Researchers presented data from two randomized Phase III trials that com-pared 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 (Half-Lytely and Bisacodyl Tablets Bowel PrepKit [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 totake, compared with 16.1% and 21.1%, respectively, of patients consuming the2-L PEG plus bisacodyl preparation. When responses for very easy and easywere combined, the difference in patient satisfaction between the two prepara-tions was significant (87.4% vs. 37.2%; P<0.001).

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 fol-lowed 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 bisaco-dyl 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 numeri-cally (but not significantly) greater efficacy of P/MC versus the compara-tor fulfilled the non-inferiority criteria (83% vs. 79.7%, respectively). On the Ottawa Scale, P/MC was numerically


‘The key question that was

asked was how easy or

diffi cult was it to consume the

prescribed bowel preparation.’

—Philip O. Katz, MD

Better for your patientsBetter for you

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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: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.

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CO2 instead of room air for GI endoscopy?

nfidence Convenience Comfort Cost Effective Confidence Convenience Comfort Cost Effective Confidence Convenience Comfort Cost Effective Confi

onfi

superior on two of the three scales evaluated, but the differences were not statistically significant. In contrast, dif-ferences in ease of use between prepa-rations were substantial. For example,although 17.4% of those taking PEG/bisacodyl found this preparation dif-ficult or very difficult to consume, only t1% of patients who used the P/MCregimen rated it as difficult or very dif-ficult (t P<0.001). When questionedabout taste, 73.7% of participants foundP/MC to be excellent or good versusd27.8% of those taking PEG/bisacodyl (P<0.001).

The results of the split-dose trialwere similar, although the efficacy of P/MC was consistently higher. In thistrial of 603 patients, the second dose of P/MC was taken on the day of the colo-noscopy. This regimen was compared with the standard day-before protocolof PEG/bisacodyl. According to Doug-las K. Rex, MD, director of endoscopy,Indiana University School of Medicine,in Indianapolis, who presented theseresults, significantly more patientsachieved successful bowel cleansing with P/MC (84.2%) compared withPEG/bisacodyl (74.4%), based on theAronchick Scale (P<0.05). On theOttawa Scale, all three measured out-comes favored P/MC. The split-dose P/MC was characterized as “superior” for bowel cleansing compared with theday-before PEG/bisacodyl regimen.Additionally, more patients in the split-dose trial preferred P/MC compared with PEG/bisacodyl.

According to Dr. Rex, the incidenceof adverse events (AEs) was low in bothgroups. The most common AEs associ-ated 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 improvepatient satisfaction—an advantage that might have implications for complianceoutside of a clinical trial.

Asked to comment on the results,Brintha K. Enestvedt, MD, of theDivision of Gastroenterology, TempleUniversity, Philadelphia, said that asplit-dose 4-L PEG preparation might have provided a more appropriate com-parison, given evidence that this regimenis more effective.

“A recent meta-analysis we did withrandomized controlled trials clearly demonstrates that split-dose 4-L PEG issuperior in bowel cleansing efficacy ver-sus all its comparators, including some2-L preparations,” said Dr. Enestvedt,referring to a study that was publishedlast year (Enestvedt et al. Clin Gastro-enterol Hepatol 2012;10:1225-1231).lHowever, “the meta-analysis did not

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 colo-noscopy,” Dr. Enestvedt said, and palat-ability is important, “especially since it influences compliance with and quality of screening exams.

“There is a need for rigorous com-parisons in which patient satisfac-tion 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 advi-sor, consultant or a member of the speaker’s bureau for AstraZeneca Pharmaceuticals,

Eisai Inc., Intec Pharma, Ironwood Phar-maceuticals, 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 Scientifi c, Braintree Laboratories, Inc., Check-Cap, Ltd.,

Epigenomics AG, Exact Sciences Corpora-tion, Given Imaging Ltd. and Olympus

Corporation.

Brintha K. Enestvedt, MD, reported no confl icts of interest.


Frank ChapmanChair, AAAHC Standards Committee

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At an American College of Gastroen-terology (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 Gastrointesti-nal and Epidemiology Training Program, discussed the measures that the Centers for Medicare & Medicaid Services (CMS) might use to gauge the quality of colonos-copy screening for colorectal cancer (CRC).

“CMS will probably require endosco-pists 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 QualityAchieving 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 [Gastroenterology 2011:140:65-72],” Dr.ySchoenfeld said. In this study, researchersreviewed a database of the Ontario Can-cer Registry to identify people with inter-val cancers, identified as CRC occurring six to 36 months after a colonoscopy, andthen stratified the data based on cecal intubation rates.

“Not surprisingly, the doctors whoachieved a cecal intubation rate of 95% or higher were significantly less likely to have patients develop interval coloncancer in the proximal colon compared with patients whose physicians achieved cecal intubation rates of 80% or less,” Dr. Schoenfeld said. Patients whosedoctors achieved a high cecal intuba-tion rate were 28% less likely to have

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

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 Med2010;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.

“At this time, however, a lot of endos-copists don’t even calculate … the ADR,” Dr. Schoenfeld said. “It’s easier to crawlbefore you walk, and easier to walk beforeyou run, so we’re just trying to encouragegastroenterologists to calculate and report a basic ADR.”

Complication rates are another mea-sure of quality. In prospective colonoscopy studies, the pooled rate of colon perfora-

tion is much less than one in 1,000. Lessclear, however, is how long gastroenter-ologists should monitor patients after acolonoscopy.

“We usually know if a perforationhas occurred at the time of colonoscopy or within 24 hours, but most colonos-copy complications, like post-polypec-tomy bleeding, may not occur for sevento 14 days after the procedure,” Dr.


Quality Benchmarkscontinued from page 1

Recent Studies Focus on Quality of Bowel PreparationBY MONICA J. SMITH

Critical to the quality of a colonoscopy forcolorectal cancer (CRC) screening is effectivebowel preparation. Several papers and posters,presented at the 2012 American Collegeof Gastroenterology annual scientificmeeting, examined approaches that mayenhance this process. Gastroenterology& Endoscopy News invited Lawrence B.Cohen, MD, clinical professor of medi-cine, Mount Sinai School of Medicineand consultant, New York Gastroenter-ology Associates, both in New York City,to comment on some of these papers.

Bowel Prep PalatabilityThe regimens recommended for ensuring a

quality bowel preparation require patients to ingestlarge 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 MedicalCenter in Lebanon, and colleagues randomizedpatients scheduled for colonoscopy to receive 4-L split-dose PEG-ES, with or without the addition of sugar-free mentho-lyptus drops, to assess theeffect of the drops on tolerability and palatabilityof the preparation, which was assessed on a five-point scale (1 = disgusting; 5 = tasty).yy

Of the 99 patients who completed the study, the 49 patients in the mentho-lyptus group registered

significantly higher palatability scores than thosewho did not receive the drops; they also weremore likely to have good or excellent bowel prep-arations than the control group (92% vs. 82%,respectively). Researchers concluded that theaddition of sugar-free mentho-lyptus to PEG-ES

is safe and effective, and improves toler-ability and bowel cleansing.

Dr. Cohen:

The authors demonstrated that a simple andinexpensive flavor additive—sugar-free mentho-lyptus—combined with 4-L PEG-ES, improvesboth bowel preparation quality and patient tol-erability. Similar studies in other cultures andgeographic regions are necessary to determinewhether these findings are generalizable. Evalu-ation also is required to establish that the additive

is safe and produces no clinically importantchanges in fluid and electrolyte balance.

Combining PEG With Sports DrinksGastroenterologists worry about the risks for

hyponatremia associated with the combinationof PEG and non–FDA-approved purgative–sportsdrinks (SD), popular among some patients.Rebecca Matro, MD, and her colleagues at theThomas Jefferson University Hospital in Philadel-phia, conducted a randomized prospective trialto compare serum electrolytes in 180 patientstaking PEG-ES and 184 patients taking PEG withan SD before undergoing a colonoscopy.

Seven patients in the PEG-SD group and fourin the PEG-ES group developed hyponatremia,with changes in electrolyte baseline being smallbut slightly significant in the PEG-SD group. Theresearchers concluded that PEG-SD did notsignificantly increase the risk for hyponatremia,which was rare in any case, and that preparationcompletion, quality and side effects were similarin both groups (paper 21; financial support pro-vided by Salix Pharmaceuticals).

Dr. Cohen:

Dr. Matro and her colleagues designed thisstudy to answer the clinical question: “Does theabsence of electrolytes in a PEG-based bowelpreparation increase the risk for hyponatremiacompared with a conventional PEG-ES prepara-tion?” Although the study failed to show mean-ingful differences in serum electrolytes among

‘The authors demonstrated

that a simple and inexpensive

fl avor additive—sugar-free

mentho-lyptus—combined with

4-L PEG-ES, improves both

bowel preparation quality and patient

tolerability.’—Lawrence B. Cohen, MD

‘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

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

Indications for colonoscopy andadherence to guidelines for screening and surveillance also will factor intowhether an endoscopist meets quality standards.

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

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

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 recom-mended, so endoscopists hope that they

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 colonos-copy,” Dr. Schoenfeld said.

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

“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

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.

Economic EffectsDisregarding these potential changes

could have economic consequences downthe road, according to David A. Johnson,MD, professor of medicine and chief of gastroenterology, Eastern Virginia Medi-cal School, Norfolk.

“Quality indicators continue to evolve and will be instrumental in defining not only physician quality, but physician pay-ment,” he said. “The emphasis on value-based purchasing as we move forward in a new health care reform era will demand that [physicians] show that their perfor-mance 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 beestablished 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 colonos-copy,” Dr. Schoenfeld explained. “But by 2015, a formula is supposed to be imple-mented that will measure how well you do on quality indicators, and that will


see Quality Benchmarks, page 16

patients using PEG-SD compared with those taking an FDA-approved preparation of PEG-ESplus ascorbic acid (MoviPrep, Salix Pharmaceu-ticals), the study population (N=364) was insuf-ficient in size to exclude a small but importantrisk for hyponatremia.

Video Education of PatientsIdeally, all endoscopists would have the time

to thoroughly explain to their patients how to take their bowel preparation and why it’simportant, but in a time-crushed office, othereducational tools may be useful to ensure thatpatients have the information they need. To investigate the effect of an instructional videoon the quality of bowel preparation for colo-noscopy, Sateesh R. Prakash, MD, of South-ern Gastroenterology Specialists Research and Educational Institute, LLC, Locust Grove, Ga.,and his colleagues randomized 127 patientsundergoing colonoscopy to watch a video about bowel preparation, or to undergo theprocedure without the video.

The researchers found a significant differencein bowel preparation quality between the patients who watched the video and those who receivedonly written instructions. The video group hadsuperior 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 instructionalvideo significantly improved the quality of bowel preparation.

Dr. Cohen:Up to 25% of colonoscopies in the United

States are reported to have an inadequate bowel preparation. Meth-ods for improving the quality of bowelpreparation include patient prescreen-ing designed to identify individualswith an increased risk for poor-quality preparation, with a split-dose bowelregimen. The studyby Dr. Prakash and his colleagues confirmsprevious work that video patient educationimproves the outcome of bowel preparation inambulatory patients undergoing colonoscopy. Similar findings have been observed using a high-quality patient brochure (Spiegel B et al. Am J Gastroenterol 2011;106:875-883). It seems that a little effort up front pays big dividends on the back end when it comes to the quality ofbowel preparation for colonoscopy.

Water Exchange ColonoscopySplit-dose bowel preparations may be more

tolerable for patients and result in a more thor-ough bowel preparation, but they are not fool-proof. To evaluate the role of the water exchange method of colonoscopy in salvage cleansing andimproving bowel preparation, Leonard Fischer, MD, of Gastrointestinal Medicine Associates,

Fairfax, Va., and his colleagues trained endos-copists in water immersion and water exchangein two coaching sessions, six months apart,

and evaluated 348consecutive patientsreceiving a stan-dard split-dose andundergoing the waterexchange method ofcolonoscopy.

They found thatstructured coachinghelped endoscopistsacquire satisfactorysalvage cleansing

maneuvers with a high final cecal intubationrate and little prolongation of insertion times.

Dr. Cohen:

Poor bowel preparation results in anincreased risk for missed lesions in colonos-copy. Consequently, updated guidelines onCRC screening recommend that colonoscopybe repeated within one year when the bowelpreparation is rated poor (Lieberman DA etal. Gastroenterology 2012;143:844-857). Dr. yFischer and his colleagues report that waterexchange may be useful for salvaging an inad-equate bowel preparation. It remains unproven,however, whether aggressive water lavage andexchange improves the quality of preparationenough to eliminate the need for repeat exami-nation within a short interval. More data on thisimportant topic are awaited.

‘The study by Dr. Prakash and his colleagues

confi rms previous work that video patient

education improves the outcome of

bowel preparation in ambulatory patients

undergoing colonoscopy.’—Lawrence B. Cohen, MD

‘Quality indicators continue to evolve and will be

instrumental in defi ning not only physician quality,

but physician payment.’—David A. Johnson, MD

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

Some reporting demands already have been established by the CMS. Asof Oct. 1, 2012, physicians are requiredto report on the presence or absence of events occurring in ambulatory surgery centers such as burns or falls, transfer toa 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. John-son 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 sur-veillance—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 surgi-cal referral for polyps, incomplete polyp-ectomy, 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.

Johnson said. “Quality measurement is nothing in the absence of responding todeficiencies in a way that is nonconfron-tational and collaborative.”

Addressing DeficienciesIn February 2012, results of the long-

term National Polyp Study (O’Brien MJ et al. Gastroenterology 1990;98:371-379) confirmed that having a colonoscopy not only protects against CRC, but alsoreduces 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 respon-sibility 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 Indianapo-lis. “If you keep that in mind, you gen-erally 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 stan-dard 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 (Impe-riali G et al. Endoscopy 2007;39:314-318).yIn this study, the approach did not increasethe average PDR of the group; however, a different study showed that endoscopists appear to conduct a better quality colo-noscopy when they know they are being recorded on video compared with when


Quality Benchmarkscontinued from page 15

‘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 defi ciencies in a way that is nonconfrontational and collaborative.’

—David A. Johnson, MD

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

The Endoscopic Quality Improve-ment Program, a study conducted by Mayo Clinic, combines education andtraining in optimal techniques to helpimprove performance. Endoscopists whounderwent the study’s intensive training session on the spectrum of disease andoptimal detection techniques experiencedan increase in ADRs from 36% to 47%;those who did not receive training saw noimprovement.

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

Another study, presented at last year’s ACG annual meeting, examinedthe effect of a software system that provides real-time feedback during a colonoscopy procedure. Study par-ticipants were third-year fellows whocould see a mark on a monitor every time they completed a rotary move-ment. A blinded review of the vid-eos of 194 endoscopists who receivedreal-time feedback and 289 who did not showed that the feedback group improved in the percentage of mucosaviewed, degree of removal score, disten-sion score and withdrawal time.

“Real-time feedback is very attractiveas a concept, and this is a promising story that we’ll need to watch,” Dr. Rex said.

The ability to recognize serratedlesions as well as conventional ones iscritical to improving performance andreducing the risk for interval cancers.There are a number of websites on which

an endoscopist can view images of ser-rated 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 high-definition 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 carmineor methylene blue—defines the border and you can more clearly resect a normalmargin,” Dr. Rex said.

“If somebody, after multiple [inter-vention] 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, over-riding issue.” ■


‘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

fi rst 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

MoviPrep®

(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.

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 PRECAUTIONSUse 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 medica-tions 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 therehave 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 treat-ment 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 Mallory-Weis 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 INTERACTIONSUse 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.

USE IN SPECIFIC POPULATIONS

Pregnancy: Pregnancy Category C. Animal reproduction studies have not been performed with MoviPrep. It is also not known if MoviPrep can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. MoviPrep should be given to a pregnant woman only if clearly needed.

Nursing Mothers: 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 hypona-tremia and/or hypokalemia, as well as dehydration and hypovolemia, with signsand 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 INFORMATIONAdvise patients to read the Medication Guide included in the full prescribing information.

Advise patients who require a diet low in phenylalanine that MoviPrep contains phenylalanine.

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

Instruct patients that each pouch needs to be diluted in water before ingestion and that they need to drink additional clear liquid (e.g., water, clear soup, fruit juice without pulp, soft drinks, tea and/or coffee without milk) according to instructions.

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

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

Tell patients that MoviPrep produces a watery stool (diarrhea) which cleanses the colon before colonoscopy. Advise patients receiving MoviPrep to adequately hydrate before, during, and after the use of MoviPrep. Patients may have clear soup and/or plain yogurt for dinner, finishing the evening meal at least one hour prior to the start of MoviPrep treatment. No solid food should be taken from the start of MoviPrep treatment until after the colonoscopy.

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

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.comE-mail: [email protected]

8510 Colonnade Center DriveRaleigh, NC 27615

Tel. 866-669-SLXP (7597)All rights reserved.

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

Another new colonoscope, the Inven-doscope (Invendo Medical), is a roboticcolonoscope that recently was approvedby the FDA. There is not yet much dataon the Invendoscope, but it may reducepatient discomfort.

“The scope elongates from the tip

instead of being pushed from the rec-tum 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 Medi-cal 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.

“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),

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

Reality CheckAs enticing as this new technology

may be, however, enthusiasm is tem-pered by the economic reality. With reimbursements for CRC screening continuing to decline, any new tech-nology that adds cost—or time—to the procedure will need to prove its value by significantly improving ADRs and mak-ing screening examinations more entic-ing 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 profes-sor 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, thelatest endoscopes. But with all these new things we see, we’re always doing reality checks,” Dr. Starpoli said.

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

“If you look at MRI [magnetic reso-nance 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 couldenvision a paradigm shift in not too many years where its utility will be reshaped for sure. It may turn into more of a therapeu-tic tool than a diagnostic tool—not com-pletely, and not tomorrow, but I think current generations of people in training need to put their thinking caps on.” ■

Drs. Pochapin and Starpoli reported noconfl icts of interest.


CRC Screeningcontinued from page 11

‘Years ago, when

endoscopy was fi rst coming

out, it was really diffi cult

not to be excited about new

technologies, the latest

endoscopes. But with all

these new things we see,

we’re always doing reality

checks.’—Anthony Starpoli, MD

www.MoviPrep.com

MoviPrep®

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

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

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.

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

Seeing is believing

# 1 prescribed

branded purgative in the United States1

ACS Tracking System Improves Care for Cancer PatientsBY CHRISTINA FRANGOU

Cancer centers that participated in aperformance tracking system signifi-cantly improved their adherence to key quality measures in oncologic care,according to a new study. Developedby the Commission on Cancer of theAmerican College of Surgeons (ACS),the system also helps hospitals to track their patients’ information, which pre-vents medical records from getting lost,the researchers said.

“Cancer care is unique in that it requires extensive coordination with pro-viders across disciplines to ensure patientsreceive all of their treatments. Patientsare not only getting surgical treatment but also chemotherapy, radiation andpossibly hormone therapy,” said EricaMcNamara, MPH, lead study author and quality improvement analyst at theACS. “Our system is built to provide anextra layer of support in the coordinationof that care.”

Ms. McNamara presented the find-ings at the American Society of Clinical

Oncology’s inaugural Qual-ity Care Symposium, held in December (abstract 286).

The ACS’ Rapid Quality Reporting System (RQRS) provides feedback to cancer centers on individual patient care while the patient is still undergoing oncologic treat-ment. Accredited cancer cen-ters submit data about their current breast or colorectal cancer cases on a monthly or 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 Qual-ity 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 adjuvant therapy for lymph node–posi-tive colon cancer patients, the removal and pathologic examination of at least

12 regional lymph nodes for resected cancer, as well as radiation therapy fol-lowing breast-conserving surgery, mul-tiadjuvant chemotherapy for hormone

receptor–negative breast cancer patients,and hormone therapy for hormone receptor–positive breast cancer patients.


see Tracking System, page 22

Participants in the program said

that they regularly ‘catch’

patients who otherwise

would have been missed,

when the system issues

an alert that the patient

should have received

adjuvant therapy.

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.

Number of Drugs in Clinical Development for Different Tumor Types

Drug DevelopmentThe U.S. has perhaps the most

rigorous and expensive drug development process in

the world.

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

the lab to patients

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

medicine from the laboratory to patients

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

human testing

Only one of those five is approved for use

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

Sources: Pharmaceutical Research and Manufacturers of America,2012, Medicine in Development for Cancer;

Tufts Center for the Study of Drug Development

0 30 60 90 120 150

121

120

117

111

102

94

72

67

66

63

62

58

57

36

35

25

23

21

9

8

Lung cancer

Leukemia

Lymphoma

Breast

Other cancers

Prostate

Unspecified cancer

Skin cancer

Colorectal cancer

Ovarian cancer

Brain cancer

Pancreatic cancer

Multiple myeloma

Liver cancer

Kidney cancer

Head/Neck cancer

Stomach cancer

Sarcoma

Bladder cancer

Cervical cancer

numbersby the

BE PREPAREDFOR CRC AWARENESS MONTH

Indication and Important Safety InformationPrepopik™ for oral solution is indicated for cleansing of the colon as a preparation for colonoscopy in adults.

perforation, toxic colitis or toxic megacolon, gastric retention, or in patients with a known allergy to any of the ingredients in Prepopik. Patients should

or signs of dehydration after taking Prepopik

(>1%) following Prepopik administration

MCGEN1894.indd 1 2/20/13 5:28 PM

To learn more, scan

this code with your

smartphone, or go to

www.prepopik.com.

© 2013 Ferring B.V.

PREPOPIKTM is a trademark of Ferring B.V.

PK/047/2013/US

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

Ferring Pharmaceuticals Inc. Parsippany, NJ 07054, USA.

* 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 effi cacy endpoint was the proportion of patients with successful colon cleansing defi ned as bowel

preparations with >90% of the mucosa seen and mostly liquid stool, assessed by blinded colonoscopists.1

Prepopik helps patients arrive ready with:

Lowest volume of active prep solution and a fl exible hydration schedule1

Demonstrated non-inferiority, with both split-dose and day-before regimen1

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*

A dual mechanism that stimulates peristalsis and produces osmotic water retention1

MCGEN1894.indd 1 2/20/13 5:28 PM

The RQRS system will send an alert to the cancer center when patients arescheduled to enter the next stage of treatment. Physicians, cancer registrarsand cancer program administrators haveaccess to the feedback. For example, ahospital will receive a color-coded alert to indicate that staff should check ona patient’s treatment status when theRQRS does not receive a timely report confirming that a treatment decision or

adjuvant therapy has been completed.Furthermore, the RQRS system pro-

vides performance rates and compari-sons with other centers, based on current patients and clinical practice.

Study researchers examined data from 64,129 colorectal and breast can-cer 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.

Analysis of the data showed that all five compliance rates rose consider-ably 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%.

“This study is really noteworthy in that the development of this database

significantly improved cancer care within a very short period of time,” said Jyoti Patel, MD, an oncologist and associate professor of medicine at Fein-berg School of Medicine of Northwest-ern University, Chicago. “This sort of innovative feedback can provide real-time improvement in care, so it’s very exciting.”

Investigators also reported that perfor-mance rates differed by patient age, race and payer status (private insurance ver-sus Medicare), but the relative number and size of the disparities were reduced in participating programs two years after implementing the RQRS system.

“The results from this analysis suggest that those differences may actually havebeen more of a reflection of incomplete data and information in the registries than a reflection of differences in care delivery to subpopulations of patients,” said Andrew Stewart, MA, study coau-thor 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 “catch” patients who oth-erwise would have been missed, when the system issues an alert that the patient should have received adjuvant therapy.

“We find that after about six to nine months of using RQRS, one-third of pro-gram participants report that they have prevented RQRS patients from slipping through the cracks or not receiving timely adjuvant care,” Ms. McNamara said.

An anonymous RQRS participant said, “We have prevented at least two patients from slipping through thecracks. The oncology providers now ask for the reports to be given to them monthly so that they can review the yel-low and orange alert cases and prevent any red alerts.”

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 addi-tional clinical measures to expand the use of RQRS to encompass adherence to quality measures for lung, stomach and esophageal cancers. ■


Tracking Systemcontinued from page 19

The following is a brief summary only; see full PrescribingInformation for complete product information.

INDICATIONS AND USAGEPREPOPIK™ (sodium picosulfate, magnesium oxide and anhydrouscitric acid) for oral solution is indicated for cleansing of the colon as apreparation for colonoscopy in adults.

CONTRAINDICATIONSPREPOPIK is contraindicated in the following conditions:

less than 30 mL/minute) which may result in accumulation of magnesium

WARNINGS AND PRECAUTIONSSerious Fluid and Serum Chemistry Abnormalities

or signs of dehydration including signs of orthostatic hypotensionafter taking PREPOPIK, consider performing post-colonoscopy

on the day of colonoscopy. In clinical trials orthostatic changes were

including cardiac arrhythmias or seizures and renal impairment. Fluid

impairment.

Seizures

history of seizures and in patients at risk of seizure, such as patients taking medications that lower the seizure threshold (e.g.,tricyclic antidepressants), patients withdrawing from alcohol or

Use in Patients with Renal Impairment

or patients taking concomitant medications that may affect renal

(creatinine clearance < 30 mL/min), accumulation of magnesium in plasma may occur.

Cardiac Arrhythmias

heart failure, or cardiomyopathy). Pre-dose and post-colonoscopy

cardiac arrhythmias.

Colonic Mucosal Ulceration, Ischemic Colitis and Ulcerative Colitis

Aspiration

PREPOPIK. Use with caution in these patients.

Not for Direct Ingestion

administered at separate times according to the dosing regimen. Ingestion of additional water is important to patient tolerance. Direct

ADVERSE REACTIONS

Clinical Trials Experience

In randomized, multicenter, controlled clinical trials, nausea, headache,

and watery diarrhea are known to occur in response to colon cleansing

a change in study drug or led to study discontinuation, therapeutic or

compared to the comparator preparation.

Table 1: Treatment-Emergent Adverse Reactions observed in at Least (>1%) of Patients using the Split-Dose Regimen and Day-Before Regimen**

Adverse Reaction

Study 1: Split-Dose Regimen Study 2: Day-BeforeRegimen

PREPOPIK (N=305) n (% = n/N)

2L PEG+E* with 2 x 5-mg bisacodyltablets(N=298) n (% = n/N)

PREPOPIK (N=296) n (% = n/N)

2L PEG+E*with 2 x 5-mg bisacodyl tablets (N=302) n (% = n/N)

8 (2.6) 11 (3.7) 9 (3.0) 13 (4.3)Headache 5 (1.6) 5 (1.7) 8 (2.7) 5 (1.7)Vomiting 3 (1.0) 10 (3.4) 4 (1.4) 6 (2.0)

Electrolyte abnormalities In general, PREPOPIK was associated with numerically higher rates

Postmarketing Experience

relationship to drug exposure.

Allergic reactions

Electrolyte abnormalities

hypermagnesemia with the use of PREPOPIK for colon preparation prior to colonoscopy.

Gastrointestinal

Neurologic

associated with and without hyponatremia in epileptic patients.

DRUG INTERACTIONS

Drugs That May Increase Risks of Fluid and Electrolyte Abnormalities

associated with hypokalemia (such as diuretics or corticosteroids,or drugs where hypokalemia is a particular risk, such as cardiac glycosides) or hyponatremia. Use caution when PREPOPIK is used

Potential for Altered Drug AbsorptionOral medication administered within one hour of the start of

Antibiotics


Pregnancy

needed.

Nursing Mothers

when PREPOPIK is administered to a nursing woman.

Pediatric Use

Geriatric Use

years of age, the proportion of patients with successful colon cleansing

Patients with impaired renal function or patients taking concomitantmedications that may affect renal function (such as diuretics,

OVERDOSAGE

and treated symptomatically for complications.

Ferring Pharmaceuticals (China) Co., Ltd.

Ferring Pharmaceuticals Inc.

www.ferringusa.com

Of Those Diagnosed With CRC Even After Age 60 YearsBut Experts Disagree on Implications for Screening Guidelines

BY MONICA J. SMITH

LAS VEGAS—The American College of Gastroenter-ology (ACG) recommends screening colonoscopy for people aged 50 years or younger, if they have a first-degree relative (FDR) who was diagnosed with colorec-tal cancer (CRC) before the age of 60 years. New research now suggests extending this recommendation to include people whose FDR was diagnosed after the age of 60 years.

The ACG guidelines are based on studies that show an increased risk for CRC in people with FDRs who were diagnosed with CRC—but those studies have limi-tations, such as patient recall bias and self-reporting of family history that may not be accurate. To quantify the risk for CRC or adenomas in FDRs, second-degree relatives (SDR) and third-degree relatives (TDR), N. Jewel Samadder, MD, MSc, assistant professor in the Department of Medicine and an investiga-tor at the Huntsman Cancer Institute, both at the Uni-versity of Utah School of Medicine in Salt Lake City, and hiscolleagues conducted a retrospective, popu-lation-based study of Utah residents aged between 50 and 80 years, who underwent a colonoscopy between1995 and 2009.

The researchers merged the group’s de-identified medical information with family history data and cancer diagnoses, con-firmed through the Utah Popula-tion Database and Utah Cancer Registry. They also performed a Cox regression analysis to calcu-late the relative risk for CRC or adenomas in relatives of CRC patients, and randomly selected age- and gender-matched con-trols in a 5:1 ratio.

They identified 126,936 patients who underwent colo-noscopy, of whom 3,804 had confirmed CRC.

“We were able to show that relatives of CRC cases and controls have similar numbers of colonoscopies performed,” Dr. Samadder noted.

FDRs, SDRs and even TDRs of patients with CRC had an elevated risk for CRC of 1.8-, 1.3- and 1.15-fold, respectively.

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.

Researchers also looked at the relative risk for adeno-mas in the relatives of patients with CRC.

“Very similar to our CRC data, FDRs, SDRs and TDRs are at an elevated risk for having adenomatous polyps,” Dr. Samadder said. FDRs, SDRs and TDRs had elevated risks of 1.82-fold, 1.2-fold and 1.1-fold, respectively, “all of which were statistically significant,” Dr. Samadder said.

In summary, relatives of patients with CRC had an elevated risk for CRC—up to 80% more than in the control group, and the all-time elevated risk for adeno-matous polyps was up to 82% higher than in the control group. Risk was highest in patients whose relatives were diagnosed with CRC before the age of 60 years, and in those with the closest degree of kinship (i.e., FDRs).

“Our data support current CRC screening guidelines, and also a consideration to expanding [screening at age 40 and every five years] to FDRs of those diagnosed over the age of 60,” Dr. Samadder said.

Carol A. Burke, MD, director of the Center for Colon Polyp and Cancer Pre-

vention, Cleveland ClinicFoundation, Ohio, saidthe research supportsother studies that con-

firm the familial ten-dency for the development of adenomas and CRC in patients with a fam-ily history of CRC, but questions whether it car-ries enough weight to

merit revisiting current screening recommendation guidelines.

“The data do not support ear-lier or more frequent screen-ing in relatives,” Dr. Burke said. “Although the study shows an increased risk for adenomas and cancer out to third-degree rela-tives, it does not provide any data on the age of onset of thoselesions. Data from previous stud-ies found that the colorectal can-cer “risk advancement periods” for those with a family history were consistently found to be betweennine and 11 years for both sexes [Brenner H et al. Am J Gastroen-terol 2008;103:2326-2331].”l

“Additionally, a major limita-tion is that the investigators were not able to discern whether there was a genetic syndrome leading to cancer and adenomas in relatives of patients with CRC. We know that Lynch syndrome accounts for about one in 35 CRCs,” Dr. Burke noted. ■


‘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.’—N. Jewel Samadder, MD, MSc

t

”

‘Our data

support current

CRC screening

guidelines, and

also a consideration

to expanding

[screening at age 40

and every fi ve years]

to FDRs of those diagnosed

over the age of 60.’—N. Jewel Samadder, MD, MSc

t

t

w

t

‘The data do not support earlier

or more frequent screening in

relatives. Although

the study shows

an increased risk

for adenomas and

cancer out to third-degree

relatives, it does not provide

any data on the age of onset

of those lesions.’

—Carol A. Burke, MD

at a young age. Gastroenterologists need to identify these patients so they can tailor screening and surveil-lance 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 meet-ing of the New York Society for Gastrointestinal Endos-copy, held last December.

CRC syndromes fall into two categories: 1) polyposis syndromes, the most typical of which is familial adeno-matous polyposis (FAP), and 2) nonpolyposis familial CRC syndromes, such as Lynch syndrome, which are more common. Although genetic syndromes are pres-ent 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-Ket-tering 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.”

Polyposis SyndromesWhen 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 adeno-mas than seen in classic FAP), which originates from a mutation in the adenomatous polyposis coli (APC(( ) CCgene. 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 hun-dreds of adenomas. Importantly, because the APC gene Cis in every cell of your body, mutations of APC can cause Cpolyps and other lesions elsewhere in the body,” Dr. Itz-kowitz 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 long-term 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. Nev-ertheless, 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 mani-festations 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 SyndromesThe third case Dr. Itzkowitz described was a 38-year-

old 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, stom-ach, 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 dic-tating 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 endome-trial cancer and other non-gastrointestinal cancers.”

Lynch syndrome is classically defined by the Amster-dam 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 some-one 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 scientifi c advisory board of Exact Sciences Corporation, from which he receives

research support.


Heritable CRCcontinued from page 1

‘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 non-

gastrointestinal cancers.’—Mark Schattner, MD

READY FOR A

POWERINUC?

MCGEN1891.indd 1 2/20/13 4:56 PM

CORE STUDY DESIGNS: Two randomized, double-blind, placebo-controlled studies were conducted in a total of 899 adult patients with active, mild to moderate UC (Ulcerative Colitis Disease Activity Index [UCDAI]: ≥4 and ≤10 at entry). The primary endpoint was induction of combined clinical remission and mucosal healing (defi ned as a UCDAI score of ≤1, with scores of 0 for both rectal bleeding and stool frequency, normal mucosa with no friability on endoscopy, and a ≥1-point reduction in the endoscopic index score) after 8 weeks of treatment.1

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

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

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONSUCERIS is contraindicated in patients with known hypersensitivity to budesonide or any of the ingredients of UCERIS.

WARNINGS AND PRECAUTIONS

glucocorticosteroid, general warnings concerning glucocorticoids should be followed.

Risk of impaired adrenal function when transferring from oral steroids with high systemic effects. Taper patients slowly from systemic corticosteroids if transferring to UCERIS.

existing tuberculosis, fungal, bacterial, viral, or parasitic

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

function affects the elimination of glucocorticosteroids.

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

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


of hypercorticism.

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

MCGEN1892.indd 1 2/20/13 4:59 PM

A POWERFUL, LOCALLY ACTING STEROID1-3

MMX® technology targets delivery of budesonide throughout the full length of the colon1,2

3 times more patients taking UCERIS achieved combined clinical remission and mucosal healing compared with placebo3*

A SAFETY PROFILE THAT OFFERS CONFIDENCE1

The rates of overall expected glucocorticoid-related side effects were similar for UCERIS and placebo at 8 weeks—10.2% vs 10.5%, respectively1*

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

The Important Safety Information does not include all ofthe 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 fi le. Santarus, Inc.

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

www.UCERIS.com

UCERIS™:

MCGEN1892.indd 1 2/20/13 4:59 PM

of patients with colorectal cancer (CRC).“We have developed a diagnostic,

single-sample predictor that allows the classification of CRC tumors of differ-ent intrinsic molecular subtypes,” said Josep Tabernero, MD, PhD, director of Vall d’Hebron Institute of Oncology in Barcelona, Spain, and lead investigator of one of the studies. “These subtypes could be clinically relevant as they differ in their underlying biology and clinical outcomes,

and consequently require different treat-ment strategies.”

Molecular classification systems couldbe 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 meth-ods. The goal of subtyping is not only to identify patients who need aggres-sive treatment, but also to pair the right patient with the right drug.

Patterns of Gene ExpressionDr. Tabernero and his team used gene

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

Three distinct molecular patterns were identified: 21.5% of samples were cat-egorized 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: epithe-lial-to-mesenchymal transition (associ-ated with aggressive tumors); deficiency

in mismatch repair genes (associated withgenetic alterations); and the rate of cellu-lar proliferation—features that are knownto independently affect outcomes, saidDr. Tabernero.

“The subtypes were significantly asso-ciated with prognosis and significantly correlated with benefit from adjuvant 5-FU-based treatment,” Dr. Tabernerosaid.

Patients with subtype A had a goodprognosis, regardless of whether chemo-therapy was given: 10-year survival rateswere approximately 65% without che-motherapy and 80% with chemotherapy (P=0.183). Patients with subtype B had aPPpronounced benefit from chemotherapy,with 10-year survival rates of approxi-mately 55% without chemotherapy ver-sus 80% with chemotherapy (P=0.014).PPPatients with subtype C, in contrast,derived no benefit from adjuvant che-motherapy, with 10-year survival rates of approximately 65% without chemotherapy and 50% with chemotherapy (P=0.542).PPThe five-year overall survival differencebetween types A and B, versus type C, wasstatistically significant (P=0.0166).PP

The findings suggest that patients withsubtypes A and B would be treated differ-ently: Subtype A patients would probably


Molecular Subtypingcontinued from page 1

‘The subtypes were signifi cantly associated with prognosis and signifi cantly correlated with benefi t from adjuvant 5-FU-based treatment.’

—Josep Tabernero, MD, PhD

BRIEF SUMMARYPlease see package insert for Full Prescribing Informationavailable at www.uceris.comUCERIS (budesonide) extended release tablets, for oral useRx OnlyINDICATIONS AND USAGE UCERIS (budesonide) extended releasetablets are indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis.CONTRAINDICATIONS UCERIS is contraindicated in patientswith hypersensitivity to budesonide or any of the ingredientsof UCERIS. Anaphylactic reactions have occurred with other budesonide formulations.WARNINGS AND PRECAUTIONSHypercorticism and Adrenal Axis Suppression Whenglucocorticosteroids are used chronically, systemic effectssuch as hypercorticism and adrenal suppression may occur.Glucocorticosteroids can reduce the response of the hypothalamus-pituitary-adrenal (HPA) axis to stress. In situations where patientsare subject to surgery or other stress situations, supplementation with a systemic glucocorticosteroid is recommended. SinceUCERIS is a glucocorticosteroid, general warnings concerningglucocorticoids should be followed. Transferring Patients fromSystemic Glucocorticosteroid Therapy Care is needed in patientswho are transferred from glucocorticosteroid treatment with higher systemic effects to glucocorticosteroids with lowersystemic effects, such as UCERIS, since symptoms attributed to withdrawal of steroid therapy, including those of acuteadrenal suppression or benign intracranial hypertension, maydevelop. 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 theimmune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can havea more serious or even fatal course in susceptible patients or patients on immunosuppressant doses of glucocorticosteroids. Inpatients 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 developinga disseminated infection is not known. The contribution of the underlying disease and/or prior glucocorticosteroid treatment tothe 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.) Ifchicken 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 UCERIStablets may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug. Increased Systemic Glucocorticoid Susceptibility Reduced liver functionaffects the elimination of glucocorticosteroids, and increased systemic availability of oral budesonide has been demonstratedin patients with liver cirrhosis. Other Glucocorticosteroid EffectsCaution 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 conditionwhere glucocorticosteroids may have unwanted effects.ADVERSE REACTIONS Systemic glucocorticosteroid use may result in the following:

from Systemic Glucocorticosteroid Therapy

Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observedin the clinical trials of a drug cannot be directly compared to ratesin the clinical trials of another drug and may not reflect the rates observed in practice. The safety of UCERIS has been evaluated incontrolled 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 (Study1 and Study 2), a total of 255 patients received UCERIS 9 mg, 254patients received UCERIS 6 mg, and 258 patients received placebo.They ranged in age from 18-77 years (mean 43), 56% were male, and75% were Caucasian. The most common adverse reactions were headache, nausea, decreased blood cortisol, upper abdominal pain, fatigue, flatulence, abdominal distension, acne, urinary tractinfection, arthralgia, and constipation. The adverse reactionsoccurring in 2% or more of patients on therapy with UCERIS 9 mgare 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)

UCERIS 9 mg

(N = 255)n (%)

UCERIS 6 mg

(N = 254)n (%)

Placebo(N = 258)

n (%)Headache 29 (11.4) 37 (14.6) 27 (10.5)Nausea 13 (5.1) 12 (4.7) 11 (4.3)Decreased Blood Cortisol 11 (4.3) 6 (2.4) 1 (0.4)

Upper Abdominal Pain 10 (3.9) 8 (3.1) 5 (1.9)

Fatigue 8 (3.1) 5 (2.0) 5 (1.9)Flatulence 6 (2.4) 8 (3.1) 5 (1.9)Abdominal Distension 6 (2.4) 4 (1.6) 2 (0.8)Acne 6 (2.4) 2 (0.8) 5 (1.9)Urinary Tract Infection 5 (2.0) 1 (0.4) 1 (0.4)Arthralgia 5 (2.0) 5 (2.0) 4 (1.6)Constipation 5 (2.0) 1 (0.4) 2 (0.8)

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 placebo-controlled studies.

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

UCERIS 9 mg

(N = 255)n (%)

UCERIS6 mg

(N = 254)n (%)

Placebo(N = 258)

n (%)

26 (10.2) 19 (7.5) 27 (10.5)Mood changes 9 (3.5) 10 (3.9) 11 (4.3)Sleep changes 7 (2.7) 10 (3.9) 12 (4.7)Insomnia 6 (2.4) 6 (2.4) 8 (3.1)Acne 6 (2.4) 2 (0.8) 5 (1.9)Moon face 3 (1.2) 3 (1.2) 4 (1.6)Fluid retention 2 (0.8) 3 (1.2) 3 (1.2)Hirsutism 1 (0.4) 0 0Striae rubrae 0 0 2 (0.8)Flushing 0 1 (0.4) 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 completedan 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 ratesof 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 mgwas 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 werein remission were randomized to UCERIS 6 mg or placebo oncedaily for 12 months. In patients who took UCERIS 6 mg for up to 12 months, similar rates of adverse reactions were seen betweenplacebo 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) ofthe patients in the placebo treatment groups had normal bone density scans. In Study 4, the glucocorticoid related effects weresimilar 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)

UCERIS 6 mg

(N = 62)n (%)

Placebo(N = 61)

n (%)9 (14.5) 7 (11.5)

Insomnia 4 (6.5) 4 (6.6)Mood changes 4 (6.5) 2 (3.3)Moon face 3 (4.8) 3 (4.9)Sleep changes 3 (4.8) 3 (4.9)Acne 3 (4.8) 0 Hirsutism 3 (4.8) 0Flushing 1 (1.6) 1 (1.6)Fluid retention 1 (1.6) 1 (1.6)

Postmarketing Experience The following adverse reactionshave 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 swingsDRUG INTERACTIONSInteraction with CYP3A4 inhibitors Concomitant oraladministration of ketoconazole (a known inhibitor of CYP3A4 activity in the liver and in the intestinal mucosa) caused an eight-fold 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. Afterextensive 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 whenUCERIS is used after treatment with gastric acid reducing agents(e.g., PPIs, H2 blockers and antacids).USE IN SPECIFIC POPULATIONSPregnancy 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 humandose on a body surface area basis) and 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human doseon a body surface area basis). There are no adequate and well-controlled studies in pregnant women. Budesonide should be used during pregnancy only if the potential benefit justifies the potentialrisk 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

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 0.007and 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 about140 minutes after drug administration to the mother) were belowquantifiable levels (<0.02 nmol/L in four infants and <0.04 nmol/L in one infant). The recommended daily dose of UCERIS extendedrelease tablets is higher (9 mg daily) compared with inhaled budesonide (up to 800 μg 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 doseof 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 thetotal 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 andoral doses is constant across all dose levels, at therapeutic dosesof UCERIS, budesonide exposure to the nursing child may be up to 10 times higher than that by budesonide inhalation. Pediatric UseSafety and effectiveness of UCERIS in pediatric patients havenot 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

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 concomitantdisease or other drug therapy. Hepatic Impairment Patients withmoderate to severe liver disease should be monitored for increased signs and/or symptoms of hypercorticism. Discontinuing the use ofUCERIS tablets should be considered in these patients. OVERDOSAGEReports of acute toxicity and/or death following overdosage of glucocorticosteroids are rare. Treatment consists of immediategastric 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 TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenicity Carcinogenicity studies with budesonide were conducted in rats and mice. In a two-year study in Sprague-Dawley 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 recommendedhuman 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 hepatocellulartumors at an oral dose of 50 mcg/kg (approximately 0.05 timesthe maximum recommended human dose on a body surface area basis). The concurrent reference glucocorticosteroids (prednisolone and triamcinolone acetonide) showed similarfindings. In a 91-week study in mice, budesonide caused notreatment-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). Mutagenesis Budesonide was not sgenotoxic in the Ames test, the mouse lymphoma cell forward gene mutation (TK+/–) test, the human lymphocyte chromosome aberration test, the Drosophila melanogaster sex-linked recessive rlethality test, the rat hepatocycte UDS test and the mousemicronucleus test. Impairment of Fertility In rats, budesonide yhad 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 duringlactation, 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).

UCERIS™ is a trademark of Santarus, Inc.

U.S. Patent Nos: 7,410,651; 7,431,943; RE43799; 8,293,273.

© 2013 Santarus, Inc. 1-UCE13033 V1

not require chemotherapy; subtype Bpatients would receive chemotherapy;and subtype C patients would requirea more aggressive and perhaps noveltreatment. The study researchers plan toevaluate these subtypes in patients whohave 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 usedas a powerful tool in the classification of patients with CRC into molecular sub-groups. The researchers, including DavidHsu, MD, PhD, of the Duke Institute for Genome Sciences and Policy, Durham,N.C., have developed a preliminary set of biomarkers that are prognostic, predictiveof treatment response and applicable topatients who have undergone resectionfor primary or metastatic tumors.

Dr. Uronis and his colleagues exam-ined microarray data, based on the activ-ity of 19 oncogenic pathways, from 850patients with primary CRC and gener-ated patterns of pathway deregulationfor each patient’s tumor. A molecular profile of CRC was created that iden-tified six molecular subgroups of CRCand showed that patients in each sub-group differed significantly in their risk for CRC recurrence. For exam-ple, although recurrence-free survivalapproached 100% for subgroup 4, it fellto about 40% for subgroup 3 (P=0.0004).PPThe model was then applied to a dataset of 133 tumor samples, of which 94patients presented with metastatic dis-ease and 34 with primary lesions. Again,

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

into gene expression signatures that were used to measure the probability of path-way activation in a panel of cell lines. With this approach, the model also was predictive of response to various drugs.

“We observed that molecular sub-groups of CRC demonstrated differen-tial 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

‘We observed that molecular subgroups of CRC demonstrated

differential sensitivity to specifi c targeted agents, such as …

inhibition of HER2 by lapatinib, and inhibition of the epidermal

growth factor receptor by erlotinib.’—Joshua M. Uronis, PhD


TheTheThe IndepeIndepend

gastroendonews.com

For more than three decades, Gastroenterology & Endoscopy Newshas been providing gastroenter ology health care professionals withspecialty-specifi c news and reviews, offering comprehensive and objective information for the practicing clinician.

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.

ACG 2012

IBS No Longer OnlyFunctional DisorderBY DAVID WILD

LAS VEGAS—For the first time, investigators have doc-umented structural abnormalities in the small bowel of patients with irritable bowel syndrome (IBS). Thesefindings “will fundamentally change our thinking on the disease,” researchers told attendees of the 2012

Best of the American CollegeeOf Gastroenterology: Part 2COMPILED AND WRITTEN BY DAVID WILD

Gastroenterology & Endoscopy News asked several experts to select their favvorite abstracts sfrom the 2012 American College of Gastroenterology (ACG) Annual Scienntific 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.)

Experienced Physicians Offer TipsTo Trainees on Landing a JobIt’s Never Too Early To Start the Search

BY CHRISTINA FRANGOU

If they haven’t already, fellowsand residents should add onemore resolution to their New Year’s list: Start the job search.

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

With recruiting seasonkicking into high gear over the next few months, Gastroenter-ology & Endoscopy News sum-smarized some practical tipsfor finding a job in academic medicine or private practice, as outlined by two gastroen-terologists with experience ineach area.

Mesalamine ElicitsResponse 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

I N S I D E


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

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

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

EXPERT REVIEW:Safeguarding Yourself Against AllegationsOf Sexual Abuse or Patient Impropriety

BY HARVEY TETTLEBAUM, JD, AND KEVIN MEYERS, JD

..................................................................

see IBS, page 8

see Mesalamine, page 9

see Best of ACG, page 14

see Job Search, page 25

The Gastric Cancers: Targeted for Personalized Medicinesee pages 10-11

PRODUCT ANNOUNCEMENT

Clinical Applications of Probiotics in Gastroenterology: Questions and Answers, An Issue of Gastroenterology Clinicssee page 37

Experts’ Picks


Oncotype DX Colon Cancer Assay Plays Infl uential Role In Treatment Recommendations, Medical CostsProspective 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 can-cer patients from 17 centers in the Mayo Clinic Can-cer 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%. Recommenda-tions 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 recommen-dations (a 22% decline, from 52% pre-assay to 30% post-assay), average total direct medical costs were cal-culated to decrease by $4,203. The net effect on average patient well-being was a gain of 0.083 quality-adjusted life-years.

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 patho-logic stage or when there are conflicting traditional clini-copathologic 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 accu-racy, and … has clinical validity from two large random-ized 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 evalu-ated 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 recur-rence, 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 Clini-cal Oncology has accepted results from the second largeyclinical validation study of the Oncotype DX ColonCancer Assay for publication. ■

Dr. Kelley reported receiving research funding fromGenomic 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.

implanted into mice. This model showed that sub-groups 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. Research-ers 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 predic-tive 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.

“[The researchers] have used a unique approach to identify molecular altera-tions that are predictive of recurrent cancer, not only for non-metastatic disease but also for metastatic dis-ease,” Dr. Grady said of the study by Dr. Uronis and his colleagues. “If these results can be validated, these molecular alteration pat-terns have the potential to be used as markers to identify which patients should receive aggressive care after surgi-cal resection of both primary and metastatic colorectal cancer and to direct the specific chemotherapeutic agents they should receive,” he said.

“The work by Uronis et al is critical for CRC care advancement, and symbolic of the new age of cancer care in general,” said Jennifer Tseng, MD, chief of sur-gical oncology and co-clinical director for surgery at Beth Israel Deaconess Medical Center, and associate

professor at HarvardMedical School, both inBoston. “For example, we as surgeons can surgically remove tumors to the best of our oncologic ability,and enable our partners, the pathologists, to stagethe tumors and help deter-mine the best treatment; however, currently, there areserious limitations.

“At the extremes, there is less controversy,” she con-tinued. “There, there is no question that chemotherapy does not (for stage I) or does (for stage III or IV) help the patient, overall. But the vast majority of patients fall into those shades of gray, stage II especially, where we are weighing potentially toxic chemotherapy risks and benefits versus disease recurrence risks and ben-efits. This type of study helps point us to personalizing cancer care for the individual tumor, and thus the indi-vidual patient,” Dr. Tseng concluded. ■

Oncotype DX ColonCancer Assay at a Glance• Cost: $3,640.00• Availability: Launched in January 2010;

availability extended to stage III patientsin June 2012.

• What It Can Do: The Oncotype DX Colon Cancer Assay is the first multi-gene expression test developed for theassessment of risk for recurrence inpatients with stage II or III colon cancer.

• What It Cannot Do: Oncotype DX is onlyintended for use in patients with stage IIor III colon cancer following surgery.

• Required Sample: The test is performedusing formalin-fixed, paraffin-embeddedcolon tumor tissue obtained by surgicalresection or biopsy.

Source: Genomic Health


Molecular Subtypingcontinued from page 29 ‘These molecular alteration patterns

have the potential to be used as

markers to identify which patients

should receive aggressive care … and

to direct the specifi c chemotherapeutic

agents they should receive.’—William M. Grady, MD

N E W P R O D U C T A N N O U N C E M E N T

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 ulcer-ative colitis. At press time, the com-pany 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 approveddosing regimen for adult patients is one, 9-mg tablettaken orally, oncedaily in the morningfor up to eight weeks.

“The FDA approval of Uceris providesan important new therapeutic option to patients and phy-sicians for the treat-ment of active, mildto moderate ulcer-ative colitis,” said William J. Sandborn, MD, chief, Division

of Gastroenterology, professor of clinical medicine, University of Cali-fornia, San Diego (UCSD) Health System and director, UCSD Inflam-matory 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 main-tenance dose was used in the 12-week budesonide safety study, which is not currently approved by the FDA.)

For more informa-tion about Uceris, visit www.uceris.com.

—Based on a press releasefrom Santarus, Inc.

US Endoscopy Announces Release of AquaShield Water Bottle for Use With CO2 InsufflationOn 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 accommo-

dates our customers using CO2 insuf-flation 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 posi-tion statement clarifying the repro-cessing 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 reprocess-ing and promotes patient safety, the company said.

—Based on a press releasefrom US Endoscopy

New Indication for Avastin With Chemotherapy for Metastatic Colon Cancer ApprovedThe FDA has approved a new use for Avastin (Genen-tech; bevacizumab) in combination with fluoropyrimidine-based 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 chemother-apy as an initial treatment (first-line) for mCRC to con-tinue to receive Avastin plus a different irinotecan- or oxali platin-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 medi-cal 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 chemother-apy 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 che-motherapy in 820 patients with mCRC whose disease had progressed following Avastin plus standard first-line chemotherapy (irinotecan- or oxaliplatin-based). The pri-mary 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 second-line, compared with those who received chemotherapy alone (hazard ratio, 0.81; P=0.0057). The median overallsurvival 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

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2013 31F D A U P D AT E & P R O D U C T N E W S

The AquaShield water bottle for CO2 delivery systemsPhoto courtesy of US Endoscopy

Photo courtesy of Santarus, Inc.

FDA Approves Single Test To Detect 11 Causes of GastroenteritisThe FDA has allowed the marketingof a first-in-kind test that can simul-taneously detect 11 viral, bacterialand parasitic causes of infectiousgastroenteritis from a single patientsample.

The xTAG Gastrointestinal Patho-gen Panel (GPP) is a multiplexednucleic acid test that can detect thefollowing bacteria that cause gas-troenteritis: Campylobacter, Clos-tridium difficile (C. difficile) toxinA/B, Escherichia coli (E. coli) O157,enterotoxigenic E. coli (ETEC) LT/ST,Salmonella, Shigella and Shiga-liketoxin-producing E. coli (STEC) stx 1/istx 2. The test also can detect noro-virus and rotavirus A, and the para-sites Cryptosporidium and Giardia.

“Tests such as the xTag GPP thatcan detect viruses, bacteria and par-asites from one sample at the sametime can help clinicians more quicklyidentify and treat what’s causinggastroenteritis,” said Alberto Guti-errez, PhD, director of the Office of In Vitro Diagnostics and Radiologyat the FDA’s Center for Devices andRadiological 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 manu-facturer 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 con-firmed infectious gastroenteritis,and on 313 specimens from pedi-atric patients with suspected infec-tious gastroenteritis. Results from the xTAG GPP test were comparable to those from the individual tests.Because of the possibility of false-positive results, all positive resultsobtained with xTAG GPP should be confirmed by additional testing.

The FDA reviewed the data for xTAG GPP through the de novoclassification process, a regulatorypathway for medical devices thatare generally low- to moderate-riskbut are not comparable to an already legally marketed device.

According to the Centers for Disease Control and Prevention,between 1999 and 2007, gastro-enteritis-associated deaths in theUnited States increased from nearly7,000 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

Crofelemer Is First FDA-Approved Antidiarrheal Drug for Patients With HIV/AIDSOn the last day of 2012, the FDA approvedcrofelemer (Fulyzaq, Salix Pharmaceuticals) for the symptomatic relief of noninfectiousdiarrhea in patients with HIV/AIDS who arereceiving antiretroviral therapy, according to an FDA press release. Diarrhea is commonin patients with HIV/AIDS and is a frequentreason for discontinuing or switching anti-retroviral therapies. Crofelemer is the firstFDA-approved antidiarrheal drug for thesepatients.

“Currently, there are no FDA-approvedtherapies for HIV-associated diarrhea,” JulieBeitz, MD, director of the Office of DrugEvaluation III in the FDA’s Center for DrugEvaluation 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 reduc-ing the high-volume water loss that occurs in patients with HIV-associated diarrhea, according to Salix. The recommended dosage is one, 125-mg delayed-release tablet taken orally, twice daily.

The FDA approval of crofelemer is based on a randomized, multicenter, double-blind, pla-cebo-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 propor-tion 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 base-line 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. Fur-thermore, crofelemer showed significantly greater efficacy compared with placebo in subgroup analyses based on duration of diar-rhea, 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 safetyof 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 ele-vated bilirubin concentration.

Crofelemer is not intended for the treatment of infectious diarrhea; infectious etiologies of diar-rhea 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 FDAand Salix Pharmaceuticals


The xTAG Gastrointestinal Pathogen Panel from Luminex Corporation

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

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Brennan Spiegel; Hetal KarsanAugust 11, 2011 Many board review manuals provide lists and bullet points lacking suffi-cient background and context. This book presents time-tested and high-yield information in a rational, useful and contextually appealing format.

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

Nicholas J. Shaheen, MDApril 11, 2013 Esophageal diseases are among the most common gastrointestinal ill-nesses encountered by both the gastroenterologist as well as the pri-mary 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.

3 Clinical Challenges and Complications of IBDMiguel D. Regueiro; Jason M. Swoger

October 15, 2012 Clinical Challenges and Complications of IBD is an invaluable guide for Dgastroenterologists, nurse practitioners, physician assistants and gas-troenterology trainees as it is a one-of-a-kind resource for recognizing and dealing with the challenges and complications in patients with IBD.

4 ERCP: Expert Consult—Online and Print: Second Edition

Todd H. BaronFebruary 27, 2013 ERCP, now in its second edition, is dedicated to simplifying and explainP -ing 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 t s co p e top c a d e p you ac e e opt a outco esthrough this complex topic and help you achieve optimal outcomes.

5 Gastroenterology & Hepatology Board Review: Pearls of Wisdom, Third Edition

John DiBaiseApril 20, 2012 The book features 3,500 questions with only the correct answers pro-

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December 26, 2012 Residents, trainees and specialists in gastroenterology, oncology andsurgery, as well as other health professionals will welcome this acces-

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7 Morson and Dawson’s Gastrointestinal PathologyNeil A. Shepherd; Bryan F. Warren; Geraint T. Williams;

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Emphasizing the important role the gastrointestinal pathologist plays in patient management, this book is a comprehensive resource for both

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8 Practical Manual of Gastroesophageal Reflux DiseaseMarcelo F. Vela; Joel E. Richter; John E. Pandolfino

February 15, 2013 Highly practical, expertly written and packed with useful tools like case

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Teduglutide Approved for Short Bowel SyndromeFirst Major Long-Term Treatment Advance for Short Bowel Syndrome in Nearly 40 Years

On Dec. 21, the FDA approvedteduglutide (Gattex [rDNA origin]for injection, NPS Pharmaceuticals,Inc.) to treat adults with short bowelsyndrome who are dependent onparenteral support, according toan FDA press release. An injectionadministered once daily, teduglutidehelps to improve intestinal absorp-tion of fluids and nutrients, reducingfrequency and volume of parenteralnutrition.

“Today’s approval expands theavailable treatment options forpatients with this life-threateningcondition,” said Victoria Kusiak, MD,deputy director of the Office of DrugEvaluation III in the FDA’s Center forDrug Evaluation and Research.

“In addition to serious medicalcomplications, patients with shortbowel syndrome can have sociallyrestricted lives,” said Ken Fujioka,MD, of the Nutrition and MetabolicResearch Center at Scripps Clinic,Del Mar, Calif., in a press statement.“Long infusion periods often disruptsleep for patients. This is coupledwith constant concern about usingrestrooms, as many patients willneed to use the bathroom up to 25times a day, or having an accidentwith unpredictable diarrhea. Otherpatients that have an ostomy baghave a fear of an ostomy bag leakage.These factors leave many patientsunable to socialize or work. Consid-ering Gattex has been shown to sig-nificantly reduce, or in some caseseven eliminate, the requirement forparenteral support, it may become acornerstone therapy in the manage-ment of short bowel syndrome.”

The safety, efficacy and tolerabil-ity of teduglutide were evaluated intwo randomized, placebo-controlled,clinical trials and two extension stud-ies. Designed to quantify the number of patients who achieved at leasta 20% reduction in the volume of weekly parenteral nutrition after 20and 24 weeks of treatment (clinicalresponse), the clinical trials showedthat 46% and 63% of patients,respectively, treated with teduglutideachieved a clinical response com-pared with 6% and 30% of patientstreated with placebo, respectively.

The most common side effects of teduglutide identified in clinical tri-als were abdominal pain, injectionsite reactions, nausea, headaches,abdominal distension and upperrespiratory tract infection. A postmar-keting 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 exec-utive officer of NPS Pharmaceuticals, stated:

“Gattex is a ground-breaking ther-apy that has been evaluated in the largest clinical program to date in

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 pep-tide 2, a protein involved in rehabilita-tion of the intestinal lining—is the first major long-term treatment advance

for short bowel syndrome in nearly 40 years.

NPS plans to make Gattex avail-able in the first quarter of 2013. Formore information, visit www.gattex.com.

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

GASTROENTEROLOGY & ENDOSCOPY NEWS • MARCH 2013 35F D A U P D AT E & P R O D U C T N E W S

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

INDICATIONS AND USAGETo 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, theyshould be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patternsmay contribute to the empiric selection of therapy.

Hepatic EncephalopathyXIFAXAN 550 mg is indicated for reduction in risk of overt hepaticencephalopathy (HE) recurrence in patients ≥ 18 years of age.

In the trials of XIFAXAN for HE, 91% of the patients were usinglactulose 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 inthe 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

HypersensitivityXIFAXAN is contraindicated in patients with a hypersensitivity torifaximin, any of the rifamycin antimicrobial agents, or any of thecomponents in XIFAXAN. Hypersensitivity reactions have includedexfoliative dermatitis, angioneurotic edema, and anaphylaxis [seeAdverse Reactions (6.2)].

WARNINGS AND PRECAUTIONSTravelers’ Diarrhea Not Caused by Escherichia coliXIFAXAN was not found to be effective in patients with diarrhea complicated by fever and/or blood in the stool or diarrhea due topathogens 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 beenproven. XIFAXAN should not be used in patients where Campylobacter jejuni, Shigella spp., or Salmonella spp. may be suspected as causative pathogens.

Clostridium difficile-Associated DiarrheaClostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XIFAXAN, andmay 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. difficilecause 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 sinceCDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use notdirected against C. difficile may need to be discontinued. Appropriatefluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

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

Severe (Child-Pugh C) Hepatic ImpairmentThere is increased systemic exposure in patients with severe hepaticimpairment. 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 inSpecific Populations (8.7), Nonclinical Toxicology (13.2) and Clinical Studies (14.2)].

ADVERSE REACTIONS

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

Hepatic EncephalopathyThe 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 hepaticencephalopathy 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:

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 placebogroup 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 IncidenceThan Placebo

Number (%) of Patients

XIFAXAN Tablets

550 mg TWICE

DAILY Placebo

MedDRA Preferred Term N = 140 N = 159

Edema peripheral 21 (15%) 13 (8%)

Nausea 20 (14%) 21 (13%)

Dizziness 18 (13%) 13 (8%)

Fatigue 17 (12%) 18 (11%)

Ascites 16 (11%) 15 (9%)

Muscle spasms 13 (9%) 11 (7%)

Pruritus 13 (9%) 10 (6%)

Abdominal pain 12 (9%) 13 (8%)

Abdominal distension 11 (8%) 12 (8%)

Anemia 11 (8%) 6 (4%)

Cough 10 (7%) 11 (7%)

Depression 10 (7%) 8 (5%)

Insomnia 10 (7%) 11 (7%)

Nasopharyngitis 10 (7%) 10 (6%)

Abdominal pain upper 9 (6%) 8 (5%)

Arthralgia 9 (6%) 4 (3%)

Back pain 9 (6%) 10 (6%)

Constipation 9 (6%) 10 (6%)

Dyspnea 9 (6%) 7 (4%)

Pyrexia 9 (6%) 5 (3%)

Rash 7 (5%) 6 (4%)

The following adverse reactions, presented by body system, have also been reported in the placebo-controlled clinical trial in greaterthan 2% but less than 5% of patients taking XIFAXAN 550 mg takenorally 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, upperrespiratory 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 ExperienceThe 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 InfestationsCases of C. difficile-associated colitis have been reported[see Warnings and Precautions (5.2)].

GeneralHypersensitivity reactions, including exfoliative dermatitis, rash,

angioneurotic edema (swelling of face and tongue and difficultyswallowing), urticaria, flushing, pruritus and anaphylaxis have beenreported. These events occurred as early as within 15 minutes of drug administration.

DRUG INTERACTIONSIn vitro studies have shown that rifaximin did not inhibit cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 andCYP3A4 at concentrations ranging from 2 to 200 ng/mL [seeClinical Pharmacology (12.3)]. Rifaximin is not expected to inhibitthese enzymes in clinical use.

An in vitro study has suggested that rifaximin induces CYP3A4 [seeClinical 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 asignificant 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 [seeClinical Pharmacology (12.3)].


PregnancyPregnancy Category Cg y g yThere 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 justifiesthe 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 infetal 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 frompregnant rabbits administered mid and high doses that resulted in 1or 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 toDay 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 MothersIt 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 UseThe safety and effectiveness of XIFAXAN 200 mg in pediatric patientswith 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 UseClinical studies with rifaximin 200 mg for travelers’ diarrhea did not include sufficient numbers of patients aged 65 and over to determinewhether they respond differently than younger subjects. In the controlled trial with XIFAXAN 550 mg for hepatic encephalopathy, 19.4% were 65and over, while 2.3% were 75 and over. No overall differences in safety oreffectiveness 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, butgreater sensitivity of some older individuals cannot be ruled out.

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

Hepatic ImpairmentFollowing 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 withmild (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.

Web site: www.salix.comE-mail: [email protected] Colonnade Center Drive, Raleigh, NC 27615Tel. 866-669-SLXP (7597) ©2012 Salix Pharmaceuticals, Inc.All rights reserved. Printed in USA. RIFHE 13/11

Important Safety Information About XIFAXAN 550 mgXIFAXAN® (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 diffi cile-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 fl ora of the colon which may lead to overgrowth of C. diffi cile. If CDAD is suspected or confi rmed, ongoing antibiotic use not directed against C. diffi cile 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.

*HE=hepatic encephalopathy.†Over a 6-month period; P=0.0129 vs placebo.3

‡ HE-related hospitalization defi ned as hospitalization directly caused by HE or a hospitalization during which an HE event occurred.3

www.Xifaxan550.comWeb 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

Prescribe. Protect. Repeat.

For overt HE* patients

OUT OF THE HOSPITAL DOESN’T MEAN OUT OF THE WOODS

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.

“ After an episode of [overt HE], prophylactic therapy with lactulose or rifaximin is recommended for an indefi nite period of time or until liver transplantation.”

—Clinics in Liver Disease, February 20121

MCGEN1889.indd 1 2/20/13 4:50 PM

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 demon-strate that colonoscopy is more effective in the pre-vention 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 PreparationsThe available purgatives for colonoscopy can be

divided into 3 categories: osmotic agents, polyeth-ylene 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 con-sist of a high-molecular-weight nonabsorbable poly-mer 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 laxa-tive effect is based on 2 mechanisms of action: stim-ulation of small intestinal secretion and increased motor activity within the colon. Dietary modifica-tion, consisting of a clear liquid or a low-fiber diet for 24 hours before the procedure, usually is combined with a purgative regimen.

LAWRENCE B. COHEN, MDClinical Professor of Medicine The Mount Sinai School of MedicineNew York City

Bowel Preparation For Colonoscopy

Maximizing Efficacy, Minimizing Risk

The 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

1

PRINTER-FRIENDLY VERSION AT GASTROENDONEWS.COM


This section provides a brief overview of the available purgatives for bowel preparation (Table 1). Several com-prehensive reviews on the comparative efficacy, safety, and tolerability of these agents recently have been pub-lished, 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. FDA-approved 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 “split-dose” 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 Low-volume 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-the-counter (OTC) product for the treatment of mild con-stipation. It also has been used as a pre-colonoscopy bowel cleansing regimen. One often recommended regimen for MiraLax is for patients to consume 4 bisa-codyl 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 Gator ade. 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,

thereby minimizing net absorption or secretion of fluid or electrolytes into the intestinal lumen, the MiraLax/Gatorade preparation is hypotonic. The safety and effi-cacy of MiraLax recently has been evaluated in sever-al randomized, investigator-blinded single-site studies. Enestvedt14 and Hjelkrem15 independently observed that 4-L PEG solution with electrolytes was more effec-tive than a solution of MiraLax in 64 oz of Gatorade. Split-dose preparations were used in both trials. How-ever, 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-split-ting, and Gerard et al17 reported that a modified pro-tocol of MiraLax (306 g PEG)/64 oz Gatorade taken at noon and between 5 and 9 PM the day before colonosco-py 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 prepara-tions has been excellent. During the 6-year period end-ing 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 perfora-tion, aspiration, and Mallory-Weiss tear.18 The use of PEG-based 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 cleans-

ing 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 recom-mended 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 prescrip-tion 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

INDEPENDENT LY DEVELOP ED BY M C M AH ON P UBL ISHIN G2

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 evidence-

based 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

Table 1. Commonly Used Purgatives for Colonoscopy PreparationClass Product Recommended Usea

Polyethylene glycol

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

4-L SF-PEG 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

Sodium phosphate

Tablet 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)

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.


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.

OTHER BOWEL PREPARATIONS

Oral sodium sulfate (Suprep, Braintree) is a newly developed bowel cleansing preparation that contains sodium sulfate, magnesium sulfate, and potassium sul-fate, plus flavoring agents in an aqueous form sup-plied 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 electro-lytes. Unlike OSP, sulfate salts do not produce renal tubular injury in animal models.26

The efficacy of oral sodium sulfate as a bowel cleans-ing preparation for colonoscopy has been established in 2 multicenter, randomized, single-blind studies.27,28 The sulfate preparation administered as a split-dose regi-men 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 appli-cation for Braintree’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 prepara-tion before colonoscopy. Prepopik (Ferring Pharmaceu-ticals, 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 bac-terial cleavage in the colon, producing the laxative com-pound bis-(P-hydroxyphenyl)-pyridyl-2-methane, the active ingredient in bisacodyl, which stimulates peristal-sis 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, assessor-blinded study compared Prepopik and HalfLytely in

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 prep-aration 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 prepara-tion in 78.9% and 78% of patients receiving picosulfate/magensium citrate and HalfLytely, respectively. Similar-ly, cleansing within the ascending colon was successful in 83% and 79.7% in the picosulfate/magnesium citrate and HalfLytely arms, respectively. Patient tolerabili-ty 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 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 sig-nificant 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 cleans-ing and provides suggestions for improving the quality and safety of bowel preparation. Recommendations for colonoscopy preparation within special patient popula-tions also are presented.

BOWEL PREPARATION: ONE SIZE DOES NOT FIT ALL Some endoscopists prefer to offer all patients a sin-

gle 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 disad-vantages, however, is an inability to adjust for differ-ences 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 cleans-ing. Differences such as these are best accommodat-ed 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 one-on-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 vol-ume depletion. The fluid loss during bowel preparation may exceed 2 to 3 L, based on an assessment of hemo-dynamic parameters and indirect measures such as body weight, serum osmolality, and hematocrit.32 Sig-nificant 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 reg-imen.33 Additionally, the use of NaP preparations often is associated with changes in serum electrolytes, includ-ing 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 asymptomat-ic. Serious electrolyte disturbances, however, have been reported with both NaP37 and PEG.38 Inadequate hydra-tion is widely believed to play an important role in such complications. Therefore, adequate hydration during bowel preparation should be emphasized, particular-ly in high-risk individuals, such as the elderly, patients on diuretics or other medications that alter electrolyte

levels, and patients with preexisting electrolyte abnor-malities. 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 remind-ed 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 exam-ination.35,41 Despite diet restriction for 24 hours, opti-mal 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 Gastroenter-ology (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 proce-dures. Patients undergoing a morning procedure should


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 proce-dures beginning at noon. This affords patients the con-venience 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 proce-dures 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 modi-fication 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 eve-ning group (4.73 vs 7.10, respectively; P<0.01), based on the validated Ottawa scale (range 0-14, 0=best). How-ever, 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 pre-procedural fasting, and consequently the literature contains a variety of recommendations on this sub-ject. 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 procedur-al sedation and analgesia, but should be considered in choosing the timing and target level of sedation.” A position statement from the American Gastroenter-ological Association51 concluded that “there is inade-quate evidence to permit the development of absolute requirements for pre-procedural fasting, and the clini-cian should be guided by the practice parameters pro-vided by various professional societies.”

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

evening-before bowel preparation showed no signifi-cant difference between the 2 regimens (19.7 vs 20.2 mL, respectively; P=0.85). Based on the current avail-able data, it is reasonable to recommend that patients undergoing colonoscopy with sedation fast for a mini-mum 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 under-going 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 complet-ing the preparation. Elderly patients using NaP also are more likely to manifest hyperphosphatemia as a result of impaired renal function, comorbid illness, and con-comitant medications.36

The efficacy, safety, and tolerability of various pur-gatives in older individuals have been evaluated in several studies. A randomized controlled trial with octogenarians compared NaP with a 4-L PEG prepa-ration.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 antic-ipated, PEG produced less change than NaP in the clin-ical parameters of dehydration and laboratory values. Fewer patients were unable to complete the NaP prep-aration than the PEG preparation, although the dif-ference 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 compa-rable 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 diar-rhea (>6-8 bowel movements per day); for this patient, the dose of cathartic may be reduced or eliminated alto-gether. NaP preparations can produce aphthoid lesions in the colon, most prominently within the rectum and sig-moid. 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 chil-dren 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 prep-aration for children is a PEG-based formulation (Mira-Lax) 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 par-ticular regimen over another. The PEG-based prepara-tions 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 disrupt-ing 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 prep-aration 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 regi-men selected, it is important to provide children with adequate hydration during the process of bowel prep-aration. 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 tran-sit 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: extend-ing the period of diet modification from 24 to 48 hours; adding oral bisacodyl or senna to a PEG or a NaP regi-men; 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 excel-lent, good, fair, and poor often are used in clinical prac-tice 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

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 effi-ciency of colonoscopy and minimize its risks (Key Points).

References

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2. Brenner H, Hoffmeister M, Arndt V, Stegmaier C, Altenhofen L, Haug U. J Natl Cancer Inst. 2010;102(2):89-95.

3. Leung K, Pinsky P, Laiyemo AO, Lanza E, Schatzkin A, Schoen RE. Gastrointest Endosc. 2010;71(1):111-117.

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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 examina-tion 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 colonos-copy 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.


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


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