VOL. 57 NO. 3 2016 JMSMA

SPECIAL COLON CANCER EDITION

VOL. LVII • NO. 3 • 2016

Colorectal Cancer P R E V E N TA B L E , T R E ATA B L E A N D B E ATA B L E !

www.nccrt.org

JOURNAL MSMA 57

VOL. LVII • NO. 3 MARCH 2016

JOURNAL OF THE MISSISSIPPI STATE MEDICAL ASSOCIATION (ISSN 0026-6396) is owned and published monthly by the Mississippi State Medical Association, founded 1856, located at 408 West Parkway Place, Ridgeland, Mississippi 39158-2548. (ISSN# 0026-6396 as mandated by section E211.10, Domestic Mail Manual). Periodicals postage paid at Jackson, MS and at additional mailing offices.

CORRESPONDENCE: Journal MSMA, Managing Editor, Karen A. Evers, P.O. Box 2548, Ridgeland, MS 39158-2548, Ph.: 601-853-6733, Fax: 601-853-6746, www.MSMAonline.com.

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The views expressed in this publication reflect the opinions of the authors and do not necessarily state the opinions or policies of the Mississippi State Medical Association.

Copyright © 2016 Mississippi State Medical Association.

EDITOR

Lucius M. Lampton, MD

ASSOCIATE EDITORS

D. Stanley Hartness, MDRichard D. deShazo, MD

MANAGING EDITOR

Karen A. Evers

PUBLICATIONS COMMITTEE

Dwalia S. South, MDChairPhilip T. Merideth, MD, JDMartin M. Pomphrey, MDLeslie E. England, MD Ex-Officioand the Editors

THE ASSOCIATION

PresidentDaniel P. Edney, MD

President-ElectLee Voulters, MD

Secretary-TreasurerMichael Mansour, MD

SpeakerGeri Lee Weiland, MD

Vice SpeakerJeffrey A. Morris, MD

Executive Director Charmain Kanosky

SCIENTIFIC ARTICLES

The Impact of Colorectal Cancer (CRC) in Mississippi, and the 62 Need for Mississippi to Eliminate Its CRC Burden Roy J. Duhé, PhD

Colonoscopy Atlas of Colon Polyps and Neoplasms 68 Shou-jiang Tang, MD and James Q. Sones, MD

How to Achieve Colon Cancer Screening in Average Risk 82 Population: A Review of Different Screening Options James Whatley, MD and James Q. Sones, MD

Review of Bowel Preparation Agents for Colonoscopy 94 Srikrishna Patnana, MD

INFOGRAPHIC

The Impact of Preventive Screening Resource Distribution 80 On Geographic and Population-Based Disparities in Colorectal Cancer in Mississippi

DEPARTMENTS

From the Editor – No More Excuses for CRC Screening 58 Lucius M. Lampton, MD, Editor

Guest Editor – Help Make Colon Cancer Screening a Priority 59 James “Jim” Sones, MD

MSMA – Nominating Committee Seeks Candidates for 88 Vacancies in Offices

President’s Page – Colon Cancer 103 Daniel P. Edney, MD

SPECIAL ARTICLES

GI Associates Serving The Community 72

Colon Cancer: Yes, It’s a Terrorist 74 Samuel C. Pace, MD

Back To Genesis or How We Got Here 90 William M. McKell, MD

Official Publication MSMA • Since 1959

ABOUT THE COVER – “CAPITOL IMPROVEMENTS”

The majestic, gleaming eagle keeps watch over the intricate, geometric scaffolding enveloping our Mississippi State Capitol Building which is getting its first restoration and repair in 30 years. The Beaux Arts-style building has been the seat of state government since 1903 with the 2016 Legislature currently in session. MSMA works tirelessly for the adoption or defeat of legislation felt to be in the best interest of the public health and our profession. Dr. Stanley

Hartness, Jackson family physician, was intrigued by the juxtaposition of the contemporary scaffolding and the classical dome.

JOURNAL EDITORIAL ADVISORY BOARD

F R O M T H E E D I T O R

No More Excuses for CRC ScreeningThis special issue of your JMSMA is focused on colorectal cancer (CRC) in Mississippi. Among cancers that impact both women and men, CRC is the second leading cause of cancer related death in this country and the third most common cancer in men and in women. Every year, almost 140,000 Americans are diagnosed and more than 50,000 die from it. Here in Mississippi, our CRC mortality rate

is the highest in the United States, according to the CDC. Despite such dismal statistics, this disease is highly preventable, with the key simply regular screening, beginning at age 50 and continuing until age 75. Regular and appropriate screening not only detects but also prevents the development of cancer by the removal of pre-cancerous polyps. Physicians of every specialty can play a significant role in decreasing CRC by encouraging the regular screenings of our patients.

Over the course of my more than two decades of medical practice, I have often battled to convince my patients of the need for colonoscopies for CRC screening. Many patients fear and avoid the procedure for a multitude of reasons. There haven’t been any good alternatives. However,

with the emergence of Cologuard, there are no more excuses for achieving 100% screening of appropriate patients for colorectal cancer. Cologuard, a stool-based FDA-approved colorectal screening test that detects the presence of hemoglobin and DNA mutations that may indicate the presence of cancer or precursors to cancer, is an easy option covered by Medicare. Patients with positive test results are advised to undergo a diagnostic colonoscopy. I highly recommend this test, not as a replacement for colonoscopies, but to achieve 100% screening in those patients refusing to undergo colonoscopies.

The point of this entire issue is to remember: the way to decrease CRC rates in Mississippi is to screen patients before they become symptomatic. CRC is preventable by removing polyps before they turn into cancer. Mississippi’s physicians must use every tool they have to increase screening in appropriate patients to 100%. Special thanks to Dr. Jim Sones and all of the other contributors for their excellent work in preparing this special issue to mark National Colon Cancer Awareness Month.

Contact me at [email protected].– Lucius M. Lampton, MD, Editor

Timothy J. Alford, MDFamily Physician, Kosciusko Medical Clinic

Michael Artigues, MDPediatrician, McComb Children’s Clinic

Diane K. Beebe, MDProfessor and Chair, Department of Family Medicine, University of Mississippi Medical Center, Jackson

Rep. Sidney W. Bondurant, MDRetired Obstetrician-Gynecologist, Grenada

Jennifer J. Bryan, MD Assistant Professor, Department of Family Medicine University of Mississippi Medical Center, Jackson

Jeffrey D. Carron, MD Professor, Department of Otolaryngology & Communicative Sciences, University of Mississippi Medical Center, Jackson

Gordon (Mike) Castleberry, MDUrologist, Starkville Urology Clinic

Matthew deShazo, MD, MPHAssistant Professor-Cardiology, University of Mississippi Medical Center, Jackson

Thomas E. Dobbs, MD, MPHState Epidemiologist, Mississippi State Department of Health, Hattiesburg

Sharon Douglas, MD Professor of Medicine and Associate Dean for VA Education, University of Mississippi School of Medicine, Associate Chief of Staff for Education and Ethics, G.V. Montgomery VA Medical Center, Jackson

Bradford J. Dye, III, MDEar Nose & Throat Consultants, Oxford

Daniel P. Edney, MDExecutive Committee Member, National Disaster Life Support Education Consortium, Internist, The Street Clinic, Vicksburg

Owen B. Evans, MDProfessor of Pediatrics and NeurologyUniversity of Mississippi Medical Center, Jackson

Maxie L. Gordon, MD Assistant Professor, Department of Psychiatry and Human Behavior, Director of the Adult Inpatient Psychiatry Unit and Medical Student Education, University of Mississippi Medical Center, Jackson

Nitin K. Gupta, MDAssistant Professor-Digestive Diseases, University of Mississippi Medical Center, Jackson

Scott Hambleton, MDMedical Director, Mississippi Professionals Health Program, Ridgeland

J. Edward Hill, MDFamily Physician, North Mississippi Medical Center, Tupelo

W. Mark Horne, MDInternist, Jefferson Medical Associates, Laurel

Daniel W. Jones, MDSanderson Chair in Obesity, Metabolic Diseases and Nutrition Director, Clinical and Population Science, Mississippi Center for Obesity Research, Professor of Medicine and Physiology, Interim Chair, Department of Medicine

Ben E. Kitchens, MDFamily Physician, Iuka

Brett C. Lampton, MDInternist/Hospitalist, Baptist Memorial Hospital, Oxford

Philip L. Levin, MDPresident, Gulf Coast Writers Association Emergency Medicine Physician, Gulfport

Lillian Lien, MDProfessor and Director, Division of Endocrinology, University of Mississippi Medical Center, Jackson

William Lineaweaver, MDEditor, Annals of Plastic Surgery, Medical Director, JMS Burn and Reconstruction Center, Brandon

Michael D. Maples, MDVice President and Chief of Medical Operations, Baptist Health Systems

Heddy-Dale Matthias, MDAnesthesiologist, Critical Care Internist, Madison

Jason G. Murphy, MDSurgeon, Surgical Clinic Associates, Jackson

Alan R. Moore, MDClinical Neurophysiologist, Muscle and Nerve, Jackson

Paul “Hal” Moore Jr., MDRadiologist, Singing River Radiology Group, Pascagoula

Ann Myers, MDRheumatologist , Mississippi Arthritis Clinic, Jackson

Darden H. North, MDObstetrician/Gynecologist , Jackson Health Care-Women, Flowood

Jack D. Owens, MD, MPHNeonatologist, Newborn Associates, Flowood

Michelle Y. Owens, MDAssociate Professor, Vice-Chair of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson

Jimmy L. Stewart, Jr., MD Program Director, Combined Internal Medicine/Pediatrics Residency Program, Associate Professor of Medicine and Pediatrics University of Mississippi Medical Center, Jackson

Shou J. Tang, MDProfessor and Director, Division of Digestive Diseases, University of Mississippi Medical Center, Jackson

Samuel Calvin Thigpen, MDHematology-Oncology Fellow, Department of Medicine, University of Mississippi Medical Center, Jackson

Thad F. Waites, MDClinical Cardiologist, Hattiesburg Clinic

W. Lamar Weems, MDUrologist, Jackson

Chris E. Wiggins, MDOrthopaedic Surgeon, Bienville Orthopaedic Specialists, Pascagoula

John E. Wilkaitis, MD Chief Medical Officer, Brentwood Behavioral Healthcare, Flowood

Sloan C. Youngblood, MDAssistant Medical Director, Department of Anesthesiology, University of Mississippi Medical Center, Jackson

58 VOL. 57 • NO. 3 • 2016 • SPECIAL COLON CANCER EDITION

J M S M A C O L O N C A N C E R S P E C I A L E D I T I O N G U E S T E D I T O R I A L

JOURNAL MSMA 59

Help Make Colon Cancer Screening a Priority

Our hope in presenting this issue of the Journal is to stimulate those on the front lines – family physicians, internists, NP’s, PA’s, and OB/GYN’s (often the only physician some women see) – to keep colon cancer screening in mind. Of all the major cancers, colon cancer has the longest period of development, from a small polyp in most cases to an invasive cancer. This period, which some believe

could be from three to eight years, unfortunately causes little or no symptoms, so our patients depend on us and our efforts in the media to remind them to get screened.

Thanks to Dr. McKell for sharing his memories of the beginning of what was a long and successful career in Mississippi practicing gastroenterology in Jackson and on the Gulf Coast. When I was reminded of the early days of training in GI, it projected me to where we are now. Like other specialties that have undergone tremendous technological development, the training of today’s new gastroenterologists has become longer and more complex. GI Fellowships now are three years (after completing four years of medical school and three years of Internal Medicine Residency). A fourth year of fellowship is available for Advanced Endoscopy, primarily endoscopic retrograde cholangio-pancreatography (ERCP) with all that it involves: stents, cytologic brushing, gallstone retrieval, etc. and endoscopic ultrasound (EUS). Transplant hepatology training requires the full three years of GI Fellowship as well followed by a fourth year of liver education. Gastroenterologists are also coming out of fellowships with extra emphasis on inflammatory bowel disease and confining their practice only to IBD. The endoscopy training obtained by our fellows includes, on average, over 1500 procedures, so they are poised for the novel future developments of rectal or oral-access GI procedures. The need for new ways of treatment for obesity is one that is rapidly developing now.

You will find information in this Journal about who needs colon cancer screening and when. There is some flux in this arena, although the standard for beginning screening is still age 50 and, in African-Americans, age 45. If you have a first degree relative with colon cancer, the screening age should be ten years younger than that person’s at the presentation of

their cancer. All this may change through the next few years. Even as we are going to press, a large study showed that 15% of colorectal cancers are now presenting under the age of 50, suggesting that screening should begin at age 40 (HealthDay, 16 Jan 2016).

Inside, you will find Dr. Roy Duhe’s article that details what a huge problem colon cancer is for our state. There are illustrations emphasizing its impact on us. Dr. Whatley describes the different ways to get screening, their costs, advantages and disadvantages. Dr. Patnana tackles the subject causing the most concern for many, and the primary reason folks avoid colonoscopy: the preps! Dr. Tang takes you on a colonoscopic journey with photos of the types of pathology we encounter during screening. There is an article describing ‘’Giveback Day,’’ an event that, for several years, GI Associates in Jackson has done at their endoscopy centers. Selected uninsured patients are given free colonoscopies on a Saturday in March, Colon Cancer Awareness Month. Hopefully, this will be an example picked up by other GI practices in the state since poverty remains one of the main impediments to getting screened for colon cancer.

OUR HOPE IN PRESENTING THIS ISSUE OF THE JOURNAL IS TO STIMULATE THOSE ON THE FRONT LINES – FAMILY PHYSICIANS, INTERNISTS, NP’S, PA’S, AND OB/GYN’S (OFTEN THE ONLY PHYSICIAN SOME WOMEN SEE) –

TO KEEP COLON CANCER SCREENING IN MIND.

Predicting the future is always fraught with risk. We are nearly always wrong in so many “sure things,” but we can say assuredly there will be a need for training gastroenterologists for many years. Often the need for specialist physicians is dictated by a single organ or one disease (think tuberculosis and sanitoria). Our specialty involves more than one organ and does not have a predominate disease. Other problems move to the forefront as some decline. Hepatitis C is now approaching 100% cure success with a regimen that is shorter and simpler than previous

JIM SONES, MDProfessor, Dept. of Medicine • Chief, Division of Gastroenterology, University of Mississippi Medical Center


treatment. But fatty liver is on the rise with the resultant chronic liver problems and transplants that will be needed. The science of genetics may help us reduce the need for colonoscopies in the future. Nanobots may one day scour our colons looking for adenoma pre-cursors and other not-yet-developed technology may amaze us, but until that day, colonoscopy remains the best way to prevent the most curable of the major cancers.

Being human, all of us tend to put off things we know we should do until something happens to stimulate us. A family member or friend gets the devastating news of advanced colon cancer, for example. Or sometimes it becomes easier, and we do it. In 2002 when Medicare decided to start paying for colon cancer screening, the number of colonoscopies soared by 42%.

Dr. Pace’s gripping story tells us that even our best guidelines and compliance to them sometime fail. He relates the important directive of where we, as physicians, should begin: get ourselves screened! It is easier to talk to a patient about screening when you can relate your experience having it done.

If we put colon cancer screening up to the priority our patients deserve, what else can we do? You can get a colon cancer screening car tag. How to do this is found in this issue. You have to have a tag anyway, so what about getting one that someday, someone might see and think, ‘’You know, I need to do that’’ ... and you, simply by driving down the road, have prevented a death by colon cancer!

Keeping the game fair...

...so you’re not fair game.

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society guidelines, please visit our society’s website at www.MSGIsociety.org.

BASTROP, LAGastroenterology and Nutritional Raj Bhandari, MD

COLUMBUSGastroenterology Associates of ColumbusRichard Heard, MD

S. Andrew Johnson, MD

Richard L. Johnston, MD

J. Stephen Rawson, MD

Alan T. Williams, MD

CORINTHMagnolia Gastroenterology ClinicFred A. Corder, MD

GREENWOODMississippi Surgical Specialties CenterGeorge V. Smith, MD

GULFPORTGastroenterology CenterHans W. Adams, MD

Peter J. Bernheim, MD

Scott M. Gioe, MD

Warren A. Hiatt, Jr., MD

HATTIESBURGHattiesburg Clinic Dept of GastroenterologyKevin P. Blanchard, MD

E. Howell Crawford, Jr., MD

Gregory R. Owens, MD

Joseph P. Phillips, MD

JACKSONDigestive Disease ClinicDeborah S. Skelton, MD

Digestive Healthcare ClinicThomas P. Mills, MD

GI Associates and Endoscopy CenterDonald Brannan, MD

Keith Brown, MD Pathologist

Albert Chiemprabha, MD

Shirley Donelson, MD

Pierce Dotherow, MD

Charles Hall, MD

Samuel Hensley, MD Pathologist

Reed Hogan, II, MD

Reed Hogan, III, MD

Jason Jones, MD Pathologist

Ronald Kotfila, MD

Makau Lee, MD

Jeffrey McCrary, MD

J. Trippe McNeese, MD

Paul Milner, MD

Michelle Petro, MD

Vonda Reeves-Darby, MD

Sara Rippel, MD PEDS

Matt Runnels, MD

Angela Shannon, MD PEDS

Vishwanath Shenoy, MD

James Underwood, MD

E. Stephens Weeks, Jr., MD

Jane-Claire Williams, MD

Mark Wilson, MD

Cindy Haden Wright, MD

University PhysiciansBrian Borg, MD

Shou Jiang Tang, MD

Nitin Gupta, MD

James Q. Sones, MD

Pegah Hosseini-Carroll, MD

Kumar Pallav, MD

John Sheehan, MD

Elizabeth Paine, MD (VAMC)

LAURELJefferson Medical AssociatesCarolyn H. Cegielski, DO

Jesse H. Ezzell, Jr., MD

Stephen P. Johnson, DO

MERIDIAN Rush Medical GroupKhondker Islam, MD

Eddie Starnes, MD

Meridian GastroenterologyV. Craig Dungan, MD

OCEAN SPRINGSRegional Digestive SpecialistsDarrell Finlay, MD

Catherine Hirsch, MD

Ronald Rinker, MD

Digestive Health Center(Offices also in Biloxi and Pascagoula)Richard Chernecky, MD

Alva Dillon, MD

Michael Loebenberg, MD

John McKee, III, MD

Alfred McNair, MD

OXFORDGastroenterology Assc. of North MSDavid Bridgers, MD

Henry Johnson, Jr., MD

S. Todd Threadgill, MD

John H. Webb, MD

Ernest Williams, MD

SOUTHAVENDelta GastroenterolgoyUlric Duncan, MD

TUPELODigestive Health SpecialistsStephen Amann, MD

John B. Averette, MD

Christopher H. Decker, MD

Barney J. Guyton, MD

Noel K. Hunt, MD

C. Allen Justice, MD

W. Garrett Ogg, MD

John O. Phillips, MD

Robert B. Smith, MD

VICKSBURG

Better Living Clinic, Endoscopy CenterYoshinobu Namihira, MD

To discuss colon cancer screening or surveillance, and for quality colonoscopy, please contact our society members.

The Impact of Colorectal Cancer (CRC) in Mississippi, and the Need for

Mississippi to Eliminate Its CRC BurdenROY J. DUHÉ, PhD

University of Mississippi Medical Center

S C I E N T I F I C A R T I C L E


How does Mississippi compare to the

rest of the nation in controlling colorectal cancer?

In business, it is widely known that maintaining the status quo while competitors offer superior products or services is tantamount to failure. Were we honest about colorectal cancer (CRC) control in Mississippi, we would recognize it as a failure, because most other states have deliberately and dramatically reduced their CRC burden while Mississippi has essentially relied on a laissez-faire approach to CRC prevention and control. The consequence is that Mississippi’s colorectal cancer mortality rate, which was one of the best in the nation two decades ago,1 remained nearly unchanged and is now the worst in the nation. While Mississippi’s overall CRC mortality rate may have declined only by 7.4% from 2003 (20.8 ± 1.7 deaths per 100,000) to 2012 (19.26 ± 1.55 deaths per 100,000), the state’s overall CRC incidence rate has declined by 14.3% over the same period, from 56.16 ± 2.79 to 48.14 ± 2.43 deaths per 100,000.2 The good news is that one can reasonably predict that the larger decrease in incidence over the past decade will translate into a more significant decrease in mortality over the coming decade, even in the absence of a well-designed, coordinated effort to prevent and control CRC in Mississippi. The bad news is that Mississippi has fallen far behind the nation’s progress over the same time frame,3

when there was a 24.2% reduction in CRC incidence and a 23% reduction in CRC mortality across America. The problem is not merely a matter of Mississippi being in last place in yet another health measure but rather that Mississippi is moving further and further away from the national norm. In 2003, Mississippi’s CRC incidence and mortality rates were only 12.1% and 8.9% above the national averages, respectively. By 2012, Mississippi’s CRC incidence and mortality rates stood out conspicuously with rates 25% and 31% higher than the national average CRC incidence and mortality rates, respectively.

As dismal as these statistics are, conceivably they could be worse, because CRC incidence rates are dramatically rising in several Eastern European nations and in many other economically transitioning nations.4 The tremendous variations in CRC incidence rates around the world is due to the fact that CRC is now highly preventable. Granted, a small percentage of colorectal cancers, such as those associated with Lynch Syndrome and Familial Adenomatous Polyposis, are attributable to uncontrollable genetic factors, and family history of CRC is a major uncontrollable risk factor. But the probability of developing common forms of CRC is associated with highly controllable risk factors,5 including smoking, lack of physical exercise, obesity, diets deficient in fruits, vegetables and high fiber content, and diets rich in processed meats.6,7 Type II diabetes, which is also considered a highly preventable disease, is another risk factor for CRC. This information can be used to interpret the changing trends in colorectal cancer observed both in the U.S. and globally over the years. Over the twentieth century, U.S. occupational patterns underwent major transformational shifts, and the percentage of Americans employed in physically-active occupations such as farmers, farm laborers and other laborers plummeted while the percentage of Americans employed in more sedentary occupations such as professionals and office workers dramatically increased;8 comparable changes are occurring in other developed nations. Classically, dietary changes occur as populations become more affluent, deriving less of

their energy from carbohydrates and more from animal sources, fats and protein.9 Globally and within the U.S.A., the availability of cheap sugar, fats, and vegetable oils has uncoupled the economic linkage to this dietary change, and low-income nations are undergoing this “nutrition transition”10 which is contributing to the global rise in obesity and non-communicable chronic diseases, including colorectal cancer. Within the U.S., changes in these types of risk factors partially explain why prior to the 1990s, the highest incidence of colorectal cancer was among high income individuals in the USA, whereas the lowest incidence of colorectal cancer was found among lower income individuals, and why those relationships are now reversed.11

THE GOOD NEWS IS THAT ONE CAN REASONABLY PREDICT THAT THE LARGER DECREASE IN INCIDENCE

OVER THE PAST DECADE WILL TRANSLATE INTO A MORE SIGNIFICANT DECREASE IN MORTALITY OVER THE COMING

DECADE, EVEN IN THE ABSENCE OF A WELL-DESIGNED, COORDINATED EFFORT TO PREVENT AND CONTROL

CRC IN MISSISSIPPI.

If increasing sedentary lifestyles, obesity rates, type II diabetes prevalence, and dietary changes are increasing the intrinsic risk of developing colorectal cancer, as documented in Eastern European nations,4 how is it possible that CRC incidence and mortality rates are declining throughout the U.S.? Highly reliable screens capable of detecting asymptomatic CRC precursor lesions and early stage CRCs have been available for decades, and the broad use of these screens has been the single-most important extrinsic factor in reducing both CRC incidence and CRC mortality. In 1971 Greegor showed that asymptomatic

JOURNAL MSMA 63

ABSTRACT

Colorectal cancer (CRC), while highly preventable and highly treatable, is a major public health problem in Mississippi. This article reviews solutions to this problem, beginning with the relationship between modifiable behavioral risk factors and CRC incidence. It then describes the impact of CRC screening on national downward trends in CRC incidence and mortality and summarizes recent data on the burden of CRC in Mississippi. While other states have created Comprehensive Colorectal Cancer Control Programs in an organized effort to manage this public health problem, Mississippi has not. Responding to Mississippi’s situation, the 70x2020 Colorectal Cancer Screening Initiative arose as an unconventional approach to increase CRC screening rates throughout the state. This article concludes by considering the current limits of CRC treatment success and proposes that improved clinical outcomes should result from research to translate recently-identified colorectal cancer subtype information into novel clinical paradigms for the treatment of early-stage colorectal cancer.


colorectal cancers could be detected via guaiac-based tests for occult blood in the stool, abbreviated as gFOBT.12 His studies were facilitated by the commercial availability of Hemoccult® guaiac-impregnated electrophoresis filter paper, which had been in production since 1959. At the time of Greegor’s work, barium enema-enhanced X-ray exams were used to confirm the presence of CRC, and it was noted that many of the CRCs detected in this landmark paper were beyond the range of sigmoidoscopy. Soon thereafter, a number of groups began to examine the feasibility of mass public screenings using this technique, and it became clear that this would be a cost-saving public health effort.13 Because this test was based on the heme-dependent oxidation of guaiac, foods containing heme (such as red meat) and foods or supplements with oxidant or anti-oxidant properties (such as vitamin C) altered the accuracy of the test. Soon an alternate test (the Fecal Immunochemical Test or FIT) for the presence of human blood in the stool was developed based on the immunochemical detection of human hemoglobin.14 Numerous head-to-head comparisons between gFOBT and FIT have been conducted over the years, and the FIT has shown superior performance, although it is important to recognize that not all FIT products on the market are of equal quality.15,16 The newest innovation in stool-based colorectal cancer screening is the multi-target stool DNA test,17 which detects aberrantly methylated BMP3 and NDRG4 promoter regions, mutant KRAS DNA and includes an immunochemical test for human hemoglobin. This test has higher detection rates for serrated sessile polyps and for high-grade dysplasias than FIT. Only one multi-target stool DNA test is approved by the U.S. Food and Drug Administration (as of this writing) and it is significantly more expensive than a FIT screen.

IF MISSISSIPPI WERE TO DEVELOP A CONVENTIONAL, PUBLIC HEALTH-ORIENTED COMPREHENSIVE CRC

CONTROL PROGRAM, IT WOULD INCLUDE EFFORTS TO ADDRESS INTRINSIC CRC RISK FACTORS SUCH AS DIET AND EXERCISE, BUT THE MAJORITY OF EFFORT WOULD FOCUS ON CRC SCREENING AS THE PRIMARY EXTRINSIC FACTOR CAPABLE OF REDUCING CRC INCIDENCE AND MORTALITY.

A second major technical advance was the introduction of colonoscopic polypectomy by Wolff and Shinya in 1973.18 This technology allowed the National Polyp Study to obtain proof-of-concept evidence that colonoscopic polypectomy reduced the incidence of colorectal cancer.19 While this evidence was sufficient to persuade innovators to promote colonoscopy as a major cancer prevention tactic, a few sticklers for evidence-based medicine maintained that there was no clinical evidence that the procedure saved lives. This argument was settled in 2012, when the National Polyp Study released the results of a long-term follow-up study showing that colonoscopic removal of adenomatous polyps reduced colorectal cancer mortality by 53%.20

Based on the large body of evidence documenting the preventive power of colorectal cancer screening, several groups have issued a similar set of

CRC screening recommendations. These agencies include the U.S. Preventive Services Task Force,21 the American College of Physicians,22 the American College of Gastroenterology,23 and joint guidelines from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology.24 From 2005 to 2009, the U.S. Centers for Disease Control and Prevention (CDC) supported a 4-year Colorectal Cancer Screening Demonstration Program (CRCSDP) at five locations throughout the country, and based on the data collected through this demonstration program,25,26 established the CDC’s larger, population-based Comprehensive Colorectal Cancer Control Program (CRCCP). The CDC has funded CRCCPs in over 29 states and tribal nations since 2009. On September 30, 2015, the CDC announced it was awarding $22.8 million to 24 state health departments, 6 universities, and 1 Native American tribe to support CRCCPs. The southeastern states included were Alabama, Arkansas, Florida, Kentucky, Louisiana, and South Carolina. Recent analysis27 of the difference between CRCCP grantees versus non-grantees revealed that CRCCP grantees were much more likely than non-grantees to: 1) use Community Guide-recommended evidence-based interventions to promote CRC screenings; 2) use patient navigation services to promote CRC screenings; and 3) provide CRC screening to uninsured and underinsured low-income adults. Mississippi does not have a comprehensive colorectal cancer control program and does not implement any of the three tactics listed above. It should come as no surprise that 48% of CRCCP grantee states have more than 67.4% of their population up-to-date with CRC screening recommendations (versus only 22.2% of non-grantee states), whereas 38.9% of non-grantee states have less than 61.8% of their population up-to-date with recommended CRC screening (versus only 16% of CRCCP grantee states). In the data used for that analysis, the CRC screening rate for Mississippi was 58.2%.26

Mississippi’s response to the CRC quandary

Using publicly-available data, my colleagues and I set out to document the distribution of CRC screening resources in Mississippi and determine whether the distribution of these resources was a significant factor affecting CRC incidence and mortality outcomes in the state.29 This analysis, averaging data from 2006 through 2010, revealed tremendous geographic and population-based disparities in colorectal cancer in Mississippi, with significantly poorer outcomes for African-ancestry (Black) Mississippians than for European-ancestry (White) Mississippians in age-adjusted CRC incidence (64.9 per 100,000 in Blacks vs. 50.5 per 100,000 in Whites; P <.0001), age-adjusted CRC mortality (26.2 per 100,000 in Blacks vs. 17.5 per 100,000 in Whites; P = .0001), and self-reported CRC endoscopic screening rates (46.8% in Blacks vs. 58.1% in Whites). However, the disparities were even greater when one examined regional data. For example, self-reported CRC endoscopy screening rates ranged from a low of 40.4% reported by Black Mississippians in Public Health District 3 to a high of 64.2% reported by White Mississippians in Public Health District 5. The strong correlations observed between variables in Mississippi’s CRC outcomes were consistent with correlations which have been observed in preceding national and international studies. For example, at the level of Public Health Districts, strong negative correlations existed between the percentage of individuals aged 50 years or older who reported

JOURNAL MSMA 65

having ever received a colonoscopy or flexible sigmoidoscopy and the age-adjusted CRC incidence rate (r = -0.800), and a similarly strong negative correlation was also observed screening rates and age-adjusted CRC mortality rates (r = -0.796). Self-reported screening data were not available at the county level, and no county-level CRC outcomes correlated in a statistically-meaningful fashion. However, a strong county-level association existed between CRC incidence rates and the percentage of residents living below the poverty level (r = 0.461, P ≤ .000).

There are many mechanisms whereby community-level poverty can affect the incidence of CRC, some of which were mentioned in the earlier discussion of the global “nutrition transition”. While it is common to discuss mechanisms involving individuals who are poor (e.g., they are less likely to be insured, they are less likely to be highly educated, etc.), it is less common for researchers and policy-makers to consider the impact of community-level poverty on resource allocations based on business practices. Only two types of health facilities can be licensed for colonoscopy facilities in Mississippi: hospitals and ambulatory surgical facilities. Only 61 of the 116 Mississippi hospitals (52.6%) offer on-site colonoscopies, in addition to 26 ambulatory surgical facilities (gastroenterology clinics). Presumably, private gastroenterology clinics select locations based on market analyses and are more likely to be located where there is a sufficiently large population of clients able to pay for services. This would explain why two Public Health Districts (PHDs 3 and 7) had no ambulatory surgical facilities which offered colonoscopies at the time of the study, as these regions have low population densities and high poverty levels. Consistent with this hypothesis, we observed that 62% of the state’s population, with a mean per capita income of $21,680, live within a 30-minute drive to a gastroenterologist’s primary practice site, whereas the remaining 38% of Mississippians who live beyond this area have a mean per capita income of $17,307.

Armed with such information, 15 key stakeholders representing a cross-section of Mississippians met on April 22, 2014, at the University of Mississippi Medical Center Cancer Institute to assess the level of statewide

commitment to a common goal and to identify critical-path activities, benchmarks, and obstacles which would affect the attainment of that goal. From this meeting the 70x2020 Colorectal Cancer Screening Initiative30 was born, with the simple goal of ensuring that at least 70% of Mississippians would be up-to-date with colorectal cancer screening recommendations by the year 2020. The initiative is supported by a growing partnership consisting of three major sectors representing the general public and non-governmental organizations, health care providers and organizations, and governmental agencies and officials. For example, the Mississippi State Medical Association, the Mississippi Primary Health Care Association, and the Mississippi Gastroenterology Society are three of the health professional organizations belonging to the partnership. Because the 70x2020 partnership is not a hierarchical organization, individual partners are free to pursue actions to exceed the 70x2020 goal. Hence, Digestive Health Specialists, PA (MS), the Mississippi Primary Health Care Association, the University of Mississippi Medical Center, and North Mississippi Medical Clinics, Inc. have committed to attaining 80% compliance within their organization by the year 2018, as have other Mississippi organizations not yet engaged in the 70x2020 Partnership, such as Mississippi Baptist Medical Center.

On October 5, 2015, after considerable planning and discussion, the 70x2020 partnership issued a Strategic Plan to reach or exceed the 70x2020 goal. This plan31 focuses on three strategic efforts: 1) change Mississippi’s attitudes about colorectal cancer, 2) change Mississippi’s colorectal cancer control tactics, and 3) address Mississippi’s geographic and population-based health disparities. The strategy employs ten tactics, each of which is being implemented by a task force of volunteers. The ten tactics of this plan are listed in Table 1.

It is important to note that the 70x2020 Colorectal Cancer Screening Initiative is not the same as a CRCCP, nor should it be considered a substitute. For this reason, the 70x2020 Strategic Plan includes preparation for the transitional year 2020, when the Initiative will end. Because the 70x2020 plan incorporates evidence-based interventions into the tactics it uses, because the plan’s priorities are based on the best available data, and because the plan includes a comprehensive approach to CRC screening, it can provide a framework for the development of an effective CRCCP for the state of Mississippi.

The future of CRC: Therapeutic

decisions based on subtype versus stage

If Mississippi were to develop a conventional, public health-oriented comprehensive CRC control program, it would include efforts to address intrinsic CRC risk factors such as diet and exercise, but the majority of effort would focus on CRC screening as the primary extrinsic factor capable of reducing CRC incidence and mortality. This would meet the status quo expected by funding agencies such as the CDC, and it would represent a great improvement over the current situation. Currently, with approximately 10 deaths per 100,000, Utah has the lowest CRC mortality rate in the nation, and with an ideal CRCCP Mississippi might reach such a low CRC mortality rate. By cutting our currently mortality rate in half, this would represent tremendous progress.

TABLE 1. Ten Tactical Elements of the 70x2020 Strategic Plan

1 90% CRC screening among eligible participants in the State and School Employees’ Health Insurance Plan

2 90% CRC screening among eligible Veterans, Military Service Members and Immediate Families

3 90% CRC screening among eligible Insured Employees via Workplace

4 Increase Stool-based CRC Screening via Primary Health Care Providers, CHCs, FQHCs and RHCs

5 Improved continuity of care linkages between Primary and Specialty Health Care

6 Community Engagement 7 Communication8 Improved Metrics via Health Data Analytics9 Mission-Focused Funding Strategy10 2020 Transition


But what if Mississippi were to go beyond the status quo? How can Mississippi eliminate CRC mortality?

Recall that the National Polyp Study data documented a 53% reduction in CRC mortality resulted from colonoscopic polypectomy.20 Numerous explanations have been offered to explain why 47% of individuals undergoing colonoscopic polypectomy died of CRC, and the most common explanation given is “interval cancers” (cancers which become detectable during the interval between colonoscopies) and/or cancers which were missed or incompletely removed are responsible for those deaths. The uniform implementation of quality assurance guidelines32 can certainly reduce the number of missed polyps and cancers, and they should be adopted by practitioners. However, there are other plausible explanations for these deaths, and the most important explanation is based on the recognition of distinct CRC subtypes. Currently, early stage CRC is treated with a “one-size-fits-all” approach. Throughout America, 86% of all stage I and stage II CRCs are treated with surgery alone.33 This stands in stark contrast to the treatment of breast cancer in which only 27% of all stage I and stage II cancers are treated by surgery alone. This difference is because the first question asked when treating CRC is “What stage?” whereas the first question asked when treating breast cancer is “What subtype?” Through the use of surrogate markers such as HER2 and ER, clinicians are able to select the proper treatment approach for breast cancers and are able to match hormonal therapies, cytotoxic chemotherapies, and/or recombinant monoclonal antibody therapies, often in combination with surgery and/or radiotherapy, in order to optimize therapy for a given breast cancer subtype.34

WHILE IT IS COMMON TO DISCUSS MECHANISMS INVOLVING INDIVIDUALS WHO ARE POOR (E.G., THEY

ARE LESS LIKELY TO BE INSURED, THEY ARE LESS LIKELY TO BE HIGHLY EDUCATED, ETC.), IT IS LESS COMMON FOR RESEARCHERS AND POLICY-MAKERS TO CONSIDER THE

IMPACT OF COMMUNITY-LEVEL POVERTY ON RESOURCE ALLOCATIONS BASED ON BUSINESS PRACTICES.

While the breast cancer analogy is informative, it is not a perfect system for a number of reasons, and one can predict these imperfections will apply to colorectal cancer subtypes. The three major imperfections are 1) there is not a perfect concordance between the underlying genomic molecular subtype and the surrogate immunochemical markers for molecular subtypes,35,36 2) treatments for aggressive, stem-like breast cancers with mesenchymal-like molecular characteristics are often not curative, and 3) the complexity of subtypes within the “poorly-differentiated”/ “stem-like”/”triple-negative” category is greater than originally anticipated and not yet completely defined.

Despite these concessions, the recent international effort to delineate colorectal cancer subtypes provides good reason to believe that the CRC mortality rate can be reduced below the current floor of 10 deaths per 100,000 and that the NPS’ observation that colonoscopy/polypectomy

can reduce CRC mortality by 53% can be improved by matching therapy to CRC subtype. One recent study conducted by American collaborators37 developed a molecular subtyping system which was highly correlated to clinical outcomes and cell of origin. In this study, Kaplan-Meier survival curves of patients who received neither chemotherapy nor radiation (i.e., untreated except for surgery) showed essentially 100% survival in patients with the “goblet-type” CRC subtype but a much lower survival rate for patients with the “stem-like” CRC subtype. This illustrates the concept that some individuals can be spared the risks of chemotherapy and/or radiotherapy and have excellent long-term outcomes, but other patients would likely benefit from consolidation therapy when their early-stage CRCs are resected. This is scientifically reasonable because “stem-like” carcinomas have a tendency to remain dormant and recur as highly heterogeneous tumors; moreover, they share characteristics found in cells undergoing the reversible epithelial-to-mesenchymal transition (EMT) and thus are predisposed to metastasis.38 The latter characteristics were emphasized in a Western European effort to define CRC subtypes39 in which the authors proposed that the poor-prognosis CCS3 tumors are highly related to serrated adenomas and that these subtypes may exhibit metastatic tendencies at an early stage of tumor development. Such micro-metastases would not be visible to the surgeon or gastroenterologist and without effective consolidation therapy, would be very likely to recur as disseminated disease.

The latest international effort to develop a uniform consensus on CRC subtypes was based on a new analysis of the six prevalent subtyping systems by the Colorectal Cancer Subtyping Consortium.40 This study involved a total of 18 CRC data sets (n = 4,151 patients). This cooperative network approach yielded four consensus subtyping clusters (CMS1 through CMS4) and an unlabeled non-consensus set of samples (n = 858); many of the non-consensus samples exhibited a mixed subtype. Thus, while it appears that we are at the verge of revolutionizing the treatment of early-stage CRCs by choosing the best treatment protocol based on precisely-defined molecular subtypes, it is clear that additional translational and clinical research is needed before this becomes standard medical practice.

In summary, Mississippi is faced with the nation’s most daunting CRC prevention and control challenge. While other states have well-funded CRCCPs to address their own CRC burdens, Mississippi has an atypical temporary volunteer network, the 70x2020 Colorectal Cancer Screening Partnership, which is primarily supported by hope, a strategic plan, and Internet access. With adequate funding and institutional support, Mississippi could create a visionary CRCCP which goes beyond standard public health programs to reduce intrinsic risks for CRC and support CRC screening efforts by including a translational and clinical research effort dedicated to eliminating CRC mortality.

Acknowledgments

The author gratefully acknowledges the University of Mississippi Medical Center Cancer Institute as the major financial supporter of the 70x2020 Colorectal Cancer Screening Initiative and acknowledges the many contributions of over three hundred 70x2020 partners. This work was supported in part through a Patient-Centered Outcomes Research Institute (PCORI) Program Award (EA-1148-UMC).

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Dr. Duhé is professor of pharmacology and toxicology, professor of radiation oncology, and associate director for cancer education. He is also one of the organizers of the 70x2020 Colorectal Cancer Screening Initiative.

Corresponding Author: Roy J. Duhé, PhD, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216. ([email protected])

Keywords: Colorectal Neoplasms; Early Detection of Cancer; Colonoscopy; Occult Blood; Preventive Medicine

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2. http://www.cancer-rates.info/ms/index.php Accessed March 1, 2016. 3. http://seer.cancer.gov/statfacts/html/colorect.html Accessed March 1, 20164. Center MM, Jemal A, Ward E. International trends in colorectal cancer incidence

rates. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2009;18:1688-94.

5. Johnson CM, Wei C, Ensor JE, et al. Meta-analyses of colorectal cancer risk factors. Cancer Causes Control : CCC 2013;24:1207-22.

6. Bouvard V, Loomis D, Guyton KZ, et al. Carcinogenicity of consumption of red and processed meat. Lancet Oncol 2015;16:1599-600.

7. Lippi G, Mattiuzzi C, Cervellin G. Meat consumption and cancer risk: a critical review of published meta-analyses. Crit Rev Oncol Hematol 2016;97:1-14.

8. Wyatt IDH, D.E. Occupational Changes During the 20th Century. MLR 2006;129:35-57.

9. Gerbens-Leenes PW, Nonhebel S, Krol MS. Food consumption patterns and economic growth. Increasing affluence and the use of natural resources. Appetite 2010;55:597-608.

10. Drewnowski A, Popkin BM. The nutrition transition: new trends in the global diet. Nut Rev 1997;55:31-43.

11. Saldana-Ruiz N, Clouston SA, Rubin MS, Colen CG, Link BG. Fundamental causes of colorectal cancer mortality in the United States: understanding the importance of socioeconomic status in creating inequality in mortality. Am J Pub Health 2013;103:99-104.

12. Greegor DH. Occult blood testing for detection of asymptomatic colon cancer. Cancer 1971;28:131-4.

13. Miller SF, Knight AR. The early detection of colorectal cancer. Cancer 1977;40:945-9.

14. Barrows GH, Burton RM, Jarrett DD, Russell GG, Alford MD, Songster CL. Immunochemical detection of human blood in feces. Am J Clin Path1978;69:342-6.

15. Allison JE, Fraser CG, Halloran SP, Young GP. Population screening for colorectal cancer means getting FIT: the past, present, and future of colorectal cancer screening using the fecal immunochemical test for hemoglobin (FIT). Gut and Liv. 2014;8:117-30.

16. Young GP, Symonds EL, Allison JE, et al. Advances in Fecal Occult Blood Tests: the FIT revolution. Dig Dis Sci. 2015;60:609-22.

17. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014;370:1287-97.

18. Wolff WI, Shinya H. Polypectomy via the fiberoptic colonoscope. Removal of neoplasms beyond reach of the sigmoidoscope. N Engl J Med. 1973;288:329-32.

19. Winawer SJ, Zauber AG, Ho MN, et al. Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med. 1993;329:1977-81.

20. Zauber AG, Winawer SJ, O'Brien MJ, et al. Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths. N Engl J Med. 2012;366:687-96.

21. Whitlock EP, Lin JS, Liles E, Beil TL, Fu R. Screening for colorectal cancer: a targeted, updated systematic review for the U.S. Preventive Services Task Force. Ann of Intern Med. 2008;149:638-58.

22. Qaseem A, Denberg TD, Hopkins RH, Jr., et al. Screening for colorectal cancer: a guidance statement from the American College of Physicians. Ann of Intern Med 2012;156:378-86.

23. Rex DK, Johnson DA, Anderson JC, et al. American College of Gastroenterology guidelines for colorectal cancer screening 2009 [corrected]. Am J Gastroenterol. 2009;104:739-50.

24. Levin B, Lieberman DA, McFarland B, et al. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin. 2008;58:130-60.

25. Seeff LC, Rohan EA. Lessons learned from the CDC's Colorectal Cancer Screening Demonstration Program. Cancer 2013;119 Suppl 15:2817-9.

26. Seeff LC, DeGroff A, Joseph DA, et al. Moving forward: using the experience of the CDCs' Colorectal Cancer Screening Demonstration Program to guide future colorectal cancer programming efforts. Cancer 2013;119 Suppl 15:2940-6.

27. Maxwell AE, Hannon PA, Escoffery C, et al. Promotion and provision of colorectal cancer screening: a comparison of colorectal cancer control program grantees and nongrantees, 2011-2012. Prev Chronic Dis. 2014;11:E170.

28. Centers for Disease C, Prevention. Vital signs: Colorectal cancer screening, incidence, and mortality – United States, 2002-2010. MMWR 2011;60:884-9.

29. Faruque FS, Zhang X, Nichols EN, et al. The impact of preventive screening resource distribution on geographic and population-based disparities in colorectal cancer in Mississippi. BMC Res Notes. 2015;8:423.

30. www.umc.edu/70x2020 Accessed March 1, 2016.31. https://www.umc.edu/uploadedFiles/UMC.edu/Content/Administration/

Centers_and_Institutes/Cancer_Institute/Education_and_Training/70x2020_Initiative/70x2020_Colorectal_Bro.pdf Accessed March 1, 2016

32. Rex DK, Schoenfeld PS, Cohen J, et al. Quality indicators for colonoscopy. Gastrointest Endo. 2015;81:31-53.

33. Siegel R, DeSantis C, Virgo K, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin. 2012;62:220-41.

34. Goldhirsch A, Winer EP, Coates AS, et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol ESMO. 2013;24:2206-23.

35. Prat A, Perou CM. Deconstructing the molecular portraits of breast cancer. Mol Oncol. 2011;5:5-23.

36. Cheang MC, Martin M, Nielsen TO, et al. Defining breast cancer intrinsic subtypes by quantitative receptor expression. The Oncol. 2015;20:474-82.

37. Sadanandam A, Lyssiotis CA, Homicsko K, et al. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med. 2013;19:619-25.

38. Elshamy WM, Duhe RJ. Overview: cellular plasticity, cancer stem cells and metastasis. Cancer Letters 2013;341:2-8.

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Colonoscopy Atlas of Colon Polyps and Neoplasms

SHOU-JIANG TANG, MD and JAMES Q. SONES, MDDivision of Digestive Diseases, Department of Medicine, University of Mississippi Medical Center



Background

Optical colonoscopy is the gold standard for colon cancer screening and adenoma detection and is the only screening option that can potentially provide therapeutic interventions and adenoma removal during the same session. When other screening strategies generate positive results, currently colonoscopy is the next step for definitive diagnosis and potentially curative therapy. The entire colon is about 150 cm or 5 feet long and is divided into five segments: the cecum 6-9 cm in length, ascending colon 20-25 cm, transverse colon 30-60 cm, descending colon 20-25 cm, sigmoid colon 40 cm, and rectum about 12 cm. During colonoscopy, white light is used to illuminate and examine the colon. Frequently, the vascular patterns and mucosal pathologies can be better visualized and demarcated under digital chromoendoscopy, such as narrow band imaging (NBI). Submucosal injection of a contrast agent (submucosal chromoendoscopy) and NBI can be used to highlight the dysplastic mucosa if present. Whenever in doubt, endoscopic biopsy is recommended for confirmation.

OUR AIM IS TO EDUCATE GASTROENTEROLOGISTS, ENDOSCOPY STAFF, OTHER HEALTH CARE PROVIDERS,

AND INTERESTED PATIENTS ON CERTAIN COLON PATHOLOGIES AND COMMON ENDOSCOPIC

INTERVENTIONS.

A polyp is defined as a small bump or growth on the colon surface. In terms of shape, polyps generally are categorized into sessile or peduncalated forms, depending whether it has a stalk. If it is attached to the surface by a narrow or broad-based stalk, it is said to be semi-pedunculated. In terms of size, polyps are categorized into diminutive polyps (≤5 mm), small (6-10 mm), and large (≥10 mm). Not all polyps are pre-malignant or cancerous. An adenoma is defined as a mucosal

dysplasia with elongated nuclei, i.e. low-grade atypia and is pre-malignant. On the flip side, other polypoid lesions such as a lipoma, granulation, inflammatory polyp, or even an inverted diverticulum are also called polyps by shape but they do not have malignant potentials. However, the terminology of polyp is often used interchangeably or synonymously with adenoma when communicating with the patients. Small serrated polyps in the distal colon, also called hyperplastic polyps, are rarely malignant. Larger serrated polyps, called sessile serrated polyps or adenomas, located in the proximal or right sided colon are pre-cancerous. Sessile serrated adenomas should be treated as traditional adenomas. Most polyps are diminutive or small (<1 cm) and have a small potential for malignancy. The risk of progression to colon cancer increases if the polyp is larger than 1 cm and contains a higher percentage of villous component. If benign adenomas are not removed from the colon, they can become malignant over time. Most colon cancers are believed to have developed from adenomas. During colonoscopy, for diminutive or some small adenomas or polyps, excisional biopsy with biopsy forceps can be performed. For polyps ≥7 mm, snare polypectomy is often utilized for curative removal. Occasionally, very large polyps can be found with the polyp size ranging from 2 cm to several inches. Not all giant polyps are malignant or cancerous, and vice versa, not all relatively smaller adenomas are free from invasive cancers. In the hands of experienced endoscopists, a very large polyp can be safely removed by performing submucosal injection followed by wither piecemeal polypectomy (endoscopic mucosal resection, or EMR) or en bloc submucosal dissection (endoscopic submucosal dissection). When the colon adenoma is extensive or wide spread, contains certain mucosal patterns that suggest submucosal invasion, with limited endoscopic skills, surgical resection should be considered. Various online resources and academic society guidelines pertinent to this review and on colon cancer screening can be found on Mississippi Gastroenterology Society website: http://www.msgisociety.org/healthcare-professionals.

Disclosure & Conflict of interests: Shou-jiang Tang and James Q. Sones have no conflict of interest or financial relationships to disclose. We have required no financial support or this publication.

Correspondence: Shou-jiang Tang , M.D., Professor in Medicine, Division of Digestive DiseasesUniversity of Mississippi Medical Center, Jackson, MS 39216Tel: 601-984-4540 Fax: 601-984-4548 [email protected]

Keywords: Colon; colonoscopy; colon polyp; neoplasm.

Acronyms: Narrow band imaging (NBI), endoscopic mucosal resection (EMR)

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Tang

Sones

ABSTRACT

Optical colonoscopy is the gold standard for colon cancer screening and adenoma detection and is the only screening option that can potentially provide therapeutic interventions and adenoma removal during the same session. When other screening strategies generate positive results, currently colonoscopy is the next step for definitive diagnosis and potentially curative therapy. For gastrointestinal endoscopists, the ileocecum is the finishing line during colonoscopy, and it is identified by three endoscopic landmarks: terminal ileum, ileocecal valve, and the appendiceal orifice. Careful and systematic examination should be stressed during endoscopic training and practice. In this pictorial review, the authors demonstrate common colon polyps and neoplasms that can be found during colonoscopy. Our aim is to educate gastroenterologists, endoscopy staff, other health care providers, and interested patients on certain colon pathologies and common endoscopic interventions.


1

8A

14B

18B

5

12B

10C

16

20A

2A

8B

14C

18C 18D

6

13A

10D

17A

20B

2B

9

14D

19A

7A

13B

11A

17B

21

3

10A

15A

19B

7B

13C

11B

17C

4

10B

15B

19C

7C

14A

12A

18A

22

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FIGURE 1. Endoscopic image of a large colonic lipoma. The lesion has a yellowish hue and is a submucosal lesion. The overlying mucosa has normal mucosal patterns. Endoscopic pillow sign can be demonstrated. Adipose tissue can be exposed if repeated tunnel biopsy is performed. Lipoma is not a pre-malignant lesion and an incidental finding during colonoscopy.

FIGURE 2. Endoscopic images of an inverted diverticulum (2A) and appendix (2B). Diverticular and diverticulosis are common in the colon, and everyone has an appendix in the cecum. Rarely, the appendix and diverticulum can be inverted, mimicking a polyp. The target sign can usually be observed around the inverted diverticulum as in image 2A. Inverted appendix is also called appendiceal intussusception. Appendiceal intussusception can result from no obvious underlying pathology as an incidental finding, a fecalith, inflammation, endometriosis, mucocele, or appendiceal neoplasm. After unintentional polypectomy, it is prudent to apply endoscopic clipping devices to close the resection margins.

FIGURE 3. Endoscopic image of a diminutive granulation polyp at the neck of a small colon diverticulum. Granulation polyp is benign without malignant potential.

FIGURE 4. Endoscopic image of a large prolapsing mucosal polyp in the sigmoid colon. Prolapsing mucosal polyps derive from mucosal prolapse syndrome. Endoscopically, mucosal erythema or hyperemia is observed without typical mucosal patterns pertaining to adenomas. Histologically, there are surface erosions with fibrin/inflammatory exudates, fibromuscular proliferation in lamina propria with mucosal architectural distortion. This is a benign polyp.

FIGURE 5. Endoscopic image of one small and one large inflammatory polyp. These are benign polyps.

FIGURE 6. Endoscopic image of a small sessile colon xanthoma. Xanthoma is an accumulation of lipid-laden macrophages and is a benign incidental finding.

FIGURE 7. Endoscopic images a small rectal carcinoid tumor. Endoscopically, it appears a solid submucosal lesion with a white-yellowish hue (7A). The overlying mucosa appears normal. Once suspected, the lesion can be removed during colonoscopy by performing ligation-assisted mucosal resection (7B & 7C).

FIGURE 8. Endoscopic images of small semi-sessile leiomyoma in the descending colon. The leiomyoma is completely removed by endoscopic mucosal resection (8B). Benign submucosal neoplasms in the colon include leiomyoma, lipoma, and neuroma.

FIGURE 9. Endoscopic image of a diminutive sessile polyp being removed by biopsy forceps.

FIGURE 10. Endoscopic images of a large semi-pedunculated adenoma. A semi-opened snare (10B) is being use to ensnare the adenoma (10C). The polypectomy base (10D).

FIGURE 11. A large adenoma found incidentally during positron emission tomography-computed tomography or PET-CT scan (11A). During colonoscopy, the culprit adenoma is noticed and removed (11B). If an adenoma is not metabolically active, it will not be seen on PET-CT scan.

FIGURE 12. Endoscopic image of a large serrated sessile adenoma covered by a mucus cap or mucoid covering (12A). They are generally flat, sessile, or slightly polypoid. They can mimic a mucus collection or a lipoma. The presence and the extent of the lesion can be highlighted by digital chromoendoscopy and by submucosal injection of a contrast agent. Increasingly, sessile serrated adenomas and pathway are being recognized to play an important role in the development of right sided colon cancer. On the flip side, a semi-pedunculated traditional adenoma has a mildly erythematous mucosal surface and adenomatous pit patterns (12B).

FIGURE 13. Endoscopic images showing a very large or giant adenoma with erythematous and adenomatous mucosal pit patterns. Despite its large size, invasive features are not noticed during colonoscopy and the adenoma is completely removed by EMR (13B & 13C). Pathological examination revealed no high-grade dysplasia or invasive cancer.

FIGURE 14. Endoscopic images showing a very large or giant adenoma in the ascending colon. Despite its large size, invasive features are not noticed during colonoscopy. The adenoma is completely lifted with submucosal injection (14B) and is completely removed by EMR (14C). A total of four endoclips (Instinct®, Cook Medical, Winston-Salem, NC) are used to close the EMR margins to minimize the risks of delayed bleeding and perforation (14D). Pathological examination revealed no high-grade dysplasia or invasive cancer.

FIGURE 15. Endoscopic images showing a malignant large (about 15 mm) sessile adenoma under white light (15A) and NBI (15B) examination. Despite its relative small size, the adenoma has a depressed center with amorphous or irregular pit patterns. These are worrisome features of a high-grade adenoma or invasive cancer. The patient underwent surgery. Surgical specimen confirmed the presence of a locally invasive colon cancer.

FIGURE 16. Endoscopic image showing a malignant large (about 13 mm) sessile adenoma. Despite its relative small size, the adenoma has amorphous or irregular pit patterns. In addition, the adenoma could not be lifted by submucosal injection. Surgical specimen confirmed the presence of a locally invasive colon cancer.

FIGURE 17. Endoscopic images showing a large pedunculated adenoma. The adenoma is completely removed by snare polypectomy on the polyp stalk (17B). After stalk snare polypectomy of very large pedunculated adenomas, there is a small risk of delayed bleeding. One endoclip (Instinct®) can be optionally used to close the stalk margins to minimize the risk of delayed bleeding (17C & 17D). Pathological examination revealed no high-grade dysplasia or invasive cancer.

FIGURE 18. Endoscopic and pathological images showing a large pedunculated malignant adenoma. The adenoma is completely removed by snare polypectomy on the polyp stalk (18B). Pathological examination reveals high-grade dysplasia or mucosal cancer (18C). Since there is cancerous invasion and the polyp stalk is free from high-grade dysplasia, the polypectomy is considered curative and the patient does not need surgical resection. 18D is an endoscopic image showing a large colon cancer that causes circumferential ulceration and moderate luminal narrowing.

FIGURE 19. Endoscopic image showing a large colon cancer that causes severe luminal obstruction (19A). After consulting with surgeons and if the patient agrees, a metal colon stent (Evolution®, Cook Medical) can be placed for short term and/or long term palliation (19B & 19C). A fluoroscopic image showing the fully deployed colon stent that crossed the entire obstruction (19C).

FIGURE 20. Endoscopic image of a large pedunculated juvenile polyp in a patient with juvenile polyposis syndrome (JPS). JPS is an autosomal dominant condition characterized by multiple juvenile polyps in the gastrointestinal tract with a lifetime cancer risk that exceeds 50%. Juvenile polyps are hamartomatous malformations and are characterized by a marked increase of the stromal cell compartment with subepidermal blisters and erosions. JPS is one of 7 inherited hamartomatous polyposis syndromes: familial juvenile polyposis syndrome, Cowden's syndrome, Bannayan-Ruvalcaba-Riley syndrome, Peutz-Jeghers syndrome, basal cell nevus syndrome, neurofibromatosis 1, and multiple endocrine neoplasia syndrome 2B. 20B is an endoscopic image showing innumerable diminutive and small sessile polyps in a patient with familial adenomatous polyposis syndrome. Other inherited polyposis syndromes include Turcot syndrome, Cowden disease, and Gardner's syndrome.

FIGURE 21. Endoscopic images of an appendiceal mucocele. Mucocele can be caused by a retention cyst or mucosal hyperplasia, mucinous cystadenoma, and mucinous adenocarcinoma. A CT scan can be used to evaluate suspected cases. All patients with a mucocele deserve a surgical consultation.

FIGURE 22. Endoscopic image of a missed cecal cancer after a recent “normal” diagnostic colonoscopy for iron deficiency anemia. This case illustrates the importance of optimal colon preparation before the colonoscopy, careful and systematic examination by the endoscopist, and adequate photo documentation of important endoscopic landmarks during colonoscopy.

GI Associates Serving The Community

FREE COLONOSCOPY TO THOSE IN NEED

S P E C I A L A R T I C L E


GI Associates began the program in March 2013 and has seen 91 people in that time. The clinic was founded in 1981 on the principle of providing the best gastroenterological care for the state, and the Giveback program continues that spirit. Patients who are uninsured or may not have the money for the procedure can be referred to GI Associates to receive a free colonoscopy during the Giveback program.

This program is one of caring. The GI staff (physicians, nurses, nurse anesthetists, pathologists, and technicians) all volunteer their time during Giveback.

“GI Associates strives to improve the health of our community,” said Lisa Jordan, GI Associates’ Chief Operating Officer. “It was amazing to see the outpouring of compassion and teamwork exhibited. We created Giveback to save lives and we are proud to report we are doing so.”

Apart from the compassion shown by GI Associates staff, a driving force behind the Giveback program is the referring physicians who see the needs of their patients and take advantage of the opportunity to refer them for a free colonoscopy. “Our referring physicians were instrumental in the success [of Giveback] by referring non-insured patients to us,” said Ron Kotfila, MD of GI Associates. If a physician recognizes this need from a patient, he/she can refer them to GI Associates for the Giveback program.

Colon cancer is the second-leading cause of cancer deaths in the U.S. GI Associates is dedicated to saving lives in order to help bring that number down. Early detection of colorectal cancer raises the survival rate to 90%. Diagnosing cancer or cancer-causing polyps is a main goal for GI Associates Giveback program. Last year alone, 70% of the patients who came for the free screenings had polyps removed.

"Screening for colon polyps prior to symptoms is helpful since polyps do not cause pain and rarely significant bleeding,” said Paul B. Milner, MD of GI Associates. “However, one of our patients in the Giveback program described symptoms of recurrent bleeding and was found at colonoscopy

to have colon cancer. Fortunately, he was referred promptly for surgery before his disease was able to progress from later detection.”

In order to continue serving the community to the best of their abilities, GI Associates is moving to a new, larger facility located on Lakeland Drive in Flowood, MS. The new building will be 88,000 sq. ft. and serve more patients. GI Associates has a history of providing the community with much needed services. They were the first GI clinic in the state to have a pediatric program, which they opened in 2007. Being the largest gastroenterology group in the state and one of the largest in the southeast region with more than 250 employees, GI Associates knows they have to be a leader.

THE CLINIC WAS FOUNDED IN 1981 ON THE PRINCIPLE OF PROVIDING THE BEST GASTROENTEROLOGICAL

CARE FOR THE STATE, AND THE GIVEBACK PROGRAM CONTINUES THAT SPIRIT.

“GI Associates has always been focused on serving the people of Central Mississippi and beyond,” said Dr. Jay Underwood, President of GI Associates. “We are now making an even more lasting commitment to the community through our newly constructed building. This modern facility will centralize patient care by providing a clinic, pharmacy, pathology lab, blood work, x-ray, and endoscopy center--all under one roof. Our patients will enjoy convenience like never before, our continued commitment to quality, and our focus on providing services at the lowest available cost.”

GI Associates is the largest gastroenterology group in Mississippi and one of the largest in the Southeast. GI Associates treats all conditions relating to the GI tract, including adult and pediatric specialties. GI Associates is located in Jackson, Madison, and Vicksburg. For more information, visit www.gi.md or find them on Facebook.

JOURNAL MSMA 73

For three years GI Associates in Jackson, MS,

has hosted their annual Giveback program

as a part of Colon Cancer Awareness Month.

This program offers colonoscopies to patients in need

at no charge when recommended by a referring physician.

Colon Cancer: Yes, It’s a Terrorist

SAMUEL C. PACE, MD, FACG

S P E C I A L A R T I C L E


As defined in the dictionary, “a terrorist is a person, usually a member of a group, who uses or advocates terrorism.” Granted, I have taken liberties in the use of terrorist. Colon cancer obviously is not a person. Yet the mention of the word cancer does terrorize people. Cancer is a living mutated tissue that kills people.

Throughout the world terrorism has become all too frequent. We all recall 9/11 and the 3000 innocent people who were killed. Recent terrorist attacks in Paris and the United States have resulted in additional deaths. As reported by the Centers for Disease Control and Prevention, homicide gun deaths in 2013 were 11,208. The 49,100 U.S. projected colon cancer deaths in 2016 are rarely mentioned. Our country is staggered by the carnage of human terrorists, yet at times seems unmoved by even more U.S. deaths from the “colon cancer terrorist”. Perhaps the national news media does not view the “colon cancer terrorist” being as scintillating as the human terrorist. Funding for colon cancer screening to prevent 50,000 American deaths annually has taken a back seat and in fact appears to be decreasing. CMS recent plan is to reduce funding by 7-8%.

Inadequate funding is occurring despite well documented evidence of the value of screening. I applaud the private insurance industry for including colon cancer screening in many of their policies. However, only 54% of eligible Mississippians have been screened. The highest death rates from colon cancer in the U.S. occur along the Mississippi River in Mississippi and Arkansas. Many Mississippians have not been screened because of lack of access to medical care, lack of insurance, and lack of information regarding the importance of screening. Long standing cultural beliefs also affect some groups: “I won't get cancer so I don’t need to be screened.”

National efforts to increase screening have been bolstered by the advent of the 80x2018 Colon Cancer Initiative Coalition. The goal is 80% of eligible citizens to be screened by 2018. Many states have funded Cancer Control programs for years. States with Cancer Control programs are closer to achieving the 80% screened already. The unfunded Mississippi 70x2020 Initiative is working to change colon cancer death rates by increasing Mississippi’s colon cancer screening rates. Our goal is to raise colon cancer screening levels to at least 70% by year 2020, NOT 80% by 2018. Although Mississippi is part of the National 80x2018 Coalition, the obstacles 70x2020 faces are significant and the name of our 70x2020’s organization reflects our difficulties.

Mississippi has never funded Cancer Control programs. States that have state funded Cancer Control programs have received federal grants from the CDC. So far our applications to CDC have been unsuccessful. The CDC has recognized that states with state supported Cancer Control programs spend federal grants more efficiently and without waste. Reducing all cancer deaths in Mississippi needs the help of the Legislature and Governor by establishing a Cancer Control program. Incorporating

the Mississippi Colon Cancer 70x2020 Initiative into a Mississippi Cancer Control program would be easy as we have developed policies and recommendations on how to increase effective screening rates.

Mississippi’s 70x2020 Coalition is located at the University Medical Center in Jackson and chaired by Dr. Roy Duhe. I am a member of the coalition and serve as its Physician Champion. The organizational structure with committees has been in place since October 2015. We have a robust group including the American Cancer Society, Federal Health Clinics in Mississippi, Mississippi GI Society, Mississippi State Medical Association, and others. “The bus is ready but we have no gas.” We hope to raise money from the sale of “Prevent Colon Cancer License Plates” but 300 license plates must be pre-sold for $31 before the plates will be manufactured. Sale of the license plates will be a start toward increasing awareness and funding.

No, it can’t be me!

The day was Monday September 26. It was a typical late September day in 2011. The transition to fall with lower humidity and cooler temperatures had not quite arrived in Tupelo. My office and endoscopy schedule were busy. The only difference was that I had blocked time that afternoon for a colonoscopy myself as part of the colon cancer screening protocol.

After 36 years as a physician and 25 years as a gastroenterologist, routine becomes habit. The task each day is to be the best you can for your patients, provide them the most up to date recommendations for their current illnesses, and, above all, prevent medical problems that could shorten their lives.

NATIONAL EFFORTS TO INCREASE SCREENING HAVE BEEN BOLSTERED BY THE ADVENT OF THE 80X2018 COLON CANCER INITIATIVE COALITION. THE GOAL IS 80% OF

ELIGIBLE CITIZENS TO BE SCREENED BY 2018.

I had followed the recommended screening protocol of colonoscopy at age 50. I had no family history of colon cancer. At age 50 my colonoscopy was uneventful and unremarkable. Now it was a decade later and time for my next colonoscopy. Patients have often said that the worst part of a colonoscopy is the day before and the requirements to have a “clean colon” by taking the colon prep. The only issue I had ever had with a prep was my first colonoscopy. I had taken the prep and decided to go to the office and do chart work. I did not anticipate getting stopped by a train in Tupelo!

Thus, it’s back to that fateful day in September 2011. As I awoke that day from my colonoscopy, even though groggy, I sensed a difference in the room. My wife’s and gastroenterologist’s demeanor were different. I will always remember these words, “Sam, you have colon cancer and you need surgery.” No way!!! I feel great. Just a few weeks prior, routine lab work was all normal. I had no rectal bleeding, loss of appetite, weight loss, abdominal pain, or a change in bowel habits. I am a gastroenterologist! I am a specialist in colon cancer and its preventions and recognition of its

JOURNAL MSMA 75

Pace


warning signs. I had done thousands of colonoscopies, diagnosed colon cancer, and removed polyps over my 25 years as a gastroenterologist. I also had sat on the edge of stretchers and shared the bad news with my patients that I had found colon cancer on their colonoscopies.

Suddenly I was on the other side of the table. No longer was I the bearer of bad news but instead the recipient. I knew the next step, and we proceeded with surgery and resection of the cancer in my right colon.

My surgery went well and a day or two later my surgeon came into the room with a smile on his face. The pathology revealed containment within the colon and 28 lymph nodes negative for metastasis. Screening colonoscopy had found the colon cancer early! I consulted with oncologists and had genomic analysis of my cancer. The consensus was there was no clear evidence that adjuvant chemotherapy was better than no adjuvant chemotherapy. This was the opinion of 3 separate oncologists and my personal review of the literature. The staging of my colon cancer indicated that at 5 years I had an 88% chance of not having a recurrence of the cancer.

Within a month, I had returned to work. I was even more resolved to prevent colon cancer. I began to share my experience. I always discussed the importance of colon cancer screening with patients. Their hesitancy to proceed with screening soon melted away when I would share; “I had colon cancer and it was found on screening.”

I was attentive and diligent in follow-up and surveillance for any recurrence of my colon cancer. CEA lab tests and recommended CT scans of chest, abdomen, and pelvis were followed per protocol. Unfortunately, my good fortunes did not last. In June 2013, my CEA became abnormal. CT scan revealed lung metastases. Resection was not an option as I had a total 3 lesions involving both right and left lungs.

I was dealt with another irony. There is that often overused statement in sports “statistics are for losers.” Just two years ago statistics and evidence based medicine had said I had an 88% chance of no recurrence in 5 years. As one of my friends said; “Gee, Sam you took one for the colon cancer team.” You are in the 12% group!!! We both laughed but again I wondered why me.

Of course it hurt. I’m human and emotions and despondency got the best of me at times. Tears and anguish haunted me for a week or so. Grieving is part of human life, and I did my share of that following the confirmation biopsies that my colon cancer had returned.

My family has always been a bulwark of support for me. My partners at Digestive Health Specialists in Tupelo were (and still are) great friends and colleagues and have always demonstrated their concern for my well-being. The employees at my office and hospital have hugged me and expressed their love. My church family and Tupelo friends have shared their concerns and prayers for me. Data is clear that patients with cancer have better survival rates and live longer when there are support groups for them. Well, my cup overflows in that regard.

FIGURE. Hotspots for colorectal cancer

Source: American Cancer Society

Three clusters of counties

with significantly high

death rates, 2000-2009

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Facing chemotherapy and stage IV metastatic colon cancer and approaching the age I had planned to retire, the decision became a bit easier. I really did not know how I might respond to chemotherapy. I did not know what time I had left but I did know my priority was to have the freedom to spend more time with my family. Those of you who have had similar experiences understand how one’s focus changes when a terminal illness is laid at your feet.

I retired December 31, 2013. To say chemotherapy has been good to me sounds a bit strange since chemotherapy is dreaded. However, I have been very blessed with my response to therapy. Though not cured, I am in remission. I tell people that my goal is to keep “kicking this colon cancer down the road.” Advances in cancer treatment are growing at almost an exponential rate. The advent and success of immune therapy has changed the paradigm in the battle against all cancers.

I have remained busy and am active in the Mississippi 70x2020 Initiative at University Medical Center to increase colon cancer screening. I am Chairman of the annual “Take a Swing at Cancer” golf tournament. Funds raised from the TASAC support the Cancer Patient Fund at the Health Care Foundation. The fund helps cancer patients with basic needs such as food, utility bills and transportation to doctors’ offices and treatments.

There are not many days that go by that I don’t receive a blessing that puts an extra kick in my step. At chemotherapy it’s not uncommon to cross paths with people I know, even some former patients. My very first day in chemotherapy a voice from the other side of the partition asked, “Is that

you, Dr. Pace?”. I responded yes, and then he reminded me that I had diagnosed him with colon cancer 20 years ago. I saw a patient of mine who was beginning treatment for breast cancer. Her mother was with her, and the daughter expressed concerns that her mom was having some blood in her stools. I called my office. She had a colonoscopy, and colon cancer in an early stage was discovered. I guess in some ways I’m still practicing medicine. The efforts and investment it takes to become a physician never leave you. By nature, physicians are always searching for ways to help.

Without screening colonoscopy, I might not have been here for the birth of 3 of my 6 grandchildren. It is my hope that sharing my story will motivate Mississippians to prevent colon cancer by getting screened. I encourage both physicians and health clinics in our state to review their procedures and policies to assure that each eligible patient gets screened either by colonoscopy or, if they refuse colonoscopy, the newer more sensitive stool test called FIT (Fecal Immunochemical Test). The older stool hemoccult test is no longer recommended for screening. Successful reduction in colon cancer deaths will require a state wide, county-by-county, community-by-community, medical clinic-by-medical clinic effort to be successful. I ask our elected Mississippi officials to explore innovative options that will be more inclusive of all residents of this state to easily access screening with NO barriers. I ask physicians and hospitals to do the same. The importance of colon cancer screening is no longer in doubt. The evidence that we can dramatically reduce colon cancer deaths is clear. There is a quote and I am not sure whom to credit. “As individuals we must become the change we want to see.” Let’s make a difference today and every day!!!

Salix Pharmaceuticals8510 Colonnade Center Drive, Raleigh, NC 27615The Xifaxan 550 mg product and the Xifaxan trademark are licensed by Alfa Wassermann S.p.A. to Salix Pharmaceuticals or its affi liates.The Gut Guy character is a copyright and trademark of Salix Pharmaceuticals or its affi liates. XIFI.0014.USA.16

TreatIBS-Diff erentlyA 2-week treatment for IBS-D1: • 10 weeks of relief from

abdominal pain and diarrhea (Median; range of 6 to 24 weeks)

• Retreat up to 2 times if symptoms recur

IBS-D=irritable bowel syndrome with diarrhea.™

Learn more at XIFAXAN.COM

Study Design: Xifaxan was evaluated in 2438 IBS-D patients. 44% (n=1074) experienced relief from an open-label course of treatment. Relief was defi ned as experiencing a ≥30% improvement from baseline in the weekly average abdominal pain score (based on daily self reports) and a ≥50% reduction in the number of days in a week with a daily stool consistency of Bristol Stool Scale type 6 or 7 compared with baseline. If patients experienced a recurrence of either of their symptoms for 3 weeks of a rolling 4-week period, they entered the randomized, double-blind treatment phase. Randomized patients then received a repeat treatment with either Xifaxan or placebo. The primary endpoint was the proportion of patients who experienced relief in both symptoms (defi ned exactly as in the open-label period) during the 4 weeks following repeat treatment.1

INDICATION

XIFAXAN (rifaximin) 550 mg tablets are indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults.

IMPORTANT SAFETY INFORMATION

• XIFAXAN is contraindicated in patientswith 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-associateddiarrhea (CDAD) has been reported with use of antibacterial agents, including XIFAXAN, and may range in severity

from mild diarrhea to fatal colitis. If CDAD is suspected or confi rmed, ongoing antibiotic use not directed against C. diffi cile may need to be discontinued.

• There is an increased systemic exposure in patients with severe (Child-Pugh Class C) hepatic impairment. Caution should be exercised when administering XIFAXAN to these patients.

• Exercise caution when administrating XIFAXAN concomitantly with a P-glycoprotein (P-gp) inhibitor such as cyclosporine. Concomitant administration of drugs that are P-gp inhibitors can substantially increase the systemic exposure to XIFAXAN.

In patients with hepatic impairment, a potential additive effect of reduced metabolism and concomitant P-gp inhibitors may further increase the systemic exposure to XIFAXAN.

• 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 for XIFAXAN in IBS-D were nausea (3%) and increased ALT (2%).

Please see brief summary of full

Prescribing Information on following page.

Reference: 1. Xifaxan [prescribing information]. Raleigh, NC: Salix Pharmaceuticals; 2015.

BRIEF SUMMARY OF PRESCRIBING INFORMATION

This Brief Summary does not include all the information needed to use XIFAXAN safely and effectively. See full prescribing information for XIFAXAN.

XIFAXAN® (rifaximin) tablets, for oral use

Initial U.S. Approval: 2004

To reduce the development of drug-resistant bacteria and maintain the effectiveness of XIFAXAN and other antibacterial drugs, XIFAXAN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

1 INDICATIONS AND USAGE

1.3 Irritable Bowel Syndrome with Diarrhea

XIFAXAN is indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults.

2 DOSAGE AND ADMINISTRATION

2.3 Dosage for Irritable Bowel Syndrome with Diarrhea

The recommended dose of XIFAXAN is one 550 mg tablet taken orally three times a day for 14 days. Patients who experience a recurrence of symptoms can be retreated up to two times with the same dosage regimen.

2.4 Administration

XIFAXAN can be taken with or without food.

4 CONTRAINDICATIONS

XIFAXAN is contraindicated in patients with a hypersensitivity to rifaximin, any of the rifamycin antimicrobial agents, or any of the components in XIFAXAN. Hypersensitivity reactions have included exfoliative dermatitis, angioneurotic edema, and anaphylaxis.

5 WARNINGS AND PRECAUTIONS

Discontinue XIFAXAN if diarrhea symptoms get worse or persist more than 24 to 48 hours and alternative antibiotic therapy should be considered.

5.2 Clostridium difficile-Associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XIFAXAN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon which may lead to overgrowth of C. difficile.C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

5.4 Severe (Child-Pugh Class C) Hepatic Impairment

There is increased systemic exposure 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 Class C).

5.5 Concomitant use with P-glycoprotein Inhibitors

Concomitant administration of drugs that are P-glycoprotein inhibitors with XIFAXAN can substantially increase the systemic exposure to rifaximin. Caution should be exercised when concomitant use of XIFAXAN and a P-glycoprotein inhibitor such as cyclosporine is needed. In patients with hepatic impairment, a potential additive effect of reduced metabolism and concomitant P-glycoprotein inhibitors may further increase the systemic exposure to rifaximin.

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Irritable Bowel Syndrome with DiarrheaThe safety of XIFAXAN for the treatment of IBS-D was evaluated in 3 placebo-controlled studies in which 952 patients were randomized to XIFAXAN 550 mg three times a day for 14 days. The adverse reaction that occurred at a frequency ≥2% in XIFAXAN-treated patients at a higher rate than placebo in Trials 1 and 2 for IBS-D was:• nausea (3% XIFAXAN, 2% placebo)The adverse reactions that occurred at a frequency ≥2% in XIFAXAN-treated patients (n=328) at a higher rate than placebo (n=308) in Trial 3 for IBS-D during the double-blind treatment phase were:• ALT increased (XIFAXAN 2%, placebo 1%)• nausea (XIFAXAN 2%, placebo 1%)

Less Common Adverse ReactionsThe following adverse reactions, presented by body system, were reported in less than 2% of patients in clinical trials of TD and IBS-D and in less than 5% of patients in clinical trials of HE:Hepatobiliary disorders: Clostridium colitisInvestigations: Increased blood creatine phosphokinaseMusculoskeletal and connective tissue disorders: myalgia

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of XIFAXAN.Infections and InfestationsCases of C. difficile-associated colitis have been reported.GeneralHypersensitivity reactions, including exfoliative dermatitis, rash, angioneurotic edema (swelling of face and tongue and difficulty swallowing), urticaria, flushing, pruritus and anaphylaxis have been reported. These events occurred as early as within 15 minutes of drug administration.

7 DRUG INTERACTIONS

7.1 Effects of XIFAXAN on Other Drugs

Substrates of Cytochrome P450 enzymesRifaximin is not expected to inhibit cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and CYP3A4 in clinical use based on in vitro studies.An in vitro study has suggested that rifaximin induces CYP3A4. However, in patients with normal liver function, XIFAXAN at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations.

7.2 Effects of Other Drugs on XIFAXAN

In vitro studies suggested that rifaximin is a substrate of P-glycoprotein, OATP1A2, OATP1B1 and OATP1B3. Concomitant cyclosporine, an inhibitor of P-glycoprotein and OATPs, significantly increased the systemic exposure to rifaximin.CyclosporineCo-administration of cyclosporine, with XIFAXAN resulted in 83-fold and 124-fold increases in rifaximin mean Cmax and AUC∞ in healthy subjects. The clinical significance of this increase in systemic exposure is unknown.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk SummaryThere are no available data on XIFAXAN use in pregnant women to inform any drug associated risks. Teratogenic effects were observed in animal reproduction studies following administration of rifaximin to pregnant rats and rabbits during organogenesis. Advise pregnant women of the potential risk to a fetus.

8.2 Lactation

Risk SummaryThere is no information regarding the presence of rifaximin in human milk, the effects of rifaximin on the breastfed infant, or the effects of rifaximin on milk production. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for XIFAXAN and any potential adverse effects on the breastfed infant from XIFAXAN or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of XIFAXAN has not been established in pediatric patients less than 18 years of age for IBS-D.

8.5 Geriatric Use

In the clinical studies of IBS-D, 11% of patients were 65 and over, while 2% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Renal Impairment

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

8.7 Hepatic Impairment

Following administration of XIFAXAN 550 mg twice daily to patients with a history of hepatic encephalopathy, the systemic exposure (i.e., AUCτ) of rifaximin was about 10-, 14-, and 21-fold higher in those patients with mild (Child-Pugh Class A), moderate (Child-Pugh Class B) and severe (Child-Pugh Class 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.

10 OVERDOSAGE

No specific information is available on the treatment of overdosage with XIFAXAN. In the case of overdosage, discontinue XIFAXAN, treat symptomatically, and institute supportive measures as required.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Malignant schwannomas in the heart were significantly increased in male Crl:CD® (SD) rats that received rifaximin by oral gavage for two years at 150 to 250 mg/kg per day (doses equivalent to 2.4 to 4 times the recommended dose of 200 mg three times daily for TD, and equivalent to 1.3 to 2.2 times the recommended dose of 550 mg twice daily for HE, based on relative body surface area comparisons). There was no increase in tumors in Tg.rasH2 mice dosed orally with rifaximin for 26 weeks at 150 to 2000 mg/kg per day (doses equivalent to 1.2 to 16 times the recommended daily dose for TD and equivalent to 0.7 to 9 times the recommended daily dose for HE, based on relative body surface area comparisons).Rifaximin was not genotoxic in the bacterial reverse mutation assay, chromosomal aberration assay, rat bone marrow micronucleus assay, rat hepatocyte unscheduled DNA synthesis assay, or the CHO/HGPRT mutation assay. There was no effect on fertility in male or female rats following the administration of rifaximin at doses up to 300 mg/kg (approximately 5 times the clinical dose of 600 mg per day for TD, and approximately 2.6 times the clinical dose of 1100 mg per day for HE, adjusted for body surface area).

17 PATIENT COUNSELING INFORMATION

Persistent DiarrheaFor those patients being treated for travelers’ diarrhea, discontinue XIFAXAN if diarrhea persists more than 24-48 hours or worsens. Advise the patient to seek medical care for fever and/or blood in the stool.Clostridium difficile-Associated DiarrheaClostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XIFAXAN, and may range in severity from mild diarrhea to fatal colitis.Treatment with antibiotics alters the normal flora of the colon which may lead to C. difficile. Patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If diarrhea occurs after therapy or does not improve or worsens during therapy, advise patients to contact a physician as soon as possible.Administration with FoodInform patients that XIFAXAN may be taken with or without food.Antibacterial ResistanceCounsel patients that antibacterial drugs including XIFAXAN should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When XIFAXAN is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by XIFAXAN or other antibacterial drugs in the future.Severe Hepatic ImpairmentInform patients with severe hepatic impairment (Child-Pugh Class C) that there is an increase in systemic exposure to XIFAXAN.

Manufactured for: Salix Pharmaceuticals, Inc. Raleigh, NC 27615

By: Patheon Whitby, Ontario L1N 5Z5, Canada

The Xifaxan 550 mg product and the Xifaxan trademark are licensed by Alfa Wassermann S.p.A. to Salix Pharmaceuticals or its affiliates.

Copyright © Salix Pharmaceuticals, Inc.

Rifaximin for Travelers’ Diarrhea, Hepatic encephalopathy and IBS are protected by US Patent Nos. 7,045,620; 7,612,199; 7,902,206; 7,906,542; 8,158,781; 8,158,644; 8,193,196; 8,518,949; 8,741,904; 8,835,452; and 8,853,231. Rifaximin for Travelers’ Diarrhea is also protected by US Patent No. 7,928,115. Rifaximin for Hepatic encephalopathy is also protected by US Patent No. 8,642,573; 8,829,017; 8,946,252; and 8,969,398. Rifaximin for IBS is also protected by US Patent Nos. 6,861,053; 7,452,857; 7,718,608; and 8,309,569.

Web site: www.Salix.com All rights reserved. XIFI.0257.USA.15

Based on 9457401 Rev. 05/2015


The Impact of Preventive ScreeningResource Distribution On Geographicand Population-Based Disparities in

Colorectal Cancer in Mississippi

JOURNAL MSMA 81

PRIMARY PRACTICING SITES OF GASTROENTEROLOGISTS

AREAS WITHIN 30 MINUTES DRIVING FROM AMBULATORY SURGICAL AND ONSITE COLONOSCOPY FACILITIES

AMBULATORY SURGICAL FACILITIES

AREAS WITHIN 30 MINUTES DRIVING FROM PRIMARY PRACTICE SITES OF

GASTROENTEROLOGISTS

Faruque et al. BMC Res Notes (2015) 8:423

How to Achieve Colon Cancer Screening in Average Risk Population:

A Review of Different Screening OptionsJAMES WHATLEY, MD and JAMES Q. SONES, MD

Division of Digestive Diseases, Department of Medicine, University of Mississippi Medical Center



Colorectal cancer (CRC) is the fourth most common cancer and second leading cause of cancer deaths in the US. CRC is responsible for roughly 50,000 deaths and is diagnosed in nearly 140,000 people in the United States (US) a year.1 The levels of CRC screening in the US lag behind those of other effective cancer screening tests. Approximately 30% of patients have risk factors for CRC, such as family history of CRC, certain inflammatory bowel diseases and polyposis syndromes. These patients should be followed by gastroenterologists for more frequent CRC surveillance that targets patients with increased CRC risks. The other 70% of patients therefore are considered average risk.2 For average risk population, by current national guidelines, colon cancer screening should be started at the age of 50 and end about 75. In selected patients who are very viable and healthy, CRC screening may extend to 80 at the patients' preference. The scope of this reviewed article focuses mainly on screening options for average risk individuals. Evidence is convincing that the different recommended screening modalities detect early stage cancer and precancerous polyps in turn reducing cancer mortality. It is the responsibility of gastroenterologists and primary care physicians working together to ensure widespread availability of CRC screening. The aim of this article is to review the screening options, their sensitivities, cost and how they can impact survival.

Optical Colonoscopy

Colonoscopy is the gold standard modality for CRC screening. It offers direct visualization of the entire colon. It also adds the element of diagnosis and treatment at the same time. Colonoscopy with polypectomy can interrupt the progression of precancerous polyps to cancer.3 On July 1, 2011, the US Congress passed legislation directing The Center for Medicaid and Medicare Services (CMS) to cover screening colonoscopies for all beneficiaries age 50 and older every 10 years.4 In multiple cohort studies the incidence of CRC has been shown to be reduced in patients undergoing colonoscopy with polypectomy.5 Lieberman et al. and Imperiale et al. showed that 50% of patients with proximal advanced neoplasia have no distal polyps. Another study of 116 average risk patients who were found to have proximal colon cancer showed that 58.6% had no distal polyps.6,7,8 There are some disadvantages to colonoscopy. These include sedation, perforation risk, bowel preparation, and cost. The use of sedation requires the patient have a person to drive them home in the post procedure period. The risk of perforation for average risk screening colonoscopy is very low (around 0.2%.9) With all colonoscopies there is also the risk of missing an adenoma or cancer. There is evidence showing most failures of colonoscopies are accounted for by operator error.10 The quality of colon preparation (cleanliness), adenoma detection rate (ADR), cecal intubation rate, and adequate withdrawal time have been shown to be important markers of colonoscopy quality.10 Kaminski et al showed that the risk of developing a cancer in the interval was 10 times higher for patients who underwent colonoscopy by a provider with an ADR less than 20%.11 Additional evidence shows that the specialty of the provider performing the colonoscopy is another factor in the quality of the exam. Studies show that the risk of interval CRC is lower after colonoscopies performed by gastroenterologists compared with surgeons or primary care physicians.12,13 It is estimated that approximately 70% of interval CRC are due to missed lesions. This means the variability in the

effectiveness of colonoscopy can be overcome with education and quality improvement initiatives.14 There are no randomized control trials completed for screening colonoscopies but there are multiple lines of evidence established that show colonoscopy reduces CRC incidence in both the proximal and distal colon. Gastroenterology societies as well as the US preventive Services Task Force (USPSTF) continue to recommend screening colonoscopy every 10 years for average risk patients. For patients with colon adenoma history, colonoscopy should be performed every 3-5 years.

Flexible Sigmoidoscopy

The use of sigmoidoscopy for CRC screening is supported by randomized controlled trial (RCT) evidence.15 Flexible sigmoidoscopy effectively protects against distal CRC. Its benefits include low risk of complications, lack of need for sedation, and cost effectiveness. Decreased incidence and mortality is suggested from case control studies of sigmoidoscopy. The benefit has been shown to persist for up to 10 years.16 The risk of colon cancer in the area beyond the reach of the sigmoidoscope does not appear to be reduced.17 A significant number of proximal adenomas occur in the absence of distal adenomas.6 Age matched comparison of men and women found men were more likely to have advanced neoplasia (66.3%) vs (34.7%) for women but more likely to be detected using flexible sigmoidoscopy. This data suggest that colonoscopy has advantages over flexible sigmoidoscopy for CRC screening in women.7 Randomized prospective studies revealed the detection rate for advanced neoplasia was 3 times higher after screening by sigmoidoscopy than fecal occult blood test (FOBT).18 If sigmoidoscopy is to be used it is recommended per the American College of Gastroenterology (ACG), American Cancer Society (ACS), and CRC task force to be done every 5 years.

CT Colonography (CTC)

CTC involves helical CT scanning of the colon after bowel preparation and colonic distention. This screening method is not currently utilized as often for several factors. Most notable is the issue of payment. In 2008 the US preventive Services Task Force gave CTC an “I” rating which indicates insufficient evidence to support CTC as a screening method.19

The USPSTF noted 3 areas of uncertainty with CTC as a screening tool. The first being increased extracolonic findings, which increases the potential harm from additional diagnostic tests. Radiation exposure, CTC perforation risk, and performance at the community level are also reasons cited for not including CTC in the USPSTF screening guidelines. In May 2009 the CMS denied coverage for CTC as a screening method for CRC.20 There are several notable positives of CTC which include no sedation, simplicity, and high sensitivity for detection of large lesions >1 cm. 90% sensitivity for detecting large (>1cm) polyps was observed in

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the ACRIN trial. 21,22,23 CTC could potentially be cost effective at $179-$237.23 The CMS had concerns regarding the low sensitivity for small (6-9mm) and flat lesions. A referral rate of up to 30% following CTC was cited. 24 The American Cancer Society does endorse CTC as a screening option every 5 years with referral for colonoscopy for patients with one or more polyps 6mm or greater. In their recommendation the ACS highlighted the risk of radiation, perforation, and extracolonic findings. The ACG has recommended that CTC replace double contrast barium enema as an alternative to colonoscopy. A lack of data regarding the effect of CTC on incidence and mortality compared with conventional colonoscopy was highlighted.25 The ACRIB trial looked at 2600 asymptomatic patients 50 years and older who underwent CTC followed by colonoscopy. CTC showed a sensitivity of 90% and specificity of 86% for large >1 cm adenomas and cancers. Sensitivity was much lower around 78% for lesions 6-9 mm.26 CTC may be an option for evaluating patients with symptoms consistent with CRC including rectal bleeding, abdominal pain, anemia, or change in bowel habits. The SIGGAR trial enrolled symptomatic patients in a 2-arm trial. Patients were randomized to CTC or colonoscopy as well as CTC or double contrast barium enema (DCBE). Preliminary results showed CTC was superior to DCBE and results were comparable to those of colonoscopy for large polyps.10 Overall studies of CTC show a wide range of sensitivity and specificity. The initial thought would suggest that patients would have higher acceptance rates of CTC vs colonoscopy; however, comparative studies show no consistent patient preference.27 No studies demonstrate the efficacy of VC in reducing CRC incidence and mortality.28 Cost effectiveness analyses indicate under most assumptions colonoscopy is more cost effective than VC. Although it is not currently recommended as a primary method of CRC screening, CTC can be

useful in patients who refuse colonoscopy, have co-morbidities preventing sedation or who have an incomplete colonoscopy. A recently published study revealed that radiologists prefer optical colonoscopy to CTC for CRC screening.29

Fecal immunochemical test (FIT)/Fecal occult blood test (FOBT)

Sometimes FOBT is used generically referring to stool testing for blood. There are a couple of options for testing patients’ stool for blood. Guaiac fecal occult blood test (gFOBT), high sensitivity FOBT, and FIT are all stool-based tests. Hemoglobin is digested and degraded differently in different regions of the gastrointestinal tract. The differences in digestion have implications for the stool-based testing modalities. Endogenous proteolytic enzymes in the stomach and small intestine digest the globin moiety of hemoglobin. This digestion of globin is slower and much more variable in the colon.30 The gFOBT is dependent on the heme portion while FIT uses antibodies specific for the globin moiety of human hemoglobin for detection.31 Therefore, FITs are selective for colorectal bleeding since proteolytic enzymes in the stomach and small intestine degrade globin from the upper gastrointestinal tract readily.32 Stool may contain a mix of intact hemoglobin as well as globin and heme at varying stages of degradation, depending on the location of the bleeding in the gastrointestinal tract. The concept of testing the stool for blood seems simple and practical but in the long run compliance becomes an issue. Primary care physicians play a vital role in proper stool-based testing for blood. In order to properly obtain a gFOBT, two stool samples from each of 3 consecutive stools should be tested.31 Prospective RCTs of FOBT showed a decrease in CRC mortality when a positive FOBT was followed by a colonoscopy.33 In other RCTs the likelihood of finding a cancer on colonoscopy was 8 to 25 times greater following a positive gFOBT than on

OPTICAL COLONOSCOPY

FOBT

FLEX SIGMOIDOSCOPY

FECAL DNA

CTC

PILL CAM

FTT

BLOOD BASED MARKERS

Every 10 years starting at age 50. Age 45 for African Americans

Annual

Every 5 years

Every 3 years

Every 5 years

Not recommended

Annual

Not recommended

Every 10 years starting at age 50

Annual

Every 5 years with hsFOBT every 3 years

Not recommended

Not recommended

Not recommended

Annual

Not recommended

$800-$4,000+

$3-$40

$150-$300

$400-$800

$170-$250

~$500

$15-$30

NA

Every 10 years in average risk, every 2 years in high risk

Every year

Every 4 years but not within 10 years of colonoscopy

Every 3 years

Not covered

Not covered

Every year

Not covered

TEST FOR AVERAGE RISK SCREENING

AMERICAN COLLEGE OF GASTROENTEROLOGY

USPSTF COST ESTIMATE MEDICARE COVERAGE

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colonoscopy without preceding positive gFOBT.34,35 This highlights the importance of following a positive test with a colonoscopy. The ACS and Multi-society task force recommend any positive result be followed by colonoscopy.36 A study conducted at several Veteran Administration (VA) centers found the sensitivity of a single digital rectal exam (DRE) FOBT for the detection of neoplasia to be 4.9% compared to 23.9% when the recommended home screening protocol was performed.37 In a national survey of over 1,000 PCPs 32.5% used DRE to obtain stool for FOBT.38 Guaiac based FOBTs are not sensitive to small bleeds, gFOBT can be affected by diet or drugs, and lab quality control measure are limited.39 In order to reduce false positive rates it is recommended patients avoid red meat and peroxidase containing foods for 3 days prior to the guaiac based test.40 Long term aspirin use does not affect the FIT but can potentially affect the specificity of FOBT.41,42 The practice of a single digital rectal exam for FOBT is considered a poor screening method for CRC and should not be performed.

Guaiac based FOBTs have deficiencies and FITs for hemoglobin have emerged as better tests.43 FIT has greater sensitivity, specificity, and detection of noncancerous advanced polyps.40 The immunoassay methods are not all the same and differ substantially between qualitative and quantitative FIT.44 Many qualitative test devices are available. These are designed for use at the point of care. Only the manufacturer can adjust the conditions of the analysis and the sensitivity for detecting globin. Few of the point of care FITs have peer-reviewed results of performance or quality control in large average risk populations.45 Quantitative FITs provide a measure of globin in feces captured in a buffered solution in the sampling device.40 The value of hemoglobin concentration in feces also known as the cutoff concentration can be readily adjusted with a quantitative FIT.46 A benefit of quantitative FITs is that the end point is easier to read and more amenable to quality assurance. These can be fully automated and well suited to large-scale population screening.47 Mentioned previously, FITs are more selective for colorectal bleeding. With this being said, FIT is not clinically specific because non-neoplastic and benign pathologies also can bleed and a baseline level of globin is in feces.40 When compared to the hemoccult and fecal DNA test, the annual FIT is recommended by the ACG as the preferred cancer detection test.

Fecal DNA

Molecular genetics of CRC provide the basis of fecal DNA testing. Fecal DNA (f DNA) testing is based on the observation that tumor cells and DNA are shed into the stool.47 The attempt to develop a viable f DNA test over the past decade has increased. Adenomas and CRC can arise from different pathways. Three different genetic pathways include chromosomal instability, microsatellite instability, and CpG island methylation.48 Fecal DNA can be tested for chromosome instability (k-ras, APC, p53), microsatellite instability (BAT-26), and DNA integrity assay. A multicenter study by EXACT sciences using the previously mentioned f DNA test compared with FOBT showed f DNA testing (18.2%) to have a higher sensitivity than FOBT (10.8%) for advanced neoplasia. The sensitivity was much lower than was hoped for with f DNA testing.49 In a large prospective trial comparing the f DNA and FOBT, the sensitivity for f DNA was 4 times that of FOBT

for cancer and high-grade adenomas. The sensitivity of f DNA compared to colonoscopy was just 51%.50 There are no studies showing f DNA reduces CRC mortality. Problems with cost($400-$800/test), determining appropriate screening intervals, and what to do with patients who have a positive test but a negative colonoscopy continue to hinder its use. Since last guidelines, the USMSTF concluded that there are now sufficient data to include f DNA as acceptable CRC screening option. The manufacturer of the test is recommending a 5-year interval for routine screening between examinations with normal results, the committee concluded that there were insufficient data upon which to endorse this interval. Further research is needed to determine the best interval between negative f DNA examinations. Currently the ACG recommends every 3 years if f DNA is used for screening.

APPROXIMATELY 30% OF PATIENTS HAVE RISK FACTORS FOR CRC, SUCH AS FAMILY HISTORY OF CRC, CERTAIN INFLAMMATORY BOWEL DISEASES, AND POLYPOSIS

SYNDROMES.

Pill Camera

Colon capsule endoscopy was introduced in 2006.50 Colon capsule endoscopy has many obvious positives. It allows direct visualization of colonic mucosa without intubation, sedation, or air insufflation. Despite being somewhat of a novel approach to screening, several advances have been made in the technology of the PillCam® (Given Imaging). The improvements in the 2nd generation PillCam® Colon2 included a wider angle of viewing-172° from each end giving almost a panoramic view. Also new to Colon2 is an adaptive frame rate via cross talk between the capsule and the DR3 recorder. This feature allows the frame rate to slow to 4 frames/s while the pill is stationary and increase up to 35 frames/s while the pill is moving.51 The data recorder on Colon2 also recognizes when the PillCam® is in the small bowel. A message is sent to the data recorder for the patient to take a booster to decrease transit down and ensure the colon remains clean. 51 A large multicenter prospective study comparing the Colon2 capsule to standard colonoscopy in the surveillance of average risk patients (n=689) was released in 2013. The sensitivity and specificity for adenomatous polyps 6 mm or larger was 88% and 82% and 92% and 95% for polyps 10 mm or larger.52 The colon capsule provides an alternative to incomplete conventional endoscopy.53 A prospective study published by Spada et al. compared capsule endoscopy to CT colonography following incomplete colonoscopy. This study compared the diagnostic sensitivity of the two tests for detecting colon polyps in the segment of colon unable to be visualized during the incomplete colonoscopy. The colon capsule detected more than twice the patients with polyps than did virtual colonography. A second colonoscopy was performed and the results of the second colonoscopy were considered true findings.54 The downside of the Colon2 is the lack of active water washing and irrigation during the procedure to obtain an optimal view, passive movement of the capsule through the colon examined, and the time it takes to read the images,


which makes it less physician-friendly. The patients also need follow up colonoscopies if significant lesions are found. Due to the duration of time to review the capsule video it is not practical to undergo same day colonoscopy therefore the patient will have to undergo additional bowel prep. A possible advantage of the Colon2 is that it could be given on the same day as colonoscopy that did not reach the cecum, avoiding an additional prep. The FDA has approved the use of the PillCam® as an alternative to incomplete or contraindicated colonoscopy.55

Blood Based Markers

A blood based marker for detection of early CRC and adenomas would be the ideal screening option. Currently the available serum markers lack sufficient performance characteristics to be used for population based CRC screening.56 Ideally a blood-based marker would have high positive predictive value and negative predictive value in the clinical setting, but blood-based markers would also be useful for patients who refuse other screening modalities. To date, no blood-based testing for CRC has shown sufficient performance characteristics to be used as a stand-alone screening tool.57 At this point the most currently utilized blood-based cancer markers are gylcoproteins such as CA125, CA15-3, PSA, and CEA as well as glycoprotein associated structures CA19-9. These markers have been shown to be useful for monitoring patients who are already known to have cancer but not for screening. The sensitivities for CEA and related molecules for screening are poor, ranging between 32-69%.58 There are still many unanswered questions such as could a noninvasive precursor lesion such as an adenoma be detected via the blood.59 Another question to be answered is will a blood-based marker be useful if the colorectal neoplasm is not invasive.60 A large number of blood-based markers have been proposed but none are approved by the FDA for CRC screening test.59

In conclusion, as with a large number of cancers, early detection of high-risk adenomas and colorectal cancer by screening significantly reduces mortality. In the USA approximately 40% of guideline eligible patients are not screened as recommended despite insurance coverage being available for CRC screening.59 The survival rate for CRC can be as high as 95% if detected early as opposed to just 7% for late stage disease.59 Regardless of the screening approach, patient adherence is needed to achieve screening goals. The best screening option must demonstrate high sensitivity for detection of early stage cancer, high-grade dysplasia, and advanced adenomas while being widely accepted to the general population and healthcare providers.61 Regardless of the method used we know that screening provides the best opportunity for detection. According to the SEER data in the US between 1991-2011 the CRC incidence fell from 59.5 cases to 39.3 cases per 100,000 with a mortality decrease of 24.0 to 15.1 deaths per 100,000. Corresponding to the incidence reduction over this time period was an increase in screening rates.62 CRC screening coverage is required by the Affordable Care Act, but the ACA does not apply to health plans initiated before its passage. Therefore, all plans started after September 23, 2010, must cover colonoscopies as well as other screening tests.63 Although colonoscopy is more invasive and time consuming, at this point it remains the gold standard for CRC screening and is unmatched for effectiveness by any other screening modality. Until we have a noninvasive screening method

that can outperform or match colonoscopy in effectiveness for screening, all patients should be offered colonoscopy as the initial screen.

Author Contributions:Study concept and design: James Whatley, MD, James Q. Sones, MD.Acquisition of Data: James Whatley, MD, James Q. Sones, MD.Drafting of the article: James Whatley, MD, James Q. Sones, MD.Critical revision for important intellectual content: James Whatley, MD, James Q. Sones, MD. Final approval of the article: James Whatley, MD, James Q. Sones, MD.

Disclosure & Conflict of interests:James Whatley and James Q. Sones have no conflict of interest or financial relationships to disclose. We have required no financial support for this publication.

Correspondence:James Q. Sones, MD, Professor in Medicine, Division of Digestive DiseasesUniversity of Mississippi Medical Center, Jackson, MS 39216Tel: 601-984-4540 Fax: 601-984-4548

Keywords: Colon cancer; colorectal cancer; colon cancer screening; colonoscopyAcronyms: Colorectal cancer (CRC), adenoma detection rate (ADR)

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48. Ahlquist DA, Harrington JJ, Burgart LJ, et al. Morphometric analysis of the “mucocellular layer” overlying colorectal cancer and normal mucosa; relevance to exfoliation and stool screening. Hum Pathol 2000;31:51-7.

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Committee Seeks Candidates for Vacancies in MSMA Offices

Delegates attending the 148th MSMA Annual Session August 12-13, 2016 in Jackson will cast ballots to fill new terms of office for a number of association posts. The Nominating Committee is seeking input from the membership as the committee prepares a slate of nominees. The list of nominees developed by the Nominating Committee will be published to the entire membership before June 12, 2016. Eligibility: All nominees must be active members of the association. No physician may be put forth on the ballot unless that physician has expressed a willingness to serve if elected. Nominations for Vacancies: A chart follows listing the vacancies that will be filled by election in 2016. The names of incumbents, the length of each term of office and the incumbent’s eligibility to be re-elected are indicated. Nominating Committee: The Nominating Committee is composed of the nine most recent Past Presidents of the association residing in Mississippi. The Immediate Past President is the chair.

Terms of Office: President-elect: 1 year 2016-2017; Officers, Trustees & Councils (physicians): 3 years 2016-2019; Delegates to the AMA:3 years; Trustees & Councils (students & residents): 1 year 2016-2017. Journal Associate Editor: 2 years 2016-2018. Incumbents NOT eligible for re-election are noted as the color grey. Email Nominations to [email protected] or contact any member of the Nominating Committee: Claude Brunson, MD: Jim Rish, MD; Steve Demetropoulos, MD; Tom Joiner, MD; Tim Alford, MD; Randy Easterling, MD;Pat Barrett, MD; Dwalia South, MD; Eric Lindstrom, MD.

OFFICERS & TRUSTEES INCUMBENT

JOURNAL MSMA INCUMBENT

AMA DELEGATES & ALTERNATE DELEGATES

COUNCILS INCUMBENT

President-elect at large Lee VoultersSecretary at large Michael MansourTrustee District 2 Brett LamptonTrustee District. 4 William GranthamTrustee District 5 Dwight KeadyTrustee Resident/Fellow Nicole LeeTrustee Student Brock Banks

Associate Editor Stanley Hartness

Position 1 Delegate at large Sharon P. DouglasPosition 2 Delegate at large J. Clay Hays, Jr.Position 3 Delegate at large Claude BrunsonPosition 4 Alternate at large Randy EasterlingPosition 5 Alternate at large Lucius LamptonPosition 6 Alternate at large James RishPosition 7 Work Team at large R. Lee GiffinPosition 8 Work Team at large Lee VoultersPosition 9 Work Team at large Jennifer J. BryanPosition 10 Work Team at large Thomas JoinerPosition 11 Work Team at large Geri Lee WeilandPosition 12 Work Team at large Hugh Gamble, II

Accreditation at large Lori MarshallAccreditation at large Crystal TateBudget & Finance at large Susan ChiaritoBudget & Finance at large Chip HolbrookConstitution & Bylaws at large John CrossConstitution & Bylaws at large J. Martin TuckerConstitution & Bylaws at large Crystal TateConstitution & Bylaws at large Victor PangEthical and Judicial Affairs S. Kenn BeemanEthical and Judicial Affairs Ryan McGaugheyEthical and Judicial Affairs Kathleen LyonsLegislation District 1 Michael MansourLegislation District 2 B. Pearson WindhamLegislation District 3 J. Murray EstessLegislation Resident James WilkinsonLegislation Student Neal BooneMedical Education District 2 DeWayne GammelMedical Education District 4 Jonathan JonesMedical Education District 5 John VossMedical Service District 4 J. Anthony CloyMedical Service District 5 Michael ShrockMedical Service Resident Jonathan BuchananMedical Service Student Daniel HesterPublic Information District 1 Robert SuaresPublic Information District 2 Son G. LamPublic Information District 3 Charlotte Magnussen

M S M A

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DIGNITY

PROTECT PATIENTS

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PROTECT PhysicianStaff

PROTECT HOSPITAL

MAXIMALPATIENTPRIVACY

EASYFORCLEAN UP

MAXIMIZEPATIENTPRIVACY

MINIMIZE BODY FLUID SPLASH

Open the double zippers.Optionally, 1-2 wash cloths can be placed inside the pants to absorb possible body fluid

Insert colonoscope, and close the zippers around the scope to creat the desired window

Open the zipper on the top for EKG leads placement

Close the zipper and secure the EKG leads on the right side.

PRIVACY PANTS®

DUAL-ZIPPER DESIGNCompletely OPENS AT BOTH ENDS

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Back To Genesis orHow We Got Here

WILLIAM M. McKELL, MD, FACP, FACG

L O O K I N G B A C K


The development of the colon-oscope and the flexible fiberoptic sigmoidoscope (aka coloscope, colonfiberoscope) followed the routine use of upper gastro-intestinal endoscopy by quite a few years. As my fellowship came to an end in 1969, the only methods available were radiological (barium enema, or preferably, barium

enema with air contrast) and by the 25 cm. rigid metal proctoscope (or as one of my patients called it, the horrorscope). Recognizing the need for the examination of the lower GI tract comparable to our abilities in the esophagus and stomach, physicians, engineers, and industry from all over the developed world worked together to create colonoscopy. Pioneering physicians in the field from the United States were Doctors Jerry Waye and Hiromi Shinya from New York, and Bergein Overholt from Tennessee.

Prior to the commercial availability of the colonoscope, our approach to a radiologically defined colonic filling defect was determined by its size. If the filling defect was 2 cm. or greater, surgical consultation with laparotomy was in order; if less than 2 cm., repeat the imaging procedure at a later date.

Dr. Overholt tells of, as a medical intern in 1961, being interviewed for a position in the Cancer Control Program of the Public Health Service. His interviewer was obviously uncomfortable with abdominal cramping, was passing gas, and generally felt miserable. He had been the recipient of 3 uncomfortable and unsuccessful rigid sigmoidoscopies an hour prior to this interview. Overholt, having recently read an article in Life magazine sent to him by his physician father, told the gassy guy what was needed was a flexible fiberoptic sigmoidoscope. The idea was accepted, promoted, and he was instructed to develop criteria for such an instrument to allow for grant proposals. He listed, among other things:

• Fiberoptics for visualization with 120 degree field of view• Flexibility to navigate the angles and flexures of the colon• 4-way tip control for navigation• A biopsy channel• Air insufflation• Water irrigation of the distal lens

The first grant by the CCP/Public Health Service was awarded to Optics Technology Inc. of California. Eder Instrument Company developed the first usable prototypes. Machida Instrument Company, American Cystoscope Makers Inc. (ACMI), and Olympus were developing their own prototypes. In 1967 Overholt presented the first series of forty patients to fellow endoscopists at the American Society of Gastrointestinal Endoscopists (ASGE) meeting in Colorado Springs. By 1969 Overholt could favorably report on the utility of the newly-introduced Olympus colonoscope (model CF-SB). The longer versions of this instrument (models CF-MB/LB), introduced in 1970, incorporated four-way tip deflection for the very first time in any

fiberoptic endoscope. The following year, Overholt cooperated with ACMI in the development of their version of the flexible sigmoidoscope. In 1972 Doctors William Wolff and Hiromi Shinya reported over 300 polypectomies with no morbidity and no mortality.

Now, let's go back home to our beloved Mississippi. At the time of my graduation from UMMC, there was no gastroenterologist on staff. Our revered Chairman of Medicine Dr. Robert Snavely had no specific training in GI, but hepatology was his love. There was a boarded gastroenterologist in Jackson, Dr. Leonard Posey, but he was not an endoscopist. By the time I returned for my medicine residency in 1965, Dr. Lidio Mora was on staff as Chief, GI Division. Dr. Mora and his elegant wife, Klara, came here from Cuba in 1962, having fled the Communist revolution. Of added interest here is that Klara had fled Hungary, again to escape the Communist takeover of her native country. Needless to say, Communism was not high on the Moras’ list of favorite things. Though I do not remember the occasion, there was a dinner party at the Moras’. After a very lovely dinner and drinks, my treasured friend Dr. John Bower decided (as he has been known to do) to inject a little needling and he chose the subject of communism. This was the only time during my entire time with Lidio that I saw the proverbial Latin temper. For a while, I thought John might get us all killed! Lidio was a great boss, knowledgeable, energetic, a superb teacher, and a pleasure to work for and with.

DR. MORA AND HIS ELEGANT WIFE, KLARA, CAME HERE FROM CUBA IN 1962, HAVING FLED THE COMMUNIST

REVOLUTION. OF ADDED INTEREST HERE IS THAT KLARA HAD FLED HUNGARY, AGAIN TO ESCAPE THE COMMUNIST

TAKEOVER OF HER NATIVE COUNTRY.

Dr. Mora's first two fellows, the late Dr. Robert McBroom and Dr. Larry Mitchell, both went to Pascagoula. Neither elected to continue endoscopy, allowing it to remain in the hands of the surgeons, but practiced: Internal medicine. At this time, one would spend two years as a medicine resident and then choose a sub-specialty if desired. In the late 1960s, the GI fellowship at UMMC was for one year. Dr. Charles Marascalco and I were fellows in 1967-1968. Charlie went to Vicksburg, and I elected to remain in my home town, Jackson. Dr. Charles McCollum followed us as Lidio's fourth fellow and set up his practice in southwest Jackson. Dr. Tom Crowson, a UMMC graduate who did his residency and fellowship at Oschner's, went to Meridian around 1974, and Dr. Walter Boone joined me in 1975, following his fellowship at Yale.

Our year with Dr. Mora was a great learning experience, and both UMMC and the VA Hospital were utilized – Charlie and I alternated six months at UMMC and six months at the VA. We were trained on the Eder-Hufford rigid esophogoscope, the Hirshowitz ACMI gastroscope, and, later in the fellowship, the Olympus gastrocamera. Though I am

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McKell


unable to recall the manufacturer, the first gastroscope I remember using required an assistant to manipulate the tip of the scope by pressure on the anterior abdominal wall, since there was no flexion control; this helped visualization of more of the gastric mucosa. Also, the light at the tip of the scope was “hot” and would burn the mucosa if allowed to remain in contact for too long. Needless to say, one could traverse the pylorus only due to sheer luck or post-pyloroplasty, due to lack of adequate tip control.

Part of our six months at the VA was rotation through Dr. Schor's Radiology department, preforming all of the GI diagnostic procedures, and back in those days, one wore the red goggles prior to entering flouroscopy to acclimate one's eyes. Lidio required us to research, write, and publish a paper in a peer-review journal. We presented all of our consults to him, and we discussed each case and our plans for each. As previously stated, he was a fantastic teacher and knew exactly how to encourage us to grow in knowledge and case management. It was not all work, however; we three had lunch each Friday, ending the lunch with flan (Lidio's favorite “Cuban desert”) was a requirement.

THE ABILITY TO OBTAIN A TISSUE DIAGNOSIS CONVINCED THE ESTABLISHED DOC THAT WE COULD BE OF VALUE,

AND THIS, ALONG WITH YOUNGER PHYSICIANS HAVING BEEN EXPOSED TO THE BENEFITS OF ENDOSCOPY IN

THEIR TRAINING PROGRAMS, INCREASED GI CONSULTS.

When my fellowship ended, I purchased the Olympus gastrocamera. I chose Olympus over ACMI (the only options at that time) because of its better local service. As I learned more about the “real world”, I convinced the local hospitals (St. Dominic, Baptist, and Doctors) to purchase updates. But initially, one could see Bill McKell and his assistant lugging the gastrocamera and its light source from one hospital to another. Upon entering private practice, unfortunately life was no longer only that of a consulting gastroenterologist. I guess that I could have done that had my wife and children not become used to food and shelter, but that being the case, a whole lot of primary practice (Internal Medicine) was required. The established practicing physician or surgeon didn't recognize the contribution that we could offer, which at that time consisted of excellent photographic evidence of gastric pathology. The only tissue that we could supply the attending and the pathologist at that time was esophageal via the Eder-Hufford rigid esophagoscope. Once the instruments allowed us to biopsy within the stomach and routinely traverse the pylorus, things improved significantly. The ability to obtain a tissue diagnosis convinced the established doc that we could be of value, and this, along with younger physicians having been exposed to the benefits of endoscopy in their training programs, increased GI consults. And as endoscopy-related articles began to appear in non-GI journals, I began to get invitations to speak to various groups across the state (e.g., Hazlehurst, Brookhaven, Canton, and Cleveland). One non-endoscopic

service for which I was frequently consulted was concerning the possible need for percutaneous liver biopsy. Remember, surgeons were performing open wedge biopsies, and we had no viral studies to guide us regarding hepatitis. During my waning years of practice, the percutaneous liver biopsy, along with the transhepatic cholangiography, had become the purview of the radiologist. I distinctly remember an assistant asking me, on one of the last liver biopsies I ever performed, “Dr. McKell, why are you requesting sonographic guidance for this procedure. You never have?” I responded, “Well, Ma’am, this case was different. The patient has had a liver transplant. On the hundreds I have done in the past, I knew where God had put the liver, but here, I had no clue as to where the surgeon had put it!”

I DISTINCTLY REMEMBER AN ASSISTANT ASKING ME, ON ONE OF THE LAST LIVER BIOPSIES I EVER PERFORMED,

“DR. MCKELL, WHY ARE YOU REQUESTING SONOGRAPHIC GUIDANCE FOR THIS PROCEDURE. YOU NEVER HAVE?” I

RESPONDED, “WELL, MA’AM, THIS CASE WAS DIFFERENT. THE PATIENT HAS HAD A LIVER TRANSPLANT. ON THE

HUNDREDS I HAVE DONE IN THE PAST, I KNEW WHERE GOD HAD PUT THE LIVER, BUT HERE, I HAD NO CLUE AS TO

WHERE THE SURGEON HAD PUT IT!”

There was one more procedure we learned under Lidio's instruction, and that was the Crosby Capsule small bowel biopsy. The problem with this technique was to get the capsule to pass through the pylorus. Lidio had brought a supply of metoclopramide from Cuba, which minimized that problem.

In many venues, there are significant advantages to being #1 (first on the moon, Super Bowl, World Series, etc.) but not necessarily of being first in the state in a sub-specialty. There is the problem of national organization membership. ASGE, for example, required a supporting letter from two members in one's state. Though Lidio later became a member of ASGE, he wasn't in 1968. They did, with a supporting letter from him as my fellowship boss, accept my application. Don't all accredited hospitals require any new staff member who performs procedures to be monitored by an experienced staff member? Well, they did back then too. There just happened to be on the medical staffs of the three hospitals to which I applied for privileges no one who had ever even seen a flexible endoscope, much less a procedure using one. Well, we obviously worked that out also. Need I bring up the fact that there were no Endoscopy Suites? Saying “Endoscopy Suite” back then would be the equivalent of saying “dot.com”. We either used the Emergency Room or, when radiology services were required, scheduled a room in the Department of Radiology.

Aren't you glad it's 2016?

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Review of Bowel Preparation Agents for Colonoscopy

SRIKRISHNA PATNANA, MD Gastroenterologist



Colorectal cancer (CRC) is the second most common cause of cancer death in the United States (US) accounting for nearly 50,000 deaths in 2015.1 Typically, it is preceded by a pre-cancerous lesion, an adenoma which is commonly called ‘polyp’. Recent studies have shown that optical colonoscopy is associated with

nearly 10% reduction in the incidence of CRC and approximately 50% reduction in CRC mortality in the last few decades.2,3 This is because colonoscopy can identify and remove polyps, thereby preventing CRC. Additionally, colonoscopy can identify CRCs at an earlier stage allowing definitive treatment to be promptly offered, improving the overall prognosis of CRC.

Importance of good bowel preparation

Although several factors can affect the quality of colonoscopy, probably the first and the most important one is the quality of bowel preparation, in other words, how clean the colon is during endoscopic examination.4 If the colon is inadequately prepared, it is associated with a higher number of incomplete studies (decreased cecal intubation rate), a higher miss rate for polyps and cancer (low adenoma detection rate [ADR] and high interval cancer), increased sedation and procedure related complications, and increased colonoscopy cancellation rates leading to increased health care costs, patient noncompliance with potential risk for future CRC.4,5 All of the above can lead to decreased efficacy of colonoscopy in the prevention and early treatment of CRC.

Additionally, participation in CRC screening programs as well as screening colonoscopy is not universal. Only 65% of the eligible population utilize one of the CRC screening programs in the US; among them, approximately 60% undergo screening colonoscopy.6 Of the numerous factors contributing to the above (physician access, lack of knowledge, financial difficulties, anxiety, embarrassment), concern regarding bowel preparation was the most common reason given for deferring screening colonoscopy.7 Mississippi is one of the states where rates of CRC screening are among the lowest and, consequently, the mortality from CRC is among the highest in the US.8

The aim of this review, therefore, is to discuss various aspects and options of colonoscopy bowel preparation which can help patients as well as primary care physicians in Mississippi understand the importance and intricacies of bowel preparation, thereby allaying their concerns and making them more agreeable to pursuing screening colonoscopy.

What do bowel preparation agents do?

All bowel preparation agents empty the colon and clean the colonic mucosa by their purgatory action. This allows the endoscopist to examine the entire colon thoroughly for abnormalities. This purge is a result of excess fluid in the colon which could not be reabsorbed as most of these agents are made up of non-absorbable solutes which are either isosmotic or hyperosmotic (the latter draws even more fluid across the

intestinal mucosa). Other formulations are a combination of the above and an agent which stimulates colonic motility; thereby, they have two mechanisms of action.

Diet and hydration before colonoscopy

Currently, most of the endoscopists recommend a clear liquid diet for at least one day before colonoscopy with last meal before initiation of bowel prep. More recent studies suggest that a low residue diet is associated with similar or even better bowel prep quality and higher patient satisfaction. Based on these studies, recently published American Society of Gastrointestinal Endoscopy (ASGE) guidelines recommended a low residue diet instead of a clear liquid diet before colonoscopy.5 Some of the shortcomings of this recommendation are the lack of clarity over what diet is considered low residue as well as the number of days before colonoscopy that a person should eat a residue diet. In view of this, individual institutions should modify their practice as per their experience. As bowel preparation agents have the potential to cause dehydration owing to their cathartic action, it is important to stay well hydrated while ingesting the bowel preparation agent. Fluids which can be taken to stay hydrated are any clear fluids which include water, clear soda, clear broth, clear fruit juices without pulp, strained limeade or lemonade, etc.

RECENT STUDIES HAVE SHOWN THAT OPTICAL COLONOSCOPY IS ASSOCIATED WITH NEARLY

10% REDUCTION IN THE INCIDENCE OF CRC AND APPROXIMATELY 50% REDUCTION IN CRC MORTALITY

IN THE LAST FEW DECADES.

Timing of bowel preparation agent administration

Traditionally, a bowel preparation agent is taken on the afternoon or evening before colonoscopy. This is done over either one session or two sessions depending on the chosen bowel preparation agent. After ingestion of a bowel preparation agent by late evening, patients present for their procedure the next day. It was noticed with this regimen that the proportion of people with inadequate bowel preparation (especially in the proximal colon) is high.9 Possible reasons for this inadequate bowel preparation are as follows: (1) Patient noncompliance with bowel preparation administration instructions is higher with traditional prep regimens.9 (2) After completing the bowel preparation agent the evening before colonoscopy, there is an interval of at least 8-20 hours before the procedure. This period is commonly called ‘prep-procedure interval’. During this time, residual small bowel contents can enter the clean colon and adhere to its mucosa, thereby rendering the preparation inadequate and manual cleaning during the procedure ineffective.5 Numerous studies have shown that the longer the prep-procedure interval is, the worse the quality of bowel preparation is.10

The negative consequences of this were mentioned previously. This could also partly explain the differential benefits of screening

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Patnana


GolytelyNulytelyColyteTrilyteGavilyte-C,N,Ga

MoviprepGavilyte-H*Gatorade (+) MiralaxOsmoprep (NaP)Magnesium citrate (+/-) PEG-ELS/NaPPrepopikSuprepSuclear

HIGH VOLUME LOW VOLUME

TABLE 1.

CLASSIFICATION OF BOWEL PREPARATION AGENTS

*Gavilyte-C,N,G,H are generics of Colyte, Nulytely, Golytely, and Halflytely respectively.

colonoscopy in left and right sided colon cancers. Current literature shows that mortality benefit of a screening colonoscopy is lower for right sided (proximal) colon cancers in comparison to distal cancers.3,11 Although this could be related to the differences in tumor morphology and biology, the importance of missed lesions because of inadequate visualization cannot be underestimated. It is estimated that 50-60% of interval post colonoscopy CRCs (CRCs arising in individuals after a negative colonoscopy in the previous 3-5 years) are a result of missed lesions.2 This led to development of new strategies to administer bowel preparation agents so as to improve the quality of bowel preparation.

One such strategy is to administer a portion of bowel preparation agent the afternoon or evening before colonoscopy and the remaining part on the morning of the procedure. This is commonly referred to as ‘split prep’. Meta-analyses comparing split prep and traditional prep showed that the quality of bowel preparation is better in the former.9 Split prep is also shown to improve ADR.5 Additionally, patient tolerance and their willingness to repeat split prep in the future is also high.5 Theoretical concerns of patient resistance to wake up early in the morning to complete bowel preparation have not been found in randomized studies even in the subset of patients undergoing early morning colonoscopies.4

MISSISSIPPI IS ONE OF THE STATES WHERE RATES OF CRC SCREENING ARE AMONG THE LOWEST AND

CONSEQUENTLY, THE MORTALITY FROM CRC IS AMONG THE HIGHEST IN THE US.

The strategy of delivering the entire bowel preparation agent on the morning of the procedure is called ‘morning only prep’. Studies of morning only prep for afternoon colonoscopies showed better bowel preparation quality and patient tolerance in comparison to classic prep and even split prep.5 This has at least two practical advantages: (1) People do not have to

take time off from work the day before colonoscopy. (2) An individual’s sleep time and quality need not be compromised from not having to take the bowel preparation agent on either side of sleep.

It is worth mentioning two additional concerns of taking a bowel preparation agent on the morning of colonoscopy: (1) Need to make more restroom stops during the drive from home to endoscopy unit. Studies of split prep showed only minimal increase in this in comparison with classic prep.4 Even though there are no studies of morning only prep looking at this issue, results from the above can be extrapolated to this scenario as well. (2) Aspiration of residual gastric contents (bowel preparation agent taken in the morning) leading to pulmonary complications. A well conducted study showed that the volume of gastric contents (collected during upper endoscopy performed before colonoscopy) is comparable between patients who took classic and split bowel prep.12 So, as long as American Society of Anesthesiology (ASA) recommendations of Nil Per Os (NPO) for clear liquid diet of two hours are followed,5 it is safe to administer a bowel preparation agent in a split or morning only regimen. Individual patient characteristics should be taken into consideration as a minimum of only two hours NPO may not be safe in patients with gastroparesis and other conditions associated with slow gastric emptying.

As discussed above, split prep and morning only prep are favorably reviewed both by physicians as well as patients. Therefore, all major US and European gastroenterological societies advocate adoption of both to further optimize bowel preparation quality.4,5,10 Irrespective of the strategy chosen for bowel preparation, it is also important to keep prep-procedure interval as short as possible to maximize the chances of an excellent bowel prep. A recent meta-analysis showed that the benefit of split prep over classic prep disappeared if the prep-procedure interval exceeded five hours.9 Also, the European Society of Gastrointestinal Endoscopy (ESGE) recommended that the prep-procedure interval be no longer than four hours in their most recent guideline.10

Different bowel preparation agents

An ideal bowel preparation agent should be easy to take, give consistent results, and should not be associated with any complications.4 Unfortunately, none of the agents currently available can be considered ideal, and the search for a perfect bowel preparation agent is still underway. A practical way to classify bowel preparation agents is by grouping them into high volume or low volume preps (Table 1). A low volume prep is usually less than three liters and a high volume prep is approximately four liters.5 It is important here to understand that a majority of low volume preps require additional fluid consumption which is not accounted for in the above classification. All available bowel preparation agents can be given in split dose regimen. However, Osmoprep (Salix Pharmaceuticals, Inc., USA) Suprep (Braintree Laboratories, Inc., USA), and Prepopik (Ferring Pharmaceuticals Inc., USA) cannot be used currently in morning only prep regimens as each portion in these formulations should be taken at least 6-12 hours apart.13,14,15 As Moviprep (Salix Pharmaceuticals, Inc., USA) and Suclear (Braintree Laboratories, Inc., USA) packs can be taken 1.5-2 hours apart, they can still be used in morning only prep regimens.16,17

JOURNAL MSMA 97

Golytely, Colyte,

Nulytely, Trilyte,

Gavilyte-C,G,N18-24

Moviprep16

Gavilyte-H25

Magnesium citrate

(+/-) PEG-ELS/NaP*

Gatorade (+) Miralax*

Mix contents in 4 lt water; flavoring available; can be chilled; drink 240 ml every 10-15 minutes.

There are 2 A pouches and 2 B pouches; mix 1 pouch A & 1 pouch B in 1 lt water each time; additional clear liquid intake required.

Mix contents in 2 lt water; flavoring available; can be chilled; take 240 ml every 10-15 minutes.

Dose varies between 1-3 bottles (each 300 ml); can be taken by itself or combined with PEG-ELS or NaP; additional 1-2 lt fluid intake recommended.

Mix 238 gm or 306 gm of Miralax in 64 ounces of Gatorade

YES

Take 4 lts on the evening before procedure within 4 hrs.

YES

On the evening before colonoscopy, take this 1 lt solution over 1 hr (240 ml every 15 minutes) and 2 hrs later, take another 1 lt over 1 hr; take 1 lt clear liquid over after this.

YES

Take 5 mg bisacodyl at noon; after a bowel movement or 6 hrs (whichever is earlier), drink 2 lts within 2 hrs.

YES

On the evening before colonoscopy, take 3 bottles over 1-2 hours & drink 1-2 lt clear liquid.

YES

Take 2 lts on the evening before procedure within 2 hrs.

YES*Take 2-3 lts on the evening before colonoscopy within 2-3 hrs & 1-2 lts on the morning of procedure within 1-2 hrs with last dose at least 2 hrs before colonoscopy.

YES

Take each 1 lt solution over 1 hr on the evening before procedure and the morning of colonoscopy; drink 500 ml clear liquid over 1 hr after each dose; last fluid intake should be at least 2 hrs before colonoscopy.

YES*Take 5 mg bisacodyl at noon; after a bowel movement or 6 hrs (whichever is earlier), drink 1 lt over 1 hr on the evening before colonoscopy & 1 lt over 1 hr on the morning of procedure with last dose at least 2 hrs before colonoscopy.

YES

On the evening before colonoscopy, take 1-2 bottles along with 1 lt clear liquid; on the morning of procedure, take 1-2 bottles (or) 2 lt PEG-ELS (or) 12-16 tabs NaP along with last fluid intake 2 hr before colonoscopy.

YES

take 1 lt within 1 hr on the evening of procedure & 1 lt within 1 hr on the morning of colonoscopy with last dose at least 2 hrs before procedure.

YES*Take 4 lts on the morning of procedure within 4 hrs with last dose at least 2 hrs before colonoscopy.

YES*Take both doses 2 hrs apart and drink 1 lt clear liquid over 2 hrs after this; last fluid intake should be at least 2 hrs before colonoscopy.

YES*Take 5 mg bisacodyl at bedtime; after 6 hrs, drink 2 lts over 2 hrs on the morning of colonoscopy with last dose at least 2 hrs before procedure.

YES

On the morning of procedure, take either 3 bottles along with excess fluid or a combination of 1-3 bottles & 2 lt PEG-ELS with last fluid intake at least 2 hr before procedure.

YES

Take 2 lts within 2 hrs on the morning of colonoscopy with last dose at least 2 hrs before procedure.

AGENT PREPARATIONTRADITIONAL

DOSE REGIMENSPLIT DOSE REGIMEN

MORNING ONLY REGIMEN

TABLE 2.

BOWEL PREPARATION ADMINISTRATION INSTRUCTIONS

* Not FDA approved but used.


The most common side effects of all bowel preparation agents include dehydration, electrolyte imbalances (and its grave complications), aspiration and its sequelae, allergic reactions, nausea, vomiting, bloating, abdominal pain, and abdominal distension. Rare complications include ischemic colitis, pancreatitis, renal injury, congestive heart failure (CHF), and syndrome of inappropriate ADH secretion (SIADH).13-25 These are possible irrespective of the type of bowel preparation agent used. These side effects can be minimized by using low volume bowel preparation agents or split dose regimen or a combination of both and maintaining adequate hydration. Specific complications of individual bowel preparation agents will be discussed in the sections below.

Polyethylene glycol-Electrolyte Solution

(PEG-ELS)-based formulations

Golytely (PEG-3350 and electrolytes oral solution, Braintree Laboratories, Inc., USA), Nulytely (PEG-3350 and electrolytes oral solution, Braintree Laboratories, Inc., USA), Trilyte (PEG-3350 sodium chloride, sodium bicarbonate, and potassium chloride for oral solution, Wallace Pharmaceuticals Inc., USA), Colyte (PEG-3350 and electrolytes oral solution, Meda Pharmaceuticals Inc., USA), Gavilyte-G (PEG-3350 and electrolytes for oral solution, Gavis Pharmaceuticals LLC, USA), Gavilyte-N (PEG-3350, sodium chloride, sodium bicarbonate, and potassium chloride for oral solution, Gavis Pharmaceuticals LLC, USA), Gavilyte-C (PEG-3350 and electrolytes for oral solution, Gavis Pharmaceuticals LLC, USA), Gavilyte-H (PEG-3350, sodium chloride, sodium bicarbonate and potassium chloride for oral solution and bisacodyl delayed-release tablet, Gavis Pharmaceuticals LLC, USA) and Moviprep are all PEG-ELS based formulations with are approved by Food and Drug Administration (FDA) for bowel preparation.16,18-25 PEG is not absorbable across the intestine and is osmotically active. When electrolytes are added to make this solution isosmolar (similar concentration to body fluids), there should be no fluid and electrolyte abnormalities theoretically. These are the most commonly prescribed bowel preparation agents in the world. Additionally, as there are minimal fluid shifts, these are the preferred bowel preparation agents in patients with heart, kidney, or liver disease.5 If well tolerated, the results of these agents are very good and currently these are the standard agents against which other agents are compared usually.4

Nulytely, and Trilyte are sulfate free PEG-ELS formulations (SF-PEG-ELS) intended to increase the palatability of these formulations by decreasing sulfate and potassium concentration.18 These are as effective as the sulfate-containing PEG-ELS formulations. But, results of clinical studies did not show better tolerance in comparison to sulfate-containing PEG-ELS which was their intended purpose.26

Moviprep is one of the two low volume PEG-ELS formulations in the market currently. It is a combination of PEG-ELS and ascorbic acid, both of which are osmotically active. Because of the latter, it should be used with caution in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency as it may lead to hemolysis.16 Gavilyte-H, a generic of Halflytely (PEG-3350, sodium chloride, sodium bicarbonate and potassium chloride for oral solution and bisacodyl delayed-release tablet, Braintree Laboratories, Inc., USA)27 which was discontinued in July 2013,28 is a

combination of 2 liter SF-PEG-ELS and bisacodyl.25 From the available literature, Moviprep is as efficacious as other PEG-ELS formulations4 but Halflytely (and presumably Gavilyte-H) is inferior to MoviPrep.29

CURRENTLY, EVEN THOUGH AN IDEAL BOWEL PREPARATION AGENT IS LACKING, THERE ARE NUMEROUS

BOWEL PREPARATION AGENTS WHICH SHOULD BE USED EITHER IN SPLIT OR MORNING ONLY REGIMENS TO ACHIEVE EXCELLENT BOWEL PREP. ALONG WITH

OTHER QUALITY IMPROVEMENT MEASURES, THIS WILL HOPEFULLY HELP IN FURTHER REDUCTION IN CRC

INCIDENCE AND MORTALITY.

Both PEG-ELS (+) magnesium citrate, and Gatorade (PepsiCo, Chicago, USA) (+) Miralax (PEG-3350, Bayer Healthcare Pharmaceuticals Inc., USA) are non FDA approved low volume PEG- based formulations used for bowel preparation and should therefore be used with caution. A combination of magnesium citrate and PEG-ELS is comparable to standard PEG-ELS in the quality of bowel preparation and is tolerated better by patients.30 But, as magnesium is excreted by kidneys, this should be avoided in patients with renal insufficiency or renal failure. A combination of Gatorade (+) Miralax, a commonly used bowel preparation agent available over the counter, is as effective as standard PEG-ELS.4 However, Miralax, unlike standard PEG-ELS formulations, does not have any electrolytes and is made up of PEG only. Therefore, when it is mixed with Gatorade or any other sports drink, the resultant solution is hyposmotic. This can lead to electrolyte imbalance and its potential complications. Supporting this, a recent study showed significant differences in serum sodium, potassium, and chloride levels from baseline values.4

Magnesium citrate

Magnesium citrate works as a laxative because of the osmotic activity of magnesium. Additionally, magnesium stimulates cholecystokinin release which increases intestinal secretions, thereby augmenting its purgatory effect.4 It can used alone or in combination with either sodium picosulfate or PEG-based formulations or sodium phosphate for bowel preparation.5 Of the above, it is approved by FDA for bowel preparation only in combination with sodium picosulfate. Because of the risk of hypermagnesemia, it should be avoided in patients with renal insufficiency or failure.

Osmoprep

Osmoprep is a hyperosmotic laxative consisting of sodium phosphate (NaP). Because of the increased concentration of unabsorbed anions and associated cations in the lumen, fluid is drawn across the intestine leading to bowel cleansing.13 The quality of bowel preparation with NaP is comparable to standard PEG-ELS and patient tolerance is better for this agent.5 In spite of this, NaP-based bowel preps are uncommonly used currently because of major complications. NaP-based oral bowel preparation agents are associated with renal injury

JOURNAL MSMA 99

(acute phosphate nephropathy) which sometimes is irreversible even requiring long term dialysis. Because of this, over the counter NaP formulations were withdrawn in the US and FDA issued a black box warning regarding acute phosphate nephropathy for the prescription formulation Osmoprep. The risk of renal injury is higher in young children, elderly, patients with preexisting renal disease, hypertensive patients, patients taking nonsteroidal anti-inflammatory drugs (NSAIDs) or angiotensin converting enzyme inhibitors (ACE

inhibitors), or angiotensin receptor antagonists (ARBs), or diuretics and should therefore be avoided in these groups.4 As fluid shifts are also more common with hyperosmotic agents like NaP than isosmotic PEG-ELS based formulations, it is safer to avoid NaP in patients with cardiac, or liver disease who cannot tolerate fluid and electrolyte abnormalities. NaP is also associated with an increased risk of prep induced colitis and should be used with caution in patients with inflammatory bowel disease (IBD).13

Osmoprep13

Prepopik15

Suprep14

Suclear17

Total dose is 32 tabs and 2 lt of any clear liquids; take 4 tabs every 15 minutes along with 250 ml clear liquids.

Consists of 2 packs; mix each in 150 ml water; additional clear liquid intake required.

Consists of 2 bottles; mix each with water for a volume of 500 ml; additional water intake required.

Has 2 components: oral solution & powder; oral solution is mixed with water for a total volume of 500 ml; powder is mixed with 2 lt water; additional water intake required.

NO

YES

Take 1st dose in the afternoon before colonoscopy & 2nd dose in the evening at least 6 hrs later; take additional 1.25 lt & 750 ml clear liquid over 5 hrs after each dose respectively.

NO

YES

On the evening before colonoscopy, take oral solution and additional 500 ml water over 2 hrs; 2 hrs later, take 2nd solution over 1-2 hrs at 240 ml every 10-15 minutes; take additional 500 ml water.

YES

Take 20 tabs the evening before colonoscopy & 12 tabs on the morning of procedure with last fluid intake at least 2 hrs before procedure.

YES

Take 1st dose in the evening before colonoscopy & 2nd dose on the morning of procedure; take additional 1.25 lt & 750 ml clear liquid after each dose respectively; last fluid intake should be at least 2 hrs before colonoscopy.

YES

Drink 1st bottle on the evening before procedure & 2nd bottle on the morning of colonoscopy at least 10-12 hrs apart; drink additional 1 lt water after each dose over 1 hr; last water intake should be at least 2 hrs before colonoscopy.

YES

On the evening before procedure, take oral solution and additional 1 lt water; on the morning of colonoscopy (10-12 hrs apart), take 2nd solution over 1-2 hrs at 240 ml every 10-15 minutes; last fluid intake should be at least 2 hrs before colonoscopy.

NO

NO

NO

YES*

On the morning of colonoscopy, take oral solution and additional 500 ml water over 2 hrs; 2 hrs later, take 2nd solution over 1-2 hrs at 240 ml every 10-15 minutes and additional 500 ml water; last fluid intake should be at least 2 hrs before colonoscopy.

AGENT PREPARATIONTRADITIONAL

DOSE REGIMENSPLIT DOSE REGIMEN

MORNING ONLY REGIMEN

TABLE 2.

BOWEL PREPARATION ADMINISTRATION INSTRUCTIONS (CONTINUED)

* Not FDA approved but used.


Prepopik

Prepopik is a combination of sodium picosulfate and magnesium citrate. Sodium picosulfate is converted by colonic bacteria to an agent which stimulates colonic motility, and magnesium citrate is an osmotic laxative.4 It was approved in the US in 2012.15 The quality of bowel prep achieved with Prepopik is comparable to that with PEG-ELS-based formulations.5 As it has magnesium citrate, it should not be used in patients with renal disease. As discussed above, this cannot be used as a morning only prep agent for afternoon colonoscopies.

Suprep

This hyperosmotic laxative is a combination of sodium, potassium, and magnesium sulfate. As sulfate salts are poorly absorbed, they exert their osmotic action and help in bowel purge. It was approved in the US in 2010.14 Suprep is comparable to PEG-ELS-based formulations in the quality of bowel preparation.4 As discussed in an earlier section, this can be used only in split dose regimen.

INSURANCE COVERAGE IN MISSISSIPPI FOR BOWEL PREPARATION AGENTS DEPENDS ON THE TYPE OF

INSURANCE AN INDIVIDUAL CARRIES ... FOR COMPLETE INFORMATION REGARDING COVERAGE AND CO-PAYS,

PATIENTS AND PRACTICES ARE RECOMMENDED TO CONTACT INSURANCE PROVIDERS ... AS CAN BE SEEN,

MOST OF THE PEG-ELS BASED GENERIC FORMULATIONS ARE AMONG THE CHEAPEST BOWEL PREPARATION

AGENTS AVAILABLE.

Suclear

Suclear is a combination of sulfate salts and SF-PEG-ELS, both of which are osmotic laxatives. It is approved in the US in 2013.17 Results of bowel preparation are similar to that achieved with standard PEG-ELS formulations but are associated with more vomiting and overall discomfort.4 This can be used in both split dose and morning only prep regimens. Please refer to Table 2 for different regimens of above bowel preparation agents.

Bowel preparations in special populations

As none of the available bowel preparation agents are ideal, some of these agents should be avoided or used with caution in certain conditions. The following section covers the preferred bowel preparation agents in select populations.

Elderly and patients with comorbidities

As these patients are at a higher risk for fluid and electrolyte imbalance as well as their complications because of their medical conditions, theoretically, low volume and iso-osmotic bowel preparation agents should be preferred over high volume and hyper-osmotic bowel preparation agents. It is better to avoid NaP-based bowel preparation

agents in these populations because of increased risk of electrolyte abnormalities and renal dysfunction.5

After bariatric surgery

Because of decreased gastric volume in these patients, it is advisable to use low volume bowel preparation agents to improve tolerance as well as results. If high volume preparations have to be used, the timelines for their ingestion should be extended.5

Pregnancy

It is uncommon to perform colonoscopy during pregnancy. When indicated, most of the bowel preparation agents are labeled by FDA as category C except Prepopik which is category B.13-19 The American Gastroenterological Association (AGA) recommends against using NaP-based preparation agents during pregnancy.5 The European Society of Gastrointestinal Endoscopy (ESGE) recommends using PEG-ELS-based formulations before colonoscopy during pregnancy.10

Inflammatory bowel disease

NaP-based preparation agents and presumably other hyperosmotic agents are associated with mucosal ulcerations owing to mucosal ischemia. Therefore, in this population, it is preferable to use PEG-ELS-based formulations to minimize the risk of prep based artefacts.10

Insurance coverage and pricing in Mississippi

Insurance coverage in Mississippi for bowel preparation agents depends on the type of insurance an individual carries. This information for a few common insurance plans in Mississippi is summarized in Table 3. For complete information regarding coverage and co-pays, it is recommended patients and practices contact insurance providers. Additionally, retail pricing information in Mississippi for the various bowel preparation agents is compiled in Table 4. As can be seen, most of the PEG-ELS-based generic formulations are among the cheapest bowel preparation agents available.

In conclusion, optical colonoscopy is the best study available for CRC screening. But its success depends on multiple factors, and the foremost among these is the quality of bowel preparation achieved. Currently, even though an ideal bowel preparation agent is lacking, there are numerous bowel preparation agents which should be used either in split or morning only regimens to achieve excellent bowel prep. Along with other quality improvement measures, this will hopefully help in further reduction in CRC incidence and mortality.

Author description:Srikrishna Patnana, Gastroenterologist, finished GI Fellowship in University of Mississippi Medical Center in June 2015. Correspondence:Srikrishna V Patnana, MD MPH1725 GreenbrierWay, Slidell, LA 70460713-825-6553 [email protected]

JOURNAL MSMA 101

Medicare

AARP MedicareRx Preferred Cigna-Healthspring RxSecure Humana National Enhanced PDP Silverscript Choice Wellcare Classic

Not covered Covered/Preferred Non-preferred but covered N/A Information not available.

Medicaid

Magnolia Health (MississippiCAN) Magnolia Health (Mississippi CHIP) Mississippi State Medicaid UnitedHealthcare Community Plan (MississippiCAN) UnitedHealthcare Community Plan (Mississippi CHIP)

Others

BCBS-MS Humana Rx5Plus Bronze UnitedHealthcare Advantage 4-Tier Bronze Humana High Deductible Traditional United Health Traditional

N/A N/A

N/A

CATEGORY/INSURANCEPEG-ELS BASED FORMULATIONS

PREPOPIKSUPREP OSMOPREPSUCLEARMOVIPREP

TABLE 3.

INSURANCE PLAN COVERAGE IN MISSISSIPPI FOR BOWEL PREPARATION AGENTS (AS OF JANUARY 2016)*

* Decision Resources, Inc. DRG Formulary Lookup. https://lookup.decisionresourcesgroup.com/. Published 2016. Accessed January 25, 2016.

* GoodRx, Inc. http://www.goodrx.com/. Published 2016. Accessed January 25, 2016. ** Drug Price Search. https://www.rxpricequotes.com/default.aspx. Accessed January 25, 2016.

Gavilyte-C,G,NGeneric formulations of Golytely, Colyte, Nulytely

GolytelyNulytely

ColyteSuclear

MoviprepSuprep

PrepopikOsmoprep

$10-$20$10-$20$20-$30$30-$40$50-$60$70-$80$80-$90$80-$90

$120-$130$170-$180

BOWEL PREP AGENT CHEAPEST PRICE RANGE

TABLE 4.

PRICING OF BOWEL PREPARATION AGENTS IN MISSISSIPPI (AS OF JANUARY 2016)* **


Acknowledgements:The author would like to thank Mr. Joseph Painich for his help in acquiring insurance coverage information for various bowel preparation agents in Mississippi. The author would also like to thank Drs. Shou-jiang Tang and James Q. Sones for their guidance in manuscript preparation.

Financial disclosure: None

Conflicts of interest: None

Keywords: Colonoscopy; colon cancer screening ; colon; bowel preparation; split dosing

1. SEER Stat Fact Sheets: Colon and Rectum Cancer. National Cancer Institute Surveillance, Epidemiology, and End Results Program. http://seer.cancer.gov/statfacts/html/colorect.html. Accessed January 25, 2016.

2. Adler J, Robertson DJ. Interval colorectal cancer after colonoscopy: exploring explanations and solutions. Am J Gastroenterol. 2015;110;1657-1664.

3. Young PE, Womeldorph CM. Colonoscopy for colorectal cancer screening. J Cancer. 2013;4:217-226.

4. Saltzman JR, Cash BD, Pasha SF, et al. Bowel preparation before colonoscopy. Gastrointest Endosc. 2015;81:781–794.

5. Johnson DA, Barkun AN, Cohen LB, et al. Optimizing adequacy of bowel cleansing for colonoscopy: recommendations from the U.S. multi-society task force on colorectal cancer. Gastrointest Endosc. 2014;80:543-562.

6. Klabunde CN, Joseph DA, King JB, White A, Plescia M. Vitals signs: colorectal cancer screening test use- United States, 2012. Centers for Disease Control and Prevention Morbidity and Mortality Weekly Report. http://www.cdc.gov/mmwr/pdf/wk/mm6244.pdf. Published November 2013. Accessed January 25, 2016.

7. Harewood GC, Wiersema MJ, Melton LJ 3rd. A prospective, controlled assessment of factors influencing acceptance of screening colonoscopy. Am J Gastroenterol. 2002;13:3186–3194.

8. Colorectal Cancer Facts & Figures 2014-2016. American Cancer Society. http://www.cancer.org/acs/groups/content/documents/document/acspc-042280.pdf. Published 2014. Accessed January 25, 2016.

9. Bucci C, Rotondano G, Hassan C, et al. Optimal bowel cleansing for colonoscopy: split the dose! A series of meta-analyses of controlled studies. Gastrointest Endosc. 2014:80:566-576.

10. Hassan C, Bretthauer M, Kaminski MF, et al. Bowel preparation for colonoscopy: European Society of Gastrointestinal Endoscopy (ESGE) guideline. Endoscopy. 2013;45:142-150.

11. Colorectal cancer screening-for health professionals: Summary of evidence. NIH National Cancer Institute. http://www.cancer.gov/types/colorectal/hp/colorectal-screening-pdq. Updated January 2016. Accessed January 25, 2016.

12. Huffman M, Unger RZ, Thatikonda C, et al. Split-dose bowel preparation for colonoscopy and residual gastric fluid volume: an observational study. Gastrointest Endosc. 2010;72:516–522.

13. OSMOPREP [package insert]. Raleigh, NC; Salix Pharmaceuticals, Inc.; Revised October 2012. https://shared.salix.com/shared/pi/osmoprep-pi.pdf. Accessed January 25, 2016.

14. SUPREP [package insert]. Braintree, MA; Braintree Laboratories, Inc.; Revised November 2012. http://www.suprepkit.com/collateral/documents/suprep/suprep%20pi-med%208-10.pdf. Accessed January 25, 2016.

15. PREPOPIK [package insert]. Parippany, NJ; Ferring Pharmaceuticals Inc.; Revised

April 2015. http://www.prepopik.com/wp-content/uploads/2015/09/prepopik_pi.pdf. Accessed January 25, 2016.

16. MOVIPREP [package insert]. Raleigh, NC; Salix Pharmaceuticals, Inc.; Revised November 2013. https://shared.salix.com/shared/pi/moviprep-pi.pdf. Accessed January 25, 2016.

17. SUCLEAR [package insert]. Braintree, MA; Braintree Laboratories, Inc.; Published January 2013. http://www.suclearkit.com/Collateral/Documents/Suclear/SUCLEAR%20PI%20MedGuide_FINAL%20MARCH%202013.pdf. Accessed January 25, 2016.

18. GOLYTELY [package insert]. Braintree, MA; Braintree Laboratories, Inc.; Revised September 2013. http://www.nulytely.com/Collateral/Documents/GoNuLytely/GoLytely_060_107.pdf. Accessed January 25, 2016.

19. NULYTELY [package insert]. Braintree, MA; Braintree Laboratories, Inc.; Revised September 2013. http://www.nulytely.com/Collateral/Documents/GoNuLytely/NuLYTELY_181.pdf. Accessed January 25, 2016.

20. TRILYTE [package insert]. Somerset, NJ; Wallace Pharmaceuticals Inc.; Revised September 2011. http://www.wallacepharmaceuticals.com/docs/TriLyte_with_flavor_packs_PI.pdf. Accessed January 25, 2016.

21. COLYTE [package insert]. Somerset, NJ; Meda Pharmaceuticals Inc.; Revised February 2014. http://www.medapharma.us/products/pi/Colyte4Liter_PI.pdf. Accessed January 25, 2016.

22. GAVILYTE-G [package insert]. Somerset, NJ; Gavis Pharmaceuticals LLC; Revised August 2012. http://www.gavispharma.com/wp-content/uploads/2015/05/website-GaviLyte-G-PI.pdf. Accessed January 25, 2016.

23. GAVILYTE-N [package insert]. Somerset, NJ; Gavis Pharmaceuticals LLC; Revised August 2012. http://www.gavispharma.com/wp-content/uploads/2015/05/website-GaviLyte-N-PI.pdf. Accessed January 25, 2016.

24. GAVILYTE-C [package insert]. Somerset, NJ; Gavis Pharmaceuticals LLC; Revised August 2012. http://www.gavispharma.com/wp-content/uploads/2015/05/website-GaviLyte-C-PI.pdf. Accessed January 25, 2016.

25. GAVILYTE-H [package insert]. Somerset, NJ; Gavis Pharmaceuticals LLC; Published December 2014. http://www.gavispharma.com/wp-content/uploads/ 2015/05/GaviLyte-H-Final-Package-Insert.pdf. Accessed January 25, 2016.

26. Mamula P, Adler DG, Conway JD, et al. Colonoscopy preparation. Gastrointest Endosc. 2009;69:1201–1209.

27. HALFLYTELY [package insert]. Braintree, MA; Braintree Laboratories, Inc.; Revised July 2010. https://www.colonoscopyassist.com/prep/Manufacturer_Prep_Instructions/Halflytely_Instructions.pdf. Accessed January 25, 2016.

28. Gaffney A. After Months of Silence, FDA Returns to 'Name and Shame' Strategy on Pediatric Trial Compliance. Regulatory Affairs Professional Society. http://www.raps.org/regulatory-focus/news/2014/05/18896/PREA-Noncompliance-Letters/. Published May 22, 2014. Accessed January 25, 2016.

29. Cohen LB, Sanyal SM, Von Althann C, et al. Clinical trial: 2-L polyethylene glycol-based lavage solutions for colonoscopy preparation-a randomized, single-blind study of two formulations. Aliment Pharmacol Ther. 2010;32:637–644.

30. Park SS, Sinn DH, Kim YH, et al. Efficacy and tolerability of split-dose magnesium citrate: low volume (2 liters) polyethylene glycol vs. single- or split-dose polyethylene glycol bowel preparation for morning colonoscopy. Am J Gastroenterol. 2010;105:1319-1326.

31. Decision Resources, Inc. DRG Formulary Lookup. https://lookup.decisionresourcesgroup.com/. Published 2016. Accessed January 25, 2016.

32. GoodRx, Inc. http://www.goodrx.com/. Published 2016. Accessed January 25, 2016.33. Drug Price Search. https://www.rxpricequotes.com/default.aspx. Accessed

January 25, 2016.

JOURNAL MSMA 103

P R E S I D E N T ' S P A G E

Colon Cancer

Circa 1974: A 58-year-old white male who smokes three packs per day unfiltered and no significant previous primary care management presents to King’s Daughters Hospital in Greenville for elective partial colectomy. He has been diagnosed with a large sigmoid tumor after rigid proctoscopy for persistent rectal bleeding. It is discovered at the time of surgery that the cancer is widely disseminated,

and there are no treatment options. The patient never leaves the hospital and is dead within two weeks. The patient is my father, and at the time I was age 14.

Fast forward to 2014: I have my screening colonoscopy four years late. (Four years late because my father being diagnosed at age 58, much less dying at 58, with colon cancer means that my screening should begin ten years before his age of diagnosis or at age 50, whichever is younger.) For me age 48 but of course I'm the “invincible physician” so those rules don't apply to me. Right? Wrong! I dodged a bullet, and not just one bullet but seven: seven adenomatous polyps, any one of which could

THERE WAS LITTLE UNDERSTANDING OR ACCESS TO PRIMARY CARE PHYSICIANS FOR ADULTS IN THE

MISSISSIPPI DELTA AMONG THE WORKING POOR IN THE 1970S WHO COULD EDUCATE AND ENCOURAGE HIM

TO BE SCREENED. IN THE 1970s, THE TECHNOLOGY HAD ADVANCED TO THE FLEXIBLE STAGE BUT SCREENING WAS STILL NOT READILY ACCESSIBLE TO THE WORKING POOR.

have become malignant down the road or at some point. I’m sure that is what happened to my father, but he did not have the benefit of my world. He lived in a world that encouraged smoking his entire adult life. There was little understanding of or access to primary care physicians for adults in the Mississippi Delta among the working poor in the 1970s who

could educate and encourage him to be screened. In the 1970s, the technology had advanced to the flexible stage but screening was still not readily accessible to the working poor. My father even had to undergo a rigid proctoscope for his procedure – for crying out loud.

These facts were all great challenges facing my father which eventually led to his death at a relatively young age. When I reflect on these hurdles he faced, I become ashamed that I foolishly risked my life, and all of its concomitant blessings, by delaying my screening for four years. I am ashamed that I was too busy to be inconvenienced to take advantage of modem preps, techniques, anesthesia, and technology available to me – not available to him.

CONSIDER HOW MANY PEOPLE, PATIENTS, AND LOVED ONES DEPEND UPON YOU AND NEED YOU TO BE ALIVE AND WELL. DON’T LET THEM DOWN.

GO GET YOUR SCREENING.

So, I write this column to all of my colleagues of a certain age who are in need of their colorectal cancer screening. Yes, I know that you are busy. I know that it’s inconvenient to do the prep, and take the time off, and yada yada yada... Instead, think about how important your medical education and training is, your years of practice experience are, and how hard you have worked to achieve what you have done. Consider how many people, patients, and loved ones depend upon you and need you to be alive and well. Don’t let them down. Go get your screening.

Truly, I write this column in memory of my father as an acknowledgement that though he was a casualty of colon cancer, I need not be. I know that he would be greatly disappointed in me should I foolishly show such disregard with my life or disrespect for his life as to not follow proper medical screening guidelines ever again.

DANIEL P. EDNEY, MD

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