Colon, Rectum & Anus, Part II

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Vol 41 | 5 | 2015

S E L E C T E D R E A DI NG S i n G E N E R A L S U RG E RY

Colon, Rectum & Anus, Part II

Vol 41 | 5 | 2015

The Genetic & Molecular Biology of Colon Cancer

Screening for Cancer Prevention & Early Diagnosis

Management of Complicated Colon Cancer

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page 10

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SE L EC T ED R E A DI NGS in GE N E R A L SU RGE RY

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A MER IC A N COLL EGE OF SURGEONS

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AMERICAN COLLEGE OF SURGEONS  |  DIVISION OF EDUCATION Blended Surgical Education and Training for Life

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Editor in chief

Editorial and business offices

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Lewis Flint, MD, FACS

ACS-SRGS

Visit www.facs.org/publications/srgs for order information. Prepayment in U.S. dollars is required to activate a subscription.

ACS steering committee L. D. Britt, MD, MPH, FACS, chair Ajit K. Sachdeva, MD, FACS, FRCSC Patrice Gabler Blair, MPH

Editorial board Nita Ahuja, MD, FACS, The Johns Hopkins Medical Institutions, Baltimore, MD L. D. Britt, MD, MPH, FACS, Eastern Virginia Medical School, Norfolk, VA Ara Darzi, MD, FACS, FRCS(Eng), KBE, FMedSci, Imperial College of London, London, UK Karen Deveney, MD, FACS, Oregon Health and Science University, Portland, OR Michael B. Edye, MD, FACS, University of Western Sydney, Seven Hills, Australia Jean C. Emond, MD, FACS, Columbia University Medical Center/New YorkPresbyterian Hospital, New York, NY John Ferrara, MD, FACS, Virginia Tech Carilion School of Medicine, Roanoke, VA Donald E. Fry, MD, FACS, Michael Pine & Associates, Chicago, IL Amy L. Halverson, MD, FACS, Northwestern Memorial Hospital, Chicago, IL Tyler G. Hughes, MD, FACS, Memorial Hospital, McPherson, KS Roger Keith, MD, FACS, University of Saskatchewan, Saskatoon, Canada Solly Mizrahi, MD, FACS, Soroka Medical Center, Beer Sheva, Israel Chandrajit Premanand Raut, MD, MSc, FACS, Brigham and Women’s Hospital, Boston, MA Raul J. Rosenthal, MD, FACS, Cleveland Clinic Florida, Weston, FL Ajit K. Sachdeva, MD, FACS, FRCSC, American College of Surgeons, Chicago, IL Eduardo de Santibañes, MD, PhD, FACS, Instituto Universitario del Hospital Italiano de Buenos Aires, Buenos Aires, Argentina Murray Shames, MD, FACS, University of South Florida, Tampa, FL Nathaniel J. Soper, MD, FACS, Northwestern Memorial Hospital, Chicago, IL Steven Steinberg, MD, FACS, The Ohio State University Hospitals, Columbus, OH Christopher B. Weldon, MD, PhD, FACS, Children’s Hospital Boston, Boston, MA Steven D. Wexner, MD, PhD(Hon), FACS, FRCS, FRCS(Ed), Cleveland Clinic Florida, Weston, FL

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The American College of Surgeons is a scientific and educational organization of surgeons that was founded in 1913 to raise the standards of surgical practice and improve the quality of care for surgical patients. The College is dedicated to the ethical and competent practice of surgery. Its achievements have significantly influenced the course of scientific surgery in America and have established it as an important advocate for all surgical patients. The College has more than 80,000 members and is the largest organization of surgeons in the world.

ACS disclosure policy In accordance with ACCME accreditation criteria, ACS must ensure that anyone in a position to control the content of SRGS has disclosed all relevant financial relationships with any commercial interest. Members of the SRGS editorial board and those providing editorial assistance are required to disclose all financial relationships. All reported conflicts are managed by a designated official to ensure bias-free content. However, if you perceive a bias, please contact us at [email protected]. The following relationships were disclosed in 2015: Nita Ahuja, MD, FACS, has disclosed a commercial interest in Astea and Celgene; Ara Darzi, MD, FACS, FRCS(Eng), KBE, FMedSci has disclosed a commercial interest in G.E. Healthymagination; Donald E. Fry, MD, FACS, had disclosed a commercial interest in CareFusion, Ethicon, IrriMax Corporation, and Merck; Raul J. Rosenthal, MD, FACS, has disclosed a commercial interest in Covidien, Ethicon, and STORZ; Murray Shames, MD, FACS, has disclosed a commercial interest in Cook, Gore, and Medtronic; Steven D. Wexner, MD, PhD(Hon), FACS, FRCS, FRCS(Ed), has disclosed a commercial interest in Asana Medical, CareFusion, Covidien, CRH Medical, Edwards LifeSciences, EZ Surgical, GI View Ltd., Incontinence Devices, Inc., Intuitive Surgical, KARL STORZ EndoscopyAmerica, Inc., LifeBond, Mederi Therapeutics, Medtronic, NeatStitch, Novadaq, novoGI, Precision Therapeutics, Renew Medical, and Unique Surgical Innovations, LLC.

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Continuing medical education

Statement of purpose

Accreditation The American College of Surgeons is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Selected Readings in General Surgery (SRGS) is a topic oriented, in-depth review of the field of general surgery presented eight times annually as an educational offering of the Division of Education of the American College of Surgeons. The mission of the Division of Education is to improve the quality of surgical care through lifelong learning, based on educational programs and products designed to enhance the competence or performance of practicing surgeons, surgery residents, and members of the surgical team. The intent of the publication is to analyze relevant medical literature to give the surgeon the knowledge necessary to practice state-of-the-art surgery. To accomplish this goal, the editor selects 100–125 pertinent articles from the literature for each issue. Each article is reviewed and an overview is written that places the content of these articles in the perspective of the best, day-to-day, clinical practice. In addition to the overview, 12–18 fulltext articles are reprinted in each issue.

CME credit The American College of Surgeons designates this enduring material for a maximum of 10 AMA PRA Category 1 Credits.™* Physicians should claim only the credit commensurate with the extent of their participation in the activity. *Of the AMA PRA Category 1 Credits™ listed above, a maximum of 10 credits meet the requirements for Self-Assessment. Learning objectives This activity is designed for general surgeons, surgical residents, and allied professionals. Regular reading of SRGS should enable learners to: • Maintain an excellent knowledge base in all areas of general surgery • Develop comparative and critical literature reading skills • Apply newly acquired knowledge to surgical practice • Prepare effectively for recertification exams Additional information at www.facs.org/publications/srgs/cme

Maintenance of certification The American Board of Surgery (ABS) recognizes SRGS as a resource for surgeons enrolled in its Maintenance of Certification (MOC) program. Successful completion of the SRGS program fulfills MOC Part 2 requirements that focus on lifelong learning and self-assessment. ACS in cooperation with ABS has created a process wherein ACS members can directly submit their ACS CME transcript to the ABS for MOC purposes. For more information, go to www.facs.org, click Member Login and enter your ACS user name and password. Then, go to My Profile, My CME, and click on “Send Credit to ABS.” For information on ABS’s MOC requirements, go to http://absurgery.org and click on “Maintenance of Certification (MOC)” or e-mail [email protected].

medical evidence evaluation, surgical education, outcomes research, standard setting, and performance improvement. SRGS is a unique resource because the overview and selected full-text articles provide the reader with the most valuable and pertinent content illuminated with informed opinion and critique. Unnecessary material is eliminated. SRGS does not present itself as infallible and the editorin-chief takes responsibility for the content that appears in each issue. The editor-in-chief and the editorial board recognize that there is no such thing as the “average” surgical patient, and that the information in the literature must be interpreted in the light of the clinical presentation of each individual patient.

Copyright Material printed in SRGS is covered by copyright law. The overview and CME tests are copyrights of the American College of Surgeons. Permission has been obtained from individual journal publishers to reprint articles that appear in SRGS. Copying all or portions of this journal for distribution to a group practice, residency program, university, hospital, or colleague is strictly prohibited.

The overview is compiled with the assistance of an 18-member, international board of editors who are experts in the various focus areas that comprise the specialty of surgery. In addition, the editorial board has representation and expertise in such important fields as

© 2015 American College of Surgeons All rights reserved

2015 SRGS Publishing Schedule Title

Volume/Issue

Publication Date

Biliary Tract & Pancreas, Part II

V41N1

Published

Small Intestine

V41N2

Published

Endocrine Surgery

V41N3

Published

Colon, Rectum & Anus, Part I

V41N4

Published

Colon, Rectum & Anus, Part II

V41N5

Published

Colon, Rectum & Anus, Part III

V41N6

September

Hernia

V41N7

October

Rural Surgery

V41N8

December

Visit www.facs.org/publications/srgs/issues/upcoming for a list of previously published topics and next year’s topics.

Questions about ACS CME can be e-mailed to [email protected] or call 866-918-4799.

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Vol 41 | 5 | 2015

Table of Contents Literature Overview

COLON, REC TUM & ANUS, PART II VOLUME 41 | 5 | 2015



Editor in Chief: Lewis Flint, MD, FACS Associate Editor: Michael McGee, MD, FACS

CME Pretest.................................................. iv Introduction................................................... 1

Diagnosis & Staging of Colon Cancer.........................................21 Clinical Diagnosis

The Genetic & Molecular Biology of Colon Cancer........................................... 2

Laboratory & Imaging Diagnosis

Colorectal Cancer Risk Factors............. 3

Preoperative Preparation for Patients with Colon Cancer

Gender & Ethnicity

Clinical & Pathologic Staging Systems for Colorectal Cancer Preoperative Risk Assessment Enhanced Recovery after Surgery

Obesity & Metabolic Syndrome

Operative Management of Colon Cancer........................................ 29

Smoking Alcohol Consumption Surviving Colorectal Cancer

Local Excision of Colorectal Cancers

Prevention of Colon Cancer.................... 6

Lymphadenectomy Blood Transfusion

Adenomatous Polyps

Anastomotic Leak

Nutrients

Laparascopic Colon Resection for Cancer

Red Meat

The Elderly Patient with Colon Cancer

Estrogen

Patient Follow-Up after Successful Surgery for Colon Cancer

Statins & Physical Activity Other Preventive Measures for Colon Cancer

Screening for Cancer Prevention & Early Diagnosis......................................10 Screening for Early Detection of Colorectal Neoplasia Screening with Endoscopy Controversies about the Efficacy of Endoscopic Screening Imaging Studies as Screening & Surveillance Tools

Management of Complicated Colon Cancer.............................................. 36 Colonic Stenting Perforated Colon Cancer Tumor Extension to Adjacent Organs Synchronous Metastatic Disease Chemotherapy for Colon Cancer

Fecal Testing

Rectal Cancer............................................. 39

Familial or Genetically Determined Colorectal Neoplasia...............................18

Chemotherapy & Radiation Therapy for Rectal Cancer

Familial Adenomatous Polyposis

Anal Cancer................................................. 45

Colorectal Cancer Surveillance Guidelines for Patients with IBD

Conclusion................................................... 46

Young-Onset Colorectal Cancer

Operative Management of Rectal Cancer

References....................................................47

Surveillance after Treatment of Colorectal Neoplasia

CME Posttest............................................. 53 Recommended Reading........................ 58 American College of Surgeons  www.facs.org/publications/srgs 

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CME Pretest

COLON, REC TUM & ANUS, PART II VOLUME 41 | 5 | 2015

To earn CME credit, completing the pretest is a mandatory requirement. The pretest should be completed BEFORE reading the overview and taking the posttest. Both tests must be completed online at www.facs.org/publications/srgs/cme.

1. All of the following statements concerning

colorectal neoplasia are true except which one? a) The proportion of patients diagnosed with colorectal cancer before age 50 is increasing b) Most patients diagnosed with colorectal cancer are in the sixth and seventh decades of life c) Patients with ulcerative colitis have a reduced risk for colorectal cancer d) Familial adenomatous polyposis and Lynch syndrome are associated with an increased risk for colorectal cancer. e) Endoscopic screening reduces incidence and mortality of colorectal cancer

4. Which of the following statements is

true regarding the role of estrogen in suppressing colorectal neoplasia? a) Estrogen receptor alpha was first recovered from rodent kidney tissue b) Estrogen receptor beta is most plentiful in rodent small intestine c) Women have a lower risk of right colon neoplasia than men d) Estrogen suppresses neoplastic changes and enhances apoptosis in colon cancer cell lines e) Estrogen is a proinflammatory hormone 5. All of the following are factors that increase the

2. Based on current scientific data, what

risk of colorectal neoplasia except which one?

cells originate the adenoma-carcinoma sequence in colorectal neoplasia?

a) Alcohol intake greater than 5 drinks per day b) Cigarette smoking

a) Stromal cells

c) Hyperinsulinemia

b) Aberrant crypt foci

d) Obesity

c) Dendritic cells

e) Red meat intake

d) Macrophages e) Apical mucosal epithelial cells

6. Which of the following is true regarding

3. All of the following statements regarding

aberrant crypt foci are true except which one?

trials of cyclooxygenase-2 (COX-2) inhibitors for prevention of colorectal neoplasia? a) Suppression of inflammation is not useful for prevention of colorectal neoplasia

a) Aberrant crypt foci are precursor lesions that progress to colon neoplasia in experimental animals b) Aberrant crypt foci have been discovered in colon tissue resected for treatment of colon cancer in humans c) Aberrant crypt foci cells rapidly progress to colon neoplasia in experimental animals treated with aspirin d) Aberrant crypt foci cells are larger than normal crypt cells

b) Severe upper gastrointestinal bleeding is a common side effect of COX-2 inhibitors c) Adverse cardiovascular events observed in patients taking COX-2 inhibitors limit the usefulness of the drugs d) COX-2 inhibition accelerates the growth of adenomatous polyps e) Hypotension was a common side effect of COX-2 inhibitor drugs

e) Aberrant crypt foci cells stain darker than normal crypt cells

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Pretest |

7. All of the following are acceptable screening

tests for colorectal cancer except which one? a) Colonoscopy b) Flexible sigmoidoscopy

COLON, REC TUM & ANUS, PAR T II

12. Practice guidelines for the management of

colon cancer recommend what minimum number of harvested lymph nodes in the resected colon specimen?

c) Immunohistochemical analysis for occult fecal blood

a) 10

d) Fecal DNA testing

c) 8

e) Blood analysis for circulating cancer cells

d) 15

b) 12

e) 24 8. Practice guidelines recommend

repeat screening colonoscopy at what interval following a negative index screening colonoscopy?

13. Which of the following is true regarding

patients treated with colectomy for colon cancer where 12 or more lymph nodes are recovered in the resected specimen?

a) 2 years b) 1 year

a) These patients more often require colostomy

c) 5 years

b) Anastomotic leak is more common in this patient group

d) 10 years

c) Pulmonary metastases are discovered more often in this patient group

e) 3 months 9. Which of the following malignancies is not

increased in patients with Lynch syndrome?

d) Survival is improved in this patient group compared to patients who have fewer than 12 nodes harvested e) Patients with 12 or more lymph nodes recovered are more likely to be younger than 50 years of age

a) Meningioma b) Endometrial cancer c) Ovarian cancer d) Skin cancer

14. Overall 5-year survival for patients with

colon cancer treated with protocols that require an optimum lymph node harvest is?

e) Colon cancer 10. Which of the following diseases

a) 50%

increase colon cancer risk?

b) 44%

a) Duodenal ulcer disease

c) 78%

b) Chronic obstructive pulmonary disease

d) 64%

c) Recurrent anorectal abscess

e) 38%

d) Crohn colitis 15. Laparoscopic colectomy for colon

e) Irritable bowel syndrome 11. Which of the following tests is recommended

cancer is associated with all of the following except which one?

prior to operation for colon cancer?

a) Longer operative duration

a) Arterial carbon dioxide tension

b) Increased risk for transfusion

b) Echocardiography

c) Decreased use of narcotic analgesia

c) CEA level

d) Shorter overall recovery time

d) Glomerular filtration rate

e) Oncologic effectiveness that is equivalent to open operation

e) Absolute lymphocyte count

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16. Which of the following statements is true

19. The most useful first-line imaging

regarding perforated colon cancer?

study for staging rectal cancer is?

a) There is consistent recovery of viable malignant cells from intestinal fluid

a) CT imaging

b) Long-term survival is less than 20%

c) Magnetic resonance imaging

c) Operative mortality is greater than 10%

b) Positron emission tomography d) Barium enema

d) Perforation of colon cancer should not be treated with urgent operation

e) Endorectal ultrasound

e) Perforation of the cecum remote from the primary tumor is uniformly fatal

20. Which of the following infections

cause anal cancer?

17. Each of the following statements regarding

colorectal cancer extending into adjacent extracolonic tissue is true except which one? a) En bloc resection of the tumor and all involved adjacent tissue is the recommended approach b) Long-term outcomes are dismal and unrelated to tumor stage c) Operative and perioperative complication rates are not increased so long as tumor perforation does not occur

a) C. difficile colitis b) Human immunodeficiency virus infection c) Human papillomavirus infection d) E. coli enteritis e) Chlamydia infection © 2015 American College of Surgeons

d) Rectal cancers extending into adjacent tissue have an increased risk of local recurrence e) CT imaging is useful for determining the extent of adjacent tissue invasion 18. Which of the following statements

regarding anastomotic leak is true? a) Anastomotic leak does not increase postoperative morbidity b) Anastomotic leak testing is not helpful for detecting potential leakage c) Anastomotic leak is associated with decreased overall survival d) Anastomotic leak is not associated with an increased risk of local tumor recurrence e) Anastomotic leak rates are not diminished by the use of temporary fecal diversion

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Vol 41 | 5 | 2015

Introduction

COLON, REC TUM & ANUS, PART II VOLUME 41 | 5 | 2015

W

elcome to Selected Readings in General Surgery (SRGS). This issue is the second in a three-part series discussing surgical conditions of the colon, rectum, and anus, and will specifically address neoplastic diseases of this region. Globally, colorectal cancer is among the top three diagnoses of malignant disease, with rankings varying depending on the country furnishing the population-based data. Colorectal cancer-related mortality has declined over time because of two primary factors: an improved understanding of the malignant potential of colorectal adenomas, and the implementation of programs for the prevention of cancer through early detection (such as fecal blood analysis) and the removal of premalignant lesions. Refinements in surgical techniques and the use of effective adjuvant and neoadjuvant chemotherapy have also helped reduce mortality rates. Despite these encouraging trends, nearly half of new patients with colorectal cancer present to general surgeons with advanced, clinically symptomatic disease. Most patients presenting with colorectal cancer are in their sixth and seventh decades of life, but the proportion of patients presenting with symptomatic advanced stages of this disease is larger among patients under 50 years; young patients presenting with colorectal cancer may have familial or genetic causes contributing to cancer development. Recognition of this fact has led to progress in the areas of genetic and molecular diagnosis of hereditary, genetically determined colorectal cancer, and many of the discoveries in this area have led to molecular testing of blood and fecal matter for specific genetic and molecular patterns that can assist the decision-making process for neoadjuvant and adjuvant therapies; fittingly, the initial sections of this overview will cover general aspects of colorectal cancer, including the epidemiology of colorectal cancer and the genetic and molecular changes that are associated with the development of colorectal malignancy. We will also discuss articles and clinical practice guidelines that provide guidance for the diagnosis and management of colon, rectal, and anal cancer (including data on the management of complicated presentations of colon cancer) as well as review guidelines for screening patients who are at an increased risk for developing colon cancer, data on the effectiveness of screening for cancer prevention and early diagnosis, current measures for early detection of colorectal neoplasia, prospects for prevention of benign and malignant neoplasms of the colon and rectum, and the uses of neoadjuvant and adjuvant chemotherapy and radiation therapy. This overview will also highlight differences in the management of colon cancer, rectal cancer, and anal cancer: in these sections, information on preoperative management, technical aspects of the operative procedures, and postoperative care will be presented. There has been recent emphasis on the importance of enhanced recovery pathways that can be implemented to reduce perioperative morbidity and lower healthcare costs; articles that present clear descriptions of the characteristics of these programs and highlight key features of successful program will be reviewed. Mucosal dysplasia can progress to malignant disease, and patients with inflammatory bowel disease (IBD) involving the colon are a high-risk group for development of mucosal dysplasia; discussions on the management of patients with colonic inflammatory disease will begin in this issue, and will be continued in greater detail in the third issue of this series, which will focus on inflammatory conditions of the colon and rectum. We will close this overview with information related to the diagnosis, staging, and operative management of rectal cancer as well as articles highlighting the important differences in the causal factors and treatment approaches for patients with anal cancer. I owe a continuing debt of gratitude to Michael McGee, MD, FACS, of Northwestern University Feinberg School of Medicine for his assistance in gathering articles to be reviewed in this series dealing with surgical conditions of the colon, rectum, and anus.

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Vol 41 | 5 | 2015

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The Genetic & Molecular Biology of Colon Cancer |

The Genetic & Molecular Biology of Colon Cancer Colorectal cancer is the third most common diagnosis of cancer and the fourth leading cause of cancer-related deaths. An overview of the clinical problem of colorectal cancer was presented in an article by Brenner and coauthors1 in Lancet, 2014. The authors presented epidemiologic data on the global incidence of colorectal cancer. They noted that 1.2 million new cases of colorectal cancer are diagnosed annually worldwide; each year, there are approximately 600,000 deaths from the disease. The median age at diagnosis is 70 years, according to data cited by the author, and men are more commonly diagnosed than women, although certain types of colon cancer (including tumors arising from sessile serrated polyps in the proximal colon) are more common in women. Brenner and colleagues stated that colorectal cancer is diagnosed most frequently in North American and Europe. Dietary factors may contribute to this high incidence: the recent increases in incidence of colorectal cancer in Spain have been linked to the adoption of diets similar in composition to those in Europe and North America. The association of dietary factors with increased (and decreased) risk of colorectal cancer will be discussed later in the overview. Brenner and coauthors cited data from studies of twins suggesting that more than one-third of colorectal cancers may have an associated hereditary component. Cancers that arise in patients with documented hereditary colon cancer syndromes (Lynch syndrome and familial adenomatous polyposis) account for less than 5% of colorectal cancer diagnoses. The inherited colorectal cancer syndromes are associated with the inactivation of tumor suppressor and DNA repair genes. Both inherited colorectal cancer syndromes are autosomal dominant disorders; Lynch syndrome cancers have high mismatch repair deficiency, while familial adenomatous polyposis tumors follow the typical adenomatous polyp-carcinoma sequence. Brenner and associates also noted that a number of genome-wide association studies have disclosed a significant number of single-nucleotide polymorphisms

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in colorectal cancer tissue, but available data indicate that these do not contribute significantly to the risk of colorectal cancer development or to prognosis. There are important contributions of genetic alterations to the adenoma-carcinoma progression that is thought to be a central mechanism for the development of colorectal cancer. The adenomatous polyposis coli (APC) gene is a tumor-suppressing gene that is inactivated as an early genetic event in the polyp-cancer sequence. This event is thought to occur in 70% or more of colorectal cancers. Other important genetic mutations in the polypcancer sequence include inactivation of the TP53 tumor suppressor gene and activation of the KRAS oncogene. The authors noted that 15% of colon cancers develop as a consequence of alterations in epigenetic molecular mechanisms. Examples of these include the lesions that develop from serrated sessile adenomatous polyps that arise in the proximal colon. This subtype of colorectal cancer is characterized by C-phosphatidyl-G bond (CpG) island methylator phenotype and activating mutations of the BRAF gene. An article reviewing the epigenetic phenomena that are important in the initiation and progression of colorectal cancer was presented by Goel and Boland2 in Gastroenterology, 2012. They noted that research into the molecular mechanisms that contribute to the development of colorectal cancer has moved from a focus on DNA sequence point mutations such as those involving the KRAS, P53, and SMAD4 genes to an emphasis on epigenetic phenomena. Modifications of gene expression that occur because of modified interactions between the regulatory portions of DNA or through alterations in messenger RNAs (mRNAs) that are not associated with changes in DNA sequence are examples of these epigenetic phenomena. Brenner and coauthors1 noted that the CpG methylator phenotype was an important molecular alteration in colorectal cancer. Goel and Boland2 emphasized that the clusters of CpG elements are not encountered frequently in the genetic sequence but, when present, they are likely to represent regulatory elements. Recent research cited by the authors has shown that hypermethylation or hypomethylation of CpG islands can influence the development and progression of malignant changes in cells. The hypermethylation phenotype of CpG islands is

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Vol 41 | 5 | 2015

Colorectal Cancer Risk Factors |

termed CIMP. CIMP changes are important mediators of the colorectal cancers that arise from serrated sessile polyps located in the proximal colon according to data cited by Goel and Boland. Research focused on MLH1, a DNA mismatch repair gene that is altered in 40% of patients with Lynch syndrome. Hypermethylation of this gene occurs in all instances of colorectal cancer that have alterations of the MLH1 gene that are not associated with the Lynch syndrome. Goel and Boland note that analyses of colorectal cancer tissue can characterize tumors as CIMP-high, CIMP-low, and CIMP-0. CIMP-high cancers are associated with BRAF mutations and occur mainly in women, while CIMP-low tumors are associated with KRAS mutations and occur in men. Another methylation-associated alteration observed in patients with colorectal cancer involves acetylation of histones that regulate chromatin structure and gene expression. Hyperacetylated histones are involved in gene activation and this alteration results in an environment that permits access of transcription factors to the DNA. Hypoacetylation impedes access of these factors. Research has shown that these changes are associated with the silencing of tumor suppressor genes, and because of this, they may contribute to progression of changes in cells that lead to a malignant cell phenotype. Additional research cited by Goel and Boland confirmed that DNA methylation and histone modifications act synergistically to promote malignant cellular changes. The authors reported an additional epigenetic alteration that contributes to the development and progression of colorectal cancer. This category involves microRNAs that can act as tumor suppressors or tumor promoters. The authors cited data from research studies that document the ability of microRNA signatures to identify microsatellite unstable colorectal cancers and microsatellite stable colorectal cancers with sufficient accuracy to be useful clinically. This diagnostic test could conceivably identify colorectal cancers as either Lynch syndrome-associated or sporadic depending upon the microRNA signature. Additional studies have shown the microRNAs are important in the initial alteration of the APC gene that leads to the development of adenomatous polyps. Assessment of DNA methylation and microRNA signatures is possible in assays of blood, fecal material and urine. These tests can be useful for the detection

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of colorectal cancers, assessment of prognosis, and determining the patterns of response of the tumor to chemotherapeutic agents. The authors noted that several pharmacologic agents that alter DNA methylation and microRNA patterns are already in use for the management of patients with colorectal cancer. An example of a DNA demethylating drug is the chemotherapeutic agent decitabine. Drugs that are histone deacetylase (HDAC) inhibitors may work synergistically with other chemotherapeutic agents such as 5-fluorouracil to increase the antitumor effect of chemotherapy regimens; vorinostat is an example of this type of drug. Favorable results have been obtained in trials of these drugs in patients with a variety of solid tumors including colorectal cancers. The authors emphasized that experience with these agents is at an early stage, but that progress in this area could lead to effective adjuvant and possibly neoadjuvant regimens for patients with colorectal cancer. Surgeons are encouraged to review available literature for signs of progress in this area.

Colorectal Cancer Risk Factors As previously mentioned by Brenner and coauthors1, male gender and advanced age are the two most prominent risk factors for colorectal cancer. Additional risk factors identified in data cited by the authors include a family history of colorectal cancer, obesity (and obesity-related conditions), diabetes, smoking, excessive alcohol use, high consumption of red and processed meat, and inflammatory bowel disease (IBD). Of all these additional risk factors, the strongest impact on risk (which is greater than a 2-fold increase) was noted in patients with first-degree relatives with colorectal cancer and in patients with IBD.

Gender & Ethnicity The relationship of gender and ethnicity to colorectal neoplasia risk was analyzed in an article by Murphy and coauthors3 in the International Journal of Cancer, 2011. These authors examined data from the Surveillance,

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Colorectal Cancer Risk Factors |

COLON, REC TUM & ANUS, PAR T II

Epidemiology, and End Results (SEER) database for the interval from 1992 to 2006. Male to female incidence ratios were evaluated for racial and ethnic groups and for anatomic sites within the colon and rectum. The data disclosed that colorectal cancer incidence was highest for African Americans and lowest for Hispanics. In addition, the male to female incidence ratio increased as the site of colorectal cancer varied from proximal to distal colon. The authors also noted that distal colorectal cancer incidence is rising in American Indian and Alaska native populations—this is a worrisome finding because endoscopic screening and fecal occult blood testing are used less often in these groups. The finding of a high incidence of colorectal cancer in black males may be the result of the interplay of risk factors (particularly diabetes) and the lack of available healthcare resources for this particular group. The declining colorectal neoplasia risk for women in anatomic sites (other than in the right colon) might be the result of the differing embryonic origins of the proximal and distal colon, or from the influence of female hormones.

Obesity & Metabolic Syndrome As previously mentioned, obesity and obesity-related conditions, such as hyperinsulinemia, insulin resistance, and metabolic syndrome, are also significant colorectal risk factors. The relationship between body weight and colorectal cancer risk was the focus of a meta-analysis by Larsson and Volk4 in the American Journal of Clinical Nutrition, 2007. Thirty prospective analyses of sufficient quality were identified. The relationship between obesity, as measured by body mass index (BMI), and increased colorectal cancer risk was not strong overall, but was still statistically significant. The risk related to BMI was stronger for men and for cancers located in the distal colon and rectum. A documented risk increase was shown only for women who did not take postmenopausal hormones. The strongest associations in men were for adiposity distributions commonly associated with metabolic syndrome (larger waist circumferences and higher waist to hip ratios). Additional features of metabolic syndrome, such as hypertriglyceridemia and elevated C-reactive protein, contributed to a metabolic environment that facilitated colonocyte proliferation. Lastly, the authors speculated

4

that the hypersecretion of insulin and type 2 diabetes (which are also associated with metabolic syndrome) disrupt the insulin-like growth factor control mechanisms and cause it to increase; elevated insulin-like growth factor levels are associated with increased colorectal cancer risk. The impact of the metabolic syndrome on colorectal cancer risk was also examined in an article by Siddiqui5 in the American Journal of the Medical Sciences, 2011. The author presented a useful diagram of possible relationships between the features of metabolic syndrome and the proliferation of colonic mucosal cells. Circulating factors associated with obesity may contribute to an increased risk for colorectal cancer, and Siddiqui noted the association between leptin—a substance secreted by adipose cells—and increased colorectal cancer risk. Additionally, hypertriglyceridemia may contribute to an intracolonic environment that favors mucosal proliferation by altering concentrations of fecal bile acids; as previously mentioned, hyperinsulinemia and hypersecretion of insulin are associated with a persistent low-grade inflammatory state that favors development of colorectal neoplasms. The author concluded by summarizing available retrospective and cohort data that suggested, but did not prove, an association between the metabolic syndrome and increased colorectal cancer risk. Additional data on the association of disordered insulin metabolism and colorectal cancer risk were presented in a meta-analysis by Pisani6 in Archives of Physiology and Biochemistry, 2008. The authors identified several studies documenting an association between elevated levels of Cpeptide (a marker of insulin hypersecretion), a persistent inflammatory state, and an increased colorectal cancer risk; however, the authors noted that all studies documenting this increased risk are retrospective. Another meta-analysis by Mulholland and coauthors7 failed to document an association between glycemic load, glycemic index, and colorectal neoplasia. Although the metabolic environment produced by disordered insulin metabolism may favor colorectal mucosal proliferation, data to document a significant increased risk that is specifically associated with hypersecretion of insulin are not available currently. Low levels of physical activity more than likely contribute to an overall health status that increases the risk of mortality from malignant disease and cardiovascu-

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lar events. An article by Vrieling and Kampman8 in the American Journal of Clinical Nutrition, 2010, examined available studies to determine if obesity, diet, physical activity, and nutrients influenced the risk for recurrence and death after a colorectal cancer diagnosis. In a previously mentioned article, Siddiqui5 noted that diabetic patients are more likely to have low levels of physical activity, which may make them vulnerable to colorectal cancer development; similarly, Vrieling and Kampman8 concluded that obesity and low levels of physical activity were weakly associated with increased all-cause mortality after the diagnosis of colorectal cancer. An association with other disease features, such as cancer-specific mortality, could not be convincingly shown.

Smoking A meta-analysis of studies relating the risk of colorectal cancer and cigarette smoking is by Boterri and coauthors9 in JAMA, 2008. The authors documented a weak, but statistically significant, increase in risk when data comparing “never” smokers and “current” smokers were analyzed; a statistically significant increase in colorectal cancer risk and mortality was demonstrated only in individuals who had smoked for more than 30 years. A dose-response relationship was established, indicating that increased intervals of smoking were linearly related to increased cancer incidences as well as mortality. This association of increased incidence and mortality from colorectal cancer in smokers was stronger for rectal cancer than for colon cancer. Evidence linking cigarette smoking to an increased risk for specific molecular subtypes of colorectal cancer is reviewed by Limsui and coauthors10 in the Journal of the National Cancer Institute, 2010. The authors reviewed data from more than 37,000 participants in the Iowa Women’s Health Study. The association between cigarette smoking and colorectal cancer incidence was statistically significant for cancers demonstrating certain molecular characteristics, such as microsatellite instability, BRAF mutations, and disordered DNA methylation; no risk increases were noted for cancers not demonstrating these characteristics.

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Alcohol Consumption An article that analyzed the effect of baseline and continuing alcohol intake on risk for colorectal neoplasia is by Ferrari and coauthors11 in the International Journal of Cancer, 2007. These authors reviewed data from nearly 480,000 individuals participating in the European Prospective Investigation of Cancer and Nutrition. Baseline data on alcohol use was obtained and patients were followed for a mean of 6.2 years. Questionnaires were used to determine alcohol use at yearly intervals. The analysis revealed that both baseline and continuing alcohol intake in excess of 30 grams per day was associated with increased colorectal cancer risk; the risk was greater for cancers of the distal colon and rectum. The authors noted that the prevailing hypothesis for the contribution of alcohol intake to colorectal cancer holds that a metabolite of ethanol, acetaldehyde, is the substance that contributes to alcohol-related carcinogenesis. Acetaldehyde concentrations increase from the proximal to distal colon; this could at least partially explain the increase in the risk of distal colon lesions in alcohol users. Beer was the type of alcohol most strongly associated with neoplasia risk.

Surviving Colorectal Cancer Brenner and coauthors1 noted that long-term survival statistics have shown steady improvements in outcome for patients with colorectal cancer. Survival tends to be better in women and in younger patients, but disease stage at the time of initial diagnosis is the most important factor associated with long-term outcomes. The authors cited data from national databases in the United States that indicate a 5-year survival of more than 90% for patients with localized disease; this 5-year survival decreases to 69% for patients with spread to regional nodes, and to 12% for patients with distant metastases discovered at the time of initial diagnosis.

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Prevention of Colon Cancer As knowledge relating to the biology of adenomatous polyps and colon cancer has progressively increased, interest has turned to means of prevention. Even though few adenomatous polyps progress to malignancy, most colon cancers develop by progression of adenoma growth, dedifferentiation of adenoma mucosa, and acquisition of molecular and genetic characteristics that favor a malignant phenotype. Adenomatous polyps have, therefore, become the target of prevention trials that seek to diminish the development and progression of these lesions. In this section of the overview we discuss a selection of prevention interventions that may have practical value.

Adenomatous Polyps The conceptual basis of prevention of adenomatous polyps is discussed by Hawk and coauthors12 in Gastroenterology, 2004. The authors first addressed the molecular and genetic changes that occur in the formation of aberrant crypt foci (discussed previously). They noted that early changes include genetic alterations in APC, Bcl2, or c-myc. Changes in the processes of DNA methylation follow, and the process progresses through disruption of apoptotic processes and elaboration of factors that promote angiogenesis. The initial results are the atypical, large cells found in aberrant crypt foci. Hawk and colleagues next reviewed the challenges to effective clinical research in preventive interventions. They noted that effective endoscopic screening is likely to reduce cancer incidence and mortality. Additional data concerning trials of effective primary prevention of colorectal neoplasia is in an article by Marshall13 in Gastroenterology Clinics of North America, 2008. Marshall noted that effective prevention trials are usually case-control studies where individuals with similar baseline characteristics and similar risk profiles for development of colorectal neoplasia are assigned to an intervention. Comparisons are made over time, with individuals using a different intervention or, alternatively, no intervention. In reviewing the trials that have been

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completed, effective reduction in colorectal neoplasia risk was observed for use of dietary calcium (15% risk reduction) and aspirin 81 mg/day (19% risk reduction). Observational data have suggested a protective effect of aspirin in patients at risk for development of colorectal cancer. A randomized trial of aspirin in a group of patients at high risk for colorectal cancer (Lynch syndrome patients) was reported by Burn and coauthors14 in Lancet, 2011. In this study, 861 patients were randomized to receive 600 mg of aspirin per day or placebo. For patients who maintained full participation for two years, a 60% reduction in risk for developing colorectal cancer was observed out to more than five years of follow-up. The authors concluded that aspirin was effective for reducing cancer risk and suggested that additional studies were necessary to confirm optimal doses and dosing intervals. The observation that colorectal neoplasia risk was reduced in patients taking aspirin has stimulated interest in using other COX-2 inhibitors. The two drugs that have been evaluated are celecoxib and sulindac, and a review of the data is by Rostom and coauthors15 in Annals of Internal Medicine, 2007. Reductions of risk varied according to study design and ranged from 28% in a randomized trial to 46% in a case-control study. The authors noted that upper gastrointestinal complication and serious cardiovascular event risks are increased by up to 45% with long-term use of nonsteroidal antiinflammatory agents. Complication risk with the use of nonsteroidal antiinflammatory agents is the focus of an article by Bertagnolli16 in Lancet Oncology, 2007. The author noted that persistent inflammation is one of the basic biologic alterations leading to colorectal neoplasia. Cyclooxygenase-2 is a key enzyme in this process and for this reason, trials of NSAIDs had a strong conceptual basis. What was unexpected was the discovery of the important role played by the COX-2 enzyme system in cardiovascular integrity. Risk of a serious cardiovascular event was increased by eight-fold in one of the studies reviewed in the article. Along with this risk came a protection against colorectal neoplasia and colorectal cancer mortality that was statistically significant even in patients receiving optimum endoscopic surveillance after removal of one or more adenomatous polyps. Bertagnolli noted that additional research is needed in the identification of patients at risk

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for NSAID-related cardiovascular events. Data cited in the article indicate that patients with no prior history of cardiovascular disease had a risk of serious cardiovascular incidents of 2.1% over three years. By contrast, patients with a history of cardiovascular disease had a 3-year risk of 8.1%. Another example cited by Bertagnolli is that some patients became hypertensive while taking NSAIDS during the trial. These factors need to be considered in future trials, so that effective intervention to reduce the inflammation that contributes to colorectal neoplasia can occur without exposing patients to toxicity from the drugs.

Nutrients The time course of the adenoma-carcinoma sequence and the risk factors for development of colorectal cancer are the topic of an article by Wei and coauthors17 in the Journal of Clinical Oncology, 2010. The authors reviewed evidence from published articles that analyze the roles of risk factors for development of colorectal neoplasms. They noted that environmental factors that disrupt normal DNA synthesis may have differing effects depending on the timing of exposure and the exposure interval for the individual stimulus. An example cited by Wei and associates concerns the role of folate in the prevention of colorectal neoplasia. They cited data that supports a benefit for normal folate levels in patients with normal colonic mucosa. After the development of colonic adenomas, however, the presence of normal folate levels alters DNA synthesis in a way that accelerates the growth of adenomas and the progression to a malignant phenotype. Population-based studies have shown that normal folate reduces the risk for development of adenomas; however, once adenomas are present, folate deficiency reduces the rate of progression to cancer. These data imply that the response to folate, a substance included, by law, in various foods in the United States and a common ingredient in vitamin supplements, might have different effects on normal vs. abnormal colonic and rectal mucosal cells. Two articles from Gastroenterology, 201118,19 further analyzed this problem: in the first of these two articles, Aune and colleagues investigated the potential for a nonlinear effect of folate levels on colorectal cancer risk. Using a meta-analysis technique, the authors evaluated 19 prospective studies. They found that there was weak

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evidence for a protective effect of fruits and vegetables in amounts consistent with amounts in a normal American diet. When the data were analyzed for nonlinearity, however, the protective effects of fruits and vegetables became stronger. In the second article, Stevens and associates investigated the potential association of dietary folate intake combined with additional folic acid in the form of vitamin supplements with an increased risk for colorectal cancer. These authors used data from a national cancer prevention study involving more than 43,000 men and 56,000 women. The analysis supported the conclusion that the combination of dietary and vitamin supplement folate did not increase risk for development of colon cancer. Overall, there was a small but significant protective effect of folate intake in amounts that are common among Americans. The above two articles are discussed in an editorial in the same issue of Gastroenterology by Lee and Chan.20 The authors noted that there are several proposed mechanisms for a protective effect against the development of colon cancer by various nutrients and dietary fiber. These substances can favorably alter the microbial ecology of the colon and dilute potential injurious substances. Nutrients such as folate can provide protective effects by lowering colonic pH and facilitating the production of short-chain fatty acids. Lee and Chan continued with a summary of the history of efforts to add fruits and vegetables to American diets in order to protect against the development of colon cancer. These began with a program sponsored by the National Cancer Institute in 1991 that supported increasing the intake of fruits and vegetables to five servings per day, based on data from case control studies that suggested a protective effect of this intake level. Further data from prospective studies did not show significant protection; the recommendation was countermanded by an expert panel in 2007. Lee and Chan noted that the approach taken by Aune and coauthors18 to evaluate a nonlinear effect of fruit and vegetable intake strongly suggests that maximum protection is provided when intakes above a minimum level are consistently achieved. Their data suggest that a fruit and vegetable intake at a level equal to one apple per day would provide significant protection against the development of colorectal cancer. Lee and Chan also emphasized that any effect of a dietary or lifestyle change would provide an effect that would be modulated by other genetic and environmental factors.

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They cited data from European studies that suggest high intakes of fruits and vegetables provide protection against colorectal cancer development; they cautioned that these data are derived from a population that is genetically different from North Americans as well as from individuals exposed to environmental factors that differ from those in North America. Lee and Chan agreed that a reduction or augmentation of cancer risk can be observed depending on diet, micronutrient intake, lifestyle, and the contributions of environmental carcinogens. In their comments on the second article by Stevens and coauthors,19 Lee and Chan stressed the importance of the data presented, especially when the data are viewed in light of data from other large, population-based studies. They also supplied a particularly clear illustration of the developmental sequence of colonic adenomas and carcinomas in relation to the effects of dietary folate, and noted that the data support the conclusion that increased levels of folate associated with dietary and vitamin supplements did not increase the risk of colon cancer. The findings serve to emphasize the importance of the timing of data acquisition when judging protective or augmenting effects of dietary and other interventions. Lee and Chan noted that nutrients are likely to have different effects on established lesions compared with normal mucosa. This conclusion supports the perspective offered in the article by Wei and coauthors17, which was discussed earlier in the overview. Viewed in this light, the data cited by Lee and Chan supporting a weak or nonexistent effect of folate to reduce the frequency of recurrent adenoma formation in subjects who had previously undergone colonoscopy (a group presumably at increased risk for adenomas) is particularly important; the authors supplied a particularly clear illustration of the developmental sequence of colonic adenomas and carcinomas in relation to the effects of dietary folate. The authors concluded the editorial by stressing that despite folate having a weak protective effect against colorectal cancer development, the nutrient may have other important health effects, such as the prevention of neural tube defects and reductions in the incidence and severity of cardiovascular disease, and therefore should not be reduced in the diet.

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Red Meat Intake of red meat has been identified as one factor contributing to the development of colorectal neoplasia. This factor is the focus of an article by Alexander and Cushing21 in Obesity Reviews, 2011. The authors provide a systematic review of the literature especially focusing on 35 prospective studies. The authors began their article by reporting that a combined committee of experts provided a 2007 opinion that red meat intake was a contributing factor for colorectal cancer development; however, the literature review accompanying this statement did not indicate a strong association between colorectal cancer and red meat intake. In fact, most of the included studies did not show a statistically significant increase in colorectal cancer risk related to red meat intake. Specifically, the definition of “red meat” and the amounts of red meat intake varied substantially across the included studies. Following their statement, the above-mentioned expert committee panel recommended a weekly red meat intake that was roughly consistent with the average North American dietary intake. Alexander and Cushing next evaluated data from the 35 prospective studies selected for analysis. They emphasized the interesting finding, consistent in most of the studies, that any increased risk for development of colorectal neoplasia appears mostly for men. They further noted that the available relationship data are frequently not statistically significant and that the studies vary, with some showing an increased risk for colorectal neoplasia related to red meat intake, and others a potentially protective effect of red meat intake. Notably, there is no evidence of a dose-response relationship of red meat intake and the risk for colorectal neoplasia. The authors concluded that the weight of evidence does not support an increased risk for colorectal neoplasm related to red meat intake.

Estrogen The potential role for female hormones as a protective mechanism that reduces colorectal cancer risk is reviewed in an article by Kenelly and coauthors22 in Lancet Oncology, 2008. The authors began by reporting that the effect of female hormones on colon cancer risk has been suggested by the facts that colon cancer is more common in men than in women, and that the addition of

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postmenopausal hormone therapy in women protects against the development of colorectal neoplasia. The authors then explored the functional characteristics of the various estrogen receptors. The authors described the two varieties of estrogen receptors: ERa and ERb. Estrogen receptor alpha was first localized in rodent uterine tissue and estrogen receptor beta was localized in rodent prostate and ovary. Estrogen receptor beta was later found to be plentiful in human colonic mucosa. Evidence cited by the authors indicates that the expression of estrogen receptors is reduced in colon cancer tissue and that the magnitude of the reduction is increased linearly with tumor stage. Although a role for estrogen in carcinogenesis is suggested, there is no clear evidence for such a role in humans; further research in this area is needed. Additional data from experimental animals cited by Kenelly and coauthors indicate that ERb enhanced colonic mucosal cell proliferation. In addition, there was a loss of differentiation and suppression of apoptosis in mice without the estrogen receptor. In other experiments, estrogen has been noted to suppress proliferation and enhance apoptosis in colon cancer cell lines. All of these findings suggest a role for the estrogen receptor and estrogen as a protective factor against the development of colorectal neoplasia. The authors do caution, however, that the varied mechanisms of estrogen receptor signaling in humans and various animal species will likely complicate efforts to confirm the role of estrogen in colorectal neoplasia. An additional mechanism for the protective effect of estrogen might occur because of the antiinflammatory actions of the hormone. This aspect of the estrogen effect on colorectal neoplasia is discussed by Slattery and Fitzpatrick 23 in Cancer Prevention Research, 2009. The authors noted that the convergence of the inflammatory process, energy metabolism processes, and hormone action could influence risk for colorectal neoplasia. Data from several studies cited by the authors suggest that the antiinflammatory actions of estrogen that are mediated through suppression of interleukin-6 could interact with energy metabolism, especially as related to insulin, to suppress inflammation, a prominent feature of the changes that occur in the colonic mucosa during the adenomacarcinoma progression. The association of disorders of insulin metabolism and colorectal neoplasia is discussed in a subsequent section of the overview.

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In experimental animal data cited by the authors, convergence of inflammation, insulin metabolism, and hormonal influences that increase the risk of colorectal neoplasia have been demonstrated. These observations, consistent in laboratory animals, along with the observation that postmenopausal hormone therapy reduces colorectal neoplasia risk, support the existence of a similar relationship in humans.

Statins & Physical Activity Two additional factors thought to be protective against colorectal neoplasia are statin use for hypercholesterolemia and physical activity. Evidence for a protective effect of statin use is the focus of a meta-analysis by Bonovas and coauthors24 in the Journal of Clinical Oncology, 2007. The authors were able to identify 18 studies that reported data on more than 1.5 million individuals. A modest reduction in risk of colorectal cancer was noted for cohort studies, but this was not confirmed in case-control or prospective trials. The authors concluded that there is no convincing evidence of reduced risk for colorectal cancer in patients taking statin drugs. Evidence that physical activity protects against the development of colorectal neoplasia is reviewed in two meta-analyses by Wolin and coauthors.25,26 The two articles appeared in the British Journal of Cancer, 2009 and 2011. The analyses disclosed that exercise at a level of 21.5 metabolic equivalent (MET) hours per week was equal to one hour of brisk walking (> 2 mph) each day. Physical activity was associated with an 18% reduction in risk for colon adenoma and a 24% reduction in risk for colorectal cancer.

Other Preventive Measures for Colon Cancer Given the fact that screening is not universally applied in many areas of the world because of several factors, including patient reluctance to participate, the prevention of colon cancer might be achieved by altering diet; prevention trials are worthwhile. If adequate compliance with an effective prevention intervention is achieved, the magnitude of the benefit can be expected to be roughly equivalent to an effective endoscopic screening and surveillance program. Vol 41 | 5 | 2015

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The main preventive measures that have been supported with quality data include dietary factors (fiber, fruits, vegetables and folate, as discussed earlier), vitamins and minerals (selenium, calcium), postmenopausal hormones, and pharmacologic measures (aspirin and other NSAIDs, used alone or in combination with agents such as difluoromethylornithine).

Screening for Cancer Prevention & Early Diagnosis One factor that may contribute to the observed decreased mortality from colorectal cancer is the implementation programs for cancer prevention using endoscopic screening and early diagnosis of advanced premalignant and malignant lesions using fecal immunochemical analysis. In this section of the overview we discuss a selection of cancer screenings and tests. Large bowel cancers develop from normal colonic and rectal mucosal cells that respond to a variety of genetic and local environmental stimuli. The cells develop a series of genetic and molecular changes in the course of a decade leading to the growth of an adenomatous polyp. During an additional interval, the polyp cells develop malignant phenotypes and acquire the capability for invasion of adjacent tissue, the lymphatic system, and the microcirculation. The initial abnormality in the adenoma-carcinoma sequence is believed to be the appearance of aberrant crypt foci in the colonic mucosa. This topic was the focus of an article by Khare and coauthors27 in Methods in Molecular Biology, 2009. The authors opened their discussion by noting that aberrant crypts have been shown to be precursors to colorectal neoplasia in experimental animals. These lesions are sensitive to certain medications such as aspirin and non-steroidal anti-inflammatory agents, and the lesions rapidly regress with administration of these medications to affected experimental animals. The authors noted that human data that link the appearance of aberrant crypt foci to the subsequent development of colorectal neoplasia are scarce. They also emphasized the

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value of enhanced endoscopic visualization techniques that may increase the ability to identify and document these lesions in colonic mucosa of patients that participate in endoscopic screening programs. If studies indicate that there is progression from aberrant crypt foci to neoplasia, or if the presence of aberrant crypt foci is indicative of a neoplasia-prone colonic mucosa, more targeted endoscopic surveillance could occur in individuals at increased risk for neoplastic change. In addition, the presence of these lesions could identify patients who would be good candidates for studies of dietary and pharmacologic prevention measures. Khare and colleagues went on to note that aberrant crypt foci were identified in the excised colons of patients with colorectal cancer. The aberrant crypt foci are larger than normal crypts and the crypt cells stain darker than normal crypt cells. The crypt openings in the aberrant crypts are noncircular compared with normal crypts. The aberrant crypts identified in humans were essentially identical in histologic appearance to those noted in experimental animals. The authors emphasized that the appearance of aberrant crypts as documented in vivo during endoscopy are significantly different from crypts identified in histologic sections. This finding reinforces the importance of developing the means of identifying these lesions in human colonic mucosa during endoscopic examination. Molecular analysis of cells from aberrant crypt foci in animals and humans indicated that many of the genetic and molecular abnormalities that characterize colorectal neoplasms are present in aberrant crypt foci (the genetics and molecular characteristics of colorectal neoplasia are discussed in a later section of the overview). The number of genetic abnormalities varies, however, depending on the presence of genetic defects associated with familial cancer syndromes and whether the patient has adenomatous polyp(s) or frank carcinoma. The authors concluded by emphasizing the need for endoscopic studies of humans to document the value of identification of aberrant crypt foci.

Screening for Cancer Prevention and Early Diagnosis As mentioned previously, the recognition of the importance of the adenoma-carcinoma sequence of development of colon cancer has formed the conceptual foundation

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of various prevention and early diagnosis screening programs, resulting in a progressive decline in mortality from colorectal cancer. Currently available evidence supports the effectiveness of colonoscopy, sigmoidoscopy, and fecal testing for the detection of adenomas and early-stage cancers. Brenner and coauthors1 cited data confirming a 25% reduction in colorectal cancer mortality in patients who participated in a program of fecal occult blood testing. For patients who participated in screening programs that used flexible sigmoidoscopy, a 50% reduction in colorectal cancer mortality was observed. Flexible sigmoidoscopy was even more effective in reducing mortality for left-sided lesions. The authors noted that fecal immunochemical testing for human hemoglobin has been shown to be effective for diagnosis of both adenomas and early carcinomas. Current data cited by Brenner and associates confirm the effectiveness of annual or biannual fecal occult blood testing, flexible sigmoidoscopy every five years, and full colonoscopy every 10 years beginning at age 50. Clinical practice guidelines for colorectal cancer screening have been promulgated by the National Comprehensive Cancer Network (NCCN).28 The guidelines document is available free at www.nccn.org. The guidelines document recommends screening with endoscopy or fecal blood testing, as noted previously. Colonoscopy is recommended if the fecal blood test is positive. If an adenomatous polyp is discovered and removed, follow-up colonoscopy is recommended based on the number of polyps removed and lesion histology: repeat colonoscopy in 5–10 years is recommended for low-risk lesions or fewer than three polyps removed, and repeat colonoscopy in three years is recommended for more than three and less than 10 lesions or for high-risk histology. An article presenting data confirming the effectiveness of colonoscopy with removal of adenomatous polyps for reduction of cancer-associated mortality is by Zauber and coauthors29 in the New England Journal of Medicine, 2012. Outcomes were available for 2,602 patients who had at least one adenomatous polyp removed. Patients were followed for a median interval of more than 15 years. The observed death rate was compared with expected colorectal cancer mortality obtained from national da-

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tabases. The data analysis showed that mortality in the polyp removal group was 53% less than the expected colorectal cancer mortality. Another article confirming a significant reduction in cancer-associated mortality was presented by Baxter and coauthors30 in the Journal of Clinical Oncology, 2012. The authors queried the SEER database and compared mortality rates from colorectal cancer in patients who underwent colonoscopy with rates in control patients. The analysis showed that there was an overall 60% reduction in cancer-associated mortality in the colonoscopy group; the reduction was larger for left-sided lesions. The authors noted that the reduction in mortality may be even larger since a significant proportion of the control group underwent colonoscopy during the study period, and this would have reduced cancer-associated mortality in the control group. The authors also found that mortality reduction was greater in patients who had colonoscopy performed by gastroenterologists. The authors acknowledged a significant limitation of their study, in that the indication for the index colonoscopy was not known. This raises the question of whether the examination was done for screening or for colon-related symptoms. The observation that colonoscopy performed by gastroenterologists was more effective than examinations by other specialists does not identify whether the specialty of the examiner is more important than other factors. An article that analyzes the impact of adenoma detection rate on the risk of colorectal cancer and colorectal cancer death rates is by Corley and coauthors31 in the New England Journal of Medicine, 2014. The authors analyzed outcomes recorded in the patient database of a single integrated health system. Nearly 315,000 colonoscopies performed by 136 gastroenterologists. The authors compared risk for colorectal cancer and cancer-related death in patients according to the adenoma detection rate. They found that the adenoma detection rate varied from 7.4% to 52.5%. When the authors compared the risk of cancer or cancer-related death according to the highest versus the lowest quintile of adenoma detection rates they found that risk of developing cancer was decreased by 50% in patients from the highest quintile compared with the lowest quintile. For each 1% increase in adenoma detection rate, a 3% reduction in the risk of developing colorectal cancer was observed.

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Given the differing outcomes for patients undergoing colonoscopy by non-gastroenterologists, the question of the frequency of incomplete colonoscopy, the causes of incomplete colonoscopy, and the risk of missed lesions all become important information. An article that focuses on this aspect of colon cancer screening is by Neerincx and coauthors32 in Endoscopy, 2010. The authors noted that reported frequencies of incomplete colonoscopy (failure to reach the cecum, incomplete visualization) range from 2% to 23% of examinations. They identified 5,278 colonoscopies performed between September and December of 2005, with patients followed for at least 18 months. The data analysis showed that incomplete colonoscopy occurred in 9.7% of cases. The most common causes were looping of the endoscope and patient discomfort. An obstructing lesion was encountered in 14% of incomplete examinations. A secondary examination (CT colonography, repeat endoscopy, abdomen-pelvis computed tomography [CT] imaging, or surgery) occurred in 54% of patients. In this group, colorectal cancer or advanced adenoma was diagnosed in 4.3% of patients. The authors concluded that secondary examinations were valuable and should be recommended in each instance of incomplete colonoscopy.

Screening for Early Detection of Colorectal Neoplasia Practice guidelines for the early detection of colorectal cancer and the detection and management of adenomatous polyps were promulgated by the American Cancer Society, the multi-society task force on colorectal cancer, and the American College of Radiology, based on expert panel discussions occurring from 2006 to 2007. These were published in an article by Levin and coauthors33 in CA-A Cancer Journal for Clinicians, 2008. The authors began with a review of the current status of screening for colorectal neoplasia in the United States. The goals of cancer screening are to detect malignant lesions while they are still localized and treatment for cure can occur. Screening for the detection and removal of adenomatous polyps, which are relatively common lesions accounting for 50% of polyps detected during colonoscopy, is conducted to detect potentially dangerous advanced polyps (polyps more than 1 cm in diameter or having either dysplastic histologic changes or villous histology). The

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authors noted that most adenomatous polyps will not progress to cancer, but structural evaluations (colonoscopy, CT colonography, or flexible sigmoidoscopy plus double-contrast barium enema) are the only dependable current measures for detection. For this reason, the cost of preventing a single invasive colorectal cancer is significant. They note that data from randomized controlled trials document the reductions in cancer incidence and mortality that occur with effective screening programs. Despite this, the majority of eligible adults in the United States do not participate in any organized screening program. An article that assesses the status of screening for colorectal neoplasia in the United States is by Holden and coauthors34 in Annals of Internal Medicine, 2010. These authors conducted a systematic review of the current literature and found 116 studies of sufficient quality to be included in the analysis. They found evidence of underuse as well as overuse of screening. Examples of overuse of screening included screening of patients older than 80 years and screening of patients who had severe comorbid conditions and were, therefore, not candidates for treatment if a lesion needing treatment was discovered. The authors identified several barriers to adequate screening for certain patient groups. The most common barrier was lack of access to healthcare because of lack of health insurance: African-American and Hispanic patients were prominent in this particular group. In addition, for some patient groups, particularly Hispanic patients, there were also language barriers. Holden and colleagues found several examples of misuse of screening techniques: most commonly, practitioners conducting fecal occult blood screening on stool samples obtained at the time of digital rectal examination, rather than on specimens properly gathered at home. The authors also identified several interventions that could be implemented to improve screening, including mailed reminders to patients about fecal occult blood screening and focused conversations that educate patients about colorectal neoplasia screening. Levin and coauthors33 further emphasized that sensitivity and specificity data for individual screening tests are well established, but the effectiveness of screening programs has not been assessed. Screening tests for colorectal neoplasia fall generally into two categories: fecal tests, including fecal occult blood testing and assessments for

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exfoliated DNA, and “structural” evaluations that include endoscopy with or without supplementary imaging and CT colonography. Levin and colleagues also noted that the main barrier to participation in screening is lack of health insurance. Other significant barriers include treating physician and patient preferences and geographic factors that may limit availability of certain screening measures, such as endoscopy.

Screening with Endoscopy The practice guidelines described in the article by Levin and coauthors33 note two endoscopic procedures that are acceptable for screening in the general population: flexible sigmoidoscopy and colonoscopy. Available data indicate that these procedures are an excellent means for detection of adenomatous polyps and colorectal cancers and that screening and surveillance programs using these procedures can be expected to lower colorectal cancer incidence and mortality by detecting cancers at an early stage and permitting polypectomy for adenomatous polyps. This said, while data supporting the effectiveness of endoscopic screening are plentiful, long-term studies of benefit are awaited. Flexible sigmoidoscopy can complete an examination of the rectum and colon up to the splenic flexure if the flexible sigmoidoscope is inserted to a length of 40 cm and if there is good mechanical bowel preparation with adequate cleansing to ensure good visualization of the colon; flexible sigmoidoscopy is usually done after bowel preparation with two enemas, and the procedure is done without sedation. Available data cited by Levin and coworkers document a sensitivity of 60%–70% for detection of advanced adenomas and colorectal cancers. Although the majority of colorectal cancers and advanced adenomatous polyps arise in the region of the colon and rectum that can be surveyed by flexible sigmoidoscopy, patients older than 65 years, Caucasian patients, and women comprise the patient groups with higher proximal colonic neoplasm risks. In these groups, sensitivity of flexible sigmoidoscopy will likely be less than for screening procedures that examine the entire colon. The authors suggested that flexible sigmoidoscopy should be performed at 5-year intervals. Recent data have supported a single flexible sigmoidoscopy

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performed between ages 55 to 64 as an effective means of lowering the incidence of colorectal cancer and lowering cancer-related mortality. This issue is discussed in more detail in the section of the overview that deals with controversies in the application of endoscopic screening. Flexible sigmoidoscopy screening can be combined with double-contrast barium enema examination to provide an acceptable means of visualizing the entire colon. Other data have supported the use of sigmoidoscopy combined with fecal occult blood testing. Sigmoidoscopy is associated with some patient discomfort and carries a small risk of colon perforation. Overall, the procedure is straightforward and relatively well accepted by patients. Efficacy of flexible sigmoidoscopy for reduction of incidence and mortality of colorectal neoplasia was evaluated in a population-based study by Hoff and coauthors35 in Annals of Internal Medicine, 2011. These authors evaluated nearly 14,000 patients who had undergone a single flexible sigmoidoscopy examination. Half the patients also underwent three rounds of fecal occult blood testing. The article reports results after a follow-up of 7 years. The analysis disclosed that there was a statistically significant reduction in colorectal cancer mortality in the group undergoing screening. There was no statistically significant difference in all-site colorectal cancer incidence, and the authors noted that the short follow-up interval may underestimate the effects on incidence and mortality. The final article discussed in this section of the overview is a randomized controlled comparison of guaiacbased fecal occult blood testing and immunochemical testing for fecal occult blood testing. The article is by Hol and coauthors36 in Gut, 2010. The analysis found that immunochemical testing and flexible sigmoidoscopy were both more effective than guaiac-based fecal occult blood testing in discovering colorectal cancer. Colonoscopic screening provides a useful means of examining the entire colon. Levin and coauthors33 noted that the test requires a clean colon and, therefore, patients usually go on a 2­­­­­­­­–3 day liquid diet, followed by the use of saline laxatives before undergoing the endoscopic examination. The authors noted that there are no randomized controlled trials that can provide data supporting the utility of colonoscopic screening for colorectal neoplasia. The authors cited data, including the large National Polyp Study by Winawer and coauthors,37 that support a reduc-

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tion in colorectal cancer incidence and mortality after colonoscopy where an adenomatous polyp was removed; reductions in cancer incidence exceeded 76%–90% in the National Polyp Study. Additional studies have failed to confirm this level of reduction in cancer incidence. Also, while Levin and colleagues noted that patients willing to undergo an invasive screening test will usually choose colonoscopy, they cited data indicating that a significant proportion of patients actually choose noninvasive screening methods. A limitation of colonoscopy acceptance is the fact that a full day is needed for completion of the study because of bowel prep and peri-procedural sedation. In addition, because of sedation, the patient must have a companion for assistance and for transportation away from the endoscopy unit after the test is completed. Although a properly performed full-colon examination by colonoscopy is very accurate, a miss rate for significant adenomatous polyps ranging from 6% to 12% has been reported. The miss rate for established colon cancers is approximately 5%. Also, colonoscopy carries a small risk of colon perforation and a significant incidence of bleeding if polypectomy is performed. Risk factors for bleeding include older age and the presence of diverticula of the colon. Perforation rates have been reported ranging from 1 per 500 examinations to 1 per 1000 examinations. Higher rates are usually found in reports using Medicare databases. Levin and associates cited one analysis from a large health system that confirms a perforation rate for all colonoscopies performed for screening and surveillance of 1 per 1000 examinations. Because the examination is performed in a large proportion of elderly patients and because of the need to use sedation, cardiopulmonary complications are observed in a significant number of patients; development of a cardiopulmonary complication is the most common reason for hospitalization after screening or surveillance colonoscopy. Other important issues related to colonoscopy are also discussed by Levin and associates, including the dramatic increase in the number of colonoscopies performed in the United States over the past decade. Data cited in their article indicate that there are two troubling factors that may be driving this increase: First, the current reimbursement system rewards a practice of doing more, rather than fewer, endoscopies. There is evidence that

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some practitioners perform post-screening surveillance colonoscopies at shorter-than-recommended intervals, even though recommended intervals are every 10 years after a negative colonoscopy in an average risk patient, and shorter intervals in higher risk patients (endoscopic surveillance intervals after polypectomy or resection of a colorectal cancer are discussed in a separate section of the overview). Because there are no fully implemented quality assurance programs for colonoscopy, practitioners may choose to err on the side of more frequent examinations if there is an incomplete understanding of the patient’s risk for adenoma or cancer recurrence. Second, the reimbursement system provides an incentive to perform shorter-duration colonoscopies. Data have indicated a relationship between adenoma and cancer discovery and withdrawal times of more than six minutes. According to available data, additional problems include a significant variability from colonoscopist to colonoscopist with regard to rates of adenoma discovery, withdrawal times, and adequacy of bowel prep; the absence of consistent, nationally implemented quality assurance programs contributes to this problem. These factors are discussed further in the following section. Surgery societies have furnished practice guidelines relating to screening and surveillance of colorectal neoplastic lesions. An example is found in an article by Ko and coauthors38 in Diseases of the Colon and Rectum, 2006. These guidelines stress the importance of risk assessment and patient education. A careful history and physical examination to exclude symptoms and signs of colorectal neoplasia is an important component of the initial evaluation. In average-risk patients, the guidelines emphasize the value of informing patients of the full range of screening and diagnostic options. The advantages and disadvantages of each test can be made available to patients so that an informed choice can be made. For average-risk patients, the guidelines agree with the recommendations of Levin and coauthors33 that fecal occult blood testing with or without flexible sigmoidoscopy is an acceptable means of screening; flexible sigmoidoscopy is recommended at 5-year intervals with fecal occult blood testing annually. Gathering of samples for fecal occult blood testing is done at a time remote from the time of flexible sigmoidoscopy. The guidelines also agree with Levin and colleagues that patients should be informed that a more invasive test will

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be needed if evidence of colorectal neoplasia is discovered. Colonoscopy is an acceptable means of screening and can be offered at 10-year intervals if the patient is at average risk and the preceding examination was negative.

Controversies about the Efficacy of Endoscopic Screening Evidence of the value of colonoscopic screening is available, but the magnitude of this benefit has varied from study to study. In addition, there is evidence of significant differences in accuracy when endoscopists are compared. Reports have noted differences according to specialty of the examining endoscopist and according to the numbers of colonoscopies performed. A summary of the data relevant to this important topic is in an editorial by Weinberg39 in Gastroenterology, 2011. The author noted the previously mentioned increase in the numbers of colonoscopies performed annually in the United States; data cited in the editorial estimate that 2 million colonoscopies for colorectal neoplasia screening or surveillance are performed each year. Available data indicate that the magnitude of the reduction in colorectal cancer incidence and mortality may be substantially smaller than predicted by the National Polyp Study (cited previously). The authors referred to population-based studies originating in Canada and Germany that reported risk reductions in the 30%–40% range, much smaller than the 76%–90% reductions predicted by the National Polyp Study data. Further examination of the data discloses that left-sided cancer reductions were encouraging at 70%, but that right-sided cancer reductions were either very small or nonexistent. An additional study by Atkin and coauthors40 offered data suggesting that a single examination of the left side of the colon using flexible sigmoidoscopy could produce equivalent cancer incidence reductions to full colonoscopy. The editorial by Weinberg also discussed an article by Brenner and coauthors41 in Gastroenterology, 2011. This German study compared more than 1,600 patients with a diagnosis of colorectal cancer with a group of nearly 2,000 control patients. After adjusting for multiple risk factors, the study found that patients who had undergone colonoscopy within the past 10 years had an overall reduction in colorectal cancer risk of 77%; reduction of risk

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for right-sided cancer was also strong at 56%, and risk reduction for left-sided cancer was 84%. Brenner and colleagues noted that this analysis dealt with patients undergoing colonoscopy for any reason, and that study did not single out patients undergoing screening colonoscopy. They also noted that risk reductions improved with time, and they emphasized that this change occurred during a time when colonoscopies were improved technically, and standardized endoscopic training in Germany resulted in a cecal intubation rate of more than 90%. Weinberg noted that adenoma detection rates in Germany increased during the same interval and averaged 26% during the period of Brenner’s study as well as the fact that adequacy of bowel preparation, cecal intubation rate, adenoma detection rate, and withdrawal time of more than six minutes are all factors that have been associated with improved protection against cancer. He further emphasized that the 26% adenoma detection rate reported from Germany is significantly higher than in studies reporting lower cancer protection rates. Weinberg also added that there are anatomic and, perhaps, biological differences in right- vs. left-sided cancers: right-sided cancers are more common in older people and in women and tend to be flat or depressed lesions that are more difficult to visualize. Whether there are differences in tumor behavior between right- and left-colon lesions is not clear from available data. Weinberg concluded that there needs to be further emphasis on measures to maximize operator effectiveness for screening colonoscopy, and he added that data support the fact that examinations performed in hospitals are more likely to comply with quality benchmarks than examinations performed in ambulatory centers and offices. He closed with a recommendation that institutions implement ongoing quality assessments for colonoscopy that will document compliance with all of the recommended benchmarks, since it is not known which of the quality benchmarks is most associated with maximum cancer protection. Another editorial by Rex42 provides additional perspective on the issue of quality control in colonoscopy. Rex noted that there are known biologic differences noted when interval cancers (those that develop during the 10year interval after a “negative” colonoscopy) are examined and compared with typical sporadic colorectal cancers.

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The interval lesions are more likely to display microsatellite instability and disorders of DNA methylation. A full understanding of the implications of these biologic differences is not available based on current research. Rex emphasized that what is available are means to lessen the interoperator variability in colonoscopy quality, and suggested that educational quality control tools be provided, including training in recognition of flat and depressed lesions, training in documentation of important quality benchmarks (listed above), and the proctoring of any colonoscopist who is found to be out of compliance with quality benchmarks. He concluded that it is impractical to expect all screening and surveillance colonoscopies to be performed by gastroenterologists. Factors including manpower, geographic location, and patient preference all support the conclusion that specialists other than gastroenterologists need to provide colonoscopy services and, therefore, incentives need to be created for these caregivers to provide high-quality examinations. Unfortunately, there has been an unwarranted and unnecessary emphasis on the quantity of procedures as a quality benchmark rather than provisions for excellent training and programs to maintain skills, in addition to the development of measures of compliance with quality indicators. The “numbers game” arises because of data showing an association of high-quality endoscopic examinations with the procedural experience of the endoscopist. Early in 2011, this emphasis led to the publication of a statement from four gastroenterologic associations that condemned the requirement of the American Board of Surgery (ABS) that surgical residents be trained in endoscopy; the statement can be found on the American Gastroenterological Society website at www.gastro.org. In essence, the statement asserted that the requirements for 35 upper endoscopies and 50 colonoscopies (included in the requirements for admission to the examinations of the ABS) would not assure “competence.” Further, the statement indicated that the requirements imposed unnecessary burdens on gastroenterologists, who were being asked to provide endoscopic experience for surgical trainees; it also asserted that surgeons who intended to perform endoscopies should be required to obtain additional training before awarded the credentials to perform these procedures. The American Board of Surgery responded with a statement supported by a number of surgery orga-

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nizations; this statement is available on its website, www. absurgery.org. The Board report provided data that “competence” could not and should not be defined by a certain caseload volume, but by proof of training followed by an adherence to quality standards—adherence to the quality standards should be periodically assessed. The Board further noted that awarding credentials at the local level could not practically be tied to any specific level of prior experience, but should be achieved by on-site assessment of expertise and ongoing measurement of quality.

Imaging Studies as Screening & Surveillance Tools Levin and coauthors33 noted that the two imaging studies available for screening and surveillance of colorectal neoplasia are double-contrast barium enema and CT colonography (sometimes referred to as “virtual colonoscopy”). The authors also commented that the expert panel that convened to develop the guidelines for screening and early detection of colorectal neoplasia found both imaging techniques to be acceptable for screening. The authors began the discussion with a review of double-contrast barium enema. The procedure requires 24 hours of bowel preparation and 20–40 minutes to complete the test. The colonic mucosa is first coated with thick barium, and then the colon is distended with air introduced via a rectal tube. Limitations of the procedure include the need for patients to be able to assume several different positions during the procedure. Discomfort of a mild or moderate degree is common, but rapid return to normal activity is the rule. The authors noted that randomized trials of this imaging modality for detection of early cancers and adenomatous polyps are not available. The authors also discussed two studies that used double-contrast barium enema as a purely screening modality. These studies reported sensitivities of 43%–73% for detection of adenomatous polyps, but detection of large polyps with advanced histology exceeded 70%. It was noted that the use of this technique has declined significantly, concurrent with the availability of endoscopic screening and CT colonography. Levin and coauthors concluded with the recommendation that double-contrast barium enema is an acceptable method of screening that should be used at 5-year intervals.

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CT colonography is used along with fecal tagging with iodinated contrast to improve sensitivity. The authors noted that available contemporary studies indicate that sensitivity for detection of small polyps exceeds 70%, and that sensitivity for detection of large (1 cm or larger) polyps exceeds 95%. Sensitivity for detection of colorectal cancer exceeds 95%. Overall, detection rates are consistent with those reported in colonoscopy studies. A 2008 study by Johnson and coauthors43 in the New England Journal of Medicine confirmed that the sensitivity and specificity of CT colonography exceeded 85% and 90%, respectively, in a large group of asymptomatic adults undergoing the examination purely for screening purposes. Current techniques use a bowel preparation regime equivalent to that used for colonoscopy so that patients can have sameday polypectomy if lesions are discovered. The guidelines recommend CT colonography every five years in average risk adults beginning at age 50.

Fecal Testing Fecal tests that have proven to be beneficial for colorectal cancer detection at an early stage include guaiac-based tests for blood in the stool and immunohistochemical analysis of stool specimens to detect hemoglobin. For each of these tests, three stool samples are required. A potential advantage for guaiac testing is that the test can be done and results recorded in the physician’s office. Single guaiac stool tests, especially testing done on stool obtained during a digital rectal examination, are not acceptable. The authors cited discouraging data from recent surveys of practitioners that documented nearly one-third of responding practitioners reporting the use of only stool obtained during digital rectal examination for fecal occult blood screening. Immunohistochemical tests for fecal blood require analysis in a laboratory; also, to be effective, these tests need to be performed annually. Positive tests will require an invasive procedure such as colonoscopy to confirm the findings. Analysis of exfoliated DNA has potential usefulness, but the stool specimen needs to be collected with appropriate preservatives and delivered to a laboratory that has expertise in performing the test. Though stool DNA analysis is considerably more expensive than guaiac tests or immunohistochemical testing, data cited by Levin

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and coauthors33 indicated that fecal DNA testing is now an acceptable method for conducting colorectal cancer screening. Also, although one of the manufacturers of fecal DNA testing materials recommends screening at 5-year intervals, the expert panel that convened to develop the guidelines for screening and early detection of colorectal neoplasia recommends annual screening. As with other fecal tests, a positive analysis will require an invasive procedure for confirmation. The sensitivities for guaiac testing of stool and immunohistochemistry analyses of stool vary depending on the agent analyzed from 37% to 79%, depending on the method analyzed. In most studies cited by Levin and associates, Hemoccult SENSA test had the highest sensitivity. Specificity for detection of a significant colorectal neoplasm approaches 90%. Additional discussion of molecular testing of stool and blood as a means of prevention and/or early diagnosis of colorectal neoplasia is in an article by Ahlquist44 in Gastroenterology, 2010. The author noted that genetic and molecular changes occur in somewhat more than 40% of colorectal neoplastic changes: these include mutations in KRAS, APC (adenomatous polyposis coli), and p53 genes. In addition, DNA methylation abnormalities occur in a similar proportion of tumors. Cells from colorectal neoplasms are exfoliated at a rate higher than for normal colonic mucosa. Stool sampling could, therefore, recover cells that could then be subjected to analysis. The author stressed that panels of genetic and molecular tests would be necessary because of the inconsistent expression of genetic and molecular changes in various tumors. Ahlquist also noted that exfoliated tumor cells may be enclosed in clumps of normal cells and this could, at least theoretically, reduce sensitivity of stool molecular testing. There is evidence that abnormal cells are lysed less efficiently than normal cells; in addition, there is distal migration of abnormal cells, which suggests that rectal swab testing may be advantageous. Lysis of abnormal as well as normal cells can occur from exposure to intraluminal bile acids, but harvesting abnormal genetic and molecular material elaborated from lysed cells is theoretically possible. Additional research into panel composition, sampling methods, and test stability is needed to progress toward more use of molecular testing as a means of screening for and prevention of colorectal neoplasia. Ahlquist stressed

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Familial or Genetically Determined Colorectal Neoplasia |

that urine and blood tests for genetic and molecular markers are unlikely to be useful as screening tests because entry of tumor cells into blood and urine is more likely to occur as tumors progress to advance stages of malignancy.

Familial or Genetically Determined Colorectal Neoplasia Practice guidelines for the management of familial colorectal neoplasia are described in an article by Balmana and coauthors45 in Annals of Oncology, 2010. The authors opened the discussion with a description of guidelines for patients with Lynch syndrome. The syndrome is transmitted in an autosomal dominant pattern and is associated with abnormalities in the genes that control DNA mismatch repair. These abnormalities lead to downstream dysfunction in tumor suppression pathways. This syndrome accounts for 1%–3% of colon cancer diagnoses. Balmana and coauthors noted that the lifetime colorectal cancer risk for patients with Lynch syndrome is 30%–70%. The risk for extracolonic neoplasms is 5%–15%. The authors noted that two strategies for identifying Lynch syndrome patients are currently in clinical practice: the first of these uses family history elements (Bethesda criteria); the alternative strategy is to use immunohistochemical tests on patients who have biopsy-proven colorectal cancer to identify microsatellite instability. A population-based analysis of the prevalence of DNA mismatch repair and microsatellite instability in young patients with colorectal cancer was the focus of an article by Limburg and coauthors46 in Clinical Gastroenterology and Hepatology, 2010. This analysis documented prevalence of 5.6% for alterations in DNA mismatch repair detectable by immunohistochemistry. The authors concluded that additional study is necessary before adoption of genetic testing for all patients with colorectal cancer. The rationale for testing all patients with colorectal cancer for microsatellite instability was discussed in an editorial by Burt47 in Annals of Internal Medicine, 2011. The author reviewed data on genetic testing of patients

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with colorectal cancer. The data suggest that more than 90% of patients with Lynch syndrome will display microsatellite instability that can be detected using immunohistochemical techniques. Approximately 10% of patients with sporadic colorectal cancer will display microsatellite instability. Burt summarized data from a decision analysis study that concluded that the most cost-effective means of identifying patients with the Lynch syndrome would be to test all colorectal cancers and endometrial cancers from microsatellite instability. In those patients with positive immunohistochemistry testing, further diagnostic testing would be done. This approach would serve to reduce the number of patients who would need extensive genetic testing if only family history elements were used to identify patients at risk. Balmana and coauthors45 went on to discuss early diagnosis and treatment strategies for patients with Lynch syndrome: family members with at-risk genetic patterns should begin colonoscopic surveillance at age 25, with endoscopy done annually. Screening for endometrial cancer should begin at age 30 to 35. They noted that currently available data do not support the use of preemptive surgery or adjunctive chemotherapy beyond the conventional indications (see later discussion). For patients diagnosed with colorectal cancers or high-risk adenomas who are confirmed to have hereditary non-polyposis colon cancer or HNPCC (Lynch syndrome is one form of HNPCC), total colectomy is recommended for lesions in the colon, and total proctocolectomy with ileoanal anastomosis is recommended for rectal cancers. The reason for these recommendations is the elevated risk of recurrent premalignant or malignant lesions after partial colectomy or proctectomy. Two articles that present data quantifying the risk of recurrence after segmental colectomy or proctectomy is by Kalady and coauthors48,49. The authors analyzed long-term follow-up data in patients listed in a prospectively maintained HNPCC database. Outcomes were recorded in 221 patients who underwent colonoscopic surveillance. After segmental colectomy, adenomas developed in 33% of patients–more than half of these were high-risk adenomas. Colorectal cancer developed in 25% of patients (n = 52 patients) and 14 of these cancers were advanced stage lesions. After total colectomy, high-risk adenomas or cancers were diagnosed in 19% of patients. For HNPCC patients undergoing proctectomy

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for rectal cancers (n = 33) who had complete long-term follow-up information, high-risk adenomas or cancers were diagnosed in 55% of patients. The authors concluded that these data support the use of total colectomy and total proctocolectomy for patients with HNPCC who develop high-risk adenomas or cancers.

Familial Adenomatous Polyposis The authors next discussed the early diagnosis and management of familial adenomatous polyposis (FAP). When patients are identified with more than 100 colorectal polyps, FAP is a likely diagnosis. The diagnosis is confirmed by documenting the presence of mutations in the APC gene. Testing of family members is begun as soon as the diagnosis is confirmed in the index case. Colonoscopic surveillance should begin in all family members regardless of whether the genetic abnormality is present. Preemptive proctocolectomy is indicated in patients with the genetic abnormality, in patients with more than 100 polyps, and in patients with advanced polyps diagnosed by size and histologic characteristics. If a portion of the rectum remains after colectomy, continued endoscopic surveillance of this segment is indicated. An analysis of outcomes in patients undergoing preemptive proctocolectomy was presented in an article by von Roon and coauthors50 in Annals of Surgery, 2011. The authors noted that mucosectomy of the residual anorectal segment has the potential to reduce the risk of recurrent neoplasia in the anorectal segment. They compared outcomes in 76 patients who had mucosectomy with hand-sewn ileoanal anastomosis with 44 patients who had stapled anastomosis without mucosectomy with a follow-up interval of more than 10 years. Recurrent neoplasia (mostly adenomatous polyps) developed in 51% of patients who did not have mucosectomy and in 23% of patients who had mucosectomy. The authors concluded from their data that mucosectomy and hand-sewn anastomosis are preferable in patients with familial adenomatous polyposis syndrome.

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Colorectal Cancer Surveillance Guidelines for Patients with IBD Guidelines for endoscopic surveillance of patients with ulcerative colitis or Crohn colitis were presented in an article by Cairns and coauthors51 in Gut, 2010. The authors recommended that colonoscopic surveillance be implemented if inflammatory disease has been present for 5–10 years. The interval of surveillance (annually, every 3 years or every 5 years) is determined on the basis of the extent of the inflammatory disease and the presence of complications or the presence of complications of inflammatory disease, such as stricture. For patients with localized disease or extensive colitis who had no sign of mucosal inflammation based on the index biopsies, follow-up colonoscopy can be done at 5-year intervals. Patients with colitis involving more than 50% of the colon (especially those who have had mucosal biopsies with mild residual inflammation), patients with inflammatory polyps, and patients with a family history of colorectal cancer are recommended to have colonoscopy every 3 years. The highest risk groups of patients are those who have persistent moderate-to-severe mucosal inflammation, biopsy-proven mild dysplasia, or who have had colectomy for colorectal cancer; annual surveillance is recommended for these patients. The authors reported controversy about the management of patients with dysplastic changes in areas of flat mucosa, and they noted that colectomy is a worthwhile option to offer these patients in order to allay anxiety concerning the development of occult malignancy. The authors recommend directed biopsies with tissue identified using indigo-carmine spraying of the mucosa. Additional data concerning the use of indigo-carmine directed biopsies is found in an article by Hlavaty and coauthors52 in the European Journal of Gastroenterology and Hepatology, 2011. The authors compared indigo-carmine spraying of colonic mucosa with conventional random biopsy techniques. The data disclosed a statistically significant increase in the diagnosis of intraepithelial neoplasia in patients having indigo-carmine spraying. The enhanced diagnosis was achieved with a much smaller number of biopsies as compared with conventional techniques.

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Young-Onset Colorectal Cancer Colorectal cancers diagnosed in young patients are more likely to be mucinous tumors or signet-ring cell tumors. Confirmation that these tumors are diagnosed at an advanced stage more frequently and are possibly associated with shorter survival times is presented in a retrospective study by Nitsche and coauthors53 in Annals of Surgery, 2013. The data analysis confirmed that these two histologic subtypes occurred in 11.9% of 3,479 patients seen in a single institution over a 30-year interval. The patients with mucinous tumors had equivalent survival compared with typical adenocarcinomas of the colon and rectum. Signet-ring cell tumors had significantly worse survival and this histologic diagnosis was significantly associated with worse outcomes on multivariate analysis. Two additional articles have dealt with the clinical characteristics of young patients with colorectal cancer: the first article was by Dozois and coauthors54 in Medicine, 2008. The authors reported a retrospective analysis of patients younger than 50 years diagnosed with colorectal cancer and treated at a single tertiary care center during a 26-year interval. More than 1,000 patients were identified. The group was nearly equally divided according to gender. The authors noted that most patients presented with overt clinical symptoms, such as rectal bleeding, abdominal pain, abdominal mass, or weight loss. The tumors discovered in these patients were diagnosed at an advanced tumor stage and mucinous histology was more common compared to older patients. The authors concluded that abdominal and intestinal symptoms in young patients should prompt aggressive diagnostic efforts to identify colorectal cancer. A follow-up analysis by You and coauthors55 was published in Annals of Surgical Oncology, 2011, and focused on a group of 333 patients younger than 50 years and without any identifiable factor that would increase colorectal cancer risk; this more recent report confirmed the advanced tumor stage and increased incidence of mucinous and signet ring histology in these younger patients. The authors noted that sphincter-preserving operations were done more commonly in the younger group. Compared with older patients, the younger group was more likely to receive chemotherapy and/or radiation therapy. The younger patients were also more likely to have identifiable recurrent or metastatic disease at the most recent follow20

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up visit. The authors reemphasized the need for aggressive diagnostic efforts in younger patients with symptoms and signs that may suggest the presence of colorectal neoplasia.

Surveillance after Treatment of Colorectal Neoplasia Two articles describe practice guidelines for patients who have undergone excisional therapy for adenomatous polyps or overt colorectal cancer. The first of these is by Winawer and coauthors56 in Gastroenterology, 2006. The authors varied the guidelines according to patient risk: Highest risk patients are patients with more than three adenomatous polyps at the index examination, patients with polyps >1 cm in diameter, and patients exhibiting dysplastic or villous histology—the recommended guidelines for highest risk patients include a colonoscopy follow-up 3 years after the index examination; Patients at modest risk include patients with tubular adenomas less than 1 cm in diameter without advanced histologic features— these patients are recommended for follow-up endoscopy 5–10 years after the index examination; patients with small hyperplastic or hamartomatous polyps should have follow-up at 10-year intervals. The second article discusses practice guidelines for surveillance of patients who have undergone colorectal resection for cancer. The article is by Rex and coauthors57 in Gastroenterology, 2006. The guidelines are relevant for patients who undergo endoscopic resection of early colorectal cancer and for patients who undergo colon resection for curing any stage of colorectal cancer. The authors stressed that preoperative colonoscopy is necessary to exclude synchronous lesions in patients who are not obstructed; patients with obstruction that does not require emergency intervention or patients with obstruction treated with stenting (see later discussion) can undergo CT colonography to exclude synchronous lesions. Patients requiring urgent resection can be evaluated by colonoscopy 6 weeks after colon resection. After colon resection, colonoscopy (or perhaps CT colonography) should be done one year after operation to exclude early metachronous lesions. If the 1-year examination is normal, endoscopic or, possibly, CT colonography examination can be done at 3-year intervals.

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Diagnosis & Staging of Colon Cancer |

Diagnosis & Staging of Colon Cancer This section of the overview features a discussion of the preoperative diagnosis and clinical staging of colon cancer and a review of current practices, along with data supporting these approaches, for the operative management of and postoperative adjuvant therapy for colon cancer. The aims of optimum management for colon cancer contrast, to a degree, with the goals of therapy for rectal cancer: the overall goals of the therapeutic approaches to colon cancer are to maximize local control of disease and prevent metastatic disease. As we review the available literature, readers will recognize that metastatic disease from primary colon cancer occurs in approximately half of patients who are followed long-term. The development of metastatic disease and the time course of the appearance of metastatic disease are dependent on the clinical and pathologic stage of disease at the time of initial therapy. Accurate pathologic and nodal staging are crucial elements of the decision process for use of postoperative chemotherapy. The use of chemotherapy will influence the probability and the time course of development of metastatic disease. Recent data have led to understanding that the number of nodes harvested at the time of the original operation is an important factor contributing to accurate pathologic staging of nodal status. External beam radiation therapy is mainly used to control advanced local disease and local recurrence of colon cancer. Neoadjuvant protocols are of limited usefulness for patients with colon cancer. This contrasts sharply with contemporary strategies for management of rectal cancer that rely heavily on use of neoadjuvant chemoradiotherapy protocols.

Clinical Diagnosis The NCCN clinical practice guidelines for management of colon cancer28 recommend specific approaches for patients who have an adenoma with invasive cancer vs. a patient who is diagnosed with a malignant lesion. For patients with a pedunculated polyp with invasive cancer that is completely excised at colonoscopy, observation with colonoscopic follow-up is recommended. Colectomy

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is recommended for sessile polyps and for polyps that are fragmented at the time of colonoscopy or polyps that cannot be completely removed. At the time of colonoscopy or prior to planned surgery, marking of the site of the lesion with ink may facilitate localization and removal. This may be particularly important for patients who do not receive mechanical bowel preparation and patients who are going to have laparoscopic colon resection. As noted in previous sections of this overview, the presence of overt clinical symptoms is associated with advanced stage colon cancer. A careful family history is helpful in identifying patients with genetically determined or familial colon cancer. The clinical practice guidelines document noted that up to 20% of newly diagnosed colon cancer patients will have family history findings suggestive of familial clustering. The NCCN guidelines recommend liberal use of genetic testing. Common symptoms of colon cancer include rectal bleeding, abdominal pain, change in bowel habits, iron deficiency anemia combined with positive fecal occult blood tests, and weight loss. Physical examination may also disclose an abdominal mass. The majority of colon cancers present as tumors located distal to the splenic flexure, and symptoms are, therefore, localized to the left abdomen. Involvement of adjacent organs, primarily the bladder, ureter, and internal reproductive organs, may give rise to symptoms suggesting disease of these organs. Abdominal distention suggests the presence of large and/ or small intestinal obstruction or the presence of ascites from peritoneal or liver metastases. Women with symptoms suspicious for colon cancer should also be evaluated for associated cancers of the breast and endometrium.

Laboratory & Imaging Diagnosis The NCCN practice guidelines recommend that a preoperative CEA level be obtained along with a complete blood count, full blood chemistry analysis, and liver function studies. CEA assessment will not assist in determining stage or prognosis as an isolated assessment, but will, if elevated, raise the suspicion for metastatic disease. If the patient has not been part of a screening program, preoperative evaluation of the entire colon is recommended; colonoscopy is the preferred method of colon evaluation.

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For patients who are, for whatever reason, not candidates for colonoscopy, alternative approaches to colon evaluation can be used: CT colonography (see previous discussion) or the combination of flexible sigmoidoscopy and doublecontrast barium enema are both useful studies. Usually, CT imaging will be chosen because of its ability for expeditious completion with minimal patient discomfort. CT imaging of the chest, abdomen, and pelvis are recommended. Magnetic resonance imaging (MRI) is recommended for patients who have an incomplete CT imaging study or who cannot undergo CT imaging. The guidelines did not recommend the use of PET/CT as a component of the initial evaluation. However, if potentially resectable liver metasFigure 1 tasis is documented, PET/CT may assist in documenting disease beyond the liver. The NCCN guidelines concluded the discussion on imaging by recommending that plain chest radiography be performed preoperatively. The practice guidelines went on to note that MRI may be helpful if there is evidence of advanced local progression of the tumor, since this modality can provide clear images of the full extent of involvement of the organs and tissues adjacent to the primary tumor.

ogy review recommendations are included in the NCCN colon cancer guidelines document.28 Recommended practices include documentation of lesion grade and depth of penetration, status of proximal and distal margins, presence of extension to the peritoneum or adjacent organs, presence of lymphovascular and/or perineural invasion, number and status of excised nodes, status of any excised non-regional nodes, and any extranodal tumor deposits. The TNM grading system is illustrated in the article by Brenner and coauthors1. The illustrations are reproduced as Figure 1 and Figure 2.

TNM classification system for colon cancer. Reproduced from Brenner and coauthors1 with permission.

Clinical & Pathologic Staging Systems for Colorectal Cancer Periodic revision of the TNM staging system for colon and rectal cancer has occurred as more long-term outcomes data have become available. Complete staging has preoperative, intraoperative, and postoperative components: Preoperative colonoscopy is useful for determining the location, size, and histologic characteristics of the lesion, and imaging may document extension into adjacent organs or distant metastases in the liver and/or lung; Intraoperatively, the objective is to achieve complete removal of the primary lesion along with at least 12 lymph nodes (articles reviewing the value of this requirement will be reviewed in a later section of the overview when technical aspects of colon resection are discussed); Postoperative pathol-

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Data supporting the basic elements of the TNM staging system were published in an article by Gunderson and coauthors58 in the Journal of Clinical Oncology, 2010. The article describes analyses of the Surveillance and End Results Reporting (SEER) database for colon and rectal cancer. Outcomes for colon and for rectal cancer were very similar according to clinical and pathologic staging; recommendations for staging are, therefore, similar for both varieties of cancers.

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Figure 2

Tumor staging according to TNM classification. Reproduced from Brenner and coauthors1 with permission.

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tumors to Stage IIIc. The authors further emphasize that there is a survival advantage for tumors that penetrate the serosa of the bowel (T4a) compared with those tumors that invade adjacent organs (T4b). This further supports upstaging T4b tumors and moving T4a tumors to an earlier stage. The proposed classification system for Stage II tumors subdivides Stage II into Stages IIa, IIb, and IIc, depending on whether T4 tumors penetrate the serosa of the colon without invasion of adjacent structures (T4aN0 tumors) vs. tumors that have invaded adjacent organs (T4bN0 tumors). T4aN0 tumors would be classified as Stage IIb and T4bN0 tumors would be classified as Stage IIc.

Preoperative Preparation for Patients with Colon Cancer

The authors emphasized that emerging data document that there are some patients with tumors staged as T4 with no nodal metastases (T4N0, normally, would reside in Stage II) who do not have outcomes as good as some patients with T2-4 cancers with one or two nodal metastases (which normally would reside in Stage III). Specifically, 5-year survival for patients with T4N0 tumors had 5-year survivals of 47% compared with 5-year survivals of more than 60% for patients with T3-4N1-2 tumors. Identification of high-risk Stage II tumors provides guidance offering adjuvant chemotherapy to these patients. Data supported a statistically significant improvement in survival after treatment with chemotherapy in the highrisk Stage II patients. Gunderson and coauthors stressed that the decision to structure Stage III tumors into substages (a, b, and c) in the sixth edition of the staging system was not based on verified outcomes data. The current proposed changes for the seventh edition make use of all currently available long-term survival data for both colon and rectal cancer. These data support shifting T1-2N1 patients from Stage IIIb to an earlier stage and shifting patients with T4N1

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Once preoperative staging has been completed, preparation for operation begins with an assessment of risk and continues with maneuvers to minimize effects of comorbid conditions and prevent intraoperative and postoperative complications. Detailed risk assessment, preoperative preparation, intraoperative maneuvers and postoperative management can serve to optimize the chances for a successful outcome.

Preoperative Risk Assessment As the proportion of elderly patients who require operative intervention for colorectal cancer increases, preoperative risk assessment and the use of interventions that can reduce operative risk have become more important. A document that provides guidelines for assessment and reduction of risk in geriatric patients has been promulgated jointly by the National Surgical Quality Improvement (NSQIP) program of the American College of Surgeons (ACS) and the American Geriatrics Society (AGS).59 This best practices statement is included as a full-text reprint accompanying some formats of SRGS. The ACS NSQIP/ AGS Best Practice Guidelines document emphasizes the importance of assessing patients older than 65 years for cognitive function; the recommended test in the MiniCog assesses recent memory and the ability to complete

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a structured task. Scores can range from 0 to 5, with 5 indicating satisfactory cognitive function. The authors recommended that patients be assessed as well for decision-making capacity, depression, alcohol and drug use, and risk for perioperative delirium; easily used assessment tools are described in the guidelines document. Risk for perioperative delirium may either relate to the cognitive and behavioral functions described above, or to other patient factors, such as anemia, renal insufficiency, chronic lung disease, and poor nutritional status. The guidelines suggest approaches for establishing risk for perioperative cardiac and pulmonary complications. Cardiac risk is influenced by a history of ischemic heart disease and/or congestive heart failure, a history of cerebral vascular disease, renal insufficiency, and diabetes. The guidelines recommend that non-invasive cardiac testing be considered for patients with 1-2 risk factors as well as for patients who are scheduled for vascular procedures, if the results would likely change management. Use of the American Heart Association’s (AHA) recommendations for perioperative beta-blocker use was recommended. The AHA guidelines were described in the perioperative betablocker module of Evidence-Based Decisions in Surgery that is available on the ACS web site at www.facs.org. The ACS NSQIP/AGS guidelines document noted that risk for perioperative pulmonary complications is increased in patients with chronic lung disease, congestive heart failure, obstructive sleep apnea, pulmonary hypertension, and in current smokers. Risk may be improved with smoking cessation and inspiratory muscle training. Preoperative smoking cessation can be useful as a means of avoiding postoperative pulmonary complications, especially in patients with symptoms and signs of chronic obstructive pulmonary disease. For overall risk assessment, the American Society of Anesthesiologists (ASA) scoring system is useful: Patients with scores of ASA 1-2 are deemed good risks for operation; Patients in ASA classes 3 and 4 are likely to have significant postoperative morbidity, especially if there is a history of congestive cardiac failure, stroke, or renal failure. Data discussed later in the overview suggest that anastomotic leak is more common in patients with severe preoperative comorbid conditions. Nutritional assessment by a nutritional specialist was recommended for any patient with a recent weight loss of more than 10% body weight, BMI of 18.5, and/or

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hypoalbuminemia. The document recommends assessing the patient’s history and records for medication use. The Beers medication list was recommended as an important resource for acquiring knowledge of potentially important medications that may impact perioperative complications.60 Recommended preoperative laboratory testing and imaging included all assessments recommended by the NCCN clinical practice guidelines for colorectal cancer. The guidelines document included recommendations for assessing functional status: directed questions to document ability to self-care as well as assessments of vision, hearing, and swallowing were recommended; a test of mobility that provides information on the patient’s ability to stand from sitting and walk a short distance was also recommended as well as an assessment of frailty, which seeks information on recent weight loss, grip strength, energy and endurance levels, recent energy expenditure, and slow walking—a score of 0-5 is possible with 0-1 being defined as not frail. An article by Revenig and coauthors61 in the Journal of the American College of Surgeons, 2015 reported an analysis of outcomes in a group of 351 patients who underwent preoperative evaluation with the Fried Frailty Score, the ASA score, and hemoglobin levels. The data showed that a history of recent weight loss and low-grip strength, when combined with the ASA score and the hemoglobin level, predicted a risk of perioperative mortality and complications with the same accuracy as the full-frailty score. The authors concluded that frailty assessment with two components was less complicated than determining the full-frailty score and recommended that this approach be validated in independent study samples. The simplified assessment may have value to assess operative risk and counsel patients concerning risk. The ACS NSQIP/AGS best practices document59 recommends that patients be counseled prior to a planned operative procedure: the first recommended counseling objective should be to determine whether the patient has an advance directive, and to offer options for creating an advance directive if the patient does not have one; second, treatment goals and plans should be discussed—this section should include a discussion of patient preferences and any concerns regarding the planned approach; the third counseling objective should be to describe the expected

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postoperative course; lastly, an assessment of the patient’s family and support system Figure 3 should be conducted. Presenting data on the effectiveness of a planned procedure in a way that the patient can understand is critically important for preoperative counseling. An article describing a systematic review of literature on ways to optimize patient understanding of probabilistic data presented during a counseling session was reported by Zipkin and coauthors62 in Annals of Internal Medicine, 2014. The authors noted that their objective was to analyze comparative effectiveness of methods of communication. Although there was significant heterogeneity among the included studies, the authors found 84 articles of acceptable quality. The data analysis showed that visual aids, especially graphs, were helpful in improving understanding. An illustration of components of risk explanation that the authors included in their article is reproduced as Figure 3. The analysis also showed that expressions of absolute risk reduction were easier for patients to understand than statements of relative risk reduction, and that patient understanding of risk decreased when numbers needed to treat were used as a means of presenting data on the effectiveness of various approaches. The authors concluded that there was not one single superior method for communicating risk, and they recommended using graphic aids and statements of absolute risk reduction.

Enhanced Recovery after Surgery Enhanced recovery after surgery (ERAS) refers to a multidisciplinary, multiple intervention approach to accelerating recovery after an operation: the pathways used focus on maintaining optimum fluid balance and optimizing pain control while minimizing the use of opioid drugs, maintaining temperature and oxygenation, encouraging early mobilization, and using a two-pronged effort that focuses on reducing the incidence and duration of

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Useful components of risk explanation strategies. Reproduced from Zipkin and coauthors62 with permission.

postoperative ileus and beginning oral nutrition as early as possible. These pathways have been implemented especially for colorectal procedures. Clinical practice guidelines for perioperative care of patients undergoing colorectal procedures have been promulgated by the Enhanced Recovery after Surgery (ERAS) Society, the European Society for Clinical Nutrition and Metabolism and the International Association for Surgical Metabolism and Nutrition. Guidelines published in an article by Gustafsson and coauthors63 in the World Journal of Surgery, 2013, begin by recommending that patients receive dedicated preoperative education that presents relevant information concerning their role in the ERAS pathway. The elements of this component are similar to the counseling elements included in the ACS

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NSQIP/AGS best practices document reviewed earlier. The guidelines also recommend that alcohol and smoking cessation be implemented four weeks prior to operation. In addition, the guidelines recommended that mechanical bowel preparation be used selectively, that oral fluids be allowed up to 2 hours prior to anesthesia induction, and that solid foods be allowed up to six hours prior to induction. Caution is recommended in patients who may be at risk for delayed gastric emptying or gastroduodenal obstruction. Carbohydrate loading with oral complex carbohydrate-enriched fluid is recommended for diabetic patients. The authors strongly recommended the avoidance of long- or short-acting sedative drugs prior to anesthesia induction. They also noted that intravenous sedative drugs could be used as an adjunct to anesthesia by the attending anesthesiologist. The perioperative use of compression stockings is yet another guideline recommendation as well as pharmacologic thromboembolism prophylaxis using low- molecularweight heparins (LMWHs), and prophylaxis for 28 days in patients with colon cancer. An article presenting data on the effectiveness of a four-week course of LMWHs compared with one week of prophylaxis was by Vedovati and coauthors64 in Annals of Surgery, 2014. This article is supplied as a full-text reprint accompanying some formats of SRGS. The authors reported a randomized controlled trial comparing eight days of LMWH therapy with four weeks of treatment. 225 patients were randomized; these randomized patients had to have no symptoms and no ultrasound evidence of deep venous thrombosis (DVT) at eight days after operation. Patients were asked to return for evaluation if any symptoms of DVT or pulmonary embolus appeared. During the four-week follow-up interval, 11 patients in the short course group developed symptoms of DVT and the presence of DVT was confirmed with ultrasound. No patient in the four-week therapy group developed DVT symptoms. No instances of pulmonary embolus occurred in either group, nor were instances of major bleeding observed in either group. The authors concluded that four weeks of DVT prophylaxis was feasible, effective, and safe in patients who had undergone surgical procedures for colon cancer. An interesting article by the Colorectal Writing Group for the Surgical Care and Outcomes Assessment Program-Comparative Effectiveness Research Translation

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Network (SCOAP-CERTAIN) Collaborative65 from the state of Washington appeared in JAMA Surgery, 2015. The article queried a statewide database to determine usage patterns and effectiveness of DVT prophylaxis for patients undergoing colorectal operative procedures. Outcomes from 16,120 patients were reported for the interval of 2006 to 2011. The authors found that DVT prophylaxis with LMWH increased from 31.6% to 86.4% for perioperative prophylaxis, and from 59.6% to 91.4% for in-hospital prophylaxis over the study interval. Prophylaxis was continued after hospital discharge in 10.6% of patients. The overall incidence of venous thromboembolism (VTE) was 2.2%, and this was similar in patients with a diagnosis of cancer and in patients without cancer. VTE occurred after hospital discharge in 39% of patients. The authors concluded that increased use of DVT prophylaxis had not resulted in a lower frequency of this complication. It would be useful if the data had been separated for patients with cancer vs. patients without cancer; reporting the rates of VTE in patients with cancer who had prolonged prophylaxis would have also been helpful. That said, the data confirm that VTE is an infrequent complication after colorectal procedures. The ERAS Society practice guidelines document63 recommends that standard intravenous antibiotic prophylaxis be used in patients undergoing colorectal procedures. The guidelines also recommend the use of regional (epidural) block anesthesia, along with low-dose opioids, and that intravenous balanced electrolyte and colloid fluids should be given based on noninvasive flow measurements, with judicious use of vasopressors for blood pressure. Intraoperative warming devices, used to maintain normothermia, are also recommended: Gustafsson and colleagues cited data indicating that the maintenance of normothermia reduces SSI risk and may have favorable effects on cardiac morbidity risk. The authors also noted that avoidance of shivering during emergence from anesthesia reduces oxygen consumption and cardiovascular stress. Of note is the fact that recent data have challenged the idea that maintenance of normothermia reduces SSI risk: data relevant to this topic was presented in an article by Baucom and coauthors66 in JAMA Surgery, 2015. The

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authors reported a retrospective medical record review. Over a four-year interval, 868 patients underwent segmental colon resection. Although the authors stated that this patient group underwent elective segmental colon resection, they later indicated that they excluded patients who underwent emergency procedures, and that this reduced the size of the cohort. The authors also excluded patients with IBD and patients who had an unplanned stoma created—the final cohort that was analyzed included 296 patients. The analysis investigated the relationship between patient temperature and the risks of superficial wound infections, deep wound infections, and organ space infections. The study could not document a relationship between body temperature and SSI. In an editorial that accompanied the article, several important points were made67: First, the inclusion of organ space infection (thought to be a marker for overt or occult anastomotic leak) might obscure a relationship between hypothermia and wound infections; Second, 93% of the patients had body temperatures higher than 35 degrees centigrade, so the cohort was at relatively low risk for the consequences of hypothermia (the editorialist pointed out that prior studies that observed a relationship between SSIs and hypothermia reported outcomes on patients with intraoperative body temperatures of 34 degrees centigrade or less); Third, most of the patients in the cohort had laparoscopic procedures performed, and this contrasts sharply with the patients included in earlier studies. In the editorial’s conclusion, the point was made that while surgeons should stop worrying about a relationship between hypothermia and SSI risk, it does not mean that intraoperative warming to prevent hypothermia should be stopped. Significant hypothermia occurs most often immediately after induction of anesthesia, and in this interval, serious cardiovascular and metabolic changes can occur that are related to hypothermia. The ERAS Society guidelines document63 recommends that postoperative nausea and vomiting be controlled by combining one the accepted intravenous antiemetic drugs with dexamethasone. Postoperative nausea and vomiting may also be reduced by the use of a transversus abdominal plane (TAP) local anesthetic block. Three articles that focus on the effectiveness of TAP blocks will be discussed at this time. In the first article, written by Walter and coauthors68 in Surgical Endoscopy,

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2013, the authors reported the results from a randomized, prospective trial of ultrasound-guided TAP blocks that were administered after induction of anesthesia, but before the beginning of laparoscopic colon procedures. The authors noted that TAP blocks are performed by local anesthetic infiltration of the plane between the internal oblique muscle and the transversus abdominis muscle bilaterally to achieve anesthetic block of the lowest six thoracic and first lumbar sensory nerves. In this study, the authors randomized 68 patients to either receive TAP blocks or no TAP block. All patients received postoperative patient-controlled analgesia using intravenous morphine and paracetamol. The data analysis showed that opioid usage was significantly lower during the first 24 hours after operation in patients having TAP blocks; pain scores were similar in the two groups. In the second article, by Ris and coauthors69 in Annals of the Royal College of Surgeons of England, 2014, outcomes of 68 patients who received epidural anesthesia (N=24) were compared with patient controlled analgesia (N=22) or TAP blocks (N=22). The data were gathered prospectively and analyzed retrospectively. The choice of analgesia approach was according to anesthesiologist preference. The analysis showed that opioid use 12 and 24 hours after operation was significantly lower in TAP patients. Return of bowel function was faster in TAP patients, and TAP patients were also discharged one day earlier than patients in the other groups. The final article is by Keller and coauthors70 in the Journal of the American College of Surgeons, 2014. This article is supplied as a full-text reprint accompanying some formats of SRGS. The authors described a retrospective experience with 200 consecutive patients who received TAP blocks with laparoscopic guidance for correct needle placement just prior to completion of the laparoscopic segmental colectomy; the operation was performed for colon cancer in the majority of patients. The technique employed is described in the article and readers are encouraged to review it. Twenty-five ml of marcaine local anesthetic were injected on each side after needle placement was confirmed. In this patient series, more than 80% of patients were discharged by the third postoperative day. Complication and readmission rates were low, at 12%

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and 6.5%, respectively. Most complications (79%) were mild. The authors concluded that TAP was a beneficial addition to their ERAS protocol. The ERAS Society practice guidelines document63 endorses using transurethral catheter bladder drainage for one or two days postoperatively; if a longer duration of bladder drainage is anticipated, then ultrasound-guided suprapubic drainage tube placement should be considered. The guidelines also recommended gum chewing and the selective use of laxatives to hastening the return of bowel function as well as early oral feeding (1 to 2 days postoperatively) in patients undergoing colorectal procedures; enteral tube feeding might be considered in selected patients. An article that describes the results of a randomized prospective trial of early enteral nutrition compared with early parenteral nutrition in patients undergoing rectal resection was by Boelens and coauthors71 in Annals of Surgery, 2014. The authors randomized 124 patients, and the data analysis showed that early enteral nutrition patients had significantly earlier first defecation, a significantly lower anastomotic leak rate, and a significantly shorter hospital length of stay compared with patients receiving parenteral nutrition. ERAS Society guidelines do not recommend routine drainage of the peritoneal cavity or pelvis, and an active audit process is advised in order to ensure that guideline compliance is optimized and that outcomes are recorded. The impact of compliance with ERAS pathways on surgical outcomes in patients undergoing colorectal procedures for cancer was the focus of an article by the ERAS Compliance Group72 in Annals of Surgery, 2015. The authors queried an international database to determine the effect of ERAS compliance and the impact of several of its components on colorectal procedure outcomes. Data from multiple centers that were at varied levels of compliance with ERAS were reported. Outcomes of 2,300 colorectal procedures for cancer were reviewed. The analysis showed that increasing ERAS compliance was associated with reduced complication rates and reduced hospital lengths of stay. Preoperative oral fluid loading and carbohydrate loading in diabetic patients, along with total intravenous anesthesia were associated with a reduced hospital length of stay; the use of laparoscopic surgery, early postoperative mobilization, and early oral feeding were also associated

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with shorter lengths of stay. The authors concluded that ERAS use was instrumental in improving outcomes for colorectal cancer operative procedures. Additional data on the impact of ERAS guideline compliance on hospital lengths of stay were presented in an article by Bakker and coauthors73 in Surgery, 2015. The authors reviewed experience from a single center over an eight-year interval. Data from more than 800 patients were analyzed. They compared compliance rates and hospital lengths of stay in periods of relatively low ERAS protocol compliance with the final two-year interval when interventions were introduced to improve compliance. In that final interval, compliance rose to 82% and hospital lengths of stay were the shortest. The authors concluded that the impact of ERAS guidelines is directly related to rates of compliance, and that specific interventions to improve compliance (use of dedicated anesthesia team, identification of a program “champion” to lead education, and training efforts) resulted in improved outcomes. Similar improvements in outcomes were observed with the introduction of a “trust-based” accountability model that involved leaders at all levels of the organization acting together to optimize ERAS compliance: this article is by Wick and coauthors74 in the Journal of the American College of Surgeons, 2015. This article is included as a fulltext reference in some formats of SRGS. Outcomes in 310 patients cared for during a baseline period were compared with 330 patients cared for after implementation of the program. Significant reductions in hospital lengths of stay and SSI rates were observed after the implementation of the program. The elements of the “trust-based” accountability model that were deemed most important were improved visibility and communication by senior leadership and the development of consistent operating room and patient care teams for patients undergoing colorectal surgical procedures; the components of this enhanced recovery protocol is illustrated as Figure 4.

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Figure 4

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Components of an effective enhanced recovery protocol. Reproduced from Wick and coauthors74 with permission.

Operative Management of Colon Cancer

Local Excision of Colorectal Cancers

The fundamental principles of resection therapy for most colorectal cancers include the removal of the involved segment of colon with tumor margins of at least 5 cm on each side of the tumor; all adjacent tissue involved with the tumor should also be removed if it can be done safely. Alternate approaches may be applicable for patients with carcinoma-in-situ and T1 lesions; advancements in endoscopic techniques have made complete excision of such lesions possible.

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Outcomes of this approach was the focus on an article by Bhangu and coauthors75 in Annals of Surgery, 2013. The authors used outcomes data from the SEER database. They determined cancer-specific survivals according to tumor grade and the treatment modality employed. Local excision was used in 7,378 patients and segmental colectomy was used in 36,116 patients. For patients with carcinoma-in-situ and T1 lesions that had well differentiated histology, cancer-specific survival at 5 years was equivalent for local excision of colon or rectal cancer. The survival equivalence was less clear for patients with poorly differentiated tumors and the authors suggest that patients with poorly differentiated T1 tumors be offered salvage segmental colectomy. The authors noted that overall survival was lower for patients undergoing local excision and

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they attributed this to the fact that the proportion of patients in the local excision group that were older than 80 was significantly larger than in the segmental resection group. The authors acknowledged that local excision does not allow for lymph node examinations and cited data that indicate lymph node metastasis rates of up to 20% in patients with T0 to T2 colon or rectal cancers. The authors recommended sequential CT imaging for colon cancers and high-resolution MRI for rectal cancers to detect lymph node enlargement. Patients with suspicious lymph nodes should be offered salvage surgery. Bhangu and coauthors noted that laparoscopic lymph node sampling may also be useful, and additional data cited by the authors suggests that local excision may be helpful for patients with rectal cancer whose lesions are downstaged to T0 or T1 after neoadjuvant chemoradiation therapy. Further research in this area is needed.

Lymphadenectomy For patients who require segmental colon resection for cancer, Brenner and coauthors1 and the NCCN practice guidelines for the management of colon cancer28 emphasize the importance of removing the involved colon segment using early isolation and ligation of the main blood vessel supplying the colon segment at its origin in order to maximize the number of pericolic and mesenteric lymph nodes in the resected segment. Available data have documented improved accuracy of staging and improved outcomes in patients having more than 12 lymph nodes harvested at the time of the initial operation. The concept of adequate lymph node harvest requires commitment by the surgeon and by the pathologist. The surgeon’s goal is to excise the involved colon with the feeding arcade of arteries to include the lymph node basin. Any enlarged lymph nodes up to the origin of the inferior mesenteric artery (for left colon resections) are also removed. During the operation, a careful check for peritoneal metastatic deposits and for liver metastases is performed. An article that presents data on the relationship of adequate lymphadenectomy to outcomes for patients with colon cancer is by Chen and coauthors76 in Annals of Surgery, 2011. The authors used data from the SEER database from an interval of 1992 to 2004. Complete out-

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comes information and information on nodal status were available for 36,712 patients. The authors calculated the ratio of nodes with metastases to total nodes excised; they stratified outcomes based on the ratio and whether fewer than 12 nodes, or 12 or more nodes, were examined. The authors hypothesized that the lymph node ratio might be helpful in establishing prognosis because the excision of fewer than 12 nodes is common for colon resections done in the United States. Cancer recurrence and cancer-related mortality in patients with no positive nodes on pathologic examination has been ascribed to the fact that too few nodes were examined. Analysis of the data showed that survival was significantly better in patients who had 12 or more nodes removed regardless of the lymph node ratio. Cancer-specific survival was, however, closely related to the lymph node ratio with survival decreasing in linear fashion with increasing ratios of positive to total lymph nodes. This relationship was present regardless of the number of lymph nodes excised. The authors concluded that the lymph node ratio was helpful in establishing prognosis for stage III colon cancer, but that the overall objective of surgical management should be complete removal of the primary tumor with at least 12 lymph nodes.

Blood Transfusion Two aspects of the operative care of patients with colon cancer might influence long-term outcomes. These include the use of perioperative blood transfusion and the development of an anastomotic leak. The effect of blood transfusions on immune function is well recognized. Practice guidelines for the management of colorectal cancer recommend that transfusions be used judiciously and according to accepted clinical indicators. Data supporting an association of perioperative transfusion and morbidity were presented in an article by Koch and coauthors77 in Annals of Surgical Oncology, 2011. These authors followed, prospectively, patients in a single institution who underwent elective colectomy for colorectal cancer. More than 500 patients were included in an interval of 6 years. The authors found that perioperative morbidity was significantly higher in transfused patients and, on multivariate analysis; transfusion was

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independently associated with morbidity. There was a linear relationship between the volume of transfusion and morbidity. The authors confirmed an increased risk for both intraoperative and postoperative complications in transfused patients, but there was no relationship between operative duration and total blood loss. This finding suggests that the complexity of the surgery was not a factor determining morbidity. Additional analysis failed to find an association of surgeon experience with both frequency of transfusion and postoperative morbidity. The authors concluded that blood transfusion with leucocyte-depleted blood does not afford uniform protection against perioperative complications. They recommend that transfusion be avoided whenever this is possible to be consistent with patient safety.

Anastomotic Leak Primary anastomosis is possible in most patients undergoing elective operation, but proximal diversion may be necessary for patients at high risk for anastomotic leak. Available data confirm that anastomotic leak is associated with worse oncologic outcomes compared with patients with no anastomotic leak. An article that presented data on this topic was by Krarup and coauthors78 in Annals of Surgery, 2014. The authors merged data from three national databases. One of these was a colorectal surgery database, one was a national pathology database, and the third was a national long-term outcomes database. They analyzed outcomes in 8,589 patients. The data analysis showed that anastomotic leak was associated with significantly greater risk for developing distant metastases. Anastomotic leak was also independently associated with worse long-term survival. The development of anastomotic leak increased the risk that the patient would not receive needed adjuvant chemotherapy. The authors acknowledged that other data do not support the association between anastomotic leak and risk of distant metastasis. They also noted that studies that have failed to show that the association could have had unknown confounders because of the inclusion of small numbers of patients, mixing emergent and elective operations, and combining groups of patients with colon cancer with rectal cancer patients. The authors recommend that additional studies

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be conducted, and they emphasized the fact that distant recurrence can be impacted by the omission of needed chemotherapy and the severe intraperitoneal inflammatory response that may accompany anastomotic leak; it is likely that both mechanisms play a role. Contrasting data were reported in an article by Mirnezami and coauthors79 in Annals of Surgery, 2011. These authors performed a meta-analysis of available studies using a standard set of meta-analysis rules. They identified 29 studies of acceptable quality. The data analysis showed that anastomotic leak was associated with an increased risk for local recurrence (in contrast to data reviewed previously). The authors acknowledged that their study includes both colon and rectal anastomoses and that the effect of anastomotic leak may differ for the two. The negative effect on long-term survival was confirmed. Another article by Merkow and coauthors80 in Annals of Surgery, 2013 examined the effect of postoperative complications including anastomotic leak on the overall rate of use and the timing of indicated adjuvant chemotherapy in patients with colon cancer. This article is supplied as a full-text reprint accompanying some formats of SRGS. They used data from the ACS NSQIP database. From a total group of more than 2,300 patients, they found 271 cases where indicated chemotherapy was omitted: the incidence of complications such as prolonged ventilation and acute renal failure were significantly higher in this group of patients. In patients who did receive chemotherapy, the time to beginning therapy was increased three-fold in patients with complications and more than five-fold in patients with anastomotic leaks. Risk factors for anastomotic leak were the focus of an article by Frasson and coauthors81 in Annals of Surgery, 2014. The authors evaluated data from 52 hospitals in a prospective observational study. All patients who underwent colon resection for colon cancer with primary anastomosis and no proximal diversion over a one-year interval were included. A total of 3,193 patients were available for analysis. The overall anastomotic leak rate was 8.7%. Patient-related factors associated with anastomotic leak after the multivariate analysis were obesity, low totalserum protein levels, ongoing anticoagulant therapy, and male gender. Intraoperative complications such as bleeding and fecal spillage were significantly associated with

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anastomotic leak. The final variable identified was hospital size: smaller hospitals had higher rates of anastomotic leaks. These findings suggest the need to assess modifiable risk factors preoperatively, take measures to avoid excessive bleeding and peritoneal contamination, and that there may be a volume-outcome relationship that serves to reduce risk of anastomotic leak. The authors created a risk factor algorithm and an anastomotic leak scoring system; these are illustrated as Figure 5 and Figure 6. Figure 5

Figure 6

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Intraoperative anastomotic testing has been suggested as a means of preventing anastomotic leaks. An analysis of the value of anastomotic testing is the focus of an article by Ricciardi and coauthors82 in Archives of Surgery, 2009. These authors used patient data from a prospectively maintained database of patients undergoing operation for colon cancer in a single institution over an interval of six years. Leak testing was done by injecting air into the lumen of the colon segment that was submerged in saline after anastomosis was completed. Air leak was noted in 7.9% of anastomoses. Air leak Anastomotic leak risk algorithm. Reproduced from Frasson and coauthors81 with permission. occurred in 7.8% of stapled anastomoses and in more than 9% of hand-sewn anastomoses. Suture repair of an air leak was associated with development of clinical evidence of anastomotic leak in more than 12% of patients. Formal reanastomosis or fecal diversion after documentation of an air leak were both associated with rates of clinical anastomotic leak of 0%. The authors concluded that anastomotic leak testing is helpful and that the response to a documented air leak should be formal reanastomosis and/or fecal diversion. Although primary anastomosis is possible in many patients, diversion will be needed in others. If a diverting stoma is a possible outcome of surgery, there are data Anastomotic leak risk score. Reproduced from Frasson and supporting the participation of a stoma coauthors81 with permission. therapist in the preoperative evaluation and preparation for operation. These data support a favorable effect on postoperative quality of life when there is formal stoma therapist participation in preoperative and postoperative care along with preoperative stoma site marking. Diverting loop ileostomy is increasingly being used for temporary diversion for patients with colon cancer. There are data indicating a significantly higher rate of restoration of bowel continuity following diversion with a loop ileostomy. Concerns over the use of diverting loop ileostomy have included the risk of prolonged

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postoperative ileus after closure and the risk of intestinal obstruction after closure. An article that presents data from a prospective, randomized trial comparing stapled with hand-sewn anastomosis for ileostomy closure is by Loffler and coauthors83 in Annals of Surgery, 2012. The data analysis shows that overall patient outcomes in terms of ileus and early intestinal obstruction (within 30 days) were not significantly different when the groups were compared. Overall incidence of ileus was 13%. Bowel obstruction during the first 30 days after operation occurred in 10.3% of the stapler group and 16.6% of the hand-suture group. Three patients required reoperation and two of these were in the stapled group. Operative time was significantly shorter with stapled anastomosis. The authors concluded that both approaches to ileostomy closure were acceptable, but that the risk of postoperative ileus was significant.

Laparoscopic Colon Resection for Cancer As expertise in laparoscopic surgery has increased, appreciation of the benefits in terms of speed of postoperative recovery and diminished postoperative pain have led to application of laparoscopic techniques to cancer surgery. Current clinical practice guidelines stress that laparoscopic colectomy is an accepted approach to resection therapy for colon cancer, so long as the surgeon has expertise with the technique and oncologic effectiveness of the procedure has been documented. In this section of the overview we will discuss articles detailing the oncologic effectiveness of laparoscopic colectomy. A prospective randomized trial comparing outcomes of patients undergoing laparoscopic colorectal procedures for colorectal cancer with open operative procedures was described in an article by Kennedy and coauthors84 in the Journal of Clinical Oncology, 2014. In this study, 204 patients were randomized. All patients participated in a multidisciplinary enhanced recovery program. The primary outcome of interest was the level of physical fatigue at one month after operation. Other outcomes of interest included overall complications and hospital length of stay. The data analysis showed that there was no difference in the primary outcome. Hospital length of stay was shorter for the laparoscopy group. The authors noted that

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other randomized studies have shown favorable effects of laparoscopic colorectal procedures on variables like pain, complication rates, and recovery times; however, they acknowledged that their trial probably did not contain enough patients to accurately assess these variables. Two older long-term trials comparing laparoscopic and open colectomy for colon cancer have been reported. These were the Clinical Outcomes of Surgical Therapy (COST) trial and the United Kingdom Medical Research Council Conventional Versus Laparoscopic-Assisted Surgery in Colorectal Cancer (CLASICC) trial. Available short- and long-term outcomes from these studies are presented at this time. The first report of the COST trial is by Weeks and coauthors85 in JAMA, 2002. This report examines short-term quality of life assessments obtained at 2 days, 2 weeks, and 2 months postoperatively in patients randomized to undergo laparoscopic-assisted vs. open colectomy for colon cancer. In this early outcomes report, patients randomized to laparoscopic surgery required less analgesic medication than did the open surgery patients. There were no statistically significant differences in quality of life scores except at the 2-week mark, where quality of life was better for the laparoscopic patients. While the scores differed by a statistically significant margin at this time assessment, the actual difference in scores was less than five points, suggesting that clinical significance may not have been achieved. The authors concluded that laparoscopic-assisted colectomy should not be offered to patients solely because of an anticipated better quality of life. Data supporting equivalent oncologic effectiveness of the two approaches should be obtained before widespread application of laparoscopic colectomy. The next report from the COST study appeared in 2004 in the New England Journal of Medicine.86 This article reviewed data on a total group of more than 800 patients from multiple institutions randomized to undergo open or laparoscopically-assisted colectomy for colon cancer. The principle endpoint of interest in this report was the incidence of local recurrence and the follow-up interval was 4.4 years. The data disclosed that the cancer recurrence rate was identical at 18% at more than 4 years in both groups of patients. Overall and cancer-specific mortality did not differ in the two groups. Patients un-

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dergoing laparoscopic surgery consistently reported faster recovery times, fewer cardiopulmonary complications, and less analgesic use compared with the open surgery patients. The authors concluded that oncologic effectiveness at four years was equivalent in the two groups. The authors stressed that since the majority of recurrences are detected within the first two years following operation, the likelihood is that long-term outcomes will be equivalent for the two procedures. One concern for patients undergoing the laparoscopic approach had been the risk of port-site metastases. The authors reported that wound metastases occurred with equal frequency in the two groups. The final report of the COST trial is by Fleshman and coauthors87 in Annals of Surgery, 2007. This report supplies at least 5 years of follow-up data on all 872 patients randomized to receive open vs. laparoscopic colectomy as a curative procedure for colon cancer. The authors reported that rates of tumor recurrence were equivalent in the two groups; overall and cancer-specific survivals were likewise similar. This report was presented to the plenary session of the 2007 annual meeting of the American Surgical Association. In the opening discussion that accompanied the article, several discussants emphasized the unusual statistical analysis that is necessary for a “non-inferiority” trial; this type of analysis is most often applied to studies comparing two pharmaceutical agents. The authors noted that an equivalence trial would have required more than 3,000 patients; because they accrued fewer than their planned 1,200 patients in 7 years they chose this design; it was unrealistic to expect adequate enrollment for an equivalency trial. One discussant noted that the disease-free survival reported in this study was lower than reported in a recent chemotherapy trial. In response, the authors commented that this occurred primarily because of a lower proportion of patients receiving oxaliplatin therapy in the COST trial. The first report from the CLASICC trial appeared in 2005 in an article by Guillou and coauthors88 in Lancet, 2005. The authors reported short-term outcomes of a multicenter randomized controlled trial conducted in Britain. The study was conducted during the interval from 1996 to 2002. More than 220 patients were randomized to receive open surgery, while more than 450 patients received laparoscopic-assisted colectomy. The authors analyzed outcomes data in a follow-up interval

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of 3 months. Primary endpoints were positive longitudinal and circumferential resection margins, proportion of early stage and advanced tumors, in-hospital mortality, and short-term recurrence rates. Analysis was done by intent-to-treat as well as actual treatment received. The authors found that there was no difference noted when groups were compared for any of the endpoints. There was a difference in the rate of positive circumferential margins when laparoscopic low anterior resection was compared with open low anterior resection for rectal cancer. More positive circumferential margins were observed in patients undergoing laparoscopic surgery. Although this difference did not reach statistical significance, the difference was such that the authors cautioned against the adoption of laparoscopic, low-anterior resection until additional experience is available. The second report from the CLASICC trial is by Jayne and coauthors89 in the Journal of Clinical Oncology, 2007. This article reports on a 3-year follow-up of a randomized patient group. Quality of life assessments as well as overall and disease-free survival comparisons were carried out in this study. There were no significant differences noted in any of the comparisons. The authors emphasized that the nonsignificant difference in the rate of positive circumferential margins in the laparoscopic surgery group did not result in any adverse effect on 3-year outcomes. The final report from the CLASICC trial is by Jayne and coauthors90 in the British Journal of Surgery, 2010. Five-year follow-up data is presented in this report. As in the prior reports, no significant differences in long-term mortality, cancer recurrence rates, or quality of life were discovered when the groups were compared. The authors concluded that surgeons with laparoscopic expertise can safely perform laparoscopic-assisted operations for colorectal cancer with long-term outcomes that are equivalent to open operations. Two systematic reviews of the literature that analyze pooled data with at least three years of follow-up provide an overview of available trial data comparing laparoscopic-assisted with open colectomy for colorectal cancer. The first of these is by Bonjer and coauthors91 in Archives of Surgery, 2007. This analysis used data from three large European trials comparing open and laparoscopic-assisted colectomy for malignant disease. At least

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3 years of follow-up are available for all of these studies. The authors reported no difference in overall or diseasefree survival when the two approaches were compared. Early analyses of data from these trials noted a slightly lower average number of lymph nodes recovered during the laparoscopic-assisted procedures as well as a slightly higher rate of positivity of circumferential margins in the patients undergoing laparoscopic-assisted operations. Some concern was raised when early data were reported regarding a conversion rate exceeding 20% in some trials. For the most part, this high conversion rate was because of requirements for conversion imposed by the rules of the trial. Bonjer and coauthors91 reported an overall conversion rate of 19%. There was no significant difference between the two treatment groups in terms of average number of nodes recovered and margin positivity. The authors concluded that laparoscopic-assisted colectomy is feasible, safe, and associated with excellent medium- and long-term outcomes. The final systematic review of the literature to be considered in this section is by Kuhry and coauthors92 in Cancer Treatment Reviews, 2008. These authors identified 12 trials of sufficient quality for analysis. When the oncologic effectiveness of the operations was compared, there was no significant difference identified in rates of recurrence, overall survival, and disease-free survival. Few data were available regarding the incidence of incisional hernia and postoperative intestinal obstruction from adhesions. The authors noted that incisional hernia rates of 20% or more have been reported after open colectomy for colorectal cancer. From the data available, the authors concluded that port-site hernias occur in significantly less than 20% of patients. They also noted that data concerning adhesion formation and complications of adhesions are scarce, although these are reportable endpoints in some ongoing trials. What data is available indicate that there is no increase in the risk of readmission for adhesive intestinal obstruction after laparoscopic-assisted colectomy for cancer.

The Elderly Patient with Colon Cancer As noted previously, the proportion of elderly patients in the general population is increasing and, therefore, the number of elderly patients with colon cancer can be

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expected to increase as well. An article dealing with the clinical characteristics of older patients with colon cancer is by Devon and coauthors93 in Diseases of the Colon and Rectum, 2009. These authors compared outcomes in a group of more than 220 patients with a mean age of 81 years with a group of younger patients in a single institution retrospective study. The analysis disclosed that operative mortality was 1% in the younger patient group as compared to 4.2% in older patients. As expected, the older cohort had more comorbid conditions and they were, as a group, higher risk than the younger patients. When longterm mortality was evaluated, overall survival was lower in the older group compared with the younger group. Cancer-specific survival, however, was identical when the groups were compared. The authors emphasized that the same principles of operative and postoperative management should be applied in older patients as are applied in younger patients. Devon and colleagues reported that the older patient group was less likely to receive postoperative chemotherapy than the younger patient group. In both groups, outcomes were predicted based on assessments of operative risk and tumor stage. The authors concluded that age should not be a determining factor for altering the standard treatment approaches for colon cancer. An article examining the use of standard approaches for treatment of colon cancer in elderly patients is by Steele and coauthors94 in the Journal of the American College of Surgeons, 2011. The authors used data from the SEER database to determine whether the rate of harvesting at least 12 lymph nodes varied according to the age of the patient. The data disclose that the 12 lymph node yield rate declined progressively as the age of the patients increased. The authors concluded that there is essentially no impact of an attempt to achieve a 12 lymph node yield on operative mortality or morbidity. Given the fact that older patients are healthier in contemporary populations than in earlier eras, there is no reason to withhold postoperative chemotherapy simply because of patient age. An article presenting a systematic review of the literature regarding the use of laparoscopic colon resection in elderly patients is by Seishima and coauthors95 in the Journal of Gastrointestinal Surgery, 2015. The authors identified 30 studies of acceptable quality. Laparoscopic approaches were used for colon resection in nearly 75% of patients reported; the remaining approaches were rectal

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procedures. The data analysis showed that laparoscopic surgery was associated with significantly decreased risk of postoperative complications and perioperative mortality. Overall, long-term mortality was not different for open vs. laparoscopic procedures. The authors concluded that the shorter recovery time and lower rates of mortality and morbidity would likely contribute to improved quality of life in patients undergoing laparoscopic colorectal procedures.

Patient Follow-Up after Successful Surgery for Colon Cancer The NCCN practice guidelines for colon cancer28 recommend that patients have a complete history and physical examination every 3 to 6 months for the first two years after operation, then every six months, for a total of five years. CEA levels should be assessed at the same intervals. Annual chest/abdominal CT imaging is recommended on an annual basis for five years. Colonoscopy is recommended at one year after operation or earlier if no preoperative colonoscopy was performed. If advanced adenoma is found at colonoscopy, then the examination should be repeated in one year. If no advanced adenoma is discovered, then colonoscopy is repeated in three years, then at five-year intervals if negative. A randomized trial comparing CEA alone, CT imaging alone, and CEA plus CT, or minimal follow-up annually for five years after curative surgery for colon cancer was presented in an article by Primrose and coauthors96 in JAMA, 2014. The study randomized 1,200 patients. The data analysis showed that CEA and CT imaging alone conveyed a small but significant advantage in detecting recurrent or new malignancy that could be treated with curative intent; however, the combination of CT and CEA offered no additional advantage. The proportion of patients who also underwent postoperative colonoscopy was not reported.

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Management of Complicated Colon Cancer Common conditions complicating the management of patients with colon cancer include colon obstruction colon perforation, local recurrence, and synchronous metastatic disease; these topics are discussed in this section of the overview. The traditional approach to an obstructing cancer of the left colon is to perform one of the two-stage operations for this condition: options include preliminary diverting colostomy with later colectomy or segmental colon resection with deferred anastomosis. Obstructing tumors of the right and proximal transverse colon may be managed with a one-stage operation that includes a primary ileocolic anastomosis.

Colonic Stenting The availability of endoscopically placed stents has altered the approach to malignant obstruction of the colon. Stenting offers the opportunity to proceed with colon preparation and elective colectomy. Stenting may also provide an opportunity for preoperative chemotherapy and provide useful palliation for patients who are not fit for operation. An article that presents data from a prospective randomized trial of colonic stenting compared with emergent operation for patients with obstructing colon cancer was by van Hooft and coauthors97 in Lancet Oncology, 2011. The authors randomized 98 patients to receive colonic stenting with definitive operation with 14 days or emergency colectomy with diversion. The analysis showed that there was no difference in operative or overall mortality when the groups were compared. Morbidity rates were equivalent in the two groups. Four of 47 patients in the stenting group developed stent-related colon perforations; five patients developed anastomotic leakage after the definitive operation. There were significantly fewer stomas created after initial management in the emergent surgery group, but this difference disappeared over longterm—follow-up, possibly because of stomas that became

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necessary when anastomotic leak occurred after definitive surgery in the stented patients. The authors concluded that there was no distinct advantage for stenting in malignant colon obstruction occurring in average risk patients. It is possible that stenting as a bridge to surgery may be helpful in patients at high risk for operation. Management of patients with acute obstructing colon cancer treated with stenting as a bridge to definitive surgery or as palliation is the focus of an article by Branger and coauthors98 in the International Journal of Colorectal Disease, 2010. These authors reported a retrospective medical record review of 66 patients. Twentyseven patients were treated with stenting with intent to perform potentially curative elective operation at a later date. Stent placement failed in 3 patients and these patients underwent emergent operation. Of the 24 patients remaining, 22 underwent definitive operation with no deaths and no major operative complications. Long-term outcomes in this group were predicted by tumor stage. Of the 39 patients treated with stenting for palliation, peri-intervention mortality was 6.5%. Stent migration occurred during follow-up in 3% of patients and stent obstruction occurred in 12% of patients. Overall success of stent placement exceeded 92%. In the discussion section of the article, the authors cited data supporting the superiority of single-stage operation for colon cancer after successful stenting. A contrasting experience is reported in an article by Fernandez-Esparrach and coauthors99 in the American Journal of Gastroenterology, 2010. These authors reported data from 44 successful stent placements in a group of 47 patients. For patients who received stents for palliation of incurable disease, the long-term complication rate was 51%. Three patients had stent-related colon perforation and all three died. Stent migration and obstruction occurred in 22% and 17% of patients, respectively. Of patients who underwent potentially curative operation following stent placement, less than half were able to avoid colostomy. Discussion of these discouraging data is continued in a letter to the editor of the journal by Manes and coauthors.100 These authors noted that the report provides data on only 47 patients treated during the course of 5 years, and they question whether this small number represents a sufficient experience to gain

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mastery in stent placement. The fact that half of the stentrelated perforations occurred during the first month after stent placement suggests that the endoscopists may not have had sufficient experience to place the stents with consistent success. Manes and colleagues additionally noted that stents were placed for “suspected impending” obstruction and not actual obstruction in 17% of patients. They stressed that stent migration rates can be expected to increase in this patient group. Manes and associates concluded that patient selection is critical to successful stent placement. In a reply, Fernandez-Esparrach and coauthors agreed that the accuracy of patient selection improves with added experience. Although stents may be beneficial in selected patients with malignant colon obstruction, surgeons have been reluctant to apply this approach broadly because of fear of stent-related complications and because avoidance of colostomy has not been a consistently observed outcome in patients treated with stents as a bridge to surgery. An article that presents data illustrating this concern is by Suen and coauthors101 in Surgery, 2015. The authors conducted a mail survey including surgeons in Australia and New Zealand. There was an admirable 65% response rate. Colonic stenting equipment and expertise was available to 98% of the respondents. Surgeons were asked if they would be willing to participate in a randomized prospective trial comparing stenting to emergency surgery. Only 29% of respondents expressed a willingness to participate. Most respondents felt that stenting was an appropriate approach for palliation of patients with advanced disease or prohibitive operative risk. In patients with colonic obstruction who were candidates for curative surgery, surgeons indicated they would choose emergent curative resection of the involved colon segment because stenting was not perceived to be cost effective or an intervention that would be accepted by patients.

Perforated Colon Cancer An article that reviews data on the management of perforated colon cancer is by Lee and coauthors102 in Colorectal Disease, 2007. These authors conducted a retrospective review of medical record data on 28 patients with perforation of the colon complicating colorectal cancer. The

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authors noted that a traditional concept in approaching patients with malignant perforation of the colon is to assume that long-term outcomes will be dismal because of tumor cell implantation in the peritoneal cavity due to the perforation. In this patient group, operative mortality was 11%, reflecting patients with severe acute disease and major associated comorbid conditions. In patients who survived operation, 5-year overall and disease-free survival exceeded 50%. There were no long-term deaths from peritoneal metastases. In the discussion section of the paper, the authors cited data indicating that recovery of viable tumor cells from the peritoneal fluid obtained at the time of operation for perforation has been very infrequent. They concluded that outcomes of treatment for colorectal tumor perforation are related to the stage of the disease and the frequency of lymph node metastasis in the resected specimen. They further recommend that patients be treated aggressively for perforation because long-term survival is possible. Another article dealing with outcomes in patients treated for perforations of the colon complicating colorectal cancer was by Abdelrazeq and coauthors103 in Colorectal Disease, 2008. These authors identified 82 patients with T4 colorectal cancers that had perforated the colon at the tumor site; they compared the short- and long-term outcomes in these patients to 82 patients matched for tumor stage without perforation. The analysis concluded that overall and cancer-specific survival was a function of tumor stage. Excess mortality in the group with tumor perforation was related entirely to perioperative mortality that was higher due to the need for emergent intervention in high-risk patients. Additional data confirming the higher perioperative mortality for patients with colorectal cancer complicated by colon perforation were presented in an article by Tan and coauthors104 in the International Journal of Colorectal Disease, 2010. The data analyzed by these authors support the conclusions of the articles discussed in this segment of the overview. Short-term mortality rates are higher compared with patients who have elective operation for colorectal cancer. Long-term outcomes are related to tumor stage.

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Tumor Extension to Adjacent Organs Advanced colon cancers occasionally involve adjacent organs such as the bladder, the internal reproductive organs, the ureter, and the small intestine. Ideally, the approach to these patients is to remove all of the involved tissue with an en bloc resection. In most situations, preoperative imaging will document the extent of involvement so that effective planning for complete resection can occur. The effect of extension of the tumor into adjacent structures in patients with colorectal cancer was the focus of an article by Darakhshan and coauthors105 in Annals of Surgery, 2008. The authors queried a single institution’s prospectively maintained database of patients undergoing operation for colorectal cancer. During a 29-year interval, 262 patients with extension of the primary tumor into adjacent tissues were identified. This group was slightly more than 10% of the total experience from this institution. The authors found that extension of colon cancer into adjacent organs did not incur an additional risk of intraoperative or perioperative complications, as long as tumor perforation and spillage did not occur. Long-term outcomes did not worsen beyond those predicted by tumor stage in patients with colon cancer extending into adjacent structures; patients with rectal cancer, however, were more likely to develop local pelvic recurrence if there was extension of the tumor into adjacent tissues. Given the adverse effects of tumor perforation and transection, the authors recommend en bloc resection of all involved tissue. They also recommend that restoration of bowel continuity be deferred in rectal cancer patients with extension of the tumor into adjacent structures because of the increased risk of pelvic recurrence.

Synchronous Metastatic Disease A few patients with colon cancer will present with synchronous metastatic disease. If the metastatic disease is in the liver or lung, resection of the metastatic lesions may contribute to improved long-term outcomes. In many, if not most, of these patients, liver and lung resections will need to occur at a time separate from the operation for removal of the colon cancer; preresection chemotherapy may be useful in these patients. In a few patients, small,

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localized metastatic lesions on the surface of the liver can be removed at the time of colectomy if these lesions can be shown to be isolated metastases. Data confirming the value of liver resection for isolated liver metastases and chemotherapy plus liver resection for selected patients with multilobar liver metastases are found in an article by Sperti and coauthors106 in Diseases of the Colon and Rectum, 2006. These authors reported data on patients treated with chemotherapy only for hepatic and extrahepatic metastatic disease and for patients with metastases confined to the liver. Overall and diseasefree survivals are reported. Progression-free survival was one year and more than two years for patients with liver metastases treated with chemotherapy followed by liver resection and primary liver resection respectively. Overall survival for these two patient groups was two years and more than four years, respectively. The authors concluded that metastatic disease confined to the liver can be treated successfully using a multi-pronged approach.

Chemotherapy for Colon Cancer The NCCN practice guidelines28 for colon cancer management recommend adjuvant chemotherapy for selected patients with Stage II disease (T3-4 N0 M0) who are deemed at high risk because of histologic evidence of lymphovascular invasion, tumor budding, and certain DNA and thymidine labeling characteristics. Testing for microsatellite instability helps to select patients who are likely to respond to chemotherapy as well as patients who will not respond.107 Data are available, furthermore, to support the use of adjuvant chemotherapy in patients with Stage II colon cancer when fewer than 12 lymph nodes are harvested from the excised specimen.108 In addition, all patients with Stage III are recommended for adjuvant chemotherapy. Chemotherapy for Stage IV patients is associated with poorer outcomes relative to overall and cancer-free survival compared with high-risk Stage II and Stage III patients. An article dealing with the use of chemotherapy for patients with colon cancer was by Saltz109 in Surgical Oncology Clinics of North America, 2010. Saltz agreed with the use of adjuvant chemotherapy for high-risk Stage II (criteria discussed above) and all Stage III patients after

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operation with curative intent for colon cancer. Saltz next reviewed the various effective chemotherapy approaches. Most protocols use fluoropyrimidine drugs (such as 5-fluorouracil) combined with leucovorin and, in some protocols, oxaliplatin. The author noted that there is an oral form of 5-fluorouracil that has been shown as effective in intravenous forms, but this drug is not available in the United States. Compared with surgery alone, the addition of adjunctive chemotherapy increased overall and disease-free survival from 62% to 76%, according to the National Cancer Institute trial data.110 Data cited in the article indicated that a small increment in survival was noted in the MOSAIC trial with the addition of oxaliplatin (72% vs. 67%), but this benefit was realized at the cost of prolonged peripheral sensory neuropathy in 1% of patients. Saltz goes on to note that the other agents used alone or in combination protocols (irinotecan, bevacizumab, cetuximab) have, to date, failed to show a clinically significant benefit over the fluoropyrimidine drugs plus oxaliplatin. Recent efforts have focused on identifying additional molecular markers that may improve outcomes of chemotherapy. Markers studied to date include P13K and Fas-associated phosphatase. These markers, and possibly others, may prove useful in the future.

Rectal Cancer The review article by Brenner and coauthors1 stressed the importance of exact staging of the primary rectal tumor in order to select patients who may be appropriate for local excision of tumors and to document the features of advanced lesions that may respond to neoadjuvant chemoradiation therapy. The use of these approaches may result in reduction of tumor size sufficiently to permit resection with restoration of intestinal continuity rather than creation of a permanent stoma. Clinical practice guidelines for rectal cancer have been promulgated by the NCCN.111 The full guidelines document is available free from the NCCN website at www.nccn.org. The guidelines document also emphasizes the importance of accurate staging. Accurate staging requires close cooperation between

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gastroenterologists who may make the initial diagnosis on endoscopy, pathologists who will be responsible for identifying high-risk histologic findings such as lymphovascular and perineural invasion, medical oncologists who will provide advice and conduct neoadjuvant and adjuvant chemotherapy protocols, and surgeons who will need to assure complete excision of the primary tumor with an adequate proximal and distal resection margins and a clear circumferential margin that is achieved using total mesorectal excision (discussed in detail in a later part of this section). The TNM staging system for rectal cancer is the same as the staging system used for colon cancer. The practice guidelines document recommends that local excision of rectal lesions be considered for cancers located within 8 cm of the anal verge and occupying 30% or less of the rectal circumference. If biopsy has shown that the lesion is T0 or T1 with no high-risk histologic features, local excision may be definitive. Adequate local excision requires deep and mucosal margins of 3 mm or more. The guidelines document does cite data indicating that nodal micrometastases may be present even in these early-stage lesions. The guidelines document emphasized that local excision does not allow for histologic examination of lymph nodes; data were cited indicating that recurrence of cancer occurs in 10% to 12% of patients treated with local excision vs. 2% to 3% of early-stage lesions treated with definitive rectal resection. One specific subtype of rectal neoplasia, rectal carcinoid, is the focus of an article by Shields and coauthors112 in Annals of Surgery, 2010. The authors obtained data from prospective colorectal neoplasia databases maintained at eight institutions in Europe and North America. Over a nine-year interval, 202 patients were identified. Complete clinical, pathologic, and outcomes data were available for all patients. The median follow-up interval was five years. The authors noted that there are several challenges in the diagnosis, staging, and surgical management of rectal carcinoid tumors. The lesions are rare, accounting for only 1.8% of rectal cancer diagnoses. There is no agreed-upon staging system, and there is a general belief that the tumors are indolent. Data have emerged, however, suggesting that rectal carcinoids metastasize to lymph nodes in a significant proportion of patients. For these reasons, the authors chose to evaluate outcomes in their cohort of patients. Analysis of the outcomes data

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using multivariate logistic regression showed that tumor size of 10 mm or greater and histologic confirmation of lymphovascular or perineural invasion were predictive of lymph node metastases. The discussion section of the article emphasized that current guidelines recommend endoscopic local resection for lesions 11 mm in diameter or smaller. The analysis further showed that overall fiveyear survival for patients with rectal carcinoids approached 90%; but this dropped to 70% if there were lymph node metastases. The authors concluded that careful examination of excised lesions is required to document lesion size and determine the presence of high-risk histologic findings so that conventional resection can be offered to patients who are at increased risk for nodal metastases.

Chemotherapy & Radiation Therapy for Rectal Cancer Assessment of the effectiveness of neoadjuvant and adjuvant chemotherapy and radiation therapy protocols for patients with rectal cancer needs to be done in light of data showing that optimum surgical technique plays a large role in controlling local recurrence. Specifically, the technique of total mesorectal excision to obtain a negative (> 2mm) circumferential margin around the excised rectum is a strong driver of decreased local recurrence rate after surgical treatment of rectal cancer. The technique of total mesorectal excision and the importance of the circumferential margin are discussed in more detail in the following section of the overview. The articles reviewed in this section of the overview assess the impact of preoperative and/or postoperative chemotherapy and radiotherapy in patients receiving optimum surgical therapy for rectal cancer. One of the earliest trials assessing the impact of a short course of preoperative radiotherapy on the rate of local recurrence after optimum surgical resection of rectal cancer is by Kapitelin and coauthors113 in the New England Journal of Medicine, 2001. These authors randomized more than 1,800 patients in multiple Dutch institutions to receive optimal resection therapy alone, using total mesorectal excision vs. optimal surgical therapy plus a short course of preoperative radiotherapy. The data disclosed that a statistically significant reduction in local

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recurrence rate was realized at two years of follow-up in the patients having radiotherapy plus optimum surgical resection. Overall, long-term survival was not different when the two treatment groups were compared. Data in an article by Murata and coauthors114 does examine anorectal function in the group of patients having low anterior resection after a short course of preoperative radiotherapy. These data indicated that fecal incontinence and fecal incontinence-related quality of life are both poorer in patients undergoing a short course of preoperative radiotherapy. Recent studies have contributed to refinements in approaches to management of patients after neoadjuvant chemoradiation therapy. The review article by Brenner and coauthors1 cited data indicating a significant reduction in local recurrence rates with the use of neoadjuvant chemoradiation therapy in patients with T3 tumors. Data cited in the report indicate a 50% reduction in local recurrence rates in patients treated with neoadjuvant chemoradiotherapy. The NCCN clinical guidelines document111 recommends the documentation of tumor stage with biopsy and histologic examination, determination of depth of tumor extent with endorectal ultrasound, and the use of MRI to document risk of nodal metastasis. An article that examined the ability of MRI to predict tumor stage in patients with rectal cancer is by Taylor and coauthors115 in Annals of Surgery, 2011. The authors reported outcomes on 374 patients enrolled prospectively in a multiinstitutional cohort study. The participating institutions included specialized colorectal disease centers and general hospitals. “Good risk” patients defined by MRI included patients with tumors that were more than 1 mm from the mesorectal fascia and tumors with no evidence of local venous invasion. For low rectal tumors “good risk” patients had, in addition, no evidence of involvement of the levator ani muscle or encroachment into the intersphincteric plane. The data analysis showed that patients deemed to be “good-risk” T1-3 rectal tumors on MRI who were treated with total mesorectal excision without preoperative chemoradiation therapy had disease specific 5-year survival of 85% and a local recurrence rate of less than 2%. The authors concluded that high-quality MRI could predict patients who could be managed without neoadjuvant therapy despite having T3 tumor grade.

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The NCCN guidelines document111 notes that preoperative neoadjuvant chemoradiotherapy using longcourse protocols will frequently be associated with tumor downstaging. This increases the chance that restoration of intestinal continuity will be possible and offers the potential for nonoperative therapy in selected patients. The guidelines document notes that neoadjuvant chemotherapy may be offered to selected patients with T2 tumors if high-risk histologic characteristics are present and/or there is imaging evidence of nodal metastases. While long-course neoadjuvant radiation therapy is the preferred approach for patients treated in North America, short course therapy (5 weeks) is used in some European countries. There is no option for tumor downstaging in short course therapy and data have suggested that long-course therapy may be associated with lower risk for local recurrence and a lower frequency of fecal incontinence. Preoperative chemoradiotherapy with a delay of 6-8 weeks before operation is used in patients with clinically advanced rectal cancer. Data are available that suggest a significant proportion of these patients will respond to the therapy and that a potentially curative resection can be anticipated in many of these patients.116 Data are also available indicating that MRI may be useful in determining the extent of response to preoperative chemoradiotherapy for patients with locally advanced rectal cancer. 117 An article that reports outcomes of short-course neoadjuvant radiation therapy combined with total mesorectal excision is by van Gijn and coauthors118 in Lancet-Oncology, 2011. The authors reported a randomized, prospective trial involving more than 1800 patients treated over a three-year interval. The data analysis showed that significant reductions in local recurrence and improved overall survival were observed in patients who had short-course radiotherapy and total mesorectal excision. The benefit was negated if there was a positive circumferential margin indicating incomplete total mesorectal excision. The benefits were most notable in patients with T3 tumors. In lower stage lesions, the toxic effects of radiation therapy outweighed the benefits. A study of short-course preoperative radiotherapy by Stephens and coauthors119 in the Journal of Clinical Oncology, 2010 presented data that sexual dysfunction in males and impaired fecal continence occurs after short-

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course preoperative radiotherapy. The authors were not able to show that sexual dysfunction was increased in patients receiving radiotherapy, but fecal incontinence was more common in the radiated patients. The method used to reestablish intestinal continuity may interact with the effects of preoperative radiation to produce improved results. An article by Parc and coauthors120 presented data suggesting that preoperative short-course radiotherapy is associated with higher rates of fecal incontinence. The incontinence rates were favorably influenced by the use of colonic J-pouch reconstruction. The data suggest that the beneficial effects of preoperative radiotherapy on local recurrence could be achieved with tolerable rates of incontinence in patients with J-pouch reconstruction. More recently, trials combining preoperative radiation therapy and chemotherapy have been reported. A metaanalysis of available data is by Latkauskas and coauthors121 in Colorectal Diseases, 2010. The authors noted that a large amount of data supported the use of postoperative chemotherapy and radiotherapy for patients at increased risk for local recurrence (positive or threatened circumferential margin) after surgery for rectal cancer. They further noted that recent data have suggested improved outcomes with the use of preoperative chemoradiation therapy. These authors were able to identify five randomized prospective trials comparing preoperative chemoradiotherapy with radiation therapy alone. The data disclosed that the complete pathologic and clinical response rates are improved by the addition of chemotherapy to radiation therapy, but that this occurs at risk of therapy-related toxicity. Additional data on patient response to preoperative chemoradiotherapy for rectal cancer are found in an article by Pucciarelli and coauthors122 in Annals of Surgery, 2011. These authors followed 142 patients over the course of 12½ months after preoperative chemoradiotherapy and at least one year after operation. Quality-of-life questionnaires were administered that specifically focused on bowel and sexual function. Response rates approached 80% at all time points. The data disclosed that anorectal function and sexual function were both reported to be worse at all time points in patients who received preoperative chemoradiotherapy. This observation was consistent even though overall quality of life had returned to baseline

42

by one year after operation. The authors concluded that preoperative chemoradiotherapy should be used cautiously in patients undergoing operation for rectal cancer. Some patients who receive neoadjuvant chemoradiotherapy experience a complete pathological response. Whether nonoperative management may be appropriate in such patients is an important question relevant to the management of this patient group. The first included study of this topic is reported by Maas and coauthors123 in Lancet-Oncology, 2010. The authors conducted a systematic review of the literature to determine outcomes in patients who had complete pathologic response to neoadjuvant chemoradiation therapy. Twenty-seven acceptable studies were included that reported outcomes on 3,105 patients; the data analysis showed that patients with pathologic complete response had significantly better long-term survival (83% vs. 65%) and the risk for local recurrence was reduced by 50%, compared with patients who did not have pathologic complete response. Another study reporting data on patients treated nonoperatively after complete clinical response is by Smith and coauthors124 in Annals of Surgery, 2012. Complete clinical response was defined as a negative digital rectal examination and only a flat scar visible on endoscopy. The index follow-up examination was performed 8–10 weeks after completion of treatment. The data analysis showed that long-term disease-specific survival was similar in patients treated operatively and nonoperatively (90% in both groups). Salvage rectal resection was successful in controlling local recurrence in all six patients who had local recurrence. The authors emphasized the importance of careful follow-up if nonoperative management is chosen. Similar results were reported in an earlier study by Maas and coauthors.125

Operative Management of Rectal Cancer The NCCN clinical practice guidelines document111 recommend that the primary cancer be resected with proximal and distal margins of 5 cm. The document notes that for lesions that are close to the anal verge a distal margin of 2 cm is acceptable. The guidelines emphasize the importance of obtaining a clear circumferential margin of 2 mm or more. The circumferential margin

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represents the distance of any malignant cells from the outermost layer of the perirectal fascia. Completion of the dissection of the rectum in the tissue plane that is external to the outermost layer of the perirectal fascia is termed “total mesorectal excision.” In the remainder of this section of the overview several articles that provided technical guidance and illustrations of the techniques of total mesorectal excision will be reviewed. The objectives of total mesorectal resection are to remove the rectum with all of the surrounding perirectal fat and lymph nodes that are contained within the perirectal fascia while preserving the autonomic nerves that are located in the presacral fascial layer and on each side of the rectum at the level of the levator ani muscle. An article reviewing the anatomy and functions of the pelvic autonomic nervous system and the techniques for preserving the nerves during rectal resection is by Guillem and Lee-Kong126 in the Journal of Gastrointestinal Surgery, 2010. This article provides a clear description of technique as well as color photograph illustrations and is included as a full-text reprint accompanying some formats of SRGS. The authors noted that the nerves of the superior hypogastric plexus receive input directly from the sympathetic trunk or from the inferior mesenteric ganglion. Parasympathetic input to the inferior hypogastric plexus comes mainly from the second sacral nerve root with some contribution from the second and fourth sacral nerve roots. The parasympathetic nerves function to achieve and maintain penile erection while the sympathetic nerves are important for ejaculation. Both types of nerves contribute to normal bladder function. The authors cited data confirming the oncologic benefit of total mesorectal excision in reducing local recurrence rates of rectal cancer as well as mortality. Preservation of the autonomic nerves has reduced the frequency of genitourinary dysfunction; data was cited indicating that adequate male sexual function was preserved by using total mesorectal excision in 86% of men having low anterior resection and more than half of male patients having abdominoperineal resection. Additional data cited in the article confirmed that the rate of bladder dysfunction in patients who had total mesorectal excision combined with visualization and preservation of the pelvic autonomic nerves was less than 5%. The authors concluded their discussion by noting that there

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is increasing interest in laparoscopic approaches for resection of rectal cancer. They noted that bladder function is maintained with laparoscopic total mesorectal excision according to available data, but reported that rates of sexual dysfunction have been higher compared with open approaches. A prospective randomized trial that compares the oncologic effectiveness of laparoscopic rectal resection with open surgery is reported by van der Pas and coauthors127 in Lancet-Oncology, 2013. The authors reported outcomes from operations on 1,103 patients randomized to either laparoscopic or open rectal resection. The data analysis showed that patients having laparoscopic procedures had lower volumes of blood loss, faster return of bowel function, and shorter hospital stay compared with patients having open procedures. Macroscopic complete resection was observed in 90% of both groups and pathologic examination confirmed a rate of positive circumferential margin of 10% in each group. Of note was the observation that for distal rectal tumors, the rate of positive circumferential margin was 10% for laparoscopic procedures and 22% for open procedures. The data analysis showed that conversion from a laparoscopic procedure to an open procedure occurred in 16% of the operations. The authors acknowledged that they do not have long-term—followup data to document outcomes in terms of local recurrence, mortality, and genitourinary dysfunction. They noted that patients with T3 and T4 tumors were excluded from the trial, and that, therefore, these findings cannot be interpreted to pertain to all patients with rectal cancer. It is noteworthy that data on the frequency of one risk factor for difficult pelvic dissection and autonomic nerve injury (a history of prior pelvic surgery) in each group is not reported. The low blood loss reported for both groups suggests that difficult dissection was infrequently encountered in the patients included in this report. Documentation of risk factors for incomplete total mesorectal resection is the focus of an article by Leonard and coauthors128 in Annals of Surgery, 2010. These authors reported a review of photographs of gross and histologic examinations of resected specimens from rectal cancer procedures. The photographic data were interpreted by a panel of pathologists and submitted by surgeons who were participating in a program of evaluation of “trainer

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surgeons” to teach total mesorectal resection to other surgeons. A complete total mesorectal resection was defined as an intact and smooth mesorectal surface with no defects deeper than 5 mm and no distal coning. A nearly complete resection was defined as an irregular mesorectal surface with defects deeper than 5 mm but no visible muscle layer and only moderate distal coning. An incomplete resection was defined as very irregular mesorectal surface with areas of visible muscle layer. A positive circumferential margin was defined as tumor tissue within 1 mm of the mesorectal fascial layer. The data analysis showed that pathologic evaluation of resected specimens was incomplete in 57% of specimens. Mesorectal resection was complete in 21%, nearly complete in 47%, and incomplete in 32% of specimens. Risk factors identified from a multivariate linear regression analysis for incomplete total mesorectal resection were obesity, absence of downstaging after long-course neoadjuvant chemoradiation and the use of laparoscopic approaches. The authors concluded that the quality of mesorectal resection is impacted by identified risk factors and that the quality of pathologic examinations needed to be improved. An article that reviewed features of the preoperative evaluation and operative techniques for tumor resection and re-establishment of intestinal continuity was by Stewart and Deitz129 in Clinics in Colon and Rectal Surgery, 2007. The authors stressed the importance of accurate imaging with endorectal ultrasound to document tumor depth of penetration. They also stressed that patient counseling concerning the fact that postoperative diarrhea and fecal incontinence may occur for at least several months after creation of a coloanal anastomosis or construction of an ileoanal pouch. The authors favored preoperative consultation with a stomal therapist and stoma marking prior to the procedure. The effectiveness of this approach was confirmed in an article reviewed previously.130 The authors cited data in the article confirming the additive benefit of neoadjuvant chemoradiation to the effectiveness of total mesorectal resection. Additional data is cited confirming that total mesorectal resection is not associated with a significantly increased risk for anastomotic leak. Long-term anorectal function outcomes were discussed by the authors. Preoperative radiation is noted as a risk factor for suboptimal anorectal function, but older age was not a risk factor. The authors cited data that suggest that preoperative testing of anorectal function may pre44

dict postoperative functional abnormalities. In the study cited, a longer anal high-pressure zone, larger maximal tolerable rectal volume, and lower rectal sensory threshold were associated with better anorectal function after tumor resection and low anorectal anastomosis. An article describing an alternative initial approach to exposing the rectum for total mesorectal resection is by Havenga and coauthors131 in Digestive Diseases, 2007. In this article the authors describe a technique that begins dissection of the plane between the presacral fascia and the mesorectal fascia from the right side rather than the left. Readers interested in this approach are encouraged to review the entire article. The final article reviewed is by Koh and coauthors132 in Diseases of the Colon and Rectum, 2005. This article is supplied as a full-text reprint accompanying some formats of SRGS. The authors pointed out the fact that the effectiveness of total mesorectal excision in reducing local recurrence of rectal cancer is in part attributable to complete resection of the primary tumor and nearby lymph nodes, but also due to the fact that there are often tumor deposits in the distal mesorectum located in the fat and connective tissue within the mesorectal envelope—these would be left behind if total mesorectal excision was not performed. The authors also stressed the fact that angulation of the coccyx and the pelvic floor may cause the mesorectum to “fan out.” This phenomenon creates a situation where a portion of the mesorectum may be interpreted as distal to the rectum. Failure to recognize this can lead to “coning” of the distal dissection, with the attendant danger of leaving a tumor nodule behind after rectal resection. From the data reviewed, it seems clear that the success of total mesorectal resection is attributable to optimal surgeon knowledge of anatomy with careful consideration of potential risk factors for difficult dissection, combined with close cooperation with the pathologist who will review the resected specimen. Diligent attention to achieving complete total mesorectal resection with a clear circumferential margin is a critically important feature of successful rectal cancer surgery.

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Anal Cancer Anal cancer is an unusual neoplasm that clusters in men who have sexual relations with men (MSM) and who are HIV positive. Data reported in a systematic review of the literature by Machelek and coauthors133 in LancetOncology, 2012, included 53 studies that were analyzed. The authors noted that development of anal cancer in MSM is believed to be associated with human papilloma virus (HPV) infection. Anal cancer is believed to arise from a precursor lesion (anal intraepithelial neoplasia) and screening efforts are directed toward detecting the precursor lesion and eradicating it. The incidence of HPV in MSM was 13% according to data cited by the authors and the incidence of anal intraepithelial neoplasia ranged from 8.5% to 15.4% in the reports reviewed in the article. The incidence of anal cancer in this patient group was 46 out of 100,000 men. The authors recommended that prospective data be gathered to inform the development of screening guidelines. An article that describes one approach to screening for high-risk anal lesions in MSM was by Hicks and coauthors134 in JAMA-Surgery, 2015. The authors reviewed data from a prospectively gathered database of high-risk patients who were screened with high-resolution anoscopy (HRA). The authors noted that current guidelines promulgated by the American Society of Colon and Rectal Surgeons recommend clinical examination of high-risk patients at 4 to 6 month intervals to detect anal dysplasia and anal cancer. The objective of the author’s study was to determine if there was added benefit from the use of high-resolution anoscopy. The authors found that biopsies guided by high-resolution anoscopy showed dysplasia in 59% of patients. Although many patients were asymptomatic, almost all the asymptomatic patients had lowgrade dysplasia. The analysis identified anal pain and the presence of an anal lesion as risk factors for high-grade dysplasia. The authors concluded that their data suggest that patients with anal pain or anal lesions might benefit from screening with high-resolution anoscopy. In an editorial than accompanied the above article, Fleshman135 noted that anal dysplasia and anal cancer are rare conditions and that high-resolution anoscopy is expensive and labor intensive. He emphasized the fact that the data presented showed that nearly all patients at risk for anal cancer in the study reported would have American College of Surgeons  www.facs.org/publications/srgs 

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been detected with biopsies guided by sequential physical examination and the presence of symptoms such as pain and anal condylomatous lesions. The editorial concluded that there was a very good chance that screening with high-resolution anoscopy would not be a cost-effective means to either prevent anal cancer or increase the rate of early diagnosis. Treatment of patients with high-grade dysplasia can be done with topical chemotherapeutic agents or excision of lesions with electrocautery. A prospective, randomized trial comparing topical imiquimod, topical 5-FU, and excision with electrocautery for treatment of anal dysplasia is by Richel and coauthors136 in Lancet-Oncology, 2013. The authors randomly assigned 156 with anal epithelial neoplasia detected by high-resolution anoscopy to receive treatment with one of the two topical agents or excision/ lesion destruction with electrocautery. The data analysis showed that resolution of the lesion at four weeks occurred significantly more often in the electrocautery group. Side effects, such as pain and itching, were observed significantly less often in the electrocautery group. Of note is the fact that recurrence rates approached 70% at 72 weeks of follow-up in all groups. Radiotherapy and chemoradiotherapy are the main treatment options for patients who develop overt anal cancer, with resectional therapy reserved for failures of these treatments. Colostomy-free survival is a frequently used indicator of successful maintenance of anal function. An article that reported data on the cause-specific rates of colostomy in patients treated for anal cancer is by Sunesen and coauthors137 in the Journal of Clinical Oncology, 2011. The authors reported a retrospective review of patient data from national registries and medical records treated for anal cancer in Denmark over an eight-year interval. Data were available on 236 patients. The data analysis showed that colostomy was required in one-third of patients during follow-up. Colostomy was done because of tumor progression (non-response to treatment and the need for salvage rectal resection in most patients). Risk factors for colostomy included tumor size > 6cm and prior local excision of the anal cancer. Of interest is that the authors noted that a colostomy created prior to the initiation of radiotherapy or chemoradiation was rarely reversed; they concluded that patients should be counselled regarding risks for colostomy and informed that pretreatment colostomies are rarely reversed. Vol 41 | 5 | 2015

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Conclusion

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T

he next issue of SRGS will conclude our three-part series on surgical issues of the colon, rectum, and anus with a review of articles focusing on the management of patients with IBD involving the colon and rectum. The final two SRGS issues of the 2015 cycle of topics will include hernia management (published in October), and rural surgery (published in December). I hope you will continue to find the content in these issues pertinent and valuable to your surgical practice.

Thanks for reading SRGS!



Lewis Flint, MD, FACS Editor in Chief

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SRGS  

Vol 41 | 5 | 2015

References

51. Cairns SR, Scholefield JH, Steele RJ, et al. Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002). Gut. 2010;59(5):

| COLON, REC TUM & ANUS, PAR T II

62. Zipkin DA, Umscheid CA, Keating NL, et al. Evidencebased risk communication: a systematic review. Ann Intern Med. 2014;161(4):270-280.

666-689.

63. Gustafsson UO, Scott MJ, Schwenk W, et al. Guidelines for

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perioperative care in elective colonic surgery: Enhanced Recovery After Surgery (ERAS((R))) Society recommendations. World J Surg. 2013;37(2):259-284. 64. Vedovati MC, Becattini C, Rondelli F, et al. A randomized study on 1-week versus 4-week prophylaxis for venous thromboembolism after laparoscopic surgery for colorectal cancer. Ann Surg. 2014;259(4):665-669. 65. Colorectal Writing Group for the Surgical C, Outcomes

54. Dozois EJ, Boardman LA, Suwanthanma W, et al. Young-

Assessment Program-Comparative Effectiveness Research

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55. You YN, Dozois EJ, Boardman LA, Aakre J, Huebner M, Larson DW. Young-Onset Rectal Cancer: Presentation, Pattern of Care and Long-term Oncologic Outcomes Compared to a Matched Older-Onset Cohort. Ann Surg Oncol. 2011. 56. Winawer SJ, Zauber AG, Fletcher RH, et al. Guidelines for colonoscopy surveillance after polypectomy: a consensus

66. Baucom RB, Phillips SE, Ehrenfeld JM, et al. Association of Perioperative Hypothermia During Colectomy With Surgical Site Infection. JAMA Surg. 2015;150(6):570-575. 67. Stamos MJ. Lessons Learned in Intraoperative Hypothermia: Coming In From the Cold. JAMA Surg. 2015;150(6):575-576. 68. Walter CJ, Maxwell-Armstrong C, Pinkney TD, et al. A ran-

update by the US Multi-Society Task Force on Colorectal

domised controlled trial of the efficacy of ultrasound-guided

Cancer and the American Cancer Society. Gastroenterology.

transversus abdominis plane (TAP) block in laparoscopic

2006;130(6):1872-1885.

colorectal surgery. Surg Endosc. 2013;27(7):2366-2372.

57. Rex DK, Kahi CJ, Levin B, et al. Guidelines for colo-

69. Ris F, Findlay JM, Hompes R, et al. Addition of transversus

noscopy surveillance after cancer resection: a consensus

abdominis plane block to patient controlled analgesia for lap-

update by the American Cancer Society and the US Multi-

aroscopic high anterior resection improves analgesia, reduces

Society Task Force on Colorectal Cancer. Gastroenterology.

opioid requirement and expedites recovery of bowel function.

2006;130(6):1865-1871.

Ann R Coll Surg Engl. 2014;96(8):579-585.

58. Gunderson LL, Jessup JM, Sargent DJ, Greene FL, Stewart

70. Keller DS, Ermlich BO, Delaney CP. Demonstrating the

AK. Revised TN categorization for colon cancer based on

benefits of transversus abdominis plane blocks on patient

national survival outcomes data. J Clin Oncol. 2010;28(2):

outcomes in laparoscopic colorectal surgery: review of 200

264-271.

consecutive cases. J Am Coll Surg. 2014;219(6):1143-1148.

59. Chow W, Ko, CY, Rosenthal, RA, Esnaola, NF. ACS NSQIP/

71. Boelens PG, Heesakkers FF, Luyer MD, et al. Reduction

AGS Best preactice guidelines: Optimal preoperative assess-

of postoperative ileus by early enteral nutrition in patients

ment of the geriatric surgical patient. Chicago, IL2014.

undergoing major rectal surgery: prospective, randomized,

60. American Geriatrics Society Beers Criteria Update Expert P. American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2012;60(4):616-631.

controlled trial. Ann Surg. 2014;259(4):649-655. 72. Group EC. The Impact of Enhanced Recovery Protocol Compliance on Elective Colorectal Cancer Resection: Results From an International Registry. Ann Surg. 2015.

61. Revenig LM, Canter DJ, Kim S, et al. Report of a Simplified

73. Bakker N, Cakir H, Doodeman HJ, Houdijk AP. Eight

Frailty Score Predictive of Short-Term Postoperative Morbid-

years of experience with Enhanced Recovery After Surgery

ity and Mortality. J Am Coll Surg. 2015;220(5):904-911 e901.

in patients with colon cancer: Impact of measures to improve adherence. Surgery. 2015;157(6):1130-1136.

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74. Wick E, Galante, DJ, Hudson, DD, et al. Organizational

84. Kennedy RH, Francis EA, Wharton R, et al. Multicenter ran-

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75. Bhangu A, Brown G, Nicholls RJ, Wong J, Darzi A, Tekkis

85. Weeks JC, Nelson H, Gelber S, Sargent D, Schroeder G.

P. Survival outcome of local excision versus radical resection

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2013;258(4):563-569; discussion 569-571.

86. A comparison of laparoscopically assisted and open colectomy

76. Chen SL, Steele SR, Eberhardt J, Zhu K, Bilchik A, Stojadinovic A. Lymph node ratio as a quality and prognostic indicator in stage III colon cancer. Ann Surg. 2011;253(1):82-87. 77. Koch M, Antolovic D, Reissfelder C, et al. Leucocyte-depleted blood transfusion is an independent predictor of surgical morbidity in patients undergoing elective colon cancer sur-

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gery in patients with colorectal cancer (MRC CLASICC

78. Krarup PM, Nordholm-Carstensen A, Jorgensen LN, Harling H. Anastomotic leak increases distant recurrence and longterm mortality after curative resection for colonic cancer: a

trial): multicentre, randomised controlled trial. Lancet. 2005;365(9472):1718-1726. 89. Jayne DG, Guillou PJ, Thorpe H, et al. Randomized trial of

nationwide cohort study. Ann Surg. 2014;259(5):930-938.

laparoscopic-assisted resection of colorectal carcinoma: 3-year

79. Mirnezami A, Mirnezami R, Chandrakumaran K, Sasapu

results of the UK MRC CLASICC Trial Group. J Clin Oncol.

K, Sagar P, Finan P. Increased local recurrence and reduced survival from colorectal cancer following anastomotic leak: systematic review and meta-analysis. Ann Surg. 2011;253(5):

JM, Guillou PJ. Five-year follow-up of the Medical Re-

890-899.

search Council CLASICC trial of laparoscopically as-

80. Merkow RP, Bentrem DJ, Mulcahy MF, et al. Effect of postoperative complications on adjuvant chemotherapy use for stage III colon cancer. Ann Surg. 2013;258(6):847-853. 81. Frasson M, Flor-Lorente B, Ramos Rodriguez JL, et al. Risk Factors for Anastomotic Leak After Colon Resection for Cancer: Multivariate Analysis and Nomogram From a Multi-

sisted versus open surgery for colorectal cancer. Br J Surg. 2010;97(11):1638-1645. 91. Bonjer HJ, Hop WC, Nelson H, et al. Laparoscopically assisted vs open colectomy for colon cancer: a meta-analysis. Arch Surg. 2007;142(3):298-303. 92. Kuhry E, Schwenk W, Gaupset R, Romild U, Bonjer J. Long-

centric, Prospective, National Study With 3193 Patients. Ann

term outcome of laparoscopic surgery for colorectal cancer: a

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cochrane systematic review of randomised controlled trials.

82. Ricciardi R, Roberts PL, Marcello PW, Hall JF, Read TE, Schoetz DJ. Anastomotic leak testing after colorectal resec-

Cancer Treat Rev. 2008;34(6):498-504. 93. Devon KM, Vergara-Fernandez O, Victor JC, McLeod

tion: what are the data? Arch Surg. 2009;144(5):407-411;

RS. Colorectal cancer surgery in elderly patients: pre-

discussion 411-402.

sentation, treatment, and outcomes. Dis Colon Rectum.

83. Loffler T, Rossion I, Bruckner T, et al. HAnd Suture Versus STApling for Closure of Loop Ileostomy (HASTA Trial):

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2007;25(21):3061-3068. 90. Jayne DG, Thorpe HC, Copeland J, Quirke P, Brown

2009;52(7):1272-1277. 94. Steele SR, Chen SL, Stojadinovic A, et al. The impact of age

results of a multicenter randomized trial (DRKS00000040).

on quality measure adherence in colon cancer. J Am Coll Surg.

Ann Surg. 2012;256(5):828-835; discussion 835-826.

2011;213(1):95-103.

American College of Surgeons  www.facs.org/publications/srgs 

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Vol 41 | 5 | 2015

References

95. Seishima R, Okabayashi K, Hasegawa H, et al. Is laparo-

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106. Sperti E, Faggiuolo R, Gerbino A, et al. Outcome of meta-

scopic colorectal surgery beneficial for elderly patients? A

static colorectal cancer: analysis of a consecutive series of 229

systematic review and meta-analysis. J Gastrointest Surg.

patients. The impact of a multidisciplinary approach. Dis Co-

2015;19(4):756-765.

lon Rectum. 2006;49(10):1596-1601.

96. Primrose JN, Perera R, Gray A, et al. Effect of 3 to 5 years of scheduled CEA and CT follow-up to detect recurrence of colorectal cancer: the FACS randomized clinical trial. JAMA : the journal of the American Medical Association. 2014;311(3):263-270.

107. Gangadhar T, Schilsky RL. Molecular markers to individualize adjuvant therapy for colon cancer. Nat Rev Clin Oncol. 2010;7(6):318-325. 108. Earle CC, Weiser MR, Ter Veer A, et al. Effect of lymph node retrieval rates on the utilization of adjuvant chemotherapy in

97. van Hooft JE, Bemelman WA, Oldenburg B, et al. Colonic stenting versus emergency surgery for acute left-sided malignant colonic obstruction: a multicentre randomised trial. Lancet Oncol. 2011;12(4):344-352.

stage II colon cancer. J Surg Oncol. 2009;100(7):525-528. 109. Saltz LB. Adjuvant therapy for colon cancer. Surg Oncol Clin N Am. 2010;19(4):819-827. 110. Wilkinson NW, Yothers G, Lopa S, Costantino JP, Petrelli

98. Branger F, Thibaudeau E, Mucci-Hennekinne S, et al. Man-

NJ, Wolmark N. Long-term survival results of surgery alone

agement of acute malignant large-bowel obstruction with

versus surgery plus 5-fluorouracil and leucovorin for stage II

self-expanding metal stent. Int J Colorectal Dis. 2010;25(12):

and stage III colon cancer: pooled analysis of NSABP C-01

1481-1485.

through C-05. A baseline from which to compare modern

99. Fernandez-Esparrach G, Bordas JM, Giraldez MD, et al. Severe complications limit long-term clinical success of selfexpanding metal stents in patients with obstructive colorectal cancer. Am J Gastroenterol. 2010;105(5):1087-1093.

adjuvant trials. Ann Surg Oncol. 2010;17(4):959-966. 111. Network NCC. Clinical Practice Guidelines: Rectal Cancer. 2015:122. 112. Shields CJ, Tiret E, Winter DC, International Rectal

100. Manes G, Callegaro D, Ardizzone S. To stent or not to stent?:

Carcinoid Study G. Carcinoid tumors of the rectum: a

palliative management of inoperable colorectal cancer. Am J

multi-institutional international collaboration. Ann Surg.

Gastroenterol. 2010;105(5):1209; author reply 1209-1210.

2010;252(5):750-755.

101. Suen MK, Zahid A, Young JM, Rodwell L, Solomon MJ, Young CJ. How to decide to undertake a randomized, controlled trial of stent or surgery in colorectal obstruction. Surgery. 2015;157(6):1137-1141.

113. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med. 2001;345(9):638-646. 114. Murata A, Brown CJ, Raval M, Phang PT. Impact of short-

102. Lee IK, Sung NY, Lee YS, et al. The survival rate and prognostic factors in 26 perforated colorectal cancer patients. Int J Colorectal Dis. 2007;22(5):467-473.

course radiotherapy and low anterior resection on quality of life and bowel function in primary rectal cancer. Am J Surg. 2008;195(5):611-615; discussion 615.

103. Abdelrazeq AS, Scott N, Thorn C, et al. The impact of spon-

115. Taylor FG, Quirke P, Heald RJ, et al. Preoperative high-reso-

taneous tumour perforation on outcome following colon can-

lution magnetic resonance imaging can identify good progno-

cer surgery. Colorectal Dis. 2008;10(8):775-780.

sis stage I, II, and III rectal cancer best managed by surgery

104. Tan KK, Hong CC, Zhang J, Liu JZ, Sim R. Surgery for perforated colorectal malignancy in an Asian population: an institution’s experience over 5 years. Int J Colorectal Dis. 2010;25(8):989-995.

alone: a prospective, multicenter, European study. Ann Surg. 2011;253(4):711-719. 116. de Campos-Lobato LF, Geisler DP, da Luz Moreira A, Stocchi L, Dietz D, Kalady MF. Neoadjuvant therapy for rectal

105. Darakhshan A, Lin BP, Chan C, Chapuis PH, Dent OF, Bokey L. Correlates and outcomes of tumor adherence in resected colonic and rectal cancers. Ann Surg. 2008;247(4): 650-658.

cancer: the impact of longer interval between chemoradiation and surgery. J Gastrointest Surg. 2011;15(3):444-450. 117. Lambregts DM, Vandecaveye V, Barbaro B, et al. DiffusionWeighted MRI for Selection of Complete Responders After Chemoradiation for Locally Advanced Rectal Cancer: A Multicenter Study. Ann Surg Oncol. 2011.

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118. van Gijn W, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol. 2011;12(6):575-582.

129. Stewart DB, Dietz DW. Total mesorectal excision: what are we doing? Clinics in colon and rectal surgery. 2007;20(3): 190-202. 130. Person B, Ifargan R, Lachter J, Duek SD, Kluger Y, Assalia A. The impact of preoperative stoma site marking on the inci-

119. Stephens RJ, Thompson LC, Quirke P, et al. Impact of short-course preoperative radiotherapy for rectal cancer on patients’ quality of life: data from the Medical Research

dence of complications, quality of life, and patient’s independence. Diseases of the colon and rectum. 2012;55(7):783-787. 131. Havenga K, Grossmann I, DeRuiter M, Wiggers T. Defini-

Council CR07/National Cancer Institute of Canada Clinical

tion of total mesorectal excision, including the perineal phase:

Trials Group C016 randomized clinical trial. J Clin Oncol.

technical considerations. Digestive diseases. 2007;25(1):44-50.

2010;28(27):4233-4239.

132. Koh PK, Seow-Choen F, Kwek BH. Total mesorectal exci-

120. Parc Y, Zutshi M, Zalinski S, Ruppert R, Furst A, Fazio VW. Preoperative radiotherapy is associated with worse functional results after coloanal anastomosis for rectal cancer. Dis Colon Rectum. 2009;52(12):2004-2014.

sion: the unrecognized pelvic plane. Diseases of the colon and rectum. 2006;49(2):280-283; discussion 283-284. 133. Machalek DA, Poynten M, Jin F, et al. Anal human papillomavirus infection and associated neoplastic lesions in men

121. Latkauskas T, Paskauskas S, Dambrauskas Z, et al. Preoperative chemoradiation vs radiation alone for stage II and III resectable rectal cancer: a meta-analysis. Colorectal Dis. 2010;12(11):1075-1083.

who have sex with men: a systematic review and meta-analysis. Lancet Oncol. 2012;13(5):487-500. 134. Hicks CW, Wick EC, Leeds IL, et al. Patient Symptomatology in Anal Dysplasia. JAMA Surg. 2015;150(6):563-569.

122. Pucciarelli S, Del Bianco P, Efficace F, et al. Patient-reported outcomes after neoadjuvant chemoradiotherapy for rectal cancer: a multicenter prospective observational study. Ann Surg. 2011;253(1):71-77.

135. Fleshman J. Considering Standards of Care for Anal Cancer. JAMA Surg. 2015;150(6):569. 136. Richel O, de Vries HJ, van Noesel CJ, Dijkgraaf MG, Prins JM. Comparison of imiquimod, topical fluorouracil, and elec-

123. Maas M, Nelemans PJ, Valentini V, et al. Long-term out-

trocautery for the treatment of anal intraepithelial neoplasia

come in patients with a pathological complete response after

in HIV-positive men who have sex with men: an open-label,

chemoradiation for rectal cancer: a pooled analysis of indi-

randomised controlled trial. Lancet Oncol. 2013;14(4):

vidual patient data. Lancet Oncol. 2010;11(9):835-844. 124. Smith JD, Ruby JA, Goodman KA, et al. Nonoperative man-

346-353. 137. Sunesen KG, Norgaard M, Lundby L, et al. Cause-specific

agement of rectal cancer with complete clinical response after

colostomy rates after radiotherapy for anal cancer: a Danish

neoadjuvant therapy. Ann Surg. 2012;256(6):965-972.

multicentre cohort study. J Clin Oncol. 2011;29(26):

125. Maas M, Beets-Tan RG, Lambregts DM, et al. Wait-and-see

3535-3540.

policy for clinical complete responders after chemoradiation for rectal cancer. J Clin Oncol. 2011;29(35):4633-4640. 126. Guillem JG, Lee-Kong SA. Autonomic nerve preservation during rectal cancer resection. J Gastrointest Surg. 2010;14(2):416-422. 127. van der Pas MH, Haglind E, Cuesta MA, et al. Laparoscopic versus open surgery for rectal cancer (COLOR II): shortterm outcomes of a randomised, phase 3 trial. Lancet Oncol. 2013;14(3):210-218. 128. Leonard D, Penninckx F, Fieuws S, et al. Factors predicting the quality of total mesorectal excision for rectal cancer. Ann Surg. 2010;252(6):982-988.

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CME Posttest

COLON, REC TUM & ANUS, PART II VOLUME 41 | 5 | 2015

To earn CME credit, the posttest should be completed AFTER taking the pretest and reading the overview. Both tests must be completed online at www.facs.org/publications/srgs/cme.

1. Data cited by Brenner and coauthors

4. Data from the SEER database reported

indicate that the annual number of deaths, worldwide, from colorectal cancer is which of the following?

by Murphy and coauthors confirmed all of the following except which one? a) Male-to-female ratio is higher for cancers of the distal colon

a) 1.2 million

b) Colorectal cancer incidence is lowest in Hispanics

b) 220,000 c) 600,000

c) Colorectal cancer incidence is highest for African-American patients

d) 144,000 e) 950,000

d) Colorectal cancer incidence is increasing in Native American patients

2. All of the following are genetic changes

e) White male patients have the highest risk for development of right-colon cancers arising from serrated polyps

associated with colorectal cancer development except which one? a) Activation of the RET oncogene

5. Data from the meta-analysis reported by

b) Inactivation of the APC gene c) Inactivation of the TP53 tumor suppressor gene d) Activation of the KRAS oncogene e) Activation of the BRAF gene

Boterri and coauthors indicated that there was as statistically significant increase in the risk of colon cancer and colon cancer mortality in which of the following groups? a) Female smokers

3. Which of the following is a clinical characteristic

of CIMP-high colorectal cancers?

b) Current smokers who had smoked for 30 years or more c) Smokers who had quit smoking for more than five years

a) They occur mainly in men b) They are more common in black patients

d) Patients younger than 30 years of age who were current smokers

c) The tumors occur most commonly in the distal rectum d) The tumors are most often diagnosed in women

e) Smokers of Hispanic ethnicity

e) The tumors are frequently diagnosed in Latino patients

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Posttest | COLON,

REC TUM & ANUS, PAR T II

6. Data reported by Ferrari and coauthors

10. Risk of mortality from colorectal cancer is

indicated that consumption of 30 grams of ethanol per day resulted in an increased risk of colon cancer in which segment of the colon?

reduced by which of the following percentages in patients who have an adenomatous polyp removed at the time of colonoscopy?

a) Appendix

a) 18%

b) Right colon

b) 2.5%

c) Proximal transverse colon

c) 53%

d) Hepatic flexure

d) 90%

e) Sigmoid colon and rectum

e) 26%

7. Which of the following is true

11. Data reported by Neerincx and coauthors

regarding the possible association of estrogen and colon cancer?

indicate that which of the following is a common cause of incomplete colonoscopy?

a) Experimental evidence suggests that estrogen levels are increased in colon cancer tissue

a) Colonoscopy performed by a general surgeon

b) Experimental evidence indicates that estrogen receptors suppress proliferation in colon cancer cell lines

c) Malfunction of the colonoscope lighting system

b) Incomplete bowel preparation d) Patient discomfort e) Colonoscopy performed in late afternoon hours

c) Estrogen receptors are absent in colon mucosal cells d) Women are more likely to develop colon cancer than men e) Premenopausal women are at an increased risk of colon cancer development 8. Brisk walking for one hour each day reduces the

12. Each of the following is an acceptable

means of detecting adenomatous polyps and early colon cancers except which one? a) Fecal occult blood testing on a sample obtained by digital rectal examination

risk of developing adenomatous polyps in the colon by which of the following percentages?

b) Colonoscopy

a) 24%

d) Fecal testing for hemoglobin

b) 1.5%

e) CT colonography

c) Flexible sigmoidoscopy plus double contrast barium enema

c) 11% d) 18%

13. Data reported by Burt and coauthors

confirmed that microsatellite instability is detectable in what percentage of patients with Lynch syndrome?

e) 39% 9. Data reported by Brenner and coauthors

indicate that colorectal cancer mortality risk is reduced by 25% for which of the following screening approaches?

a) 1.5%

a) Colonoscopy annually

d) 90%

b) Flexible sigmoidoscopy every 5 years

e) 27%

b) 13% c) 44%

c) Digital rectal examination every 6 months d) Colonoscopy every 5 years e) Fecal occult blood testing performed as a part of a colorectal cancer detection program

54

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Vol 41 | 5 | 2015

Posttest |

14. Clinical practice guidelines state that

COLON, REC TUM & ANUS, PAR T II

18. Guidelines published in the report by

segmental colectomy is indicated in which of the following clinical situations? a) Completely excised adenomatous polyp in a female patient

Gustafsson and coauthors suggest that smoking and alcohol consumption cease at what interval before elective colectomy. a) 2 hours

b) Completely excised adenomatous polyp with invasive cancer at the tip

b) 24 hours

c) Complete excision of two or more adenomatous polyps

d) 10 days

d) Female patient with sessile polyp of the right colon e) Excision of more than five hyperplastic polyps

c) 4 weeks e) 3 months 19. Which of the following statements is

true regarding transversus abdominal plane (TAP) anesthetic blocks?

15. Studies of outcomes of patients according

to TNM stage have confirmed that patients with T3 tumors with one or two lymph node metastases have 5-year survival rates of 60%. Five-year survival for patients with T4 tumors and no lymph node metastases is which of the following percentages?

a) TAP block is a type of epidural anesthetic

a) 71%

d) The TAP block must be performed 8 hours prior to operation

b) 84%

b) The TAP block uses local anesthetic infiltration to block sensation in the lowest six thoracic sensory nerves and the first lumbar sensory nerve c) The TAP block does not reduce perioperative opioid use

e) The TAP block cannot be used in patients undergoing laparoscopic colon resection

c) 66% d) 47% e) 90%

20. Long-term survival after colon resection

for colon cancer is related to disease stage at the time of operation. The most important factor associated with long-term mortality risk is which of the following?

16. Patient factors that increase the risk

of perioperative delirium include all of the following except which one?

a) Tumor margin of at least 30 cm proximal and distal to the tumor

a) Anemia b) Poor nutritional status

b) Use of stapled anastomoses

c) Chronic renal insufficiency

c) Use of open rather than laparoscopic procedures

d) Female gender

d) Avoidance of oral antibiotic bowel preparation

e) Low scores on the Mini-Cog assessment

e) Removal of at least 12 lymph nodes along with the excised colon segment

17. Data reported by Zipkin and coauthors

suggested that effective risk communication could be improved by the use of which of the following? a) Explanation of statistical significance b) Use of number needed to treat (NNT) c) Explanation of propensity score analysis d) Use of examples from cohort studies e) Use of visual aids, such as graphs

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Posttest | COLON,

REC TUM & ANUS, PAR T II

The following four questions are required by the American College of Surgeons for accreditation purposes. You must complete these four questions before submitting your answers. 21. This issue met the stated learning objectives. a) Strongly agree b) Agree c) Neutral d) Disagree e) Strongly disagree 22. The content was relevant to my educational

needs and practice environment. a) Strongly agree b) Agree c) Neutral d) Disagree e) Strongly disagree 23. There are potential barriers to

incorporating what I have learned from this issue into my practice. a) Strongly agree b) Agree c) Neutral d) Disagree e) Strongly disagree 24. The content was fair, objective, and unbiased. a) Strongly agree b) Agree c) Neutral d) Disagree e) Strongly disagree

© 2015 American College of Surgeons

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American College of Surgeons  www.facs.org/publications/srgs 

SRGS  

Vol 41 | 5 | 2015

57

Recommended Reading

COLON, REC TUM & ANUS, PART II VOLUME 41 | 5 | 2015

The full-text reprints of articles cited in the literature review are included in some formats of Selected Reading in General Surgery (SRGS). The articles appear in order of overview citation. All of the articles reviewed in this issue also appear in the reference list at the end of the literature review (47–52). SRGS has obtained permission from journal publishers to reprint these articles. Copying and distributing these reprints is a violation of our licensing agreement with these publishers and is strictly prohibited.

1. ACS NSQIP/AGS Best practice guidelines: Optimal preoperative assessment of the geriatric patient…(59–110)

5. Effect of postoperative complications on adjuvant chemotherapy use for stage III colon cancer…(152–158) Merkow RP, Bentrem DJ, Mulcahy MF, et al.

Chow W, Ko CY, Rosenthal RA, Esnaola NF

The authors present data documenting the negative effect of postoperative complications on the timely use of adjuvant chemotherapy.

This best practices document, which has been promulgated jointly by NSQIP, ACS, and AGS, provides guidelines for the assessment and reduction of risk in geriatric patients. 2. A randomized study on 1-week versus 4-week prophylaxis for venous thromboembolism after laparoscopic surgery for colorectal cancer…(111–115) Vedovati MC, Becattini C, Rondelli F, et al. The data presented support the use of a 4-week interval of LMWH for VTE prophylaxis in patients undergoing colon resection for cancer. 3. Demonstrating the benefits of transversus abdominis plane blocks on patient outcomes in laparoscopic colorectal surgery: a review of 200 consecutive cases…(116–121) Keller DS, Ermlich BO, Delaney CP. Keller and coauthors provide data supporting the use of TAP blocks, as well as a clear description of their technique.

6. Autonomic nerve preservation during rectal cancer resection…(159–165) Guillem JG, Lee-Kong SA. This article provides a clear description, with illustrations, of the technique of total mesorectal excision with automatic nerve preservation. 7. Total mesorectal excision: the unrecognized pelvic plane…(166–170) Koh PK, Seow-Choen F, Kwek BH. Koh and colleagues provide valuable information on techniques for avoiding “coning” during the most distal components of total mesorectal excision. They emphasize that avoidance of “coning” is important for ensuring that distal tumor deposits have been removed.

4. Organizational culture changes result in improvement in patient-centered outcomes: implementation of an integrated recovery pathway for surgical patients… (122–151) Wick E, Galante, DJ, Hudson, DD, et al. The authors describe an effective method for improving outcomes of colon cancer surgery.

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American College of Surgeons  www.facs.org/publications/srgs 

SRGS  

Vol 41 | 5 | 2015

The American College of Surgeons offers a variety of surgical patient education products for your colon and rectal practice.

Colonoscopy Brochure

Ostomy Home Skills Kit

Pediatric Ostomy Home Skills Kit

There is a value to membership—member discounts apply. Order online at www.surgicalpatienteducation.org or call 312-202-5263.

American College of Surgeons  www.facs.org/publications/srgs 

SRGS  

Vol 41 | 4 | 2015

59