PeaceHealth Physicians Journal Volume 5, Number 1, Fall 2012

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1 Exceptional Medicine PeaceHealth Physicians Journal Volume 5, Number 1, Fall 2012 Mortality from colorectal cancer has declined over the last three decades mainly related to earlier diagnosis through screening and novel therapeutic options. - Aruna K. Reddy, MD Medical Oncology/Hematology, PeaceHealth Medical Group 2012 ANNUAL REPORT

2 Exceptional Medicine Physicians Journal PeaceHealth Southwest Medical Center (PHSW) PeaceHealth St. John Medical Center (PHSJ) Fall 2012 Volume 5, Number 1 PUBLISHING STAFF Editorial Director Kenneth Cole Contributing Editors Alden Roberts, MD Brian Harwood, MD Sheila Lynam, MD Chris O Hara, RN Submission Guidelines Exceptional Medicine is a free, editorial-reviewed publication by credentialed Medical Center staff for regional physicians. For complete details and submission guidelines, go to or contact the editorial staff (kcole@swmedicalcenter.org or ). TABLE OF CONTENTS Aruna Reddy, MD, Medical Oncology, PHSW Nathan Suh, MD, Pathology, PHSW Kara Makin-Bond, Research RN, PHSW Marie Tesdale, RHIT, CTR, PHSW Rhonda Wrolson, CTR, PHSJ 1 Overview of Colorectal Cancer The second leading cause of cancer death, colorectal cancer is often curable in its early stages. In this report, we explore the detection, pathology, staging, and management of colorectal cancer. We also address prevention, risk factors, and genetics that affect colon and rectal health. We include incidence and survival data for PeaceHealth Southwest and PeaceHealth St. John Medical Centers and discuss research options for CRC. Kevin Meitz, DO, The Vancouver Clinic 35 CRC Screening and Endorectal Ultrasound for Rectal Cancer Colorectal cancer is the fourth most common cancer and the second leading cause of death from cancer. With improved adherence to screening guidelines there would likely be a more substantial decrease in the incidence of CRC cancer. The purpose of screening is to reduce mortality by decreasing the incidence of disease. Andrea Lange, MD, PHSW 41 Surgery for Colorectal Cancer Surgery is the primary modality for treatment of colorectal cancer. The most important step in the surgical care of patients is to define an oncologically safe and effective treatment. It requires an individualized approach, which considers both the tumor with its pathology, stage and location, as well as the patient with their symptoms, health, GI tract, and family history. Keeping this in mind leads to the most costeffective diagnostic evaluation and treatment. Mission Statement We carry on the healing mission of Jesus Christ by promoting personal and community health, relieving pain and suffering, and treating each person in a loving and caring way. Choong R. Kim, MD, PHSJ 47 Radiation Therapy for Colorectal Cancer While surgery is the primary treatment modality for colorectal cancer, radiation therapy (RT) is administered as an adjuvant to decrease the frequency of local recurrence and distant metastases and to improve survival. In this article, we explore the advantages and disadvantages of radiation therapy as part of treatment, as well as techniques and side effects. Copyright 2012 PeaceHealth Southwest Medical Center, Marketing Department, PO Box 1600, Vancouver, WA 98668

3 Overview of Colorectal Cancer The second leading cause of cancer death, colorectal cancer is often curable in its early stages. In this report, we explore the detection, pathology, staging, and management of colorectal cancer. We also address prevention, risk factors, and genetics that affect colon and rectal health and discuss research options for CRC. Aruna K. Reddy, MD, Medical Oncologist, PHSW Nathan Suh, MD, Pathologist, PHSW Kara Makin-Bond, Research RN, PHSW Marie Tesdale, RHIT, CTR, PHSW Rhonda Wrolson, CTR, PHSJ Correspondence: Aruna K. Reddy, MD PeaceHealth Medical Group Oncology 505 NE 87th Avenue, Suite 320 Vancouver, WA Table 1: Estimated Cancer Deaths from Colorectal Cancer 2011 Estimated Cancer Deaths from Colorectal Cancer 2011 Washington State 960 United States 49,380 *Data from ACS Cancer Facts and Figures 2011 and National Cancer Institute Volume 5, Number 1 Exceptional Medicine 1

4 INTRODUCTION Colorectal cancer (CRC) is the second leading cause of cancer death and the fourth most common cancer in the United States.1 It is estimated that in the year 2012, there will be 103,170 new cases of colon cancer, 40,290 cases of rectal cancer, and a total of 51,690 deaths related to colorectal cancer.1 In 2011, approximately 2,720 new cases were reported in Washington State, 95 cases at PeaceHealth Southwest Medical Center, and 64 cases at PeaceHealth St. John Medical Center. Figures 1 and 2 show 10-year colorectal cancer incidences at PHSW and PHSJ. Colorectal cancer is often curable in its early stages. Mortality from colorectal cancer has declined over the last three decades mainly related to earlier diagnosis through screening and novel therapeutic options.2 RISK FACTORS Environmental, genetic and lifestyle factors can increase the likelihood of developing CRC. The risk of developing colorectal cancer increases with age, and more than 90% of cases occur in individuals over the age of 50.3 (See Figure 3) The mean age for diagnosis for CRC is 71 years. A diet that is high in red meats and processed meats has Figure 1: 10-year Colorectal Cancer Incidence PHSW Colorectal cancer rates seen at PHSW in 2011 were the second lowest in the past decade Number of Cases Year Figure 2: 10-year Colorectal Cancer Incidence PHSJ Incidence of colorectal cancer cases at PHSJ decreased slightly in 2011 from a high of 72 in Number of Cases Year 2 swmedicalcenter.org Fall 2012

5 Figure 3: Increasing Incidence of Colorectal Cancer With Age The age-specific incidence of colorectal cancer was measured between 2002 and 2006 in men and women of all races Rate per 100, Age in Years Data from: Surveillance, Epidemiology, and End Results (SEER) Program, Available online at been associated with increased colorectal cancer risk.4 African Americans have a higher risk of colorectal cancer than whites, and men have a higher risk of colorectal cancer than women. 5,6 Lifestyle factors that may contribute to increased risk include excessive alcohol use [Relative Risk (RR) of 1.41] for consumption greater than 45g/ day, cigarette smoking with a RR of 1.18 for current smokers versus never smokers, obesity with a BMI over 29 with a RR of 1.3 for men.7-11 Diabetics also have a higher risk of getting colorectal cancer. 12 There is evidence suggesting that survivors of childhood malignancy who increased risk of developing colorectal cancer, and radiation therapy for prostate cancer is associated with an increased risk of rectal cancer.13,14 Other risk factors include a personal history of history of colorectal cancer or adenomatous polyps or other polyposis syndromes or genetic cancer syndromes. (See Table 2) Table 2: Summary of Major Risk Factors for Colorectal Cancer Comparison of disease risk among people with a particular exposure to the risk among people without that exposure. Relative Risk* Factors that increase risk: Heredity and Medical History Family history 1 first-degree relative more than 1 relative relative with diagnosis before age Inflammatory bowel disease 36 Crohn disease (colon) 2.6 Ulcerative colitis colon 2.8 rectum 1.9 Diabetes Other factors Obesity Red meat consumption Processed meat consumption Smoking Alcohol consumption Factors that decrease risk: Physical activity (colon) 43 Men 0.8 Women 0.7 Calcium Milk consumption *Relative risk compares the risk of disease among people with a particular exposure to the risk among people without that exposure. Dietary risk factors are usually evaluated by comparing highest with lowest consumption. If the relative risk is greater than 1.0, then risk is higher among exposed than unexposed. American Cancer Society Colorectal Facts and Figures Volume 5, Number 1 Exceptional Medicine 3

6 A colorectal polyp is a growth occurring from a rectum. Polyps can be benign or premalignant or malignant and are usually asymptomatic but may ulcerate and bleed or may cause obstructive symptoms if very large. Some polyps could be precursors to development of CRC. However, not all polyps lead to cancer, and it may take many years for a polyp to become cancerous. Sessile polyps are those in which the base is attached to the colon wall, and pedunculated polyps are polyps that have a mucosal stalk attaching them to the colonic wall. Colonic polyps are or hamartomatous polyps. Other varieties include serrated polyps and submucosal polyps that can be either neoplastic or nonneoplastic. Hyperplastic polyps are the most common nonneoplastic polyps and are generally benign, but the serrated variety of hyperplastic polyps can be benign or malignant. Neoplastic polyps may include serrated polyps, hamartomatous polyps, or adenomatous polyps. All adenomas are dysplastic and are graded as high or low grade. tubular or villous or tubulovillous with varying malignant potential. A personal history of adenomatous polyps increases risk of developing CRC. Siblings and parents of individuals with adenomatous polyps are also at increased risk for colorectal cancer, particularly when the adenoma is diagnosed before the age of Not all colorectal polyps are adenomas, and more than 90% of adenomas do not progress to cancer. 16 Individuals with a personal history of CRC are at a higher risk of developing a new primary CRC compared to the general population. New primary cancers may develop in 1.5-3% of this risk is higher in the setting of familial cancer syndromes.17 Most cases of colorectal cancer are sporadic, but genetic syndromes including Lynch syndrome caused by mutations in the Mismatch Repair genes(mmr), Familial adenomatous polyposis (FAP) caused by mutations in the APC gene, Peutz-Jeghers syndrome caused by mutations in the gene STK1, MUTYH-associated polyposis (MAP) caused by mutations in the gene MUTYH are associated with an increased risk of developing colorectal cancer. (See Figures 4 and 5) Figure 4: Colon Cancer cases arising in various family risk settings <0.1% Hamartomatous Polyposis Syndromes <1% Familial Adenomatous Polyposis 2% to 3% Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer 10% to 30% Cases with Familial Risk Sporadic Cases The fractions of colon cancer cases that arise in various family risk settings. Reprinted from Gastroenterology, Vol. 119, No. 3, Randall W. Burt, Colon Cancer Screening, Pages , Copyright (2000), with permission from Elsevier. 4 swmedicalcenter.org Fall 2012

7 Figure 5: Risk of colon cancer associated with a family history Lifetime relative risk No FH of CRC or adenoma FH adenoma 1 st degree relative with CRC Dx CRC <age 45 >1 relative with CRC The highest risk is in people with multiple first-degree relatives or relatives who have developed colorectal cancer at a relatively young age. Data from: Johns, LE, Houlston, RS, Am J Gastroenterol 2001; 96:2992. SCREENING Screening is the process of looking for cancerous or precancerous conditions in asymptomatic individuals. Regular colorectal cancer screening at recommended intervals based on risk assessment is one of the most powerful tools for preventing colorectal cancer and decreasing mortality from colorectal cancer. Screening is based on the principle that in general it takes years for an abnormal cell that divides uncontrollably to develop into a polyp and for the polyp to develop into cancer. This duration can be much shorter in individuals with high risk cancer syndromes. There are several modalities used for screening. Colonoscopy is the most complete screening procedure, allowing examination of the entire large bowel, and also has the advantage of polyp removal at the time of colonoscopy. It is the preferred screening method and is the gold standard against which other modalities are compared. For purposes of screening National Comprehensive Cancer Network (NCCN) guidelines recommend stratifying patients into three risk categories to include average risk, increased risk and high risk syndromes.18 Average risk patients include individuals over 50 years of age with no history of adenomas or disease (IBD). Increased risk individuals include individuals with a personal history of adenomas or serrated polyps or IBD or a positive family history of CRC or advanced adenomas. High risk syndromes include a family history or personal history of Lynch syndrome or a family or personal history of polyposis syndromes. Screening intervals and methodology recommendations vary depending on the individual risk. CRC risk assessment should be performed at age 40 in individuals without a family history to determine the appropriate age to begin screening. Screening will be discussed in more detail in the next section. PREVENTION OF COLORECTAL CANCER A number of studies have shown that being overweight increases the risk of colorectal cancer in both men and women, but the link seems to be stronger in men.19 Moderate to intense physical exercise and maintaining an ideal body weight can lower the risk of developing colorectal cancer. Overall, diets that are high in vegetables (especially cruciferous vegetables), fruits, and been linked with lower colorectal cancer risk, although it s not exactly clear which factors are most important. Several studies have shown that calcium and Vitamin D supplementation may lower risk of colorectal cancer.20 Avoiding smoking and limiting alcohol intake are also important. 5-7 Many retrospective studies have found that people Volume 5, Number 1 Exceptional Medicine 5

8 who regularly use aspirin and other nonsteroidal risk of colorectal cancer and adenomatous polyps. Several prospective studies have provided evidence that aspirin can prevent the growth of polyps in individuals who were previously treated for early stages of colorectal cancer or who previously had polyps removed or individuals with a family history of CRC or high risk CRC syndromes Chemoprevention with ASA could be considered in select individuals after carefully weighing the risks may reduce CRC risk, and there are ongoing trials evaluating this. Obviously appropriate screening at regular intervals depending on risk assessment is also extremely important. DIAGNOSIS, STAGING AND PATHOLOGY Symptoms of CRC include abdominal pain change in bowel habits, melena or hematochezia, anemia, tenesmus or weight loss. If metastatic spread has occurred then symptoms related to distant organ spread may occur. Individuals can present with abdominal pain, distension, nausea or vomiting with an obstructing tumor or may present with bowel perforation. Other times CRC may be detected based on routine screening evaluation. Diagnosis of CRC is based on biopsy of a suspicious mass seen on endoscopy or imaging studies and pathology evaluation. Staging provides information about the extent of spread of CRC and stage at diagnosis clearly correlates with prognosis. Staging is considered clinical when it is performed using visualization with endoscopic procedures, physical exam and using imaging studies which may include CXR, CT scan of chest abdomen and pelvis, MRI, endorectal ultrasound, PET/CT scan or bone scan. Pathologic staging includes a pathologic assessment of the resected surgical specimen or biopsy of areas suspicious for metastatic spread. Pathologic assessment of the resected surgical specimen provides data that is essential for patient management and helps with the estimation of postoperative outcomes and decision making regarding adjuvant therapy. The essential elements of the pathological assessment of colorectal cancer resection specimens include the pathologic determination of tumor type, histologic grade, status of resection margins, vascular invasion and Tumor Node Metastasis (TNM) stage. The 7 th edition of American Joint Committee on Cancers Tumor Node Metastasis (AJCC- TNM) Cancer staging is the staging version currently in use and includes changes to the previous version of staging for CRC. The depth of penetration of the tumor through the bowel staging, lymphovascular invasion which requires endothelial-lined channel or surrounded by an elastic lamina, perineural invasion, grade of the tumor are all factors that determine outcomes and survival. Grade of the tumor is determined based on the degree of differentiation or gland formation which is present to greater or lesser degrees in well-differentiated and moderately differentiated tumors respectively. Poorly differentiated or undifferentiated or high-grade tumors do not form marked cellular pleomorphism. The 2010 TNM system uses the term satellite tumor deposits to designate discrete rounded nodules of tumor of any size within the pericolic or perirectal fat or in adjacent mesentery. They are considered the equivalent of nodal metastases even if they lack a nodal architecture and are staged as N1c disease in the absence of other nodal metastases. Each site should be counted separately in the involved lymph node count that determines pn status and NCCN guidelines endorse the above approach. Other tissue-based prognostic factors that have stage independent prognostic value or predict response to adjuvant therapy include perineural immune response to tumor, and molecular features such as microsatellite instability (MSI). 6 swmedicalcenter.org Fall 2012

9 CLASSIFICATION AND TUMOR TYPE Epithelial derived colorectal tumors (carcinoma) can on morphologic assessment of tumor histology. ADENOCARCINOMA It is the most common type of carcinoma arising in the colorectum. The majority of colorectal adenocarcinomas are gland forming the glandular structures. Adenocarcinoma by mucosae into submucosa. Lesions with the morphological characteristics of adenocarcinoma lamina propria alone and lack invasion through the muscularis mucosae into the submucosa have virtually no risk of metastasis. These lesions are called in-situ carcinoma and intramucosal carcinoma, respectively. MUCINOUS ADENOCARCINOMA A variant of gland forming adenocarcinoma, the name mucinous carcinoma is designated when more than 50% of tumor volume is composed of mucin produced by the tumor cells. Many highfrequency micro-satellite instability (MSI-H) carcinomas are of this histopathologic type. SIGNET-RING CELL CARCINOMA by presence of more than 50% tumor cells with prominent intracytoplasmic mucin giving them a signet-ring appearance when examined under the microscope. Signet ring cell carcinomas tend to have poorer prognosis compared to traditional adenocarcinomas. SMALL CELL (NEUROENDOCRINE) CARCINOMA Small cell neuroendocrine carcinomas, show similar histologic appearance to their counterpart in the lung. However, they are a rare tumor in the colorectum. Histologically they are composed of small anaplastic cells with small hyperchromatic nuclei and scant cytoplasm. As their name implies, these tumor cells display immunoreactivity for neuroendocrine markers by immunohistochemical chromogranin, synaptophysin and Leu-7. SQUAMOUS CELL CARCINOMA This unusual carcinoma tends to arise more commonly in the distal part of rectum. cell carcinoma arising from rectum from anal squamous cell carcinoma especially if the tumor is located near the anorectal junction. Adenosquamous cell carcinoma shows features of both squamous carcinomas and adenocarcinomas, either as separate areas within the tumor adenosquamous, there should be more than just occasional small foci of squamous differentiation. MEDULLARY CARCINOMA carcinoma, medullary carcinoma is composed of sheets of polygonal tumor cells with prominent nucleoli, abundant cytoplasm and is associated Medullary carcinomas are less likely to show K-ras and P53 mutation than usual colorectal adenocarcinomas and more likely harbor defects in DNA mismatch repair and may be associated with HNPCC syndrome. Also, these tumors tend to show CK20(-)/CK7(+) and reduced CDX2 for a colorectal carcinoma and thus can create a diagnostic dilemma for pathologists. Medullary carcinomas tend to show better prognosis compared to conventional adenocarcinomas. UNDIFFERENTIATED CARCINOMA The term undifferentiated carcinoma is restricted to cancers that contain evidence of epithelial differentiation but without obvious gland formation. Thus, most undifferentiated tumors probably represent extremely poorly differentiated adenocarcinoma. True undifferentiated carcinomas are rare, and they are more likely to contain a the tumor is associated with prominent tumor Volume 5, Number 1 Exceptional Medicine 7

10 TUMOR GRADE A conventional four-tiered grading system is used and is as detailed below. Grade 1: Well differentiated Grade 2: Moderately differentiated Grade 3: Poorly differentiated Grade 4: Undifferentiated Histologic grade has been shown by numerous multivariate analyses to be a stage-independent prognostic factor in colorectal cancer. to be an adverse prognostic factor. A two-tiered grading system for colorectal carcinoma (i.e., low grade and high grade) has been proposed to reduce inter-observer variability and to improve diagnostic consistency and is currently recommended by the College of American Pathologists and is as detailed below. Low Grade: Well differentiated and moderately differentiated High Grade: Poorly differentiated and undifferentiated PATHOLOGIC STAGE The best estimation of prognosis in colorectal cancer is related to the anatomic extent of disease determined on pathologic examination of the resection specimen. Although a large number of staging systems have been developed for colorectal cancer over the years, use of the TNM staging system of the AJCC is widely recommended. Other staging systems include and are also illustrated below. In the TNM system, T refers to the local extent of the primary tumor at the time of diagnosis, before the administration of treatment of any kind. The designation N refers to the status of the regional lymph nodes, and M refers to distant metastatic disease, including nonregional lymph nodes. The symbol p, used as a prescript, refers to the pathologic determination of the TNM (e.g., pt1), as opposed to the clinical Colorectal Carcinoma Primary Tumor (T) TX: Primary tumor cannot be assessed T0: No evidence of primary tumor Tis: Carcinoma in situ (intraepithelial or intramucosal carcinoma) T1: Tumor invades the submucosa T2: Tumor invades the muscularis propria T3: Tumor invades through the muscularis propria into the subserosa or into the nonperitonealized pericolic or perirectal tissues T4a: Tumor penetrates to the surface of the visceral peritoneum T4b: Tumor directly invades or is adherent to other organs or structures Regional Lymph Nodes (N) NX: Regional lymph nodes cannot be assessed NO: No regional lymph node metastasis N1: Metastasis in 1 to 3 lymph nodes N1a: Metastasis in one regional lymph node N1b: Metastasis in 2-3 regional lymph nodes N1c: Tumor deposit(s) in the subserosa, mesentery, or nonperitonealized pericolic or perirectal tissues without regional nodal metastasis N2: Metastasis in 4 or more regionallymph nodes N2a: Metastasis in 4-6 regional lymph nodes N2b: Metastasis in seven or more regional lymph nodes Distant Metastasis (M) MX: Presence of distant metastasis cannot be assessed M0: No distant metastasis M1: Distant metastasis M1a: Metastasis confined to one organ or site M1b: Metastasis in more than one organ /site or peritoneum determination, designated by the prescript c. It is the grouping of a T, an N, and M parameter that determines the stage of the tumor and relates to prognosis. (See Tables 3-5) Tables 6, 7 and Figures 6, 7 demonstrate diagnosis and survival by stage at PHSW and PHSJ. 8 swmedicalcenter.org Fall 2012

11 Table 4: Staging of Colorectal Carcinoma AJCC Anatomic Stage/ Prognostic Group comparison with other staging Stage T N M Dukes MAC 0 Tis NO MO - - I T1 NO MO A A T2 NO MO A B1 IIA T3 NO MO B B2 IIB T4a NO MO B B2 IIC T4b NO MO B B3 IIIA T1-T2 N1/N1c MO C C1 T1 N2a MO C C1 IIIB T3-T4a N1/N1c MO C C2 T2-T3 N2a MO C C1/C2 T1-T2 N2b MO C C1 IIIC T4a N2a MO C C2 T3-T4a N2b MO C C2 T4b N1-N2 MO C C3 IVA Any T Any N M1a - - IVB Any T Any N M1b - - Table 5: Observed Survival Rates for 28,491 Cases With Adenocarcinoma of the Colon Stage I Stage IIA Stage IIB Stage IIC Stage IIIA Stage IIIB Stage IIIC Stage IV Years from diagnosis Data from the SEER Public Use File diagnosed in years Stage I includes 7417; Stage IIA, 9956; Stage IIB, 997; Stage IIC, 725; Stage IIIA, 868, Stage IIIB, 1492; Stage IIIC, 2000; and Stage IV, Volume 5, Number 1 Exceptional Medicine 9

12 Figure 6: AJCC Colorectal Cancer Stage at Diagnosis, PHSW 2011 Figure 7: AJCC Colorectal Cancer Stage at Diagnosis, PHSJ % 23% 16% 6% 6% 10% 17% Stage 0 Stage 1 Stage 2 Stage 3 Stage 4 Unknown 3% 3% 14% 22% 6% 23% 35% Stage 0 Stage 1 Stage 2 Stage 3 Stage 4 Unknown More than half of the cases of CRC diagnosed at PHSW in 2011 were stage II or stage III. More than a third of the cases of CRC diagnosed at PHSJ in 2011 were stage II. Table 6: 5-year Relative Survival by Summary Stage at Diagnosis for Nation vs. PHSW Stage at Diagnosis 5-year Relative Survival (%) Summary Stage : National PHSW Localized (confined to primary site) Regional (by direct extension &/or lymph nodes) Distant (cancer has metastasized) *5 Year Relative Survival by Stage National numbers based on NCI/SEER statistics Table 7: 5-year Relative Survival by Summary Stage at Diagnosis for Nation vs. PHSJ Stage at Diagnosis 5-year Relative Survival (%) Summary Stage : National PHSJ Localized (confined to primary site) Regional (by direct extension &/or lymph nodes) Distant (cancer has metastasized) *5 Year FAMILIAL CANCER SYNDROMES Lynch syndrome or otherwise called Hereditary Nonpolyposis Colorectal Cancer (HNPCC) is the most common of the hereditary cancer syndromes and accounts for 2-3% of all CRC. It is an autosomal dominant disorder with variable penetrance and is caused by a germline mutation in one of the four mismatch repair genes including MLHI, MSH2, MSH6 and PMS2 which code for MMR proteins and is characterized by microsatellite instability (MSI).32 Germline deletions in EPCAM gene, which is not a mismatch repair gene, can inactivate MSH2 in about 1% of individuals with Lynch syndrome/hnpcc. Lynch syndrome/ HNPCC is characterized by an increased risk of CRC and cancers of the endometrium, ovary, stomach, pancreas, small intestine, hepatobiliary tract, ureter and renal pelvis, brain(usually GBM), and skin including keratoacanthomas or sebaceous gland adenomas.32 The mean age of diagnosis of CRC is around 45 years, and this is much lower than the mean age for sporadic CRC. Lynch syndrome cancers seem to evolve from adenomas, but the transition from adenomas to carcinoma appears to occur much more rapidly than sporadic CRC. Synchronous colon cancers, 10 swmedicalcenter.org Fall 2012

13 separated by normal bowel and not due to direct extension or metastasis, occur in 2.5% of CRC when Lynch syndrome/hnpcc patients are excluded and in about 3-5% if Lynch syndrome/ HNPCC patients are included. Several guidelines or criteria have been used to identify individuals or families at a high risk of CRC who should be considered for genetic testing for Lynch Syndrome. These include the revised version of the older Amsterdam criteria (Amsterdam II) and also the revised Bethesda guidelines. The Amsterdam II Criteria include an individual with at least three relatives with colorectal cancer or other HNPCC associated cancers and all of the following: One should be a first-degree relative (parent, sibling, or child) of the other two relatives. At least two successive generations must be affected. At least one relative must have been diagnosed with CRC when they were younger than age 50. Familial adenomatous polyposis must have been excluded, and tumors should be verified by pathology exam. Approximately 50% of patients with HNPCC/ Lynch will be missed by using the above criteria, and 50% of patients that meet these criteria may not have HNPCC. Revised Bethesda guidelines have been used to determine which individuals with colorectal cancer should have their tumor tested for genetic markers to be described in next section and include (see below): An individual with any of the following: CRC diagnosed less than 50 years of age. Synchronous or metachronous CRC or other Lynch syndrome cancers regardless of age. CRC with MSI-H (MSI-High) status or MSI-H like histology including presence of tumor infiltrating lymphocytes, mucinous/signet ring pathology or a medullary growth pattern in a person less than 60 years of age. CRC in a patient with one or more first or second degree relatives with an HNPCC related cancer with one diagnosed less than 50 years of age or two or more first or second degree relatives regardless of age. However, many institutions have adopted universal screening of all CRC tumors in individuals less than years of age to help identify individuals that could have Lynch syndrome. The diagnosis of Lynch syndrome can be made in individuals on the basis of family history in families meeting the Amsterdam criteria and have microsatellite instability (MSI-H) or by molecular genetic testing in an individual or family to identify a germline mutation in one of four mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) or in EPCAM. Initial screening can be done by evaluation of tumor tissue for MSI through molecular MSI testing and/ or immunohistochemistry (IHC) of the four MMR proteins. Approximately 15-20% of CRC have MSI but majority of MSI is caused by sporodic methylation of the promoter region of proteins by IHC helps identify the MMR gene that most likely harbors a germline mutation and further guides molecular genetic testing. Screening for CRC in individuals with Lynch syndrome/hnpcc includes a colonoscopy with removal of precancerous polyps every one to two years beginning between ages 20 to 25 years diagnosis in the family if diagnosed before age 25. Prophylactic removal of the colon prior to the development of colon cancer is generally not recommended for individuals known to have Lynch syndrome/hnpcc because routine colonoscopy is an effective preventive measure. Prophylactic removal of the uterus and ovaries can be considered after childbearing is completed. Testing should be offered to relatives of an individual diagnosed with Lynch Syndrome/HNPCC. Volume 5, Number 1 Exceptional Medicine 11

14 Other polyposis syndromes include familial adenomatous polyposis (FAP) and attenuated FAP syndrome, MUTYH associated polyposis, juvenile polyposis syndrome and Peutz- Jeghers syndrome. Disorders associated with adenomatous polyps include familial adenomatous polyposis (FAP) which is an autosomal dominant disease caused by mutations in the adenomatous polyposis coli (APC) gene. Denovo mutations can also occur. FAP accounts for less than 1% of the CRC risk in the United States. Genetic testing is available.41 FAP should be considered a possibility in any individual with more than 100 lifetime adenomas. Other associated features include congenital hypertrophy of retinal pigment, osteomas, supernumery teeth, odontoms, desmoids, epidermoid cysts, gastric fundic gland polyps. There is an increased risk of meduloblastoms, papillary thyroid carcinoma, pancreatic and gastric cancers. Attenuated familial adenomatous polyposis (AFAP) is an autosomal dominant disorder with a milder presentation of FAP and is also caused by mutations in APC gene but presents with fewer than 100 polyps and at later ages than classic FAP. Many of the extracolonic manifestations observed in classic FAP may be absent in AFAP. MUYTH associated polyposis syndrome is associated with autosomal recessive inheritance and fewer than 100 adenomas and occurs as a result of mutation in the MUYTH gene.42 30% of individuals with polyps and also a small portion of individuals with a classic of colon cancer in the absence of multiple polyps.43 Genetic testing is available and should be considered in the appropriate setting. Other disorders associated with an increased risk for hamartomatous polyps and colon cancer include Juvenile polyposis syndrome (JPS) caused by mutations in SMADA4 and BMPR1A and Peutz- Jeghers syndrome (PJS) caused by mutations in STK11 gene44, and PTEN associated hamartomatous syndromes caused by mutations in PTEN gene. Juvenile polyposis syndrome can be suspected in an individual with at least three juvenile polyps throughout the gastrointestinal (GI) tract or any number of juvenile polyps with a family history of JPS. The term juvenile refers to the polyp pathology and not to the age of onset. 45 Genetic testing is available and should be considered in the appropriate setting as juvenile polyps can also be benign. Serrated polyposis syndrome also known as hyperplastic polyposis syndrome should be suspected in proximal to the sigmoid colon with at least two being more than a centimeter or any number degree relative with serrated polyposis syndrome or in an individual with greater than 20 serrated risk of CRC is elevated in individuals with the above mentioned polyposis syndromes and these individuals should be screened using disease 46 Screening recommendations for the above high-risk syndromes vary depending on the diagnosis and age of the individual and family history. Consideration should be given to NSAID chemoprevention after weighing the risks and syndromes is beyond the scope of this article. Further details regarding diagnosis and screening and genetic testing of individual and at risk family members can be obtained at PROGNOSTIC AND PREDICTIVE MARKERS For decades clinicopathologic features including advancing T stage, nodal status, tumor perforation, lymphovascular or perineural invasion and poorly differentiated histology have all been used to assess risk of recurrence and prognosis. Despite the prognostic utility of stage, outcomes for patients with tumors of similar 12 swmedicalcenter.org Fall 2012

15 stage can be quite heterogeneous. Novel research techniques have provided deeper insight into the molecular basis of cellular transformation and have demonstrated the heterogeneity that exists at a molecular level even in tumors that are in a similar subclass.25 Systematic several abnormalities including chromosomal aberrations and deletions, overexpression of oncogenes, deletions or mutations of tumor suppressor or DNA repair genes.26 A large number of tissue-based prognostic indicators including molecular, protein, and carbohydrate markers have been investigated to better predict individual outcomes. A prognostic marker is a biomarker that is indicative of patient outcome independent of the treatment received. A predictive marker is a biomarker be a target for therapy.27 Several markers have been studied in colorectal cancer including 18q LOH, microsatellite instability (MSI)/ hypermethylation, K-ras, p16, EGFR, BRAF and p53 mutations The markers that are currently most used in clinical practice include MSI/MMR determination, K-ras, BRAF and CEA. Genes in the mismatch repair (MMR) pathway including MLH1, MSH2, MSH6, and PMS2 code for MMR proteins which are responsible for identifying and repairing single nucleotide mismatches that occur during the process of cell division.32 Approximately 15-20% of colorectal cancers have sporadic or an inherited (germ line) leading to altered DNA repair and accumulation of somatic mutations in a cell, which may result in the cell becoming malignant.33 Some sporadic MMR proteins detectable by IHC or MSI (Micro Satellite Instability). Microsatellites are stretches of DNA with a repetitive sequence of nucleotides (e.g., AAAAA or CGCGCGCG) that are particularly susceptible to acquiring errors when mismatch repair gene function is impaired. Cancers arising in cells with defective mismatch repair gene function exhibit an inconsistent number of microsatellite nucleotide repeats referred to as microsatellite instability (MSI). 32 MSI can be detected based on tumor testing. Tumors displaying alterations in greater than as microsatellite instability high (MSI-H). Such tumors are characteristically located proximally and may have a mucinous histology with tumor prognosis than the microsatellite stable (MSS) tumors.34 biomarker associated with a lower recurrence risk in patients with stage II colon cancer. MSI could be done to obtain stage-independent predictors of recurrence risk and possibly help in adjuvant therapy decision making. It could also be done to screen for hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome. However, the majority of MSI is caused by somatic methylation of the promoter region of MLH1 gene that silences gene expression MMR status on IHC testing. Thus detecting MLH1 hypermethylation can help rule out Lynch syndrome in most situations. Molecular genetic testing should still be considered in individuals with an early age of diagnosis or a strong family history.32 BRAF mutations occur in around 15% of CRC and are thought to be rare in Lynch syndrome, and a positive BRAF mutation essentially rules out Lynch syndrome. MLH1 promoter methylation is also correlated with tumor BRAF V600E mutation status and both are strong predictors of negative MMR mutation status.35,36 Positive mutations of K-ras and BRAF have been associated with poorer outcomes.37 Patients whose tumors test positive for K-ras or BRAF V600E allele are not Volume 5, Number 1 Exceptional Medicine 13

16 Cetuximab or Panitumumab, and this can be used in the metastatic setting for the selection of therapies. 35,37 Gene expression arrays such as a 12-gene recurrence score assay (Oncotype DX Colon (ColoPrint) are also in clinical use and have been independently validated in an analysis of data from the prospective QUASAR trial. Recurrence Score (RS) can be used as a prognostic marker and has the ability to better estimate a patient s risk of recurrence, but it has not been established that increased recurrence risk can be overcome by use of adjuvant chemotherapy.38,39 Other prognostic markers include serum levels of the tumor marker carcinoembryonic antigen (CEA). CEA should be routinely measured preoperatively in patients undergoing potentially curative resections for CRC. Preoperative CEA values are than >5.0 ng/ml have an adverse impact on survival that is independent of tumor stage. Also, CEA levels that do not return to normal post resection may signify residual disease. MANAGEMENT This section reviews management of all variants of adenocarcinoma, medullary or undifferentiated carcinoma. Small cell carcinoma, and pure squamos cell carcinoma of colon and rectum are managed differently. Patients presenting with invasive CRC require a complete staging work up. NCCN guidelines recommend pathology review, total colonoscopy a baseline contrast enhanced CT scan of chest abdomen and pelvis. This is to rule out potential metastatic disease that may change management. A PET/CT scan use is not routinely recommended in staging of colon cancer but could be considered to further evaluate lesions that are suspicious but inconclusive for metastatic disease, if it would have an impact on overall management. Surgery is the primary treatment modality for CRC. For colon cancer that has not metastasized the standard treatment is colectomy (the extent of which depends on the tumor location) and also enbloc removal of regional lymph nodes. Regional lymph node involvement is one of the strongest predictors of outcome following surgical resection of CRC and is an indication for adjuvant therapy for both colon and rectal cancer. The number of involved nodes and the total number of lymph nodes in the surgical without tumor involvement of lymph nodes Guidelines from expert groups recommend that at least 12 nodes be examined histologically to accurately determine nodal status.18 Less than 12 despite repeat pathology attempts to identify more nodes may be an indication for adjuvant therapy for stage II colon cancer. Neoadjuvant therapy includes chemotherapy and/or radiation given before surgery and aims to reduce the size of the tumor before surgical excision, thus making it easier and more likely to achieve negative margins. It is predominantly used in rectal cancer but could also be used in the more advanced stages of colon cancer to facilitate surgical resection with negative margins. Depending on the stage at diagnosis following surgery alone. Adjuvant therapy is the additional treatment given after the primary treatment where all grossly detectable disease has been removed. It includes chemotherapy and/or radiation given after surgery. Treatment intention is palliative and not curative for the majority of patients with metastatic colon or rectal cancer (mcrc). The goal in this situation is to control symptoms related to cancer and potentially shrink or stabilize the cancer with acceptable treatment-related toxicity while maintaining a reasonable quality of life. Tables stage at PHSW and PHSJ. 14 swmedicalcenter.org Fall 2012

17 Table 8: Colorectal Cancer First Course Treatment by AJCC Stage, PHSW 2011 Stage 0 Stage I Stage II Stage III Stage IV Unknown Total D 4 4 D,P 1 1 D,S D,R 2 2 D,C 3 3 D,S,R D,S,C D,R,C D,C,P 2 2 D,S,R,C S S,C 6 6 Hospice only 2 2 Total Table 9: Colorectal Cancer First Course Treatment by AJCC Stage, PHSJ 2011 Stage 0 Stage I Stage II Stage III Stage IV Unknown Total D 2 4 D,P 1 D,S D,R D,C 2 2 D,S,R 1 1 D,S,C D,R,C D,C,P D,S,R,C S S,C C 2 2 S,R,C 1 1 Total D = Diagnostic procedure DP = Diagnostic procedure, palliative procedure DS = Diagnostic procedure, surgery D,R = Diagnostic procedure, radiation D,C = Diagnostic procedure, chemotherapy D,S,R = Diagnostic procedure, surgery, radiation D,S,C = Diagnostic procedure, surgery, chemotherapy D,R,C = Diagnostic procedure, radiation, chemotherapy D,C,P = Diagnostic procedure, chemotherapy, palliative procedure D,S,R,C = Diagnostic procedure, surgery, radiation and chemotherapy S = Surgery alone S,C = Surgery, chemotherapy H = Hospice only Volume 5, Number 1 Exceptional Medicine 15

18 ADJUVANT THERAPY FOR COLON CANCER Adjuvant therapy is given with the hope of eradicating local and distant occult or microscopic disease and to potentially decrease the chances of relapse and improve outcomes. Adjuvant chemotherapy should be administered as soon as the patient has reasonably recovered from surgery. A recent analysis showed that each four-week delay in chemotherapy administration results in a 14% decrease in overall survival.50 Adjuvant therapy options for resected colon cancer are dependant mainly on the stage of disease and pathology features including grade of the tumor, lymphovascular and perineural invasion. Patient factors including general health, personal preferences and philosophy regarding (5-FU) has been the mainstay of therapy for several decades, but with the approval of Oxaliplatin the outcomes of adjuvant therapy by impairing DNA synthesis via inhibition of thymidylate synthase. Leucovorin (LV) enhances 5-FU cytotoxicity by interacting with thymidylate synthase and prolongs its inhibition by 5-FU. 5-FU can be administered in a bolus fashion or as a continuous infusion with differing toxicities. Capecitabine is an orally active 5-FU analog with treatment of colorectal cancer. Patients with resected stage I colon cancer do not require any adjuvant therapy. Stage II colon cancer patients have a good prognosis with surgery alone with an overall survival adjuvant chemotherapy in stage II colon cancer patients has been addressed in several clinical trials. Results from a meta-analysis stage III patients. 51 Two retrospective analyses using a SEER-medicare databases of large numbers of medicare patients aged who underwent colectomy for colon cancer could not chemotherapy for stage II disease even in the presence of poor prognostic features including obstruction, perforation, emergent admission for surgery, T4 primary, poorly differentiated or undifferentiated histology, and fewer than 12 nodes examined.52,53 This is in contrast to stage III disease, where adjuvant chemotherapy 54,55 MOSIAC trial involving a total of 2,246 patients was a phase III randomized trial comparing continuous infusion 5FU and Leucovorin alone versus the same chemotherapy combined with Oxalipatin in patients with stage II and III colon cancer.56 Six-year overall survivial (OS) rates for patients with stage III disease were 72.9% and 68.7% with and without Oxaliplatin P =.023). When Stage II patients were analyzed separately, analysis of patients with stage II disease showed that there was a trend towards improved DFS in high risk stage II patients characterized by T 4 tumor, perforation, obstruction, higher grade, lymphovascular invasion and inadequate nodal sampling. The frequency of grade III peripheral sensory neuropathy related to Oxaliplatin was 1.3% at 12 months after treatment and 0.7% at 48 months. Four years after completion of therapy, 15.5% of patients had residual neuropathy of any grade.54 colon cancer patients, the QUASAR trial which randomly assigned approximately 2,291 patients with stage II CRC to receive chemotherapy with Fluorouracil and Leucovorin or observation concluded that chemotherapy with Fluorouracil survival of patients with stage II colorectal cancer, although the absolute improvements were small and around 3.6%. 16 swmedicalcenter.org Fall 2012

19 NCCN guidelines recommend against routinely administering chemotherapy for stage II colon cancer patients based on lack of adequate data supporting its use and related to long-term side effects of chemotherapy. The discussion regarding adjuvant chemotherapy should include information about the evidence supporting morbidity and/or mortality related to treatment, patient preferences and philosophy regarding months of commitment to adjuvant therapy outweigh the potential risks for the individual patient. In general the evidence suggests that chemotherapy for typical stage II patients may not improve survival by more than 5%. Online risk calculators which estimate survival with and without chemotherapy taking into account age, tumor grade, nodal status, and T stage are available at and These calculators may assist the patient and physician in analyzing an individual patient s risk. There is also evidence that for stage II colon or MSI-H status is a marker of a more favorable therapy with 5FU alone, and this should be used in decision making regarding chemotherapy.57 A utility of MMR and MSI status in patients with stage II colon cancer, but there have been while other studies have not shown any such Low-risk stage II colon cancer patients, including patients with MSI-H status or MMR chemotherapy. Other low-risk patients without based therapy understanding that the absolute helpful in identifying individuals at a higher risk of recurrence in the setting of a normal MSI. Highrisk stage II colon cancer patients include those with T4 or high grade tumors, lymphovascular invasion or perineural invasion, bowel obstruction or perforation or close indeterminate or positive margins or pathology showing fewer than 12 nodes sampled. Higher tumor grade is not considered a high risk feature in patient with MSI-H status or 18 High-risk patients could be offered chemotherapy with 5FU and Leucovorin alone if there is no evidence of MSI-H status or based therapy after a thorough discussion of patients NCCN guidelines recommend a total of six months of adjuvant chemotherapy following surgery, and options include a combination of 5FU/LV and Oxaliplatin (mfolfox6)56 or bolus 5FU/LV/Oxalipatin (FLOX) 61, or a combination of Capecitabine and Oxaliplatin(CapeOX) 62 or single agent Capecitabine or 5FU/LV 63 if patients are felt not to be candidates for Oxalipatin-based therapy. Participation in clinical trials should always be encouraged. TREATMENT OF METASTATIC COLORECTAL CANCER The majority of patients with metastatic colon or rectal cancer (mcrc) cannot be cured with the exception of a subset of patients with liver and or lung-isolated limited volume disease who could be potentially cured with surgery. For most other patients treatment is palliative and generally consists of systemic chemotherapy and or radiation with the goal of prolonging survival while maintaining a reasonable quality of life (QOL) for as long as possible. NCCN guidelines recommend surgical resection of the of impending obstruction as surgery delays administration of chemotherapy.18 Most other patients diagnosed with metastatic colon cancer can proceed with palliative chemotherapy. The median overall survival for patients with Volume 5, Number 1 Exceptional Medicine 17

20 mcrc who receive best supportive care (BSC) advances in systemic chemotherapy with novel therapeutic agents has produced meaningful improvements in average survival which now (5FU) was the sole active agent, but with the approval of Irinotecan, Oxaliplatin, and three humanized monoclonal antibodies (MoAbs) that target vascular endothelial growth factor (Bevacizumab) and the epidermal growth factor receptor (Cetuximab and Panitumumab) there are several options for treatment. The best way to combine and sequence these agents is still not established, but in general combination therapy is associated with higher response rates. Exposure to all active chemotherapeutic and biologic agents during the disease course is Irinotecan is a topoisomerase I inhibitor and has activity as a single agent but has higher responses when used in combination with 5FU and or Oxaliplatin or biologic agents like Bevacizumab, Cetuximab or Panitumumab. Biliary excretion is one of the routes of metabolism and elevations in bilirubin increase the risk for severe neutropenia and diarrhea with Irinotecan. Saltz regimen or IFL is a combination of bolus 5FU and Irinotecan. FOLFIRI is a combination of Irinotecan with infusional 5FU and has toxicity and is the preferred approach.64 UGT1A1 metabolizes the active form of Irinotecan, SN-38. Enzymatic activity of UGT1A1 could be reduced related to genetic polymorphisms leading to slow excretion of the active metabolite of Irinotecan. This includes patients with Gilbert s syndrome, and these patients may be at a higher risk for Irinotecan-related gastrointestinal (GI) toxicity and neutropenia. Genetic testing for the presence of the UGT1A1*28 allele is available and could be considered in the appropriate setting.65,66 Oxaliplatin by itself has a very low level of activity in CRC, but acts synergistically when combined with 5FU(FOLFOX or FLOX) resulting in greater responses and progression free survival. Growth factors such as epidermal growth factor (EGF) and its receptor (EGFR) may be involved in CRC cell cycle regulation and tumorigenesis. Two monoclonal antibodies targeting the EGFR, Cetuximab and Panitumumab have activity in mcrc but are only effective in the subset of patients (approximately 40% of all mcrcs) whose tumors have the unmutated or wildtype K-ras. 67 Cetuximab works synergistically with Irinotecan and could also be used in combination with infusional 5FU and Irinotecan (FOLFIRI).68,69 Cetuximab with FOLFIRI is FDA CRC. Cetuximab and Panitumumab have not been compared head to head but probably have vascular endothelial growth factor (VEGF) which is involved in tumor angiogenesis or growth of new blood vessels and is approved for the with chemotherapy NCCN guidelines recommend any of the following options for or FOLFIRI or CapeOX with or without Bevacizumab or FOLFIRI with or without Cetuximab (if K-ras wild type) or FOLFIRI or FOLFOX with or without Panitumumab (if K-ras wild type), or FOLFOXIRI (5FU/ LV/Oxaliplatin, Irinotecan).18,64,73,74,75 or infusional 5FU/LV or Capecitabne. Decision is usually made based on patient preferences and other comorbid conditions. The available data from head-to-head comparisons suggest LV (FOLFOX) and Irinotecan/5FU/LV infusion (FOLFIRI) are similar, and the optimal sequence of Oxaliplatin and Irinotecan-containing chemotherapy remains unresolved and is based primarily on physician preference and patientrelated factors.76 NCCN guidelines recommend against switching to Cetuximab or Panitumomab after failure of the other drug based on lack of adequately convincing data.18 There is evidence 18 swmedicalcenter.org Fall 2012

21 supporting the continuation of Bevacizumab in combination with alternative chemotherapy containing chemotherapy regimen. 77 During chemotherapy, response is typically assessed using imaging studies every two to three months and also by periodic measurement of serum carcinoembryonic antigen (CEA) levels. Persistently rising CEA levels are highly correlated with disease progression, and before changing therapeutic strategy. Treatment breaks could be considered after four to six months of treatment, and this decision is based upon several factors including ongoing response to chemotherapy versus stable disease, toxicity, symptomatology and QOL. In some situations Oxaliplatin could be discontinued after three to four months of therapy before the onset of severe neurotoxicity while maintaining treatment with 5FU and could be reintroduced at disease progression.78 Treatment could be maintained in responding patients who have no clinically that planned discontinuation of chemotherapy may have a negative impact on outcomes.79 If chemotherapy is discontinued or held, close follow-up with imaging every two to three months with early resumption of chemotherapy Overall outcomes of metastatic CRC have Other newer agents including Regorafenib clinical trials in pretreated patients with mcrc. The CORRECT trial was a randomized study that enrolled 760 patients with mcrc whose disease has progressed after approved standard therapies, and patients received Regorafenib plus best supportive care (BSC) or placebo plus BSC. Regorafenib increased overall survival in patients with heavily pretreated mcrc and FDA approval is pending. 80 for treatment of mcrc that has progressed on Oxaliplatin-based therapy based on results of VELOUR trial which showed that in heavily pretreated patients with mcrc median overall versus 12.1 months).81 MANAGEMENT OF LIVER AND LUNG METASTASIS IN CRC Liver is the dominant site for metastasis in patients with CRC. Some individuals have disease isolated to the liver while a majority of individuals have additional extra hepatic spread. Patients with synchronous metastatic disease (detected at time of initial diagnosis) that is resectable could undergo upfront resection of the primary and metastatic lesions or in a staged fashion. Patients with metachronously detected metastatic disease should have a complete staging work up to assess the extent of approached with the intention of cure or longterm disease-free survival. Staging work up includes a contrast enhanced CT scan of chest, abdomen and pelvis and a bone scan. PET/ CT scan could be used to rule out other areas of spread that may preclude surgery. Contrast enhanced MRI may be better at showing the extent of metastatic disease in the liver compared to CT imaging with contrast. Resectable CRC liver metastases are metastasis that can be resected completely, leaving an adequate liver remnant and most surgeons require imaging evidence of lack of involvement of hepatic artery, major bile ducts, main portal vein and celiac or paraaortic nodes.82,83 If patients have resectable disease, complete surgical resection is the recommended approach. If it is determined that complete resection with negative margins cannot be achieved, neoadjuvant chemotherapy can be utilized to potentially shrink the tumor and make it resectable. Combination Volume 5, Number 1 Exceptional Medicine 19

22 chemotherapy regimens with high response rates are used followed by reassessment two months later and at two-month intervals thereafter. 84,85 Approximately 10-30% of patients with initially unresectable hepatic metastases a subsequent complete resection. NCCN guidelines recommend FOLFOX or FOLFIRI or XELOX with or without bevacizumab or FOLFIRI with or without cetuximab (if K-ras wild type) or FOLFIRI or FOLFOX with or without panitumumab (if K-ras wild type), or FOLFOXIRI The total duration of preand post-operative chemotherapy should be following surgery for colorectal liver metastasis approaches 30-40%, and these results are year survival is around 10%. Some patients cannot undergo surgical resection related to comorbid conditions or location of metastatic lesions and/or related to possible inadequate liver volume post resection. In these situations, radiofrequency ablation is an alternative form of therapy for palliation. In general RFA is inferior to resection with negative margins with respect to local recurrence and overall survival. Other nonsurgical options for palliation include transarterial chemoembolization(tace), radioembolization using various techniques, stereotactic radiotherapy or brachytherapy. At PHSW patients diagnosed with potentially resectable metastatic cancer undergo evaluation by a multidisciplinary team, including consultation with a hepatobiliary surgeon. Interventional radiologists at PHSW can perform CT guided radiofrequency ablation- for three or fewer metastatic lesions that are approximately less than 3 cm in size. Other options for localized treatment of metastatic liver lesions include chemoembolization with drug eluting beads (drug usually used is Irinotecan) and Yttrium- 90(Y-90) Therasphere treatment. Y-90 Therasphere treatment is not FDA approved for treatment of liver metastasis from CRC and requires a special IRB (institutional review board) exception at PHSW. Other interventional radiology techniques available at PHSW include preoperative portal vein embolization prior to a partial hepatectomy which can be used in situations requiring a partial right or left hepatectomy to help with hypertrophy of the remaining liver thus increasing hepatic reserve. Cyberknife radiosurgery may also be an option in select individuals and is available at PHSW. MANAGEMENT OF RECTAL CANCER located within 12 cm of the anal verge by rigid proctoscopy. Most of the principals of staging, management, and risk factors are similar to colon cancer with a few exceptions. This is because the rectum is in close proximity to pelvic organs and structures and lacks serosa. Also, its location in the pelvis makes achieving wide surgical margins Surgery is the primary treatment modality, and the goal is complete resection with negative margins while maintaining continence if at all possible. Depth of tumor penetration and nodal status determines the need for neoadjuvant or adjuvant chemoradiation. Imaging modalities including Endorectal Ultrasound and or MRI are used for preoperative staging to adequately determine the depth of tumor penetration. Options for surgery include transanal excision for very early stage cancers with no adverse features or low anterior resection or abdominoperineal resection for more advanced tumors depending on the location. Total Mesorectal Excision (TME) involves enbloc removal of the mesorectum including vascular and lymphatic structures, fatty tissue, and mesorectal fascia as a tumor package by sharp dissection, making sure nerves are spared. This is designed to radically remove all the draining lymphatics. Following surgery the specimen should be assessed by pathology to determine the circumferential margin of 20 swmedicalcenter.org Fall 2012

23 resection (CRM) which is an important feature in the management of rectal cancer. CRM is the closest radial margin between the deepest penetration of the tumor and the edge of the resected soft tissue around the rectum and includes the retroperitoneal or subperitoneal aspect of the tumor. Positive tumor within 1 a positive margin based on NCCN guidelines. CRM has shown to be a strong predictor of local recurrence and overall survival.18 Stage I patients proceed directly to surgery, and if the post operative stage remains unchanged no adjuvant therapy is required. Neoadjuvant therapy including radiation or chemoradiation is considered for all patients with stage II or III disease. Some patients with low risk proximal tumors including T3 N0 pathologically staged tumors could potentially skip radiation given a relatively lower incidence of local recurrence. Chemotherapy is generally administered with radiation and involves total of six months of therapy given pre- or post-surgery. 5FU is used concurrently with radiation, and subsequent therapy may include 5FU-based therapy alone Capecitabine can be substituted for 5FU. The 5FU-based or FOLFOX-based should be discussed with all patients with stage II and II disease post completion of neoadjuvant chemoradiation. The principles of management of metastatic rectal cancer are similar to colon cancer. FOLLOW UP, SURVEILLANCE, AND SURVIVORSHIP After initial surgery and administration of any chemotherapy and/or radiotherapy, it is recommended that individuals with CRC be offered a post-treatment surveillance program. The goal is to monitor for any side effects related to treatment and early detection of potentially curable new cancers or local disease recurrence and isolated or limited volume metastatic disease. A recent report of a collection of pooled data from 18 clinical trials involving approximately 21,000 patients with stage II or III CRC treated with 5FU-based adjuvant therapy showed that most relapses occur within two years following surgery. Relapse rate was less than 1.5% per year and less than 0.5 % per year 90 NCCN guidelines recommend a history and physical exam every three to six months for two years and then every six months for a total of 18 A CEA is also recommended every three to six months for two years and then every abdomen and pelvis is recommended annually or III colon cancer, especially for patients with high risk features including LV invasion or poorly differentiated tumors. A complete colonoscopy is recommended preoperatively but in the setting of obstruction a double contrast barium enema or computed tomography colonography should be done preoperatively, and colonoscopy should be performed three to six months after surgery to rule out synchronous disease. Subsequently a follow up colonoscopy should be performed in one year to rule out new primary tumors which could occur in 3-5% of patients. Subsequent sooner depending on other risk factors. Patients undergoing low anterior resection of rectal cancer generally have higher rates of local cancer recurrence, compared to patients with colon cancer. Consideration could be given to follow up proctoscopy at six-month intervals to detect a potentially resectable local recurrence of rectal cancer.17 Annual chest, abdomen and pelvic CT is also recommended for rectal cancer patients at high risk of recurrence, including patients with lymphovascular invasion or poorly differentiated or node positive tumors. In general close follow up with CEA and imaging studies should only be considered if patients are candidates for Volume 5, Number 1 Exceptional Medicine 21

24 aggressive treatment including surgery for any limited volume metastatic disease or local recurrence. Figures 8 and 9 show observed survival for Colorectal Cancer diagnosed in at PHSW and PHSJ. Figure 8: Observed Survival for Colon, Rectum, Rectosigmoid Cases Diagnosed in , PHSW (n=249 c/w NCDB n=139, 018) year 2 years 3 years 4 years 5 years PHSW NATIONAL PHSW NATIONAL PHSW NATIONAL PHSW NATIONAL PHSW NATIONAL Stage 0 100% 95% 92% 92% 92% 89% 92% 85% 85% 82% Stage 1 97% 94% 93% 91% 87% 87% 87% 83% 87% 79% Stage 2 97% 84% 91% 84% 83% 78% 74% 73% 72% 67% Stage 3 78% 88% 70% 77% 67% 69% 65% 62% 56% 57% Stage 4 42% 54% 20% 33% 10% 21% 8% 15% 3% 11% Overall 80% 84% 70% 75% 64% 68% 60% 62% 56% 58% Figure 9: Observed Survival for Colon, Rectum, Rectosigmoid Cases Diagnosed in , PHSJ (n=119 c/w NCDB n=139, 018) year 2 years 3 years 4 years 5 years PHSJ NATIONAL PHSJ NATIONAL PHSJ NATIONAL PHSJ NATIONAL PHSJ NATIONAL Stage 0 100% 95% 100% 92% 100% 89% 89% 85% 89% 82% Stage 1 92% 94% 83% 91% 83% 87% 79% 83% 79% 79% Stage 2 95% 84% 82% 84% 77% 78% 72% 73% 72% 67% Stage 3 92% 88% 70% 77% 62% 69% 54% 62% 50% 57% Stage 4 54% 54% 22% 33% 16% 21% 16% 15% 16% 11% Overall 87% 84% 71% 75% 67% 68% 62% 62% 61% 58% 22 swmedicalcenter.org Fall 2012

25 PHSW CANCER RESEARCH For the past 25 years, participation in cancer research, including research for colon and rectal cancers, has been and remains an important commitment for PHSW Regional Cancer Center. PHSW cancer research began offering patients participation in national clinical trials in was consented and treated at PHSW on a national clinical trial protocol from Southwest Oncology Group (SWOG 8591). PHSW is an active member of Columbia River Oncology Program (CROP), which is a National Cancer Institute-accredited consortium of local healthcare systems and providers, and through CROP has access to all of the major research bases and their protocols. Today s cancer treatments are the result of patient participation in past clinical trials. Throughout the past 25 years in cancer research, PHSW has offered patients participation in colorectal studies from the leading national research bases including, NCCTG, NSABP, SWOG, CALGB and ECOG. The clinical trials treatments for patients diagnosed with cancer. Patient participation is key to the success of cancer research, and advancements in the understanding of colorectal cancer and its treatment are possible because patients choose to participate in clinical trials. Many patients gain from the trial itself, but they also feel empowered by the opportunity to contribute to the wellbeing of future generations. PHSW cancer research has offered clinical trials to hundreds of our colon and rectal cancer patients, and we have treated nearly 100 of those patients on a clinical trial protocol. Today we are accruing to two national trials for A phase III trial of six versus 12 treatments of adjuvant FOLFOX plus Celecoxib or placebo for patients with resected stage III colon cancer. This phase III study s rationale is to potentially reduce the total amount of cytotoxic chemotherapy to the patient, thus decreasing toxicity and possibly improving outcomes. Given the issues of neuropathy associated with oxaliplatin as well as the costs of adjuvant therapy, potential reduction in the number of required treatments Furthermore, there are still an appreciable number of patients with stage III colon cancer recurring despite recommended therapy, and thus continued testing of additional agents for sulfa NSAID and selective COX-2 inhibitor) will be initiated at the start of FOLFOX chemotherapy and continued for three years total. Patients eligible for this study must have a diagnosis of adenocarcinoma of the colon that was completely resected within 56 days of beginning treatment on study. The patient should have node positive disease and no evidence of residual involved lymph node disease or metastatic disease at the time of registration. Patients are ineligible if they plan on regular use of NSAIDs at any dose more than two times per week or aspirin at more than 325 mg at least three times per week. Low dose aspirin is permitted. The second clinical trial that we are currently enrolling patients to is NSABP P5: Statin Polyp Prevention Trial in Patients with Resected Colon Cancer. The primary aim of this Phase III randomized, placebo controlled study is to determine if the administration adenomatous polyps of the colon or rectum, metachronous colorectal carcinoma, and colon cancer recurrence (APMC+R) in patients with resected colon cancer. Patients with stage I or stage II colon cancer are eligible if the surgical resection is completed within one year before randomization. Adjuvant therapy, if given, must be completed before randomization. Also patients with related familial conditions such as Classic Familial Adenomatous Polyposis, Attenuated Familial Adenomatous Polyposis, Volume 5, Number 1 Exceptional Medicine 23

26 or Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) are not eligible. Patients must also have undergone either a preoperative or a postoperative colonoscopy to the cecum with adequate bowel preparation and all polyps must have been removed. Chronic use of NSAIDs is prohibited while on study therapy. For more information regarding participation in the above clinical trials please contact the PHSW cancer research staff at CANCER INCIDENCES AND DEMOGRAPHICS OF 5 MAJOR CANCERS AT PHSW AND PHSJ The next section of graphs and tables demonstrate 10-year cancer incidences, frequency of cancer by and comparative national statistics. Figure 10: 10-Year Cancer Incidence PHSW Diagnosis Year Number of Cases Year 24 swmedicalcenter.org Fall 2012

27 Table 10: Comparative Cancer Incidence PHSW vs WA State vs Nation 2011 PHSW WA State National Site Number Percent Number Percent Number Percent Breast , , Lung & , , Bronchus Colorectal , ,210 9 Melanoma , ,230 4 Corpus/ , ,470 3 Uterus Thyroid 55 5 * * 48,020 3 Brain/Other 53 5 * * 22,340 2 CNS Prostate , , Bladder , ,250 4 Lymphoma , ,360 4 Other , , Total , ,596, *Washington State and National Data from ACS Cancer Facts and Figures 2011 Figure 11: Frequency of Cancer by Gender PHSW Breast Lung/Bronchus Colorectal Site Melanoma CorpusUterus Thyroid Brain/Other CNS Prostate Bladder Lymphoma Number of Cases Volume 5, Number 1 Exceptional Medicine 25

28 Table 11: Primary Site Table PHSW 2011 Primary Site: Number of cases % Oral Cavity and Pharynx Lip Tongue Salivary Glands Floor of Mouth Tonsil Nasopharynx Hypopharynx Digestive System Esophagus Stomach Small Intestine Colon Rectum and Rectosigmoid Anus and Anal Canal Liver & Intrahepatic Bile Duct Gallbladder Other Biliary Pancreas Peritoneum, Omentum & Mesentery Respiratory System Nose, Nasal Cavity & Middle Ear Larynx Bronchus and Lung Bones and Joints Soft Tissue (including Heart) Skin excluding Basal & Squamous Malignant Melanoma Skin Other Non-epithelial Skin Basal/Squamous Cell Skin Breast Female Breast Male Breast Female Genital System Cervix Corpus Uteri Vagina Ovary Vulva Other Female Genital Organs Male Genital System Prostate Testis Other Male Genital Organs Urinary System Urinary Bladder Kidney & Renal Pelvis Other Urinary Organs Brain & Other Nervous System Brain Other Nervous System Endocrine System Thyroid gland Other Endocrine (including Thymus) Lymphomas Hodgkin s lymphoma Non-Hodgkin s lymphoma (Nodal=28, Extranodal=11) Myeloma Leukemia Lymphocytic Leukemia Myeloid & Monocytic Leukemia Other Leukemia Mesothelioma Ill-Defined/Unspecified swmedicalcenter.org Fall 2012

29 Figure 12: 5 Major Cancers Stage at Diagnosis PHSW 2011 Number of Cases Breast Lung/Bronchus Colorectal Melanoma 46 Corpus/Uterus Stage 0 Stage 1 Stage 2 Stage 3 Stage 4 Unknown/NA Site Figure 13: 10-year Cancer Incidence PHSJ Diagnosis year Number of Cases Year Volume 5, Number 1 Exceptional Medicine 27

30 Figure 14: PHSJ 2011 Analytic cases by site male/female and average age at diagnosis Average age at diagnosis Non-Hodgkins Breast Lung Prostate Colon/Rectal Hematopoietic Bladder Melanoma Lymphoma Male Female Table 12: Comparative Cancer Incidence PHSJ vs WA State vs Nation 2011 PHSJ WA State National Site Number Percent Number Percent Number Percent Breast , , Lung & , , Bronchus Colorectal , ,210 9 Melanoma , ,230 4 Corpus/ , ,470 3 Uterus Thyroid 22 4 * * 48,020 3 Brain/Other 9 2 * * 22,340 2 CNS Prostate , , Bladder , ,250 4 Lymphoma , ,360 4 Other , , Total , ,596, *Washington State and National Data from ACS Cancer Facts and Figures swmedicalcenter.org Fall 2012

31 Table 13: Primary Site Table PHSJ 2011 Primary Site: Number of cases % Oral Cavity and Pharynx Tongue Salivary Glands Gum & Other Mouth Tonsil Hypopharynx Digestive System Esophagus Stomach Colon Rectum and Rectosigmoid Anus and Anal Canal Liver & Intrahepatic Bile Duct Other Biliary Pancreas Respiratory System Larynx Bronchus and Lung Soft Tissue (including Heart) Skin excluding Basal & Squamous Malignant Melanoma Skin Breast Female Breast Male Breast Female Genital System Cervix Corpus Uteri Ovary Vulva Male Genital System Prostate Penis Urinary System Urinary Bladder Kidney & Renal Pelvis Other Urinary Organs Brain & Other Nervous System Brain Other Nervous System Endocrine System Thyroid gland Other Endocrine (including Thymus) Lymphomas Hodgkin s lymphoma Non-Hodgkin s lymphoma (Nodal = 9, Extranodal = 8) Myeloma Leukemia Lymphocytic Leukemia Myeloid & Monocytic Leukemia Other Leukemia Mesothelioma Miscellaneous Volume 5, Number 1 Exceptional Medicine 29

32 Figure 15: Most Common Cancers by Stage at Diagnosis PHSJ Number of Cases Breast Lung Prostate Colon Rectum Uterus 3 Stage 0 Stage 1 Stage 2 Stage 3 Stage 4 Unknown/NA References 1. Siegel R, Naishadham D, Jemal A Jan-Feb;62(1): doi: /caac Epub 2012 Jan 4. Cancer statistics, CA Cancer J Clin Jul-Aug;61(4): Epub 2011 Jun 17.Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. Siegel R, Ward E, Brawley O, Jemal A. 3. Surveillance, Epidemiology, and End Results (SEER) Program, Available online at 4. Gatof D, Ahnen D. Primary prevention of colorectal cancer: diet and drugs. Gastroenterol Clin North Am 2002;31: American Cancer Society. Colorectal Cancer Facts & Figures Jemal A, Siegel R, Ward E, et al. Cancer statistics, CA Cancer J Clin 2006;56: Alcohol intake and colorectal cancer: a pooled analysis of 8 cohort studies.aucho E, Smith-Warner SA, Ritz J, van den Brandt PA, Colditz GA, Folsom AR, Freudenheim JL, Giovannucci E, Goldbohm RA, Graham S, Holmberg L, Kim DH, Malila N, Miller AB, Pietinen P, Rohan TE, Sellers TA, Speizer FE, Willett WC, Wolk A, Hunter DJ. Ann Intern Med. 2004;140(8): Smoking and colorectal cancer: a meta-analysis.aubotteri E, Iodice S, Bagnardi V, Raimondi S, Lowenfels AB, Maisonneuve P JAMA. 2008;300(23): Meat consumption and risk of colorectal cancer.auchao A, Thun MJ, Connell CJ, McCullough ML, Jacobs EJ, Flanders WD, Rodriguez C, Sinha R, Calle EE JAMA. 2005;293(2): Leisure-time physical activity, body size, and colon cancer in women. Nurses Health Study Research Group.AUMartínez ME, Giovannucci E, Spiegelman D, Hunter DJ, Willett WC, Colditz GASOJ Natl Cancer Inst. 1997;89(13): Physical activity, obesity, and risk for colon cancer and adenoma in men.augiovannucci E, Ascherio A, Rimm EB, Colditz GA, Stampfer MJ, Willett WCSOAnn Intern Med. 1995;122(5): Is diabetes mellitus an independent risk factor for colon cancer and rectal cancer?auyuhara H, Steinmaus C, Cohen SE, Corley DA, Tei Y, Buffler PA Am J Gastroenterol. 2011;106(11): Secondary gastrointestinal cancer in childhood cancer survivors: a cohort study.auhenderson TO, Oeffinger KC, Whitton J, Leisenring W, Neglia J, Meadows A, Crotty C, Rubin DT, Diller L, Inskip P, Smith SA, Stovall M, Constine LS, Hammond S, Armstrong GT, Robison LL, Nathan PCSOAnn Intern Med. 2012;156(11): Increased risk of rectal cancer after prostate radiation: a populationbased study.aubaxter NN, Tepper JE, Durham SB, Rothenberger DA, Virnig BA Gastroenterology. 2005;128(4):819. Primary Site 15. Risk of colorectal cancer in the families of patients with adenomatous polyps. National Polyp Study Workgroup.AUWinawer SJ, Zauber AG, Gerdes H, O Brien MJ, Gottlieb LS, Sternberg SS, Bond JH, Waye JD, Schapiro M, Panish JFSON Engl J Med. 1996;334(2): Adenomatous Polyps of the Colon. Joel S. Levine, M.D., and Dennis J. Ahnen, M.D.N Engl J Med 2006; 355: December 14, CA Cancer J Clin May-Jun;56(3):160-7; Guidelines for colonoscopy surveillance after cancer resection: a consensus update by the American Cancer Society and US Multi-Society Task Force on Colorectal Cancer. Rex DK, Kahi CJ, Levin B, Smith RA, Bond JH, Brooks D, Burt RW, Byers T, Fletcher RH, Hyman N, Johnson D, Kirk L, Lieberman DA, Levin TR, O Brien MJ, Simmang C, Thorson AG, Winawer SJ. 18. NCCN guidelines, COlorectal Cancer Obesity and colon and rectal cancer risk: a meta-analysis of prospective studies Larsson SC, Wolk A. Am J Clin Nutr. 2007; 86(3): Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Am J Clin Nutr. 2007; 85(6): Lancet Dec 17;378(9809): Epub 2011 Oct 27.Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Burn J, Gerdes AM, Macrae F, Mecklin JP, Moeslein G, Olschwang S, Eccles D, Evans DG, Maher ER, Bertario L, Bisgaard ML, Dunlop MG, Ho JW, Hodgson SV, Lindblom A, Lubinski J, Morrison PJ, Murday V, Ramesar R, Side L, Scott RJ, Thomas HJ, Vasen HF, Barker G, Crawford G, Elliott F, Movahedi M, Pylvanainen K, Wijnen JT, Fodde R, Lynch HT, Mathers JC, Bishop DT; CAPP2 Investigators. 22. N Engl J Med Mar 6;348(10):891-9.A randomized trial of aspirin to prevent colorectal adenomas.baron JA, Cole BF, Sandler RS, Haile RW, Ahnen D, Bresalier R, McKeown-Eyssen G, Summers RW, Rothstein R, Burke CA, Snover DC, Church TR, Allen JI, Beach M, Beck GJ, Bond JH, Byers T, Greenberg ER, Mandel JS, Marcon N, Mott LA, Pearson L, Saibil F, van Stolk RU. 23. Lancet Oncol May;13(5): Epub 2012 Mar 21.Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials.algra AM, Rothwell PM. 24. Am J Gastroenterol Jul;106(7): doi: / ajg Epub 2011 Mar 15. Non-steroidal anti-inflammatory drugs and colorectal cancer risk in a large, prospective cohort.ruder EH, Laiyemo AO, Graubard BI, Hollenbeck AR, Schatzkin A, Cross AJ. 25. Tumor heterogeneity in neoplasms of breast, colon, and skin Jian Li, Kai Wang, Thomas Dyrsø Jensen, Shengting Li,1 Lars Bolund,and Carsten Wiuf. BMC Res Notes. 2010; 3: swmedicalcenter.org Fall 2012

33 26. Feero et al: Genomic Medicine An Updated Primer.N Engl J Med 2010; 362: May 27, Prognostic versus predictive value of biomarkers in oncology. Oldenhuis CN, Oosting SF, Gietema JA, de Vries EG.Eur J Cancer May;44(7): Prognostic and predictive factors in colorectal cancer: Kirsten Ras in CRC (RASCAL) and TP53CRC collaborative studies. Russo A, Bazan V, Agnese V, Rodolico V, Gebbia N.Ann Oncol May;16 Suppl 4:iv Microsatellite Instability and Loss of Heterozygosity at Chromosomal Location 18q: Prospective Evaluation of Biomarkers for Stages II and III Colon Cancer A Study of CALGB 9581 and Monica M. Bertagnolli?, Mark Redston, Carolyn C. Compton, Donna Niedzwiecki, Robert J. Mayer, Richard M. Goldberg, Thomas A. Colacchio, Leonard B. Saltz and Robert S. Warren. JCO August 10, 2011 vol. 29 no Biomarker Use in Colorectal Cancer Therapy. Robin K. Kelley, MDa, Grace Wang, PhDb and Alan P. Venook, MD. Natl Compr Canc Netw 2011;9: K-ras and p16 Aberrations Confer Poor Prognosis in Human Colorectal Cancer; M. Esteller, S. González, R. A. Risques, E. Marcuello, R. Mangues, J. R. Germà, J. G. Herman, G. Capellà and M. A. PeinadoJCO January 15, 2001 vol. 19 no Lynch Syndrome. Gene reviews. Wendy Kohlmann, MS and Stephen B Gruber, MD, PhD. 33. Defective Mismatch Repair in Colon Cancer: A Prognostic Or Predictive Biomarker? David J. Kerr Journal of Clinical Oncology, Vol 28, No 20 (July 10), 2010: pp Mucinous carcinoma of the colon: correlation of loss of mismatch repair enzymes with clinicopathologic features and survival. Kakar S, Aksoy S, Burgart LJ, Smyrk TC. Mod Pathol Jun;17(6): Selection of patients with germline MLH1 mutated Lynch syndrome by determination of MLH1 methylation and BRAF mutation. Bouzourene H, Hutter P, Losi L, Martin P, Benhattar J. Fam Cancer Jun;9(2): Correlation of tumour BRAF mutations and MLH1 methylation with germline mismatch repair (MMR) gene mutation status: a literature review assessing utility of tumour features for MMR variant classification.parsons MT, Buchanan DD, Thompson B, Young JP, Spurdle AB.J Med Genet Mar;49(3): Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. Van Cutsem E, Köhne CH, Láng I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F. J Clin Oncol May 20;29(15): D. Kerr, R. Gray, P. Quirke, D. Watson, G. Yothers, I. C. Lavery, M. Lee, M. J. O Connell, S. Shak, N. Wolmark, Quasar Colon Teams; J Clin Oncol 27:15s, 2009 (suppl; abstr 4000) 39. Path Toward Prognostication and Prediction: An Evolving Matrix. Al B. Benson III, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL Stanley R. JCO December 10, 2011 vol. 29 no Microsatellite Instability at the US National Library of Medicine Medical Subject Headings. 41. Familial adenomatous polyposis. Elizabeth Half, Dani Bercovich, and Paul Rozen. Orphanet J Rare Dis. 2009; 4: Curr Genomics September; 9(6): MUTYH Associated Polyposis (MAP) M.L.M Poulsen and M.L Bisgaard 43. Evidence for accelerated colorectal adenoma carcinoma progression in MUTYH-associated polyposis? M H Nieuwenhuis1, S Vogt, N Jones, M Nielsen4, F J Hes, J R Sampson, S Aretz, H F A Vasen1. Gutgut.bmj.comGut 2012;61: Peutz-Jeghers Syndrome. Gene Reviews. Christopher I Amos, PhD, Marsha L Frazier, PhD, Chongjuan Wei, PhD, and Thomas J McGarrity, MD 45. Juvenile Polyposis Syndrome. GeneReviews. Joy Larsen Haidle, MS, CGC and James R Howe, 46. Serrated polyposis syndrome: Molecular, pathological and clinical aspects. Carla Guarinos, Cristina Sánchez-Fortún, María Rodríguez- Soler, Cristina Alenda, Artemio Payá, and Rodrigo Jover. World J Gastroenterol May 28; 18(20): J Clin Oncol Aug 1;21(15): Colon cancer survival is associated with increasing number of lymph nodes analyzed: a secondary survey of intergroup trial INT Le Voyer TE, Sigurdson ER, Hanlon AL, Mayer RJ, Macdonald JS, Catalano PJ, Haller DG 48. J Clin Oncol Aug 1;21(15): Colon cancer survival is associated with increasing number of lymph nodes analyzed: a secondary survey of intergroup trial INT-0089.Le Voyer TE, Sigurdson ER, Hanlon AL, Mayer RJ, Macdonald JS, Catalano PJ, Haller DG. 49. Eur J Cancer Jan;41(2): Number of lymph nodes examined and prognosis of TNM stage II colorectal cancer. Sarli L, Bader G, Iusco D, Salvemini C, Mauro DD, Mazzeo A, Regina G, Roncoroni L. 50. JAMA Jun 8;305(22): Association between time to initiation of adjuvant chemotherapy and survival in colorectal cancer: a systematic review and meta-analysis. Biagi JJ, Raphael MJ, Mackillop WJ, Kong W, King WD, Booth CM. 51. Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) investigators. J Clin Oncol 17: , J Clin Oncol Oct 1;20(19): Adjuvant chemotherapy use for Medicare beneficiaries with stage II colon cancer. Schrag D, Rifas-Shiman S, Saltz L, Bach PB, Begg CB. 53. J Clin Oncol Sep 1;29(25): Adjuvant chemotherapy for stage II colon cancer with poor prognostic features.o Connor ES, Greenblatt DY, LoConte NK, Gangnon RE, Liou JI, Heise CP, Smith MA. 54. Mamounas E, Wieand S, Wolmark N, et al: Comparative efficacy of adjuvant chemotherapy in patients with Dukes B versus Dukes C colon cancer: Results from four National Surgical Adjuvant Breast and Bowel Project adjuvant studies (C-01, C-02, C-03, and C-04). J Clin Oncol 17: , J Clin Oncol May 15;22(10): Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much? Gill S, Loprinzi CL, Sargent DJ, Thomé SD, Alberts SR, Haller DG, Benedetti J, Francini G, Shepherd LE, Francois Seitz J, Labianca R, Chen W, Cha SS, Heldebrant MP, Goldberg RM. 56. J Clin Oncol Jul 1;27(19): Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial.andré T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, Bonetti A, Clingan P, Bridgewater J, Rivera F, de Gramont 57. N Engl J Med Jul 17;349(3): Tumor microsatelliteinstability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer.ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, Hamilton SR, Laurent-Puig P, Gryfe R, Shepherd LE, Tu D, Redston M, Gallinger S. 58. Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. Hutchins G, Southward K, Handley K, Magill L, Beaumont C, Stahlschmidt J, Richman S, Chambers P, Seymour M, Kerr D, Gray R, Quirke P., J Clin Oncol Apr 1;29(10): J Clin Oncol Jul 10;28(20): Defective mismatch repair in colon cancer: a prognostic or predictive biomarker?kerr DJ, Midgley R. 60. J Clin Oncol Jul 10;28(20): Microsatellite instability and adjuvant fluorouracil chemotherapy: a mismatch? Ng K, Schrag D 61. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07.Kuebler JP, Wieand HS, O Connell MJ, Smith RE, Colangelo LH, Yothers G, Petrelli NJ, Findlay MP, Seay TE, Atkins JN, Zapas JL, Goodwin JW, Fehrenbacher L, Ramanathan RK, Conley BA, Flynn PJ, Soori G, Colman LK, Levine EA, Lanier KS, Wolmark N. J Clin Oncol Jun 1;25(16): Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. Haller DG, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Gilberg F, Rittweger K, Schmoll HJ. J Clin Oncol Apr 10;29(11): Volume 5, Number 1 Exceptional Medicine 31

34 63. N Engl J Med Jun 30;352(26): Capecitabine as adjuvant treatment for stage III colon cancer. Twelves C, Wong A, Nowacki MP, Abt M, Burris H 3rd, Carrato A, Cassidy J, Cervantes A, Fagerberg J, Georgoulias V, Husseini F, Jodrell D, Koralewski P, Kröning H, Maroun J, Marschner N, McKendrick J, Pawlicki M, Rosso R, Schüller J, Seitz JF, Stabuc B, Tujakowski J, Van Hazel G, Zaluski J, Scheithauer W. 64. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J. J Clin Oncol Oct 20;25(30): The invaderugt1a1 molecular assay HOLOGIC; invaderchemistry.com/invader_applications/invader-ugt1a1.html 66. J Clin Oncol Oct 1;24(28): Uridine diphosphate glucuronosyltransferase (UGT) 1A1 and irinotecan: practical pharmacogenomics arrives in cancer therapy. O Dwyer PJ, Catalano RB. 67. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, André T, Chan E, Lordick F, Punt CJ, Strickland AH, Wilson G, Ciuleanu TE, Roman L, Van Cutsem E, Tzekova V, Collins S, Oliner KS, Rong A, Gansert J. J Clin Oncol Nov 1;28(31): Cetuximab plus FOLFIRI: Final data from the CRYSTAL study on the association of KRAS and BRAF biomarker status with treatment outcome. 69. Fluorouracil, Leucovorin, and Oxaliplatin With and Without Cetuximab in the First-Line Treatment of Metastatic Colorectal Cancer. Carsten Bokemeyer, Igor Bondarenko, Anatoly Makhson, Joerg T. Hartmann, Jorge Aparicio, Filippo de Braud, Serban Donea, Heinz Ludwig, Gunter Schuch, Christopher Stroh, Anja H. Loos, Angela Zubel and Piotr Koralewski. JCO February 10, 2009 vol. 27 no Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study.saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Cassidy J. Clin Oncol Apr 20;26(12): Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. N Engl J Med Jun 3;350(23): E. Van Cutsem, I. Lang, G. Folprecht, M. Nowacki, C. Barone, I. Shchepotin, J. Maurel, D. Cunningham, I. Celik and C. Kohne. Journal of Clinical Oncology, 2010 ASCO Annual Meeting Proceedings Vol 28, No 15_suppl (May 20 Supplement), 2010: J Clin Oncol Jun 1;23(16): Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Saltz. J Clin Oncol Apr 20;26(12): Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: a final report of the AIO Colorectal Study Group. Porschen R, Arkenau HT, Kubicka S, Greil R, Seufferlein T, Freier W, Kretzschmar A, Graeven U, Grothey A, Hinke A, Schmiegel W, Schmoll HJ; AIO Colorectal Study Group. J Clin Oncol Sep 20;25(27): Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, Crinò L, Benedetti G, Evangelista W, Fanchini L, Cortesi E, P J Clin Oncol May 1;25(13): FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study.tournigand C, André T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A.J Clin Oncol Jan 15;22(2): Arnold D, Andre T, Bennouna J, et al. Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first progression in patients with metastatic colorectal cancer (mcrc) previously treated with BEV plus CT: Results of a randomized phase III intergroup study (TML study). J clin Oncol 30, 2012 (suppl; abstract CRA3503). 78. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer- -a GERCOR study. J Clin Oncol Jan 20;24(3): Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 Study. Chibaudel B, Maindrault-Goebel F, Lledo G, Mineur L, André T, Bennamoun M, Mabro M, Artru P, Carola E, Flesch M, Dupuis O, Colin P, Larsen AK, Afchain P, Tournigand C, Louvet C, de Gramont A. J Clin Oncol Dec 1;27(34): Phase III Trial of Regorafenib in Metastatic Colorectal Cancer Meets Primary Endpoint of Improving Overall Survival. bayer.com/baynews/baynews.nsf/id/phase-iii-trial-regorafenib- Metastatic-Colorectal-Cancer-Meets-Primary-Endpoint-Improving- Overall?Open&ccm=001. Retrieved Van Cutsem E, Tabernero J, Lakomy R, et al. Intravenous aflibercept versus placebo in combination with irinotecan/5-fu (FOLFIRI) for second-line treatment of metastatic colorectal cancer (MCRC): results of a multinational Phase III trial (EFC10262-VELOUR) (ESMO abstract O-0024). Ann Oncol 2011; 22(suppl). 82. Curable metastatic colorectal cancer: recommended paradigms. AUBerri RN, Abdalla EKSOCurr Oncol Rep. 2009;11(3): Is hepatic resection justified after chemotherapy in patients with colorectal liver metastases and lymph node involvement?auadam R, de Haas RJ, Wicherts DA, Aloia TA, Delvart V, Azoulay D, Bismuth H, Castaing DSOJ Clin Oncol. 2008;26(22): J Clin Oncol Apr 10;26(11):1830-Bevacizumab, capecitabine, and oxaliplatin as neoadjuvant therapy for patients with potentially curable metastatic colorectal cancer. Gruenberger B, Tamandl D, Schueller J, Scheithauer W, Zielinski C, Herbst F, Gruenberger T. 85. Chemotherapy and regional therapy of hepatic colorectal metastases: expert consensus statement. Bartlett DL, Berlin J, Lauwers GY, Messersmith WA, Petrelli NJ, Venook AP.Ann Surg Oncol Oct;13(10): Patients with initially unresectable colorectal liver metastases: is there a possibility of cure?auadam R, Wicherts DA, de Haas RJ, Ciacio O, Lévi F, Paule B, Ducreux M, Azoulay D, Bismuth H, Castaing D J Clin Oncol. 2009;27(11): Oxaliplatin, fluorouracil, and leucovorin for patients with unresectable liver-only metastases from colorectal cancer: a North Central Cancer Treatment Group phase II study.aualberts SR, Horvath WL, Sternfeld WC, Goldberg RM, Mahoney MR, Dakhil SR, Levitt R, Rowland K, Nair S, Sargent DJ, Donohue JH J Clin Oncol. 2005;23(36): Chemotherapy permits resection of metastatic colorectal cancer: experience from Intergroup N9741.AUDelaunoit T, Alberts SR, Sargent DJ, Green E, Goldberg RM, Krook J, Fuchs C, Ramanathan RK, Williamson SK, Morton RF, Findlay BP Ann Oncol. 2005;16(3): Tritherapy with fluorouracilleucovorin, irinotecan and oxaliplatin (FOLFIRINOX): a phase II study in colorectal cancer patients with non-resectable liver metastases.auychou M, Viret F, Kramar A, Desseigne F, Mitry E, Guimbaud R, Delpero JR, Rivoire M, Quénet F, Portier G, Nordlinger B Cancer Chemother Pharmacol. 2008;62(2): J Clin Oncol Feb 20;27(6): Evidence for cure by adjuvant therapy in colon cancer: observations based on individual patient data from 20,898 patients on 18 randomized trials. Sargent D, Sobrero A, Grothey A, O Connell MJ, Buyse M, Andre T, Zheng Y, Green E, Labianca R, O Callaghan C, Seitz JF, Francini G, Haller D, Yothers G, Goldberg R, de Gramont A. 32 swmedicalcenter.org Fall 2012

35 CRC Screening and Endorectal Ultrasound for Rectal Cancer Colorectal cancer is the fourth most common cancer and the second leading cause of death from cancer. With improved adherence to screening guidelines there would likely be a more substantial decrease in the incidence of CRC cancer. The purpose of screening is to reduce mortality by decreasing the incidence of disease. Kevin Meitz, DO, The Vancouver Clinic Correspondence: Kevin Meitz, DO kmeitz@tvc.org The Vancouver Clinic, Gastroenterology 2529 NE 139th Street, Suite 240 Vancouver, WA Volume 5, Number 1 Exceptional Medicine 33

36 SCREENING FOR COLORECTAL CANCER INTRODUCTION In the United States, colorectal cancer is the fourth most common cancer and the second leading cause of death from cancer.1 The mean age of diagnosis is 71, and it is estimated that one in 20 persons will develop colorectal cancer. 2 Recent trends suggest that the incidence of colorectal cancer (CRC) has diminished slightly by 2.2% in women and 2.8% in men.3,4 These declining rates have been attributed to risk factor reduction and the effective use of early detection and prevention through colonoscopy with polypectomy. Yet, there has been an increasing relative incidence of proximal colonic adenocarcinoma that is not entirely understood.4 Unfortunately, the majority of individuals are not receiving regular age- and formal recommendation being issued in With improved adherence to screening guidelines there would likely be a more substantial decrease in the incidence of CRC cancer. The purpose of screening is to reduce mortality by decreasing the incidence of disease. CRC screening can achieve this by the detection of early-stage adenocarcinomas and removal of adenomatous polyps. While most adenomatous polyps will not progress to adenocarcinoma, size and histology are important factors that determine this risk. Polyps > 10 mm in size, villous histology and the presence of high-grade dysplasia increases the risk of developing CRC. These polyps are traditionally referred to as advanced adenomas. Table 14: CRC Screening Recommendations Colonoscopy every 10 years is the preferred test for preventing CRC. Over the last 20 years, numerous societies have endorsed a menu-of-options strategy for CRC screening. In 2008, the American College of Gastroenterology (ACG) reinforced that clinicians should have a preferred strategy for making CRC screening recommendations in order to simplify and shorten discussions with patients. It was also emphasized that clinicians understand that screening tests for CRC fall into two categories: cancer detection tests vs cancer prevention 34 swmedicalcenter.org Fall 2012

37 tests. Cancer detection tests include fecal immunochemical test, Hemoccult Sensa and fecal DNA test. Cancer prevention includes colonoscopy, The ACG recommends that colonoscopy be offered every 10 years based on indirect but substantial data (see below) for patients older than 50 years of age. For patients that decline colonoscopy one of the alternate prevention tests should be offered. Although prospective, randomized controlled trials that compare colonoscopy with no screening are lacking, cohort studies have shown a 76-90% reduction in the incidence of CRC.5,6 A randomized with subsequent colonoscopy for any polyps detected were compared with no screening and resulted in an 80% reduction in CRC.7 Additional data has shown not only decreasing incidence of CRC in patients that have undergone colonoscopy but also earlier and more favorable stages in CRC presentation.8 Case-controlled studies of sigmoidoscopy further support that colonoscopy reduces the incidence of CRC when used for screening.9 Pursuing a prospective randomized considered unethical given the clear evidence. There are several advantages of colonoscopy as a preferred screening test. It is widely available, and the entire colon is examined. Colonoscopy allows for the detection and removal of polyps. Additionally, it is the only test recommended at 10-year intervals. However, the procedure is not without risks, particularly colonic perforation. This is largely dependent upon risk factors and if polypectomy is performed. The reported incidence of colonic perforation in the literature ranges from % for diagnostic procedures. One recent series of more than 30,000 cases published from 2000 onward showed that the incidences varied from to ,11 factor for perforation is age over 75 years. There is little doubt regarding the impact colonoscopy has on CRC screening or its use in evaluating patients with symptoms that suggest CRC. Arguably the most critical improvement in colonoscopy recently has been the development of quality indicators. 12,13 There is an increasing emphasis that colonoscopies be performed by appropriately trained and skilled examiners who are dedicated to high quality examinations. Appropriate technique and mucosal inspection time directly impact the effectiveness of colonoscopy to reduce CRC and support the 10-year interval. Colonoscopists should continually monitor their adenoma detection rate (percentage of screening patients found to have an adenoma). At least 25% of men and 15% of women over the age of 50 years will have one or more adenomas. Withdrawal times have also been shown to correlate with high-quality examinations. A minimum of at least six minutes should be taken in normal colonoscopies in which no polyps are removed. There is additional data that suggest that eight minutes results in even higher rates of detection.14 A colonoscopist s adenoma detection rate is now part of the National Performance Measure Set that the Department of Health and Human Services will use to rate physician performance. Other data included will be adherence to surveillance recommendations made by the performing clinician. The National set of indicators that primary care providers can use to assess the quality of colonoscopy services when choosing an endoscopist.15 With the implementation of the Accountable Care Act, we will also see greater emphasis on connecting performance to clinical outcomes. Absent from the 2009 ACG guidelines is the routine use of double contrast barium enema as an alterative volumes resulting in decreased effectiveness for polyp detection as compared to CT colonography (CTC). However, if performed by high volume operators with expertise in the technique the DCBE could be considered. CT colonography is an option for patients who decline colonoscopy as it is sensitive for polyps larger than 1 cm in size based on data from the National CT Colongraphy Trial.16 Unfortunately, CT colonography performs poorly Volume 5, Number 1 Exceptional Medicine 35

38 for polyps 5mm and smaller which account for 80% of colorectal polyps and whose natural history is not understood.12,17 This uncertainty necessitates that CTC is not without risks. Critics point to increased radiation exposure and potential patient harm from the work up of incidentialomas. PREFERRED CRC DETECTION TEST: ANNUAL FIT The basis of the fecal occult blood test (FOBT) and fecal immunochemical test (FIT) is that CRC and advanced adenomas are more likely to bleed than normal mucosa. FOBT are guaiac-based tests that detect blood in stool through peroxidase activity. Aspirin, NSAIDs, vitamin C, red meat, citrus fruits and iron supplements can negatively impact the performance of the test. 18 The sensitivity and brand, version of the test, collection technique, rehydration and number of samples collected Sensitivities for cancer ranges from 37.1% for unrehydrated Hemoccult II to 79.4% for Hemocult SENSA. 19 A meta analysis of four randomized trials showed only a 16% reduction in CRC if an annual FOBT strategy is used.23 The FIT is an antibody- making dietary restrictions unnecessary, which result in 10-12% gains in adherence. The sensitivity is 91-98%. The improved adherence, doubling of detection with little loss of positive predictive value led to the FIT being the preferred cancer detection test if performed on a yearly basis.24,25 Fecal DNA 36 swmedicalcenter.org Fall 2012

39 testing has approximately the same performance characteristics as FIT, but it s cost are substantial. There is little rationale to use this in place of the FIT even though it is included in recent guidelines. Lastly, it is important to note that all guidelines recommend colonoscopy follow up of a positive FOBT. One-third of physicians inappropriately follow up a positive test with a repeat FOBT. 26 All patients with a positive test should be referred for a colonoscopy. COLORECTAL CANCER SCREENING RECOMMENDATIONS Due to its effectiveness in CRC prevention, quality colonoscopy performed by appropriately trained physicians should occur every 10 years beginning at age 50 for average risk individuals. In patients that decline colonoscopy, an alternative CRC prevention cancer detection test (FIT). African Americans should begin screening at age A family history of polyps no longer requires earlier onset screening or adjustment in screening, unless there is evidence that the polyps were advanced adenomas. STAGING AND SURVEILLANCE OF RECTAL CANCER Most rectal cancers are discovered during an endoscopic evaluation when performed as part of an evaluation of symptoms such as bleeding, anemia or a change in bowel habits. In most cases a complete evaluation of the large bowel can be completed to rule out synchronous neoplasms. In the situation when a complete colonoscopy cannot be completed prior to surgical intervention, one should be performed three to six months after surgery. The rationale for accurate staging of rectal tumors is to identify patients with locally advanced, nonmetastatic disease (Stage IIA or greater) who will The Swedish Rectal Cancer trials demonstrated a reduction in recurrence rates among patients with locally advanced disease following the administration of preoperative radiation therapy compared with postoperative radiotherapy. 28 Subsequent studies 29,30,31 The primary imaging modalities to assess the extent of the primary tumor are endorectal ultrasound (ERUS), CT and MRI. ERUS has been shown to consistently be the most accurate in predicting the T stage of rectal cancers.32 ERUS has a T-stage accuracy of 85% as compared to 65-75% for CT and 75-85% for MRI Additionally, the staging performance of ERUS appears to translate into a change in patient management. One prospective trial showed 31% of patients had a change in therapy, most often by the addition of neoadjuvant therapy.37 ERUS does not appear to have superiority over other modalities in assessing nodal (N) stage of rectal cancer. At least 27 studies have addressed ERUS performance in N-staging. The accuracy of 81.5% which is similar to CT and MRI. The accuracy of ERUS for the detection of involved perirectal lymph nodes is improved with the perirectal lymph nodes are not visualized in healthy patients. If possible, perirectal lymph nodes should be sampled, but traversing tumor to gain access to these lymph nodes should be avoided. Recurrent rectal cancer rates can vary between 20-50% with the rate of recurrence greatest in the occur in the extraluminal space making endoscopic setting. Surveillance of the extraluminal space often is undertaken by pelvic CT. Two small studies have suggested that ERUS may be more sensitive, 100% vs 82-85%.38,39 in patients with more advanced initial tumor stage. A major limiting factor of ERUS in the post that often obscure the detail of rectal wall and diminish sensitivity.38 If surgical staples are used this will create echo bright regions potentially obscuring the evaluation as well. FNA of suspicious areas will help overcome this limitation. Volume 5, Number 1 Exceptional Medicine 37

40 Although several studies have shown value in periodic surveillance, the optimal interval is unclear. Although the effectiveness is not proven, the US Multi-Society Task Force on Colorectal Cancer and American Cancer Society ultrasound at three- to six-month intervals for are independent of colonoscopic examination performed for metachronous disease. References 1. Siegel R, Naishadam D, Jemal A Jan-Feb;62(1): doi: /caac Epub 2012 Jan 4. Cancer statistics, Jemal A, Thun MJ, Ries LA et at (2008) Annual report to the nation on the status of cancer, , featuring trends in lung cancer, tobacco use, and tobacco control. J Nathl Cancer Inst 100: Jemal A, Siegel R, Ward E, et al. Cancer statistics, CA Cancer J Clin. 2008;59: Troisi RJ, Freedman AN, Devesa SS (1999) Incidence of colorectal carcinoma in the US: an update of trends by gender, race, age, subsite, and stage, Cancer 85: Winawer SJ, Zauber AG, Ho MN et al. Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med 1993;329: Citarda F, Tomaselli G, Capocaccia R et al. The Italian Multicentre Study Group. Efficacy in standard clinical practice of colonoscopic polypectomy in reducing colorectal cancer incidence. Gut 2001;48: Sedjo RL, Byers T, Barrera E Jr et al. A midpoint assessment of the American Cancer Society challenge goal to decrease cancer incidence by 25% between 1992 and CA Cancer J Clin 2007;57: Selby JV, Friedman GD, Quesenberry CP Jr et al. A case-control study of screening sigmoidoscopy and mortality from colorectal cancer. N Engl J Med 1992;326: Newcomb PA, Storer BE, Morimoto LM et al. Long-term efficacy of sig- moidoscopy in the reduction of colorectal cancer incidence. J Natl Cancer Inst 2003;95: Lohsiriwat V. Review of colonoscopic perforation. World journal of Gastroenterology 2010; 16(4): Rathgaber SW, Wick TM. Colonoscopy completion and complication rates in a community gastroenterology practice. Gastrointest Endosc 2006; 64: Rex DK, Petrini JL, Baron TH et al. Quality indicators for colonoscopy. Am J Gastroenterol 2006;101: Rex DK et al. ACG Guidelines for Colorectal Cancer Screening. Am J Gastroenterol 2009; 104: Barclay RL, Vicari JJ, Greenlaw RL Effect of a time-dependent colonoscopic withdrawal protocol on adenoma detection during screening colonoscopy. Clin Gastroenterol Hepatol Oct;6(10): Epub 2008 Jul Fletcher RH, Nadel MR, et al. The Quality of Colonoscopy Services Responsibilities of Referring Clinicians: A Consensus Statement of the Quality Assurance Task Group, National Colorectal Cancer Roundtable. Journal of General Internal Medicine Johnson CD, Chen MH, Toledano AY et al. Accuracy of CT colonography for detection of large adenomas and cancers. N Engl J Med 2008;359: Levin B, Lieberman DA, McFarland B et al. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. Gastroenterology 2008;134: Ransohoff DF, Lang CA. Screening for col- orectal cancer with the fecal occult blood test: a background paper. American College of Physicians. Ann Intern Med 1997;126: AllisonJE,TekawaIS,RansomLJ,AdrainAL. A comparison of fecal occult-blood tests for col- orectal-cancer screening. N Engl J Med 1996;334: Collins JF, Lieberman DA, Durbin TE, Weiss DG. Accuracy of screening for fecal occult blood on a single stool sample obtained by digital rectal examination: a comparison with recommended sampling practice. Ann Intern Med 2005;142: Lieberman DA, Weiss DG. One-time screen- ing for colorectal cancer with combined fecal occult-blood testing and examination of the distal colon. N Engl J Med 2001;345: Simon JB. Occult blood screening for colorec- tal carcinoma: a critical review. Gastroenterology 1985;88: Hewitson P, Glasziou P, Watson E, Towler B, Irwig L (2008) Cochrane systematic review of colorectal cancer screening using the fecal occult blood test (hemoccult): an update. Am J Gastroenterology 103: van Rossum LG, van Rijn AF, Laheij RJ et al. Random comparison of guaiac and immunochemical fecal occult blood tests for colorectal cancer in a screening population. Gastroenterology 2008;135: Hol L, van Leerdam ME, van Ballegooijen M et al. Attendance to screening for colorectal cancer in the Netherlands; randomized controlled trial com- paring two different forms of faecal occult blood tests and sigmoidoscopy. Gastroenterology 2008;134:A Nadel MR, Shapiro JA, Klabunde CN, et al. A national survey of primary care physicians meth- ods for screening for fecal occult blood. Ann Intern Med 2005;142: Agrawal S, Bhupinderjit A, Bhutani MS et al. Colorectal cancer in African Americans. Am J Gastroenterol 2005;100:515 23; discussion Swedish Rectal Cancer Trial. Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 1997; 336: Medical Research Council Rectal Cancer Working Party. Randomized trial of surgery alone versus radiotherapy followed by surgery for potentially operable locally advanced rectal cancer. Lancet 1996; 348: Grann A, Feng C, Wong D, et al. Preoperative combined modality therapy for clinically resectable ut3 rectal adenocarcinoma. Int J Radiat Oncol Biol Phys 2001; 49: Hyams DM, Mamounas EP, Petrelli N, et al. A clinical trial to evaluate the worth of preoperative multimodality therapy in patients with operable carcinoma of the rectum: a progress report of National Surgical Breast and Bowel Project Protocol R-03. Dis Colon Rectum 1997; 40: Bipat et al (2004) Recal cancer: local staging and assessment of lymph node involvement with endoluminal US, CT, and MR imaging a meta-analysis. Radiology 232 (3): Kwok H, Bissett IP, Hill GL. Preoperative staging of rectal cancer. Int J Colorectal Dis 2000; 15: Thaler W, Watzka S, Martin F, et al. Preoperative staging of rectal cancer by endoluminal ultrasound vs. magnetic resonance imaging. Preliminary results of a prospective, comparative study. Dis Colon Rectum 1994; 37: Meyenberger C, Huch Boni RA, Bertschinger P, et al. Endoscopic ultrasound and endorecta magnetic resonance imaging: a prospective, comparative study for preoperative staging and followup of rectal cancer. Endoscopy 1995; 27: Guinet C, Buy JN, Ghossain MA, et al. Comparison of magnetic resonance imaging an computed tomography in the preoperative staging of rectal cancer. Arch Surg 1990; 125: Harewood GC, Wiersema MJ, Nelson H, et al. A prospective blinded assessment of the impact of preoperative staging on the management of rectal cancer. Gastroenterology 2002; 123: Novell F, Pascual S, Viella P, et al. Endorectal ultrasonography in the follow-up of rectal cancer. Is it a better way to detect early local recurrence? Int J Colorectal Dis 1997; 12: Rotondano G, Esposito P, Pellecchia L, et al. Early detection of locally recurrent rectal cancer by endosonography. Br J Radiol swmedicalcenter.org Fall 2012

41 Surgery for Colorectal Cancer Surgery is the primary modality for treatment of colorectal cancer. The most important step in the surgical care of patients is to define an oncologically safe and effective treatment. It requires an individualized approach, which considers both the tumor with its pathology, stage and location, as well as the patient with their symptoms, health, GI tract, and family history. Keeping this in mind leads to the most cost-effective diagnostic evaluation and treatment. Andrea Lange, MD PHSW Correspondence: Andrea Lange, MD, FACS PeaceHealth Medical Group Surgery 505 NE 87th Avenue, Suite 301 Vancouver, WA Volume 5, Number 1 Exceptional Medicine 39

42 INTRODUCTION Colorectal adenocarcinoma is the second leading cause of cancer death in western countries. Approximately 25% of these large bowel malignancies arise within the rectum. Surgical resection with anastomosis is currently the rule for these cancers, rather than the exception. The most important step in the surgical care of these effective treatment. It requires an individualized approach, which considers both the tumor with its pathology, stage and location, as well as the patient with their symptoms, health, GI tract, and family history. Keeping this in mind leads to the most cost-effective diagnostic evaluation and treatment. PREOPERATIVE ASSESSMENT Preoperative assessment begins with the history and physical. This encompasses not only cardiac and pulmonary evaluation, but also nutritional assessment and obtaining a family medical history. The family medical history should identify patterns consistent with genetic syndromes such as hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis and familial colorectal cancer. This survey should also lead to and guide in the selection of surgical management. Most patients present to the surgeon with the some colonic evaluation. If it has not already occurred, it is recommended that a full colonic evaluation, ideally colonoscopy, be performed to exclude other lesions. Synchronous benign polyps have been reported in 13-62% of cases 2-9%. Colonoscopy is the most accurate test and allows biopsy with histologic evaluation of any less accurate, double-contrast barium enema may be used for those patients unable to undergo complete colonoscopy. Virtual colonoscopy or CT colonography is a noninvasive total colonic evaluation for the detection of cancers and polyps. It uses data acquired by helical CT scan to create two and three dimensional images. Limitations include its ability to distinguish between polypoid lesions and fecal matter as well as its ability to cannot be examined preoperatively, colonoscopy Standard preoperative laboratory evaluations for patients with colorectal cancer include CEA, CBC, antigen (CEA) is known to be elevated in some patients with colorectal cancer, as well as in a variety of conditions. An elevated preoperative CEA that returns to normal is associated with complete resection, whereas persistently elevated values indicate residual disease.1,2 Also, elevated preoperative CEA levels have been found to be independently predicative of poor survival.3 Other important laboratory studies include assessment of anemia, nutrition, and blood glucose control in diabetics. Liver function tests should be obtained as elevation may indicate metastatic spread to the liver. Other preoperative staging workup may include a CT of the abdomen and pelvis. Distant metastases, tumor location, regional lymphadenopathy and adjacent organ invasion the use of abdominal/pelvic CT prior to surgery has been debated in colon cancer, there is a trend toward its routine use in the preoperative evaluation, especially in cancer centers. It is generally accepted that it should be performed in patients with rectal cancer who are potentially surgical candidates.4 The rationale for the optional nature of its use in colon cancer patients is that nearly all of the information obtained in the time of surgery. However, NCCN guidelines recommend preoperative CT scans of the chest, abdomen, and pelvis. Overall management may change with additional information obtained from preoperative imaging studies especially if there are no symptoms of obstruction or bleeding related to primary tumor in the colon which would warrant immediate surgery. Surgery could be avoided if advanced metastatic disease 40 swmedicalcenter.org Fall 2012

43 is detected in the liver or lung. Surgery could be postponed and neoadjuvant chemotherapy could be administered in the setting of relatively limited volume metastatic disease that could potentially become resectable in the setting of response to chemotherapy.5 Metastatic spread to the lungs without liver metastases is more common in rectal cancer than colon cancer, so routine chest radiograph or CT scan should be obtained.4 Although the yield is low in chest x-ray with colon cancer, the cost is small and its routine performance is considered acceptable. 5 PREPARATION FOR SURGERY Mechanical bowel preparation is nearly universally used in elective surgery. Despite the the proven safety of the methods used for cleansing as well as their low cost. Prophylactic antibiotics are recommended for patients undergoing colon resection as they have proven effectiveness in decreasing the rate of infection, mortality, and cost of hospitalization.6 It is unclear whether the use of oral in addition to parenteral antibiotics has an additive effect in lowering infection rates. 7 Regardless of the antibiotic regimen, it is agreed that to be effective, it must be administered prior to the start of the operation and need not be continued longer than 24 hours postoperatively.8,9 All patients undergoing surgery for colorectal cancer should receive prophylaxis against thromboembolic disease5 given their high incidence of venous thromboembolism.10,11 A prospective randomized trial in colorectal surgery patients demonstrated low molecular weight heparin (LMWH) and subcutaneous heparin to be equally effective in preventing thromboembolism, with the patients receiving LMWH having a slightly higher rate of minor bleeding events.12 Subcutaneous heparin has been found to be more cost effective according to economic analysis.13 While the use of pneumatic calf compression has been found to decrease the risk of thromboembolism in cancer patients,14 the additive effect of more than one mode has not been proven. SURGICAL MANAGEMENT OF COLON CANCER The key to an oncologically safe and effective resection of a colon cancer is to: 1) obtain clear lateral margins, 2) resect the locoregional lymph node bearing mesentery for both cure and staging, 3) create a well vascularized anastomosis. The extent of resection should correspond to the lymphovascular drainage along with the primary feeding arterial vessel. The length of bowel resected is generally governed by the blood supply to that segment. Tumors located in watershed areas or border zones should be resected with neighboring lymphatic regions to include both possible directions of spread. High ligation of the vessels is controversial. It has not been found to confer improved survival15, but may be necessary to obtain a tension free anastomosis. Many studies have shown the feasibility and safety of laparoscopy for patients with colon cancer while adhering to oncologic principles. Disease-free margins with adequate lymphadenectomy can be achieved. There has been concern about port site evacuated prior to the removal of any ports. Current guidelines set forth by the American Society of Colorectal Surgeons state that the relative merits of laparoscopic versus open resection for colon cancer remain unproven at this time.5 As mentioned, synchronous tumors have been found to occur in 2-9% of cases.16 The location of the tumors and other patient factors should guide the decision as to whether to perform two separate resections verses a subtotal colectomy. There does not seem to be a difference between the two techniques, in either complication rate or outcome.16 in 15% of cases, 17 and it has been demonstrated that these adhesions harbor malignant cells 40% of the time.18 In these cases, en bloc resection is necessary to obtain tumor free margins, as it is impossible to distinguish between malignant adhesions surgically has been found to decrease 19,20 Volume 5, Number 1 Exceptional Medicine 41

44 The incidence of metastatic disease to the liver at the time of colon resection is 10-20%. It is generally believed that it is best to address these metastases at a later date after recovery from the initial colon resection. It is considered acceptable to proceed with removal of the metastasis after colectomy if the following conditions are met: 1) there has been minimal blood loss or contamination, 2) the patient 3) resection may be accomplished with a 1 cm margin, 4) the incision is appropriate for the added liver resection, 5) the surgeon is comfortable performing the hepatic resection.21 Between 2-8% of patients with colon cancer will have synchronous metastatic disease to the ovaries, and this leads to the recommendation that the ovaries be inspected at the time of laparotomy. There is however no proven survival advantage to prophylactic oophorectomy, as the risk of occult metastatic disease is low.22,23 Bilateral oophorectomy is advised when one or both ovaries are grossly abnormal or involved with contiguous extension of the colon cancer.5 Many patients present to the surgeon in an emergent fashion with obstruction, bleeding or perforation. Oncologic principles should still be followed, but the procedure selected should be individualized. Patients with an obstructing right or transverse colon cancer should undergo a right or extended right colectomy. Anastomosis is dependent on the patient s condition at the time of surgery, as multiple studies show it to safe and effective without colonic lavage For patients who present with an obstructing left colon cancer, the most frequently used surgical options are resection with end colostomy, on table lavage with anastomosis, and subtotal resection with ileorectal anastomosis. The literature does not strongly support any one of these options over the other. A colonic wall stent in selected patients may convert an urgent surgery into an elective one, and multiple studies have demonstrated its safety In cases of colonic perforation it is recommended that the site of compromise be resected if at all possible.5 With limited fecal spillage, the surgeon may choose to create an anastomosis with or without diversion depending on the patient s status. Peritonitis may make an anastomosis unwise. Acutely bleeding cancers requiring emergent resection should be removed following the same principles as in elective resection. 5 Again, the decision to proceed with an anastomosis verses an end stoma is based on the surgeon s judgment about the patient s current clinical state.5 Palliative resection should be limited to those with life-threatening comorbidities or advanced incurable disease. SURGICAL MANAGEMENT OF RECTAL CANCER Anatomically, the rectum is the distal 18 cm of the large bowel leading to the anal canal. Cancers of the intraperitoneal or proximal rectum behave like colon cancers with regard to recurrence patterns and prognosis.31 The distal to the bony pelvis, and constitutes the rectum from the oncologic standpoint. Although much of the preoperative assessment and preparation of patients with rectal cancer is similar to colon cancer, the management of cancers in the distal rectum is varied and complex. This is due to new approaches with multimodality therapy the optimal strategy for the patient requires prior to the initiation of therapy. Digital rectal exam and rigid proctosigmoidoscopy are typically required for accurate tumor assessment. Rectal low rectal tumors. Rigid proctoscopy usually allows the most precise assessment of tumor location and distance from the anal verge, which is critical in optimizing preoperative planning. In addition to CT scan of the abdomen and pelvis, endorectal ultrasound (ERUS) or magnetic resonance imaging (MRI) should be performed. Although CT scans may be useful in identifying the presence of metastatic disease, its role in local staging is limited. ERUS more accurately 42 swmedicalcenter.org Fall 2012

45 assesses bowel wall penetration and lymph node involvement. 32 MRI has similar accuracy to ERUS in tumor staging, but ERUS is more accessible, portable, and less expensive. selection of appropriate therapy for rectal cancer. The local stage will guide the surgeon s decision in choosing amongst the three curative options currently available. These include local excision, sphincter sparing abdominal surgery, and abdominoperineal resection (APR). Again, palliative therapy should be limited to those with life-threatening comorbidities or advanced incurable disease. Curative local excision is an appropriate treatment for carefully selected T1 rectal cancers, which have a low risk of lymph node metastases.4 This is dependent upon depth of tumor invasion, tumor differentiation and lymphovascular invasion The tumor must be excised intact by full thickness excision with clear margins. Comparative trials to abdominoperineal resection support transanal local excision with curative intent for T1 welldifferentiated cancers that are less than 3 cm in diameter and occupy less than 40% of the circumference.34,36,37 If unfavorable features are excision is warranted.34,38 APR entails the complete removal of the rectum and anus via a combined abdominal and perineal approach, with the creation of a permanent colostomy. It is reserved for patients whose tumors are either invading the anal sphincter or are so close to the sphincter that a safe distal margin cannot be obtained. Patients with poor from resection with colostomy, although they are candidates for sphincter-sparing surgery. Some obese male patients with mid rectal tumors may require APR due to technical limitations. Low anterior resection (LAR) with sphincter preservation involves dissection and anastomosis require complete mobilization down to the is adequate for most rectal cancers, 1 cm is the minimal acceptable length for cancers of the distal rectum. 4 The ultimate procedure in sphincter-sparing operations is the ultra LAR with coloanal anastomosis. This operation preserves the anal sphincter in patients with very low-lying rectal cancers in whom the distal margin is at the minimally acceptable level yet oncologically adequate. Contraindications to this procedure include: invasion of the anal sphincter mechanism or rectovaginal septum, baseline fecal body habitus, tumor location, or size. Neoadjuvant therapy may be helpful in downsizing the tumor, possibly altering factors to enable the surgeon to perform an anastomosis. A diverting stoma is advisable because of the potential for anastomotic leak or vascular compromise of the left colon. Total mesorectal excision (TME) in conjunction with LAR or APR involves the precise sharp dissection and removal of the entire rectal mesentery, including that distal to the tumor, as an intact unit. This enables the en bloc removal of the primary cancer and any associated lymphatic, vascular or perineural tumor deposits. Its use in distal rectal cancers is recommended, considered adequate in upper rectal cancers.4 Proximal lymphovascular ligation at the origin of the superior rectal artery is adequate for most rectal cancers.4 In patients with clinically suspicious nodes, removal of all of them up to the origin of the inferior mesenteric artery (IMA) is recommended.39 High ligation of the IMA may provide added mobility to create a tensionfree anastomosis and is often required for a low resection. Laparoscopy may be utilized during resection for rectal cancer, and may play either a supportive or major role. In laparoscopically assisted resections, the procedure is initiated with the laparoscope and completed in the traditional manner. More recently the use of robotics has been utilized for the pelvic dissection during laparoscopy. The outstanding questions are Volume 5, Number 1 Exceptional Medicine 43

46 whether it provides the same TME specimen as traditional open techniques and if there are there biologic factors that may change survival or recurrence patterns. Because of the absence rectal cancer, the American Society of Colorectal Surgeons considers it premature to endorse it for curable rectal cancer. 4 References 1. Lavin PT, Day J, Holyoke ED, et al. A statistical evaluation of baseline and follow-up carcinoembryonic antigen in patients with resectable colorectal carcinoma. Cancer 1981;47: Steele G, Ellenberg S, Ramming K, et al. CEA monitoring among patients in multi-institutional adjuvant therapy protocols. Ann Surg 1982;196: Harrison LE, Guillem JG, Paty P, Cohen A. Preoperative carcinoembryonic antigen predicts outcomes in node-negative colon cancer patients: a multivariate analysis of 572 patients. J Am Coll Surg 1997; 185: Tjandra JJ, Kilkenny JW, Buie WD, et al. Practice parameters for the management of rectal cancer (revised). Dis Colon Rectum 2005; 48: Otchy D, Hyman NH, Simmang C, et al. Practice parameters for colon cancer. Dis Colon Rectum 2004;47: BaumML, Anish DS, Chalmers TC, et al. A survey of clinical trials of antibiotic prophylaxis in colon surgery: evidence against further use of no-treatment controls. N Eng J Med 1981; 305: Fry DE. Antibiotics in surgery. An overview. Am J Surg 1988;155: Polk HC, Lopez-Mayor JF. Postoperative wound infection: a prospective study of determinant factors and prevention. Surgery 1969;66: Stone HH, Hooper CA, Kolb LD, et al. Antibiotic Prophylaxis in gastric, biliary and colonic surgery. Ann Surg 1976; 184: Collins R, Scrimgeour A, Yusuf S, et al. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of heparin. Overview of results of randomized trials in general, orthopedic and urologic surgery. N Engl J Med 1988; 318: Kakkar VV, Howe CT, Nicolaides AN, Renney JT, et al. Deep venous thrombosis of the leg: is there a high risk group? Am J Surg 1970;120: McLeod RS, Geerts WH, Sniderman KW, et al. Subcutaneous heparin versus low-molecular-weight heparin as thromboprophylaxis in patients undergoing colorectal surgery. Results of the Canadian colorectal DVT Prophylaxis Trial: a randomized, double-blind trial. Ann Surg 2001;233: Etchells E, McLeod RS, Geerts W, et al. Economic analysis of lowdose heparin vs the lowmolecular weight heparin Enoxaparin for prevention of venous thromboembolism after colorectal surgery. Arch Intern Med 1999;159: Clagett GP, Reisch JS. Prevention of venous thromboembolism in general surgery patients. Results of metaanalysis. Ann Surg 1988;208: Kawamura YJ, Umetani N, Sunami E, et al. Effect of high ligation on the long-term of patients with operable colon cancer, particularly those with limited nodal involvement. Eur J Surg 2000; 166: Welch JP. Multiple colorectal tumors: an appraisal of natural history and therapeutic options. Am J Surg 1981;142: Sugerbaker PH, Corlew S. Influence of surgical techniques on survival in patients with colorectal cancer: a review. Dis Colon Rectum 1982;25: Lopez MS, Monafo WW. Role of extended resection in the initial treatment of locally advanced colorectal carcinoma. Surgery 1993;113: Gall FP, Tonak J, Altendorf A. Multivisceral resections in colorectal cancer. Dis Colon Rectum 1987;30: Hunter JA, Ryan JA, Schultz P. En bloc resection of colon cancer adherent to other organs. Am J Surg 1987;154: Hughes KS, Rossi RL. Colorectal cancer metastatic to the liver: resection. In: Cameron J, ed. Current surgical therapy. 4th ed. St. Louis: Mosby 1992: Cutait R, Lesser ML, Enker WE. Prophylactic oophorectomy in surgery for large-bowel cancer. Dis Colon Rectum 1983;26: Young-Fadok TM, Wolff BG, Nivatrongs S, Metzger PP, Ilstrup DM. Prophylactic oophorectomy in colorectal carcinoma: preliminary results of a randomized, prospective trial. Dis Colon Rectum 1998;41: Runkel HS, Hinz U, Lehnert T, Buhr HJ, Herfarth C. Improved outcome after emergency surgery for cancer of the large intestine. Br J Surg 1998;85: Smithers BM, Theile DE, Cohen JR, et al. Emergency right hemicolectomy in colon carcinoma: a prospective study. ANZ J Surg 1986;56: Matheson NA. Management of obstructed and perforated large bowel carcinoma. Bailleires Clin Gastroenterol 1989;3: Dauphine CE, Tan P, Beart RW, Vukasin P, et al. Placement of selfexpanding metal stents for acute management of large-bowel obstruction: a collective review. Ann Surg Oncol 2002;9: Spinelli P, Mancini A. Use of self-expanding metal stents for palliation of rectosigmoid cancer. Gastrointest Endosc 2001;53: Binkert CA, Ledermann H, Jost R, et al. Acute colonic obstruction: clinical aspects and cost-effectiveness of preoperative and palliative treatment with self-expanding metallic stents a preliminary report. Radiology 1998;206: Camunez F, Echenagusia A, Simo G, et al. Malignant colorectal obstruction treated by means of self-expanding metallic stents: effectiveness before surgery and in palliation.radiology 2000;216: Pilipshen SJ, Heilweil M, Quan SH, et al. Patterns of pelvic recurrence following definitive resections of rectal cancer. Cancer 1984;53: Gualdi GF, Casciani E, Guadalaxara A, et al. Local staging of rectal cancer with transrectal ultrasound and endorectal magnetic resonance imaging: comparison with histologic findings. Dis Colon Rectum 2000;43: Brodsky J, Richard G, Cohen A, Minsky B. Variables correlated with the risk of lymph node metastasis in early rectal cancer. Cancer 1992;69: Sengupta S, Tjandra JJ. Local excision of rectal cancer: what is the evidence? Dis Colon Rectum 2001;44: Morson BC. Factors influencing the prognosis of early cancer of the rectum. Proc R Soc Med 1966;59: Russell AH, Harris J, Rosenberg PJ, et al. Anal sphincter conservation for patients with adenocarcinoma of the distal rectum: long-term results of radiation therapy oncology group protocol Int J Radiat Oncol Biol Phys 2000;46: Steele GD, Herndon JE, Bleday R, et al. Sphincter-sparing treatment for distal rectal adenocarcinoma. Ann Surg Oncol 1999;6: Mellgren A, Sirivongs P, Rothenberger DA, Madoff RD, Garcia- Aguilar J. Is local excision adequate therapy for early rectal cancer? Dis Colon Rectum 2000;43: Stanetz CA, Grimson R. Effect of high and intermediate ligation on survival and recurrence rates following curative resection of colorectal cancer. Dis Colon Rectum 1997;40: swmedicalcenter.org Fall 2012

47 Radiation Therapy for Colorectal Cancer While surgery is the primary treatment modality for colorectal cancer, radiation therapy (RT) is administered as an adjuvant therapy to decrease the frequency of local recurrence and distant metastases and to improve survival. In this article, we explore the advantages and disadvantages of radiation therapy as part of treatment, as well as techniques and side effects. Choong R. Kim, MD PHSJ Correspondence: Choong Kim, MD PeaceHealth St. John Medical Center Radiation Oncology 1615 Delaware Street Longview, WA Volume 5, Number 1 Exceptional Medicine 45

48 ADJUVANT RADIATION FOR RECTAL CANCER Multimodality therapy including surgery, chemotherapy, and radiation therapy is considered standard of care in stage II and III rectal cancer. Surgery, however, is the most important treatment modality of rectal cancer. Radiation therapy (RT) is administered mainly as an adjuvant treatment to decrease the frequency of local recurrence and distant metastases and to improve survival. Local recurrence rate after surgery alone for patients with T1 or T2 rectal cancer is less than 10%. Therefore, post-operative adjuvant radiation is rarely indicated in the early stages of rectal cancer. However, the failure rate with surgery alone for locally advanced rectal cancers that are deeply such as the sacrum, pelvic sidewalls, prostate, vaginal wall, or bladder (T3 or T4 lesions), with or without lymph node involvement, ranges from 15-65%.1,2 Local recurrences of rectal cancer following obtaining optimal surgical clearance of the radial margin. It is widely accepted that adjuvant RT alone, without chemotherapy, for clinical stage T3, T4 rectal cancer improves local control rate but has very little impact on the survival compared to surgery alone.3,4 In contrast to RT alone, concomitant chemotherapy and radiation therapy (CRT) improved local control, distant metastases, and survival in locally advanced rectal cancer. RT based chemotherapy or oral agent capecitabine. Effectiveness of adjuvant CRT was established in early Gastrointestinal Tumor Study Group (GITSG) which showed patients treated with or distant metastatic rate than those undergoing surgery alone.5 A second major randomized trial by the Mayo Clinic/North Central Cancer Treatment Group (NCCTG) showed that post- 47% reduction in the risk of relapse, and a 36% reduction in the risk of cancer-related death. 6 Local recurrence rates were diminished by 46%, and the likelihood of developing distant metastases by 37%. In contrast to the GITSG trial, CRT was generally well tolerated and longterm toxicity was not observed in NCCTG trial. Adjuvant CRT is considered the standard for treatment of rectal carcinoma after the curative surgical resection for locally advanced disease (T3 or T4 lesion or any T stage with lymph node involvement). CRT can be given in the preoperative or post-operative setting, and there are only a few randomized studies comparing preoperative and post-operative adjuvant therapy. The Swedish multicenter group randomized for patients with resectable rectal cancer to 25 Gy in fractions post-operatively.7 Even though, the preoperative RT dose was lower than post-operative in local failure in the pre-operative radiation group of patients. The German Rectal Cancer Study randomized patients with clinically staged T3, T4, or nodepositive rectal cancer to the same CRT regimen administered either pre-operatively or postoperatively: 50.4 Gy in 28 daily fractions to the tumor and pelvic lymph nodes concurrent with 8 All patients underwent TME and four additional cycles of adjuvant single agent 5FU (500 mg/m2 bolus daily relapse rate (6% versus 13% with post-operative survival rates were similar for both groups. Tumor down-staging and sphincter-sparing effects were noted in the pre-operative patients. The NSABP trial R-03 randomly assigned patients with rectal cancer to pre-operative therapy, which consist of weekly 5FU and leucovorin concomitant with pelvic irradiation (50.4 Gy), 46 swmedicalcenter.org Fall 2012

49 surgery, then post-operative bolus weekly 5FU and leucovorin, versus post-operative therapy, which consisted of surgery, weekly 5FU and leucovorin concomitant with pelvic RT. 9 While pre-operative therapy was associated with a survival (DFS, 65 versus 53 percent), there was no difference in locoregional control. In addition CRT could not be shown in a Korean trial that compared pre-operative versus post-operative CRT using capacitabine alone (1650 mg/m2 daily during RT) in 240 patients with clinical T3 or node positive rectal cancer.10 The sphinctersparing rate was similar in the two groups, although among patients with low-lying tumors, the pre-operative CRT arm had a higher rate of sphincter-sparing surgery (68% versus 42%). Currently pre-operative CRT is preferred and used more widely due to several advantages of pre-operative CRT over the post-operative CRT for rectal cancer. The advantages are: (1) increasing sphincter preservation rate11,12, (2) resulting in better long-term rectal function by removing irradiated segment of the rectum, (3) decreasing small bowel adhesions and late small bowel injury, (4) reducing the tumor size and improving respectability of the tumor, (5) improving tissue perfusion with uninterrupted vascular structure resulting in better drug delivery of radiation sensitizing 5FU and better radiation7, (6) improving the control of tumor in lymph nodes, and (7) decreasing viability of the tumor cells that may spread with in the surgical bed at the time of surgery. The disadvantages of pre-operative CRT include a possible delay in surgical resection and unnecessary treatment of the earlier stages of rectal cancer related to false positive results from preoperative staging studies. However, pre-operative evaluation with endoluminal rectal ultrasound (ERUS) accurately stage the depth of invasion and the incidence of unnecessary irradiation has decreased. The advantages of post-operative RT include from adjuvant therapy. For patients with small wall (T1 or T2), local excision techniques may offer local control and survival rates that are comparable to abdominoperineal resection (APR), while preserving sphincter function. In post-operative setting, surgeons could identify the possible high-risk local recurrence areas during surgery and mark with surgical clips to aid RT planning. Surgeons may also displace the small bowel away from the area to be irradiated during surgery, thus minimizing radiation toxicity. The disadvantage of post-operative CRT is that surgery may interrupt the vascular system leading to hypoxia with the potential of decreased sensitivity of cancer cells to ionizing radiation. Surgery may also reduce the radiosesitizing effects of 5FU by interrupted vascular supply causing less availability of 5FU to the surgical bed. The post-operative CRT may have a higher incidence of radiation induced enteric and skin side effects compared to pre-operative CRT. The area of treatment after the surgery may increase, especially in APR where the perineum should be included within the treatment area. The perineum is very sensitive to radiation and post-operative CRT may add much unnecessary discomfort to patients. Post-operative RT may also increase incidence of wound dehiscence. Intra-operative RT with electron or orthovoltage beams is known to improve local control in certain clinical conditions but always accompanied with external beam radiation therapy. It is rarely used, only in clinical protocol or major academic medical center settings due to its high complication rate and lack of linear accelerator facilities in the operating room. Therefore, its discussion is the beyond the scope of this report. Volume 5, Number 1 Exceptional Medicine 47

50 RT TECHNIQUE Modern RT for the rectal cancer is generally given on a daily basis from Monday through Friday for the total radiation dose ranging 50 to 60 Gy either pre-operatively or post-operatively. The local recurrence rate is higher with the dose less than 50 Gy. In case of gross residual disease after the surgical resection, more than 60 Gy can be administered in certain clinical situations. At our institutions, most patients with locally advanced rectal cancer receive full dose preoperative RT with infusional 5FU or oral capecitabine throughout the six-week course of pre-operative RT. The initial RT dose is 45 Gy to the posterior pelvis followed by additional 9 Gy to the tumor bed. Therefore, the total dose to the tumor bed is 54 Gy in daily 1.8 Gy per fraction over six-week period. In our experience, this RT dose schedule has been well tolerated in conjunction with chemotherapy. In case of preoperative CRT, surgical resection is done in about six to 10 weeks after the completion of CRT. In the post-operative CRT setting, CRT should start within four to eight weeks after surgery. In modern radiation therapy, rectal cancer should be treated with three-dimensional conformal radiation technique using multiple MV. The area of treatment should include the rectal mass or canal and regional peri-rectal lymph nodes and presacral plexus. This is determined with CT image guidance. ADJUVANT RADIATION THERAPY FOR COLON CANCER While a combination of CRT may be useful for rectal cancer, its use in colon cancer is not routine because of the different patterns of spread of colon cancer than rectal cancer, the the bowels to radiation which limits the optimal dose to control the tumor. Colon cancer spreads mainly to mesenteries, para-aortic, peritoneal, and the liver. Therefore, it requires regional and larger areas of treatment. Post-operative adjuvant chemotherapy alone plays a more important role than the radiation therapy. Post-operative or pre-operative radiation therapy for colon cancer is indicated in (1) clinical trial settings (2) unresectable or marginally resectable tumor (3) perforated or obstructed cancer (4) microscopic or gross residual disease with adhesion to abdominal or peritoneal wall after the resection (5) or recurrent colon cancer. In case of gross residual disease, suspected microscopic residual disease, or positive margins, the surgeon may place surgical clips or radiological markers in the area of concern to aid radiation treatment planning. 5FU or capecitabine can be used as a radiation sensitizer. RADIATION THERAPY SIDE EFFECTS Side effects of radiation therapy for colorectal cancer are divided into two major phases acute side effects that happen during the therapy and late side effects that can happen many months or even years after the treatments. The acute side effects usually start after fractions (daily treatments) toward the end of the RT. They irritation. These symptoms usually improve without intervention after two to three weeks after completion of treatment. Late side effects of radiation are rare but may happen many months post treatment and can be permanent. Rectal and/or bladder irritation can lead to diarrhea and frequent urination with or without hematuria or rectal bleeding. Mild vaginal dryness or dyspareunia can occur. In these cases, vaginal dilators with or without topical lubricants may be helpful. 48 swmedicalcenter.org Fall 2012

51 References 1. Minsky BD, Mies C, Recht A, Rich TA, Chaffey JT., Resectable adenocarcinoma of the rectosigmoid and rectum. I. Patterns of failure and survival., Cancer. 1988;61(7): Rich T, Gunderson LL, Lew R, Galdibini JJ, Cohen AM, Donaldson G, Patterns of recurrence of rectal cancer after potentially curative surgery., Cancer. 1983;52: Fisher B, Wolmark N, Rockette H, Redmond C, Deutsch M, Wickerham DL, Fisher ER, Caplan R, Jones J, Lerner H, Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01., J Natl Cancer Inst. 1988;80: Colorectal Cancer Collaborative Group., Adjuvant radiotherapy for rectal cancer: a systematic overview of 8,507 patients from 22 randomised trials. Lancet., 2001;358: Gastrointestinal Tumor Study Group., Prolongation of the diseasefree interval in surgically treated rectal carcinoma. Gastrointestinal Tumor Study Group., N Engl J Med., 1985;312: Krook JE, Moertel CG, Gunderson LL, Wieand HS, Collins RT, Beart RW, Kubista TP, Poon MA, Meyers WC, Mailliard JA, Effective surgical adjuvant therapy for high-risk rectal carcinoma., N Engl J Med., 1991;324: Pahlman L, Glimelius B., Pre- or post-operative radiotherapy in rectal rectosigmoid carcinoma: report from a randomized multicenter study., Ann Surg., 1990; 211: Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351: Roh MS, Colangelo LH, O Connell MJ, et al. Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol 2009; 27: Park JH, Yoon SM, Yu CS, et al. Randomized phase 3 trial comparing preoperative and postoperative chemoradiotherapy with capecitabine for locally advanced rectal cancer. Cancer 2011; 117: Valentini V, Coco C, Cellini N, et al, Preoperative chemoradiation therapy for extraperitoneal T3 rectal cacner: acute toxicity, tumor response and sphincter preservation., Int J Radiat Oncol Biol Phys., 1998; 40: Crane CH, Skibber JM, Feug BW, et al., Response to preoperative chemoradiation therapy increases the use of sphincter preservation surgery in patients with locally advanced low rectal carcinoma., Cancer., 2003; 97: Volume 5, Number 1 Exceptional Medicine 49

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