CANCER COLORECTAL

Colorectal cancer

Overview and Recommendations

Background

• Colorectal cancer is the third most common cancer worldwide.
• It most commonly affects elderly persons ≥ 60 years old, and more men are affected than women.
• The causes of the disease are accumulation of genetic and epigenetic alterations.
• Likely risk factors include:
  • hereditary syndromes, such as Lynch syndrome and familial adenomatous polyposis;
  • diet, including consumption of processed and red meat, consumption of alcohol, and low consumption of nonstarchy vegetables and fruits;
  • lifestyle factors, including sedentary lifestyle and smoking;
  • concurrent diseases, particularly inflammatory bowel disease.
• Common presenting symptoms include rectal bleeding, occult blood in stool, weight loss, abdominal pain, and change in bowel habit.
• The 5-year relative survival is 71%-90% for locoregional disease and 14% for distant stage disease in the United States.

Evaluation

• Perform assessment with a multidisciplinary team of radiologists, surgeons, radiation oncologists, medical oncologists, pathologists, and gastroenterologists (Strong recommendation).
• For initial testing to establish diagnosis:
  • Perform a complete history and physical examination, including digital rectal examination for rectal cancer.
  • Perform a total colonoscopy (Strong recommendation).
  • Perform a biopsy for histopathological confirmation of diagnosis (Strong recommendation).
• For staging after diagnosis:
  • Perform abdominal, pelvic, and chest computed tomography (CT) ( Strong recommendation).
  • Consider magnetic resonance imaging (MRI) and contrast-enhanced ultrasound for lesion characterization in case of uncertainty in CT findings (Weak recommendation).
• Pretreatment testing aimed at staging and treatment planning typically includes blood tests, imaging studies (CT, MRI, and endorectal ultrasound), pathology review, and tumor testing (microsatellite instability or DNA mismatch repair testing); also consider genetic testing based on age, personal medical history, and family history of colorectal cancer syndromes such as Lynch syndrome - see Lynch syndrome for details.
• See Colorectal cancer diagnosis and staging for details.

Management

Management of nonmetastatic colon cancer

• Management of malignant polyps after endoscopic polypectomy:
  • Perform complete endoscopic polypectomy to remove all adenomatous tissue if possible.
  • For single polyp that has been completely removed with favorable histology and clear margins:
    • If the polyp is pedunculated, perform surveillance (Strong recommendation).
    • If the polyp is sessile with invasive carcinoma, consider either surveillance (Weak recommendation) or colectomy with en bloc removal of regional lymph nodes (Weak recommendation).
  • For a fragmented specimen, or if the margin cannot be assessed, or if the polyp has unfavorable histology, consider colectomy with en bloc removal of regional lymph nodes (Weak recommendation).
  • For stage 0 (Tis, N0, M0) disease, consider segmentary en bloc resection for larger lesions not amenable to local excision.
• Management of possibly resectable nonmetastatic colon cancer:
  • If the tumor is nonobstructing, offer colectomy with en bloc removal of regional lymph nodes (Strong recommendation), and then follow with adjuvant therapy.
  • If the tumor is obstructing, options include 1-stage colectomy with en bloc removal of regional lymph nodes (Weak recommendation), resection with diversion (Weak recommendation), colonic stent (depending on tumor location) followed by colectomy (Weak recommendation), or diversion followed by colectomy with en bloc removal of regional lymph nodes (Weak recommendation); then, follow with adjuvant therapy.
  • If clinical T4b tumor, consider colectomy with en bloc removal of regional lymph nodes (Weak recommendation) after neoadjuvant chemotherapy (Weak recommendation); then, follow with adjuvant therapy.
  • If the tumor is locally unresectable or medically inoperable, consider neoadjuvant therapy and evaluation for conversion to resectable disease, and then consider following with surgery with or without intraoperative radiation therapy, if possible (Weak recommendation).
• Adjuvant therapy includes either chemotherapy or chemoradiation therapy; the choice of appropriate adjuvant treatment is based on pathologic stage.
• See Management of nonmetastatic colon cancer for details.

Management of nonmetastatic rectal cancer

• Management of malignant polyps:
  • Consider en bloc resection of polyps to accurately assess the level of invasion in the resection margin and the deepest area (Weak Recommendation).
  • For single specimen that has been completely removed with favorable histology and clear margins (T1 only):
    • If the polyp is pedunculated, consider surveillance (Weak recommendation) or perform transanal excision with transanal endoscopic microsurgery (Strong recommendation).
    • If the polyp is sessile, consider surveillance, transanal excision if appropriate, or transabdominal resection (Weak recommendation).
  • For fragmented specimen, or if the margin cannot be assessed, or if the polyp has unfavorable histologic features, consider transanal excision if appropriate based on risk assessment (Weak recommendation), or perform transabdominal resection with removal of lymph nodes (Strong recommendation).
• Management of nonmetastatic rectal cancer:
  • For very early disease, for patients who are poor surgical candidates, consider local radiation therapy, either alone or in combination with chemoradiation therapy, with brachytherapy or contact therapy using Papillon technique as an alternative to local surgery (Weak recommendation).
  • For T1-T2, N0, or early disease, consider transanal excision if appropriate based on risk assessment (after neoadjuvant radiation or chemoradiation therapy if indicated) (Weak recommendation), or perform transabdominal resection with total mesorectal excision (TME) (Strong recommendation); then, follow resection with adjuvant therapy.
  • For T3, N0, or any T, N1-N2, or T4 and/or locally unresectable or medically inoperable disease, consider either:
    • transabdominal resection using TME (Strong recommendation for TME) after neoadjuvant therapy with chemoradiation or short-course radiation therapy (Strong recommendation); then, follow with adjuvant therapy
    • transabdominal resection after neoadjuvant chemotherapy and primary chemoradiation therapy (Weak recommendation)
• Adjuvant therapy includes either chemotherapy or chemoradiation therapy; the choice of appropriate adjuvant treatment is based on pathologic stage.
• See Management of nonmetastatic rectal cancer for details.

Management of metastatic colorectal cancer

• Management of metastatic disease depends on whether metastases are synchronous or metachronous as well as tumor resectability.
• Management of synchronous metastatic colon cancer:
  • For resectable liver and/or lung synchronous metastases, consider any of the following treatment options:
    • synchronous or staged colectomy with surgical resection of liver or lung (preferred) and/or local ablative procedures (Weak recommendation), followed by adjuvant chemotherapy
    • colectomy, followed by 2-3 months of chemotherapy, then staged resection of metastatic disease, followed by adjuvant chemotherapy (Weak recommendation)
    • neoadjuvant chemotherapy (2-3 month course) prior to synchronous or staged colectomy with surgical resection of liver or lung, followed by adjuvant chemotherapy (Weak recommendation)
  • For unresectable liver and/or lung synchronous metastases:
    • consider primary treatment with systemic chemotherapy with or without targeted therapy (Weak recommendation); see also Systemic chemotherapy for metastatic colorectal cancer and Targeted therapy for metastatic colorectal cancer
    • reevaluate patient for conversion to resectable disease every 2 months, if conversion is a reasonable goal (Weak recommendation). Base subsequent treatment on resectability after reevaluation
  • For management of synchronous abdominal or peritoneal metastases:
    • if metastases are nonobstructing, consider systemic chemotherapy (Weak recommendation)
    • if colon is obstructed or obstruction is imminent, consider any of colon resection, diverting ostomy, bypass of impending obstruction, or stenting, followed by systemic chemotherapy (Weak recommendation)
• Management of synchronous metastatic rectal cancer:
  • For resectable synchronous metastases:
    • Consider neoadjuvant treatment with any of chemotherapy (2-3 month course), chemoradiation, or short-course radiation therapy (not recommended for T4 tumors) (Weak recommendation).
    • After neoadjuvant chemotherapy, consider primary and adjuvant treatment with any of the following options:
      • staged or synchronous resection (preferred over local ablative procedures), and/or local ablative procedures for metastases and resection of rectal lesion plus adjuvant chemoradiation (Weak recommendation)
      • primary chemoradiation or short-course radiation therapy (not recommended for T4 tumors) plus adjuvant treatment with staged or synchronous resection (preferred over local ablative procedures), and/or local ablative procedures for metastases and resection of rectal lesion with optional adjuvant chemotherapy using the same regimen as neoadjuvant chemotherapy (Weak recommendation)
    • After neoadjuvant chemoradiation or short-course radiation therapy, consider primary treatment with staged or synchronous resection (preferred over local ablative procedures), and/or local ablative procedures for metastases and resection of rectal lesion plus adjuvant chemotherapy (Weak recommendation).
  • For unresectable synchronous metastases:
    • If the patient is symptomatic, consider primary treatment with any of systemic chemotherapy, chemoradiation, resection of the involved rectal segment, diverting ostomy, stenting, or short-course radiation therapy (not recommended for T4 primary tumors) (Weak recommendation); then, consider subsequent treatment with systemic chemotherapy (Weak recommendation).
    • If the patient is asymptomatic, consider systemic chemotherapy (Weak recommendation).
    • See also Systemic chemotherapy for metastatic colorectal cancer.
• Management of metachronous metastatic colorectal cancer:
  • For resectable metachronous metastases:
    • surgical resection (preferred over local ablative procedures) and/or local ablative procedures are primary treatment options, with or without neoadjuvant chemotherapy (Weak recommendation)
    • base decision on adjuvant treatment on whether neoadjuvant chemotherapy was given, and whether there was tumor growth during neoadjuvant chemotherapy
  • For unresectable metachronous metastases:
    • consider chemotherapy and/or targeted therapy (Weak recommendation)
    • reevaluate patient for conversion to resectable disease every 2 months, if conversion is a reasonable goal (Weak recommendation). Base subsequent treatment on resectability after reevaluation
• Management of oligometastatic disease:
  • Use systemic chemotherapy as initial part of any treatment approach; see also Systemic chemotherapy for metastatic colorectal cancer.
  • Evaluate response to systemic chemotherapy at 6-8 weeks with multi-disciplinary team to determine the best treatment strategies (Weak recommendation); options include surgery and local ablative procedures.
  • After surgery or local ablative procedures, consider re-introduction of systemic chemotherapy, but total duration should be ≤ 6 months.
  • Consider ablative therapy with noncurative intent to eradicate all visible metastatic lesions in suitable patients despite the lack of high-quality evidence (Weak recommendation).
• See Management of metastatic colorectal cancer for details.

Related Summaries

• Colorectal cancer (list of topics)
• Colorectal cancer screening
• Colorectal cancer diagnosis and staging
• Colorectal cancer prognostication
• Colorectal cancer prevention
• Management of nonmetastatic colon cancer
• Management of nonmetastatic rectal cancer
• Management of metastatic colorectal cancer
• Systemic chemotherapy for metastatic colorectal cancer
• Targeted therapy for metastatic colorectal cancer
• Lynch syndrome
• Physician Quality Reporting System Quality Measures

General Information

Description

• malignant neoplasm of colon or rectum, and third most common cancer worldwide⁽¹⁾

Epidemiology

Who is most affected

• persons ≥ 60 years old^(1, 5)
  • about 75% of patients diagnosed with sporadic rectal cancer are ≥ 60 years old (median age at diagnosis 70 years)
  • about 80% of patients diagnosed with sporadic colon cancer are ≥ 60 years old
• men affected more than women⁽¹⁾

Incidence/Prevalence

• estimated global colorectal cancer incidence 1,360,000 cases in 2012
  • based on population-based cancer registries, vital registration data, and verbal autopsy data from 184 countries with total population > 200,000 during 2012
  • incidence
    • estimated new colorectal cancer cases 1,360,000
    • age-standardized ratio 17.2 per 100,000 persons
    • cumulative global lifetime risk (ages 0-74 years) 2%
  • colorectal cancer incidence varies by global region
    • in more developed regions, age-standardized ratio per 100,000 persons (ASR) 36.3 for men and ASR 23.6 for women
    • in less developed regions, ASR 13.6 for men and ASR 9.8 for women
    • in Africa, ASR 7 for men and ASR 5.8 for women
    • in the Americas, ASR 22.3 for men and ASR 17.6 for women
    • in Asia, 16.5 for men and ASR 11.1 for women
    • in Europe, ASR 37.3 for men and ASR 23.6 for women
    • in Australia, ASR 44.8 for men and ASR 32.2 for women
  • Reference - GLOBOCAN 2012 (Int J Cancer 2015 Mar 1;136(5):E359)
• age- and sex-adjusted incidence of colorectal cancer in Ontario, Canada 1996-2005
  • distal colorectal cancer in 107 per 100,000 persons
  • proximal colorectal cancer in 79 per 100,000 persons
  • Reference - Am J Gastroenterol 2008 Aug;103(8):2075EBSCOhost Full Text
• prevalence of left-sided advanced colorectal neoplasms appears reduced for 10 years after colonoscopy
  • based on cross-sectional study
  • 3,287 adults ≥ 55 years old having screening colonoscopy and self-reported colonoscopy history
  • advanced colorectal neoplasm (cancer or advanced adenoma) in
    • 11.4% with no previous colonoscopy
    • 6.1% having previous colonoscopy within last 10 years
  • adjusted prevalence ratios for previous colonoscopy in last 10 years
    • 0.52 (95% CI 0.37-0.73) overall
    • 0.99 (95% CI 0.5-1.97) cecum and ascending colon
    • 1.21 (95% CI 0.6-2.42) hepatic flexure and transverse colon
    • 1.05 (95% CI 0.63-1.76) right-sided colon combined (cecum to transverse colon)
    • 0.36 (95% CI 0.16-0.82) splenic flexure and descending colon
    • 0.29 (95% CI 0.16-0.53) sigmoid colon
    • 0.07 (95% CI 0.02-0.4) rectum
    • 0.33 (95% CI 0.21-0.53) left colon and rectum combined (splenic flexure to rectum, referred to as left-sided elsewhere)
  • Reference - J Natl Cancer Inst 2010 Jan 20;102(2):89, editorial can be found in J Natl Cancer Inst 2010 Jan 20;102(2):70
• incidence may vary by ethnicity
  • incidence of colorectal cancer varies with ethnicity in United States
    • based on annual report of cancer status in United States with data of incidence rates for 2009-2013

      Age-adjusted Colorectal Cancer Incidence per 100,000 by Race/Ethnicities:

      	Incidence Rate
      	Men	Women
      All races	46.9	35.2
      Non-Hispanic white	46.1	35.2
      Non-Hispanic black	58.3	42.7
      Asian/Pacific Islander	37.8	27.8
      American Indian/Alaska native	51.4	41.2
      Hispanic	42.8	29.8

    • Reference - CA Cancer J Clin 2017 Jan;67(1):7EBSCOhost Full Text
  • incidence of interval colorectal cancer appears higher in black adults than in white adults
    • based on population-based cohort study
    • 61,433 adults aged 66-75 years in United States national database who had colonoscopy between 2002 and 2011 were followed until interval colorectal cancer, unenrollment from Medicare program, or death
      • 7% were black, 83% were white, and 10% were Asian, Hispanic, or other race
      • interval colorectal cancer defined as first case of primary invasive colorectal cancer diagnosed 6-59 months following index colonoscopy
    • 2,735 incident cases of interval colorectal cancer were diagnosed over 235,146 person-years of follow-up
    • incidence of interval colorectal cancer per 1,000 person-years by race
      • 14.6 in black patients (adjusted hazard ratio 1.31 vs. white patients, 95% CI 1.13-1.51)
      • 11.7 in white patients
      • 7.9 in Asian patients
      • 8.8 in Hispanic patients
    • Reference - Ann Intern Med 2017 Jun 20;166(12):857EBSCOhost Full Text
  • prevalence of advanced colorectal neoplasia on screening colonoscopy appears greater in white men than black men
    • based on cross-sectional study of 2,853 average-risk adults aged 50-79 years having screening colonoscopy
    • advanced colorectal neoplasia detected with screening colonoscopy in
      • 6.8% white adults vs. 5% black adults (p = 0.04)
      • 9.3% white men vs. 5.7% black men (p < 0.05)
      • 3.5% white women vs. 4.3% black women (not significant)
    • Reference - Ann Intern Med 2013 Jul 2;159(1):13EBSCOhost Full Text
• colorectal neoplasms may occur at younger age in males than in females
  • based on birth cohort analysis with 2,185,153 adults aged 55-75 years in Germany
  • age of equivalent prevalence in men 3.4 years (95% CI 2.6-4.3 years) younger for colorectal cancer and 6.9 years (95% CI 6.4-7.4 years) younger for advanced adenoma compared to women
  • Reference - Ann Intern Med 2010 Jun 1;152(11):697EBSCOhost Full Text
• incidence of colorectal cancer by age at first surveillance colonoscopy
  • based on retrospective cohort study
  • 2,398 patients had surveillance colonoscopy (any colonoscopy occurring within 10 years of diagnostic colonoscopy that followed abnormal results from baseline flexible sigmoidoscopy)
  • 21 incident cases of colorectal cancer observed during mean follow-up of 8.2 years
  • colorectal cancer incidence rates per 10,000 person-years by age at first surveillance colonoscopy
    • 6.6 for age 55-69 years
    • 9.5 for age 70-74 years
    • 11.4 for age 75-80 years
  • due to small number of incident colorectal cancer cases, unable to estimate hazard ratio for colorectal cancer in patients ≥ 70 years old having surveillance colonoscopy
  • Reference - JAMA Intern Med 2015 May 1;175(5):858EBSCOhost Full Text
• trends in colorectal cancer incidence
  • colorectal cancer incidence has generally been declining since 1998 in adults aged ≥ 50 years in United States, but appears to be rising in adults aged < 50 years
    • since 1994. colorectal cancer increased 51% among adults aged < 50 years; rectal cancer incidence rates in adults aged 20-49 years increased from 2.6 per 100,000 in 1991 to 5.2 per 100,000 in 2014
    • decline in adults older than 50 years is thought to be due to influence of screening practices and change in exposure to risk factors, while factor(s) behind increase in younger cohorts is currently unknown
    • in adults younger than age 50 years, incidence since 1975 had remained generally stable among black Americans (who generally have higher rates than white Americans), and appears to be rising among white Americans; estimated incidence reported to be about 12.1 per 100,000 persons aged < 50 years for both groups in 2013
    • Reference - American Cancer Society 2018 guideline on colorectal cancer screening for average-risk adults CA Cancer J Clin 2018 Jul;68(4):250
  • increases in colon cancer incidence reported between 1980s (for ages 20-39 years) or mid-1990s (for aged ≥ 40 years) and 2013 in American adults aged ≤ 54 years by age group
    • 2.4% per year in adults aged 20-29 years
    • 1% per year in adults aged 30-39 years
    • 1.3% per year in adults aged 40-49 years
    • 0.5% per year in adults aged 50-54 years
    • References - CA Cancer J Clin 2018 Jul;68(4):250 full-text, J Natl Cancer Inst 2017 Aug 1;109(8)
  • increases in rectal cancer incidence reported in American adults between 1980s (for ages 20-39 years) or mid-1990s (for aged ≥ 40 years) and 2013 in American adults aged ≤ 54 years by age group
    • 3.2% per year from 1974-2013 in adults aged 20-29 years
    • 3.2% per year from 1980-2013 in adults aged 30-39 years
    • 2.3% per year from early-to-mid-1990s to 2013 in adults aged 40-54 years
    • References - CA Cancer J Clin 2018 Jul;68(4):250 full-text, J Natl Cancer Inst 2017 Aug 1;109(8)
  • incidence of colorectal cancer declined in United States among adults aged ≥ 50 years between 1975 and 2010, but increased among adults aged 20-49 years
    • based on retrospective Surveillance Epidemiology and End Results (SEER) cohort study
    • 393,241 adults ≥ 20 years old (50.4% male) diagnosed with colon or rectal cancer from 1975 to 2010 in United States from SEER database stratified by tumor site, stage at diagnosis, and age in 15-year intervals
      • colon cancer in 71.6%
        • right colon cancer in 38.8%
        • left colon cancer in 30.9%
        • disease not otherwise specified in 1.9%
      • rectosigmoid and rectal cancer in 28.4%
    • decline in age-adjusted incidence of colon and rectal cancers overall by 0.92% between 1975 and 2010 (annual percentage change -0.92%, 95% CI -1.14% to -0.7%)
    • change in age-adjusted incidence of colon and rectal cancers between 1975 and 2010 by age
      • increase in adults aged 20-34 years (annual percentage change 1.99%, 95% CI 1.48%-2.51%)
      • increase in adults aged 35-49 years (annual percentage change 0.41%, 95% CI 0.14%-0.69%)
      • decrease in adults aged 50-74 years (annual percentage change -0.97%, 95% CI -1.17% to 0.76%)
      • decrease in adults ≥ 70 years old (annual percentage change -1.15%, 95% CI -1.47% to -0.84%)
    • consistent decline in incidence of both colon and rectal cancers in adults ≥ 50 years old when stratified by stage
    • consistent increase in incidence of rectal cancer in adults aged 20-49 years when stratified by stage
    • consistent increase in incidence of colon cancer in adults aged 20-34 years when stratified by stage
    • Reference - JAMA Surg 2015 Jan;150(1):17EBSCOhost Full Text full-text, editorial can be found in JAMA Surg 2015 Jan;150(1):22EBSCOhost Full Text

Likely risk factors

• likely risk factors include
  • hereditary syndromes, such as Lynch syndrome and familial adenomatous polyposis
  • demographic factors, including male gender and increasing age
  • lifestyle factors, including diet, sedentary lifestyle, and smoking
  • medical history, including previous colon polyps or other neoplasms, and history of inflammatory bowel disease
  • prediction model incorporating medical history, family history, and lifestyle factors helps assess risk of colorectal cancer in white adults (level 1 [likely reliable] evidence)
    • based on prognostic cohort study with independent derivation and validation cohorts
    • derivation cohort included pooled data from 2 case-control studies of 2,263 non-Hispanic white adults ≥ 50 years old with colon (70.7%) or rectal cancer (29.3%) matched with 2,833 controls
      • factors significantly associated with increased risk of colon and rectal cancer included
        • cancer-negative sigmoidoscopy/colonoscopy within past 10 years
        • history of polyps on sigmoidoscopy/colonoscopy within past 10 years
        • ≥ 1 first-degree relatives with history of colorectal cancer
        • in men only, for colon cancer
          • ≥ 1 cigarettes smoked per day
          • body mass index (BMI) ≥ 25
        • in women only for colon cancer, statistical interaction between negative estrogen status (as assessed by menopausal status and hormone-replacement therapy [HRT] use) and BMI ≥ 29.9
      • factors significantly associated with decreased risk of colon cancer included
        • regular use of aspirin/nonsteroidal anti-inflammatory drug (NSAID)
        • ≥ 5 servings of vegetables per day
        • in women only
          • > 4 hours of vigorous leisure-time activity per week
          • age > 65 years
          • positive estrogen status within last 2 years
      • factors significantly associated with decreased risk of rectal cancer included
        • ≥ 1 hours (men) or ≥ 2 hours (women) of vigorous leisure-time activity per week
        • in women only
          • regular use of aspirin/NSAID
          • positive estrogen status within last 2 years
      • risk factors used to develop an online questionnaire for absolute risk assessment in persons aged 50-85 years; risk calculator available at National Cancer Institute Colorectal Cancer Risk Assessment Tool
      • Reference - J Clin Oncol 2009 Feb 10;27(5):686EBSCOhost Full Text full-text
    • validation cohort included 263,402 white adults (59% male) aged 50-71 years (mean age 63 years) from National Institutes of Health (NIH)-American Association of Retired Persons (AARP) Diet and Health Study who completed self-administered questionnaire on demographics, lifestyle, diet, and medical health history
      • using model questionnaire, overall expected at-risk population for colorectal cancer was 2,075 for men and 1,009 for women
      • over mean follow-up 6.9 years, actual incident cases of colorectal cancer in validation cohort was 2,092 for men and 965 for women
      • model questionnaire reported to perform well for predicting risk of colorectal cancer (c-statistic 0.61 for both men and women)
      • Reference - J Clin Oncol 2009 Feb 10;27(5):694EBSCOhost Full Text full-text
• genetic and familial factors
  • hereditary syndromes^{(1, 2, 3, 4)}
    • about 20% of colorectal cancer associated with familial clustering
    • first-degree relatives of patients with colorectal adenomas or invasive colorectal cancer at increased risk for colorectal cancer
    • Lynch syndrome (reportedly accounts for 3%-5% of colorectal cancer), caused by mutation in 1 of the following DNA mismatch repair genes: MLH1, MSH2, MSH6, PMS2, or EPCAM
    • familial adenomatous polyposis variants, such as Gardner syndrome and Crail syndrome (previously called Turcot Syndrome)
      • reportedly accounts for 1% of colorectal cancer
      • caused by mutations in familial polyposis coli (APC) and associated with family history of colorectal adenomatous polyp
      • also including mutY DNA glycosylase (MUTYH)-gene associated polyposis (MAP), an autosomal recessive form of familial adenomatous polyposis
    • Peutz-Jeghers Syndrome (hamartomatous polyposis)
    • juvenile polyposis syndrome
    • serrated polyposis
    • adenomatous polyps in first-degree relatives associated with increased risk of colorectal cancer
      • based on systematic review of observational studies
      • systematic review of 10 case-control studies and 2 cross-sectional studies evaluating risk of colorectal cancer in persons reporting first-degree relatives with colorectal cancer or adenomatous polyps
      • 2 studies had data to assess risk of colorectal cancer in patients with vs. without first-degree relatives with adenomatous polyps
      • in 1 cross-sectional study with 6,139 adults (10.6% reporting first-degree relative with adenoma) who had screening colonoscopy
        • 0.7% had colorectal cancer
        • adenoma in first-degree relative associated with increased risk of colorectal cancer (relative risk 4.36, 95% CI 1.6-10.2)
      • in 1 cross-sectional study with 475 adults (35% with first-degree relatives having adenoma ≥ 1 cm) who had screening colonoscopy
        • 5.7% had colorectal cancer or adenoma ≥ 1 cm
        • adenoma ≥ 1 cm in first-degree relative associated with increased risk of colorectal cancer or adenoma ≥ 1 cm (relative risk 2.27, 95% CI 1.01-5.1)
      • Reference - Ann Intern Med 2012 May 15;156(10):703EBSCOhost Full Text
    • having ≥ 2 first-degree relatives with colorectal cancer associated with increased risk of advanced colorectal neoplasia
      • based on cohort study
      • 6,053 persons (mean age 56 years, 56% female) from 1 prospective cohort study and 2 randomized trials receiving first lifetime screening colonoscopy were evaluated for association of familial history of colorectal cancer and risk of advanced colorectal neoplasia (≥ 3 nonadvanced adenomas, advanced adenomas, or invasive cancer)
        • 3,015 were familial-risk (90% with 1 first-degree relatives with colorectal cancer and 10% with ≥ 2 first-degree relatives with colorectal cancer)
        • 3,038 adults aged 50-69 years were average-risk (no family history of colorectal cancer)
      • 2,474 (median age 66.2 years, 56.5% men) index cases of advanced neoplasia
      • comparing average-risk of colorectal cancer to familial risk in
        • persons with ≥ 2 first-degree relatives with colorectal cancer
          • having 2 relatives associated with increased risk of advanced neoplasia (adjusted odds ratio [OR] 1.9, 95% CI 1.36-2.66)
          • no significant differences in risk of colorectal cancer
        • persons with 1 first-degree relative with colorectal cancer
          • having 1 relative diagnosed at age < 60 years associated with nonsignificantly increased risk of colorectal cancer (adjusted OR 2.31, 95% CI 0.98-5.42)
          • no significant differences in risk of advanced neoplasia or colorectal cancer for those having 1 relative diagnosed at age ≥ 60 years
      • Reference - PLoS Med 2016 May;13(5):e1002008EBSCOhost Full Text full-text
• demographic factors
  • male gender
    • risk of colorectal neoplasias about 2 times higher in men than in women
      • based on cohort study
      • 44,350 screening colonoscopies in adults aged 30-100 years (median age 60.6 years in men and 60.7 years in women) referred by physicians for screening and performed in 2007-2010
      • comparing men vs. women
        • adenoma found in 24.9% vs. 14.8% (p < 0.001)
        • advanced adenoma found in 8% vs. 4.7% (p < 0.001)
        • colorectal cancer found in 1.5% vs. 0.7% (p < 0.001)
      • Reference - JAMA 2011 Sep 28;306(12):1352EBSCOhost Full Text, commentary can be found in Gastroenterology 2012 Jun;142(7):1616, commentary can be found in JAMA 2012 Jan 11;307(2):142EBSCOhost Full Text
  • increasing age^(1, 2)
  • increasing height
    • increasing height associated with increased risk of colon and rectal cancer
      • based on systematic review of observational studies
      • systematic review of 21 cohort and 10 case-control studies evaluating association of height and risk of colorectal cancer in 13,077,848 persons
      • 93,818 patients had colorectal cancer
      • compared to lowest height category, highest height category associated with increased risk of
        • colorectal cancer overall (relative risk [RR] 1.25, 95% CI 1.18-1.32) in analysis of all studies, results limited by significant heterogeneity
        • colon cancer (RR 1.32, 95% CI 1.22-1.43) in analysis of 18 studies, results limited by significant heterogeneity
        • rectal cancer (RR 1.12, 95% CI 1.05-1.19) in analysis of 18 studies, results limited by significant heterogeneity
      • in dose-response analysis, every 10-cm increase in height associated with increased risk of
        • colon cancer (RR 1.02, 95% CI 1-1.02) in analysis of 10 studies
        • rectal cancer (RR 1.01, 95% CI 1-1.01) in analysis of 8 studies
      • Reference - Eur J Cancer Prev 2017 Jul 4 early online
    • adults attained height (WCRF/AICR Convincing evidence) associated with increased risk of colorectal cancer in World Cancer Research Fund International/American Institute for Cancer Research (WCRF/AICR) Continuous Update Project (CUP) on diet, nutrition, and physical activity (WCRF/AICR 2017 PDF)
• lifestyle factors
  • WCRF/AICR CUP on diet, nutrition, and physical activity associated with increased risk of colorectal cancer
    • consumption of processed meat (by smoking, curing, salting, or addition of preservatives) (WCRF/AICR Convincing evidence)
    • consumption of alcohol approximately > 30 g/day (about 2 drinks/day) (WCRF/AICR Convincing evidence)
    • body fatness based on BMI, waist circumference, or waist-hip ratio (WCRF/AICR Convincing evidence)
    • consumption of red meat (beef, pork, lamb, and goat) (WCRF/AICR Probable evidence)
    • low consumption (< 100 g/day) of nonstarchy vegetables (WCRF/AICR Suggestive - limited evidence)
    • low consumption (< 100 g/day) of fruits (WCRF/AICR Suggestive - limited evidence)
    • consumption of foods containing heme iron (red and processed meat, fish, and poultry) (WCRF/AICR Suggestive - limited evidence)
    • Reference - WCRF/AICR 2017 PDF
  • diet (for instance, increased intake of red meat and fat and inadequate fiber intake) and high alcohol intake^{(1, 2, 3, 5)}
    • increased intake of red meat or processed meat associated with increased risk of colorectal cancer
      • based on review by International Agency for Research on Cancer and separate systematic review
      • review by International Agency for Research on Cancer of > 800 epidemiological studies evaluating association between consumption of red meat or processed meat and risk of cancer
        • compared to low consumption, high consumption of red meat associated with increased risk of correctable cancer in
          • 7 of 14 cohort studies with available data
          • 7 of 15 case-control studies with available data
        • compared to low consumption, high consumption of processed meat associated with increased risk of correctable cancer in
          • 12 of 18 cohort studies with available data
          • 6 of 9 case-control studies with available data
        • Reference - Lancet Oncol 2015 Dec;16(16):1599, commentary can be found in Int J Cancer 2016 May 15;138(10):2539
      • systematic review of 28 prospective studies evaluating association of red and processed meats with risk of colorectal cancer
        • 21 studies included in dose-response meta-analyses
        • increased risk of colorectal cancer (colon cancer, rectal cancer, or combined colorectal cancer) associated with increased
          • red and processed meat intake for every 100 g/day (pooled relative risk [RR] 1.14, 95% CI 1.04-1.24) in analysis of 11 studies, results limited by significant heterogeneity
          • red meat intake for every 100 g/day (pooled RR 1.17, 95% CI 1.05-1.31) in analysis of 8 studies
          • processed meat intake for every 50 g/day (pooled RR 1.18, 95% CI 1.1-1.28) in analysis of 9 studies
        • increased risk of colon cancer associated with increased
          • red and processed meat intake for every 100 g/day (pooled RR 1.25, 95% CI 1.1-1.43) in analysis of 8 studies, results limited by significant heterogeneity
          • red meat intake for every 100 g/day (pooled RR 1.17, 95% CI 1.02-1.33) in analysis of 10 studies
          • processed meat intake for every 50 g/day (pooled RR 1.24, 95% CI 1.13-1.35) in analysis of 10 studies
        • increased risk of rectal cancer
          • associated with increased red and processed meat intake for every 100 g/day (pooled RR 1.31, 95% CI 1.13-1.52) in analysis of 5 studies
          • nonsignificantly associated with
            • increased red meat intake for every 100 g/day (pooled RR 1.18, 95% CI 0.98-1.42) in analysis of 7 studies
            • increased processed meat intake for every 50 g/day (pooled RR 1.12, 95% CI 0.99-1.28) in analysis of 8 studies
        • Reference - PLoS One 2011;6(6):e20456EBSCOhost Full Text full-text
    • increased intake of processed red meat, but not unprocessed red meat, associated with increased risk of distal colon cancer in adults
      • based on meta-analysis of cohort studies
      • meta-analysis of 2 cohort studies (Nurses' Health Study and Health Professionals Follow-Up Study) evaluating association between red meat intake and risk of colorectal cancer in 134,497 adults
      • 2% developed colorectal cancer over 3,452,754 person-years of follow-up
      • increased intake of processed red meat associated with increased risk of distal colon cancer (adjusted hazard ratio 1.36, 95% CI 1.09-1.69 per 1 serving/day increase) in analysis of 2 studies
      • increased intake of unprocessed red meat associated with decreased risk of distal colon cancer (adjusted hazard ratio 0.75, 95% CI 0.68-0.82 per 1 serving/day increase) in analysis of 2 studies
      • no significant differences in risk of proximal colon cancer or rectal cancer with increased intake of processed or unprocessed red meat
      • Reference - PLoS One 2015 Aug 25;10(8):e0135959EBSCOhost Full Text full-text
    • Western dietary pattern and increased alcohol consumption associated with increased risk of colorectal cancer
      • based on systematic review of observational studies
      • systematic review of 22 cohort studies, 17 case-control studies, and 1 cross-sectional study evaluating association between dietary pattern and risk of colorectal cancer
      • Western dietary pattern defined as high intake of red and/or processed meat, refined grains, sweets, high-fat dairy products, butter, potatoes and high-fat gravy, and low intake of fruits and vegetables
      • healthy dietary pattern defined as high intake of vegetables, fruits, whole grains, olive oil, fish, soy, poultry, and low-fat dairy
      • all results limited by significant heterogeneity
      • compared to lowest intake, highest intake of
        • Western dietary pattern associated with increased risk of colorectal cancer (odds ratio [OR] 1.4, 95% CI 1.26-1.56) in analysis of 25 studies with 522,428 persons
        • alcohol consumption (beer, wine, and white spirits) associated with increased risk of colorectal cancer (OR 1.44, 95% CI 1.13-1.82) in analysis of 18 studies with 728,128 persons
        • healthy dietary pattern associated with decreased risk of colorectal cancer (OR 0.75, 95% CI 0.68-0.83) in analysis of 26 studies with 526,543 persons
      • Reference - Eur J Cancer Prev 2017 May;26(3):201
    • increasing alcohol consumption associated with increased risk of colon and rectal cancers
      • based on systematic review of observational studies
      • systematic review of 27 cohort and 34 case-control studies evaluating relationship between alcohol intake and risk of colorectal cancer
      • 1 drink defined as ethanol content of 12.5 g
      • compared to nondrinkers and occasional drinkers
        • heavy drinking (ethanol ≥ 50 g/day) associated with increased risk of
          • colorectal cancer overall (relative risk [RR] 1.52, 95% CI 1.27-1.81) in analysis of 19 studies with 6,653 colorectal cancer cases, results limited by significant heterogeneity
          • colon cancer (RR 1.43, 95% CI 1.23-1.64) in analysis of 16 studies
          • rectal cancer (RR 1.59, 95% CI 1.18-2.15) in analysis of 15 studies
        • moderate drinking (ethanol 12.6-49.9 g/day) associated with increased risk of
          • colorectal cancer overall (RR 1.21, 95% CI 1.13-1.28) in analysis of 53 studies with 20,700 colorectal cancer cases, results limited by significant heterogeneity
          • colon cancer (RR 1.15, 95% CI 1.06-1.24) in analysis of 39 studies
          • rectal cancer (RR 1.23, 95% CI 1.13-1.35) in analysis of 35 studies
      • in dose-response analysis, increased risk of colorectal cancer associated with increase in alcohol intake for every
        • 10 g/day (RR 1.07, 95% CI 1.04-1.1)
        • 50 g/day (RR 1.38, 95% CI 1.28-1.5)
        • 100 g/day (RR 1.82, 95% CI 1.41-2.35)
      • Reference - Ann Oncol 2011 Sep;22(9):1958
  • high BMI or obesity and metabolic syndrome^{(1, 2, 3, 5)}
    • weight gain in adulthood associated with increased risk of colorectal cancer
      • based on systematic review of observational studies
      • systematic review of 13 prospective cohort studies evaluating association between body weight change and risk of colorectal cancer in adults
      • compared to reference weight category
        • highest category weight gain associated with increased risk of colorectal cancer (adjusted hazard ratio [HR] 1.16, 95% CI 1.08-1.24) in analysis of all studies
        • no significant difference in risk of colorectal cancer associated with highest category of weight loss in analysis of 10 studies
      • each 5-kg increase in weight associated with increased risk of colorectal cancer (adjusted HR 1.03, 95% CI 1.02-1.05), results limited by significant heterogeneity
      • Reference - Am J Epidemiol 2015 Jun 1;181(11):832
      • similar results in separate systematic review can be found in Obes Rev 2015 Jul;16(7):607
    • obesity associated with increased risk of colorectal cancer
      • based on systematic review of observational studies
      • systematic review of 43 prospective cohort studies evaluating association between general obesity by BMI and/or central obesity by waist circumference and risk of colorectal cancer in 9,000,000 persons
      • colorectal cancer diagnoses in 92,481 (1%)
      • compared to normal category of BMI, obesity by BMI associated with increased risk of
        • colorectal cancer (adjusted relative risk [RR] 1.33, 95% CI 1.25-1.42) in analysis of 39 studies, results limited by significant heterogeneity
        • colon cancer (adjusted RR 1.47, 95% CI 1.35-1.6) in analysis of 32 studies, results limited by significant heterogeneity
        • rectal cancer (adjusted RR 1.15, 95% CI 1.1-1.2) in analysis of 25 studies, results limited by significant heterogeneity
      • compared to lowest category of waist circumference, highest category of waist circumference associated with increased risk of
        • colorectal cancer (adjusted RR 1.46, 95% CI 1.33-1.6) in analysis of 12 studies
        • colon cancer (adjusted RR 1.61, 95% CI 1.42-1.84) in analysis of 9 studies
        • rectal cancer (adjusted RR 1.35, 95% CI 1.11-1.63) in analysis of 5 studies
      • results in comparison of BMI (9 studies) and waist circumference (2 studies) remained significant in both proximal and distal colon cancers
      • Reference - PLoS One 2013;8(1):e53916EBSCOhost Full Text full-text
      • similar results in 2 separate systematic reviews can be found in Eur J Cancer Prev 2013 Nov;22(6):492and Am J Clin Nutr 2007 Sep;86(3):556EBSCOhost Full Text
    • preexisting metabolic syndrome associated with increased colorectal cancer incidence
      • based on systematic review of observational studies
      • systematic review of 17 observational studies evaluating association between preexisting metabolic syndrome and incidence and mortality of colorectal cancer
      • 11,462 patients had colorectal cancer
      • metabolic syndrome included abdominal obesity, dysglycemia, raised blood pressure, elevated triglyceride, and low high-density lipoprotein (HDL) cholesterol levels
      • metabolic syndrome associated with increased
        • risk of colorectal cancer in men (relative risk [RR] 1.33, 95% CI 1.18-1.5) in analysis of 12 studies, results limited by significant heterogeneity
        • risk of colorectal cancer in women (RR 1.41, 95% CI 1.18-1.7) in analysis of 11 studies, results limited by significant heterogeneity
      • metabolic syndrome significantly associated with increased risk of colorectal cancer in pooled analysis of men and women included abdominal obesity, dysglycemia, and raised blood pressure
      • Reference - Endocrine 2013 Dec;44(3):634EBSCOhost Full Text
  • sedentary lifestyle^(3, 4)
    • higher daily sedentary time associated with increased risk of colorectal cancer
      • based on systematic review of observational studies
      • systematic review of 17 cohort and 11 case-control studies evaluating relationship between self-reported daily sedentary time and risk of colorectal cancer in 4,784,339 adults
      • 46,071 adults had colorectal cancer
      • sedentary time defined as television (TV) viewing time, occupational sitting time, and/or total sitting time
      • increased risk of colorectal cancer associated with
        • daily total sitting time in analysis of 3 studies
          • comparing highest to lowest time (relative risk [RR] 1.06, 95% CI 1.03-1.09); results remained significant when stratified to colon and rectal cancers
          • for every increase of 2 hour/day (RR 1.02, 95% CI 1.01-1.06)
        • daily occupational sitting time in analysis of 21 studies, results limited by significant heterogeneity
          • comparing highest to lowest time (RR 1.15, 95% CI 1.08-1.22); results remained significant when stratified to colon and rectal cancers
          • for every increase of 2 hour/day (RR 1.04, 95% CI 1.01-1.08)
        • daily TV viewing time in analysis of 5 studies
          • comparing highest to lowest time (RR 1.17, 95% CI 1.09-1.24); results remained significant when stratified to colon and rectal cancers
          • for every increase of 2 hour/day (RR 1.07 95% CI 1.05-1.1)
      • Reference - Medicine (Baltimore) 2017 Jun;96(22):e7049 full-text
    • sedentary behavior associated with increased risk of colon cancer but not rectal cancer
      • based on systematic review of observational studies
      • systematic review of 23 studies evaluating sedentary behavior and risk of colon and rectal cancer in 4,324,462 persons
      • sedentary behavior defined as activities done sitting or reclining that expend < 1.5 times basal metabolic rate; examples include watching television, desk-bound work, using computers and game-consoles, sitting at work, and/or sitting in automobiles
      • 27,231 cases of colon cancer and 13,813 cases of rectal cancer were observed
      • sedentary behavior associated with increased risk of colon cancer (relative risk 1.3, 95% CI 1.22-1.39) in analysis of 22 studies
      • no significant association between sedentary behavior and risk of rectal cancer in analysis of 19 studies
      • Reference - Br J Cancer 2014 Feb 4;110(3):817EBSCOhost Full Text full-text, commentary can be found in Br J Cancer 2014 Nov 25;111(11):2202EBSCOhost Full Text
  • cigarette smoking^{(1, 2, 3, 5)}
    • smoking associated with increased risk of colorectal cancers
      • based on systematic review of observational studies
      • systematic review of 24 prospective cohort studies evaluating relationship between cigarette smoking and risk of colorectal cancer
      • colon cancer in 14,186 patients and rectal cancer in 6,814 patients
      • compared to never smoking
        • current smoking
          • associated with increased risk of
            • colon cancer overall (relative risk [RR] 1.09, 95% CI 1.01-1.18) in analysis of 23 studies, results limited by significant heterogeneity
            • proximal colon cancer (RR 1.31, 95% CI 1.13-1.52) in analysis of 4 studies
            • rectal cancer (RR 1.24, 95% CI 1.16-1.39) in analysis of 20 studies, results limited by significant heterogeneity
        • no significant difference in risk of distal colon cancer in analysis of 4 studies
        • former smoking associated with increased risk of
          • colon cancer (RR 1.16, 95% CI 1.11-1.28) in analysis of 21 studies
          • proximal colon cancer (RR 1.3, 95% CI 1.15-1.48) in analysis of 4 studies
          • distal colon cancer nonsignificantly (RR 1.14, 95% CI 0.97-1.33) in analysis of 4 studies
          • rectal cancer (RR 1.2, 95% CI 1.11-1.30) in analysis of 19 studies
      • in dose-response analysis, increased risk of colon and rectal cancer associated with every increase of
        • 10 cigarettes/day
          • RR for colon cancer 1.05 (95% CI 1.02-1.09) in analysis of 16 studies, results limited by significant heterogeneity
          • RR for rectal cancer 1.11 (95% CI 1.02-1.21) in analysis of 16 studies, results limited by significant heterogeneity
        • 10 pack-years
          • RR for colon cancer 1.08 (95% CI 1.04-1.11) in analysis of 6 studies
          • RR for rectal cancer 1.1 (95% CI 1.01-1.2) in analysis of 7 studies, results limited by significant heterogeneity
        • 10 years
          • RR for colon cancer 1.02 (95% CI 1-1.04) in analysis of 11 studies, results limited by significant heterogeneity
          • RR for rectal cancer 1.06 (95% CI 1.03-1.1) in analysis of 11 studies, results limited by significant heterogeneity
      • Reference - Eur J Cancer Prev 2015 Jan;24(1):6
    • smoking associated with increased risk of colorectal cancer
      • based on systematic review of observational studies
      • systematic review of 121 observational studies evaluating association between cigarette smoking and risk and mortality of colorectal cancer
      • absolute annual incidence of colorectal cancer 65.5 cases/100,000 person-years with smokers vs. 54.7 cases/100,000 person-years with nonsmokers (p < 0.05) in analysis of 19 cohort studies
      • absolute annual colorectal cancer death in 41.3/100,000 person-years with smokers vs. 35.3/100,000 person-years with nonsmokers (p < 0.05) in analysis of 10 cohort studies
      • compared to never smokers
        • increased risk of colorectal cancer associated with
          • ever smokers (adjusted relative risk [RR] 1.18, 95% CI 1.11-1.25) in analysis of 25 studies
          • current smokers nonsignificantly (adjusted RR 1.07, 95% CI 0.99-1.16) in analysis of 45 studies
          • former smokers (adjusted RR 1.17, 95% CI 1.11-1.22) in analysis of 47 studies
        • risk of colorectal cancer increased by
          • 7.8% (95% CI 5.7%-10%) for every 10 cigarettes/day increase in smoking for ever smokers
          • 4.4% (95% CI 1.7%-7.2%) for every 10 pack-years increase in smoking for ever smokers
      • Reference - JAMA 2008 Dec 17;300(23):2765EBSCOhost Full Text
• medical history
  • previous colon polyps or other neoplasms⁽²⁾
    • risk index predicts advanced colorectal neoplasia within lesions < 10 mm in size in adults (level 1 [likely reliable] evidence)
      • based on prognostic cohort study with independent derivation and validation cohorts
      • 1,077,956 adults (56% women) without chronic inflammatory bowel disease who had colonoscopies were randomized into
        • derivation cohort with 718,637 adults
        • validation cohort with 359,319 adults
      • in overall cohort
        • 198,954 diminutive (≤ 4 mm) lesions identified, of which 3.7% contained advanced neoplasia (defined as high-grade dysplasia, villous histology, or cancer)
        • 106,270 intermediate (5-9 mm) lesions identified, of which 13% contained advanced neoplasia
      • 8,840 adults (0.8% of adults with advanced neoplasia) had colon cancer
      • risk factors associated with advanced neoplasia used to derive risk index (total score 0-30 points)
        • age - 4 points if 45-54 years, 5 points if 55-64 years, 7 points if 65-74 years, 9 points if 75-84 years, 10 points if ≥ 85 years old
        • male - 1 point
        • no family risk - 2 points
        • blood in stool - 3 points if overt blood, 4 points if occult blood
        • location of polyps - 1 point if proximal and distal
        • multiplicity of polyps - 2 points if 2-4 polyps, 5 points if > 4 polyps
        • morphology of polyp - 3 points if flat, 8 points if pedunculated
      • number needed to screen (NNS) to identify 1 lesion carrying advanced neoplasia by risk index score based on observed rates of advanced neoplasia in validation cohort
        • in patients with diminutive lesions
          • 48 for 4 points
          • 35 for 7 points
          • 24 for 11 points
          • 18 for 14 points
          • 6 for 25 points
        • in patients with intermediate lesions
          • 13 for 6 points
          • 10 for 9 points
          • 6 for 14 points
          • 4 for 19 points
          • 2 for 28 points
      • for entire cohort, median NNS = 15, which differentiated patients into high-risk (NNS ≤ 15) vs. low-risk (NNS > 15) groups
      • in validation cohort
        • 2.59% of 66,281 patients with diminutive lesions were in high-risk group
        • 96.6% of 35,460 patients with intermediate lesions were in high-risk group
      • Reference - Gut 2013 Jun;62(6):863
    • serrated polyps associated with increased risk of synchronous advanced neoplasia, with higher risks associated with proximal and large serrated polyps
      • based on systematic review of observational studies
      • systematic review of 9 observational studies (7 cross-sectional, 1 cohort, 1 randomized trial) evaluating association between serrated polyps and risk of advanced neoplasia in 34,084 patients
      • 7 studies consisted of consecutive asymptomatic patients having screening for colonoscopy
      • pooled prevalence of serrated polyps
        • 15.6% (95% CI 10.3%-22.9%) for all serrated polyps
        • 6.1% (95% CI 4.5%-8.4%) for proximal serrated polyps
        • 1.5% (95% CI 1.1%-2.1%) for large serrated polyps
      • detection of synchronous advanced neoplasia associated with presence of
        • serrated polyps (odds ratio [OR] 2.05, 95% CI 1.38-3.04) in analysis of 4 studies, results limited by significant heterogeneity
        • proximal serrated polyps (OR 2.77, 95% CI 1.71-4.46), results limited by significant heterogeneity
        • large serrated polyps (OR 4.1, 95% CI 2.69-6.26), results limited by significant heterogeneity
        • proximal and large serrated polyps (OR 3.35, 95% CI 2.51-4.46)
      • serrated polyps not significantly associated with risk of synchronous colorectal cancer in analysis of 4 trials, results limited by significant heterogeneity
      • Reference - Am J Gastroenterol 2015 Apr;110(4):501EBSCOhost Full Text
    • nonpolypoid colorectal neoplasms associated with greater risk of colorectal cancer compared to polypoid neoplasms
      • based on cohort study
      • 1,819 adults (mean age 64 years, 95% male) having elective colonoscopy at a veteran's hospital were analyzed
        • 34% were asymptomatic
        • 36% had personal or family history of colorectal neoplasm (including cancer)
        • 30% were symptomatic; symptoms included
          • anemia
          • rectal bleeding
          • diarrhea
          • positive results from fecal occult blood test
          • weight loss
          • abdominal pain
          • inflammatory bowel disease
      • commercially available high-resolution adult colonoscopes were used, 0.1%-0.4% diluted indigo carmine 10-25 mL sprayed through accessory channel if suspected nonpolypoid colorectal neoplasms
      • 9.35% prevalence of nonpolypoid colorectal neoplasms (170 patients) of whom 0.82% had in situ or submucosal invasive colorectal carcinoma
        • 5.84% in asymptomatic adults, of whom 0.32% had colorectal carcinoma
        • 15.44% in adults with personal or family history of colorectal neoplasm
        • 6.01% in symptomatic adults
      • compared to polypoid neoplasms, increased risk of in situ or invasive colorectal carcinoma associated with
        • nonpolypoid neoplasms (adjusted odds ratio [OR] 9.78, 95% CI 3.93-24.4)
        • flat nonpolypoid neoplasms (adjusted OR 5.18, 95% CI 1.84-14.6)
        • depressed nonpolypoid neoplasms (adjusted OR 209, 95% CI 44-1002), but number of depressed lesions (18) was too few to accurately assess association
      • Reference - JAMA 2008 Mar 5;299(9):1027EBSCOhost Full Text, editorial can be found in JAMA 2008 Mar 5;299(9):1068EBSCOhost Full Text, commentary can be found in JAMA 2008 Jun 18;299(23):2743EBSCOhost Full Text
  • history of inflammatory bowel disease (such as Crohn disease or ulcerative colitis)^(1, 2, 5)
    • inflammatory bowel disease reportedly associated with 1% of colorectal cancer in western population
    • inflammatory bowel disease (IBD) associated with increased risk of colorectal cancer, especially in patients with diagnosis before age 30 years or with extensive ulcerative colitis
      • based on systematic review of cohort studies
      • systematic review of 59 cohort studies reporting risks of colorectal cancer in patients with IBD including Crohn disease or ulcerative colitis
      • 9 studies were population-based
      • compared to general population, increased risk of colorectal cancer associated with
        • any IBD (standardized incidence ratio [IR] 1.7, 95% CI 1.2-2.2) in analysis of 9 studies with 13,010 patients
        • any IBD diagnosis before age 30 years (standardized IR 8.2, 95% CI 1.8-14.6) in analysis of 5 studies with 3,276 patients
        • extensive ulcerative colitis (standardized IR 6.9, 95% CI 1.9-11.9) in analysis of 4 studies with 1,887 patients
      • cumulative risks of colorectal cancer after IBD diagnosis were
        • 1% after 10 years
        • 2% after 20 years
        • 5% after ≥ 20 years
      • IBD also associated with significantly increased risk of colorectal cancer in analysis of studies conducted at referral centers
      • Reference - Inflamm Bowel Dis 2013 Mar-Apr;19(4):789
    • 3.7% overall prevalence of colorectal cancer in patients with ulcerative colitis, overall incidence rate 3 per 1,000 person-years duration (6 per 1,000 in children)
      • based on systematic review of observational studies
      • systematic review of 116 studies evaluating risk of colorectal cancer in 54,478 patients with ulcerative colitis
      • mean age 43.2 years at diagnosis of colorectal cancer in 43 studies with 22,730 patients (844 cancer cases)
      • mean duration 16.3 years of ulcerative colitis at cancer diagnosis in 61 studies
      • prevalence of colorectal cancer
        • 3.7% prevalence (95% CI 3.2%-4.2%) in analysis of all studies
        • 5.4% prevalence (95% CI 4.4%-6.5%) in analysis of 35 studies with 8,351 patients with pancolitis
      • in analysis of 19 studies which stratified incidence into 10-year intervals of disease duration, incidence per 1,000 person-years duration was
        • 2 for first 10 years, corresponding to cumulative probability of 2% by 10 years
        • 7 for second decade, corresponding to cumulative probability of 8% by 20 years
        • 12 for third decade, corresponding to cumulative probability of 18% by 30 years
      • Reference - Gut 2001 Apr;48(4):526 full-text
    • ulcerative colitis associated with increased risk of colorectal cancer, especially in those who are < 29 years old and have extensive disease
      • based on systematic review of observational studies
      • systematic review of 8 cohort studies evaluating risk of colorectal cancer in 10,385 patients with ulcerative colitis
      • 1.6% were diagnosed with colorectal cancer during 14 years of follow-up
      • standardized incidence ratio for colorectal cancer (compared to expected in age- and gender-matched background population)
        • 2.4 (95% CI 2.1-2.7) overall in analysis of all studies
        • 2.6 (95% CI 2.2-3) for men in analysis of 4 studies
        • 1.9 (95% CI 1.5-2.3) for women in analysis of 4 studies
        • 8.6 (95% CI 3.8-19.5) for patients aged 0-29 years in analysis of 3 studies
        • 2.1 (95% CI 1.3-3.3) for patients aged 30-49 years in analysis of 3 studies
        • 1.7 (95% CI 1.2-2.4) for patients ≥ 50 years old in analysis of 3 studies
        • 4.8 (95% CI 3.9-5.9) for patients with extensive colitis in analysis of 4 studies
      • Reference - Clin Gastroenterol Hepatol 2012 Jun;10(6):639, commentary can be found in Clin Gastroenterol Hepatol 2012 Oct;10(10):1179
    • ulcerative colitis diagnosed at < 40 years old and ulcerative colitis with primary sclerosing cholangitis each associated with increased risk of colorectal cancer
      • based on prospective cohort study
      • 8 million persons in Denmark were followed for 178 million person-years
        • 32,911 patients diagnosed with ulcerative colitis
        • 268 developed colorectal cancer
      • compared to general population, increased risk of colorectal cancer associated with ulcerative colitis diagnosed at age
        • 0-19 years (relative risk [RR] 43.8, 95% CI 27.2-70.7)
        • 20-39 years (RR 2.65, 95% CI 1.97-3.56)
      • ulcerative colitis with primary sclerosing cholangitis associated with increased risk of colorectal cancer compared to ulcerative colitis without primary sclerosing cholangitis (RR 9.13, 95% CI 4.52-18.5)
      • Reference - Gastroenterology 2012 Aug;143(2):375, editorial can be found in Gastroenterology 2012 Aug;143(2):288, commentary can be found in Gastroenterology 2013 Mar;144(3):e21
  • history of diabetes mellitus^{(1, 3, 4, 5)}
    • diabetes mellitus associated with increased risk of colorectal cancer
      • based on systematic review of observational studies
      • systematic review of 16 cohort studies and 8 case-control studies evaluating association between diabetes mellitus (type 1 or 2) and risk of colorectal cancer in 3,659,341 persons
      • 38,182 patients had colorectal cancer in 22 studies
      • increased risk of colorectal cancer associated with
        • diabetes mellitus, compared to no diabetes mellitus, in analysis of all studies
          • risk ratio (RR) 1.26 (95% CI 1.2-1.31)
          • association consistent between males and females
        • insulin therapy (RR 1.61, 95% CI 1.18-1.35) compared to no insulin therapy in analysis of 4 studies, results limited by significant heterogeneity
      • Reference - Dig Dis Sci 2012 Jun;57(6):1576EBSCOhost Full Text, editorial can be found in Dig Dis Sci 2012 Jun;57(6):1427EBSCOhost Full Text
    • type 2 diabetes mellitus associated with increased risk of colorectal cancer
      • based on systematic review of observational studies
      • systematic review of 8 cohort studies evaluating association between type 2 diabetes mellitus and risk of colorectal cancer in 924,632 persons
        • 113,868 patients had type 2 diabetes
        • 51,931 patients had colorectal cancer
      • type 2 diabetes associated with increased risk of colorectal cancer (relative risk 1.21, 95% CI 1.02-1.42) in analysis of all studies, results limited by significant heterogeneity
      • Reference - World J Gastroenterol 2015 May 21;21(19):6026 full-text
    • insulin use associated with increased risk of colorectal cancer in patients with type 2 diabetes mellitus
      • based on systematic review of observational studies
      • systematic review of 5 cohort and 7 case-control studies evaluating insulin use and risk of colorectal cancer in 491,384 patients with type 2 diabetes mellitus
      • 7,947 patients had colorectal cancer
      • duration of insulin use was ≥ 1 years in 5 studies and not reported in 7 studies
      • insulin use associated with increased risk of colorectal cancer (relative risk 1.69, 95% CI 1.25-2.27) in analysis of all studies, results limited by significant heterogeneity
      • Reference - Diagn Pathol 2014 May 12;9:91EBSCOhost Full Text full-text
      • similar results in separate systematic review can be found in Br J Clin Pharmacol 2014 Aug;78(2):301 full-text

Possible risk factors

• genetic and familial factors
  • TCF7L2 rs7903146 polymorphism may be associated with increased risk of colon and breast cancer but decreased risk of prostate cancer
    • based on systematic review of observational studies
    • systematic review of 19 studies evaluating association between transcription factor 7-like 2 (TCF7L2) gene polymorphism and risk of cancer in 48,670 persons
    • TCF7L2 is a gene involved in Wnt/beta-catenin signaling pathway and variant rs7903146 was identified and confirmed as a susceptibility marker of type 2 diabetes in a genome-wide association study
    • single-nucleotide polymorphisms studied included rs7903146 and rs12255372, which is in high linkage disequilibrium with rs7903146
    • 14,814 cancer cases included breast, prostate, colorectal, lung, and ovarian cancers
      • 5,623 breast cancer cases
      • 4,344 prostate cancer cases
      • 2,503 colorectal cancer cases (mixed colon and rectal cancer) and 1,701 colon cancer cases
      • 239 lung cancer cases
      • 391 ovarian cancer cases
    • TCF7L2 rs7903146 polymorphism associated with (results from heterogeneous codominant model)
      • increased risk of colon cancer (odds ratio [OR] 1.15, 95% CI 1.01-1.31) in analysis of 2 studies with 15,082 persons
      • increased risk of breast cancer (OR 1.11, 95% CI 1.03-1.2) in analysis of 5 studies with 23,059 persons
      • decreased risk of prostate cancer (OR 0.89, 95% CI 0.84-0.95) in analysis of 5 studies with 26,851 persons
    • no significant differences in risks of colorectal cancer overall (4 studies), lung cancer (2 studies), and ovarian cancer (1 study)
    • Reference - PLoS One 2013;8(8):e71730EBSCOhost Full Text full-text
  • patients previously treated for Hodgkin lymphoma who develop colorectal cancer appear to have higher frequency of microsatellite instability and mutations in mismatch repair genes compared to patients with colorectal cancer from general population (Gut 2018 Mar;67(3):447)
• medical history and medication use
  • external beam radiation therapy for primary prostate cancer may be associated with increased risk of secondary rectal cancer
    • based on systematic review of observational studies
    • systematic review of 20 observational studies evaluating risk of secondary cancers after radiation therapy for primary prostate or rectal cancer
    • 16 studies evaluated patients with primary prostate cancer
    • all analyses limited by significant statistical heterogeneity
    • in analyses by type of radiation therapy
      • external beam radiation therapy associated with increased risk of secondary rectal cancer (risk ratio 1.58, 95% CI 1.23-2.03) in analysis of 6 studies with primary prostate cancer patients
      • no significant difference in risk of secondary rectal cancer with brachytherapy in analysis of 3 studies with primary prostate cancer patients
    • no significant difference in risk of secondary rectal cancer comparing any radiation therapy to no radiation therapy in analysis of 4 studies
    • Reference - World J Surg 2016 Apr;40(4):895EBSCOhost Full Text
  • history of renal pelvis cancer or ureteral cancer may be associated with increased risk for colorectal cancer
    • based on retrospective cohort study
    • 186,972 patients diagnosed with urologic cancer from 1973 to 2000 were analyzed
      • bladder cancer in 124,376 patients
      • renal parenchymal cancer in 52,441 patients
      • renal pelvis cancer in 6,403 patients
      • ureteral cancer in 3,744 patients
    • compared to general population
      • increased risk of colorectal cancer in
        • patients with renal pelvis cancer (standardized incidence ratio [SIR] 1.44, 95% CI 1.2-1.72)
        • patients with ureteral cancer (SIR 1.80, 95% CI 1.46-2.2)
      • no significant difference in risk of colorectal cancer associated with patients with bladder or renal parenchymal cancer
    • Reference - Arch Intern Med 2008 May 12;168(9):1003EBSCOhost Full Text
  • hospitalization for gallbladder disease with or without cholecystectomy may be associated with increased risk of colorectal cancers within 4 years
    • based on retrospective cohort study
    • 460,574 patients hospitalized with gallbladder disease (gallstones or cholecystitis, 71% with cholecystectomy) were compared to 3,000,000 patients with hospitalization for other medical or surgical causes (controls)
    • compared to controls, hospitalization for gallbladder disease within 1 year associated with increased risk of cancer
      • in patients without cholecystectomy
        • small intestine (rate ratio [RR] 21.24, 95% CI 15.81-28.59)
        • colon (RR 7.12, 95% CI 6.47-7.83)
        • rectum (RR 3.97, 95% CI 3.41-4.59)
      • in patients with cholecystectomy
        • small intestine (RR 10.43, 95% CI 7.79-13.99)
        • colon (RR 3.91, 95% CI 3.56-4.29)
        • rectum (RR 2.85, 95% CI 2.49-3.24)
    • hospitalization for gallbladder disease with or without cholecystectomy associated with significantly increased risk of cancer of small intestine, colon, and rectum 1-4 years following hospitalization
    • no significant association between gallbladder disease and cancer risk at ≥ 5 years following hospitalization
    • Reference - Ann Surg 2012 Dec;256(6):1068
  • computed tomography (CT) scans in childhood or adolescence may be associated with increased risk of cancer, including digestive organ cancers
    • based on retrospective cohort study
    • 10.9 million persons aged 0-19 years from 1985 to 2005 in Australia were assessed for CT scans and were followed through 2007 for incident cancers
      • 680,211 persons had ≥ 1 CT scan before any cancer diagnosis
      • 60,674 cancers were diagnosed, including 3,150 cancers in persons with previous CT scan
    • mean follow-up after CT exposure 9.5 years
    • analysis excluded cancers diagnosed within 1 year of CT scan
    • compared to no CT exposure, ≥ 1 CT scan associated with increased risk of
      • any cancer (incidence rate ratio [RR] 1.24, 95% CI 1.2-1.29)
      • digestive organ cancers (incidence RR 1.29, 95% CI 1.09-1.52)
    • increasing number of CT scans associated with increasing risk of any cancer (increase in incidence RR 0.16 per scan, 95% CI 0.13-0.19)
    • younger age at CT scan associated with increased cancer risk (p for trend < 0.001)
    • Reference - BMJ 2013 May 21;346:f2360 full-text, editorial can be found in BMJ 2013 May 21;346:f3102, commentary can be found in Cancer Epidemiol 2016 Jun;42:60, Evid Based Med 2014 Feb;19(1):36
  • history of childhood cancer diagnosed at age < 21 years may be associated with increased risk of colorectal cancer and gastrointestinal cancer
    • based on retrospective cohort study
    • 14,358 persons who had previous cancer diagnosed at childhood (age < 21 years) and survived ≥ 5 years after initial diagnosis were evaluated for risk of gastrointestinal cancer and followed for median 22.8 years
    • childhood cancers included leukemia in 34%, central nervous system (CNS) tumors in 13%, Hodgkin lymphoma in 13%, Wilms tumor in 9%, soft tissue sarcoma in 9%, bone tumors in 8%, non-Hodgkin lymphoma in 8%, and neuroblastoma in 7%
    • 45 gastrointestinal cases (24 colorectal cancer cases) developed at median age 34 years
    • compared to general population, childhood cancer associated with increased risk of
      • colorectal cancer (standardized incidence ratio [SIR] 4.2, 95% CI 2.8-6.3)
      • subsequent gastrointestinal malignant neoplasms (SIR 4.6, 95% CI 3.4-6.4)
    • compared to general population, abdominal radiation exposure associated with greatest increased risk of subsequent gastrointestinal malignant neoplasms (SIR 11.2, 95% CI 7.6-16.4)
    • Reference - Ann Intern Med 2012 Jun 5;156(11):757EBSCOhost Full Text full-text
  • higher C-reactive protein level in blood may be associated with increased risk of colon cancer but not rectal cancer
    • based on systematic review of observational studies
    • systematic review of 20 studies evaluating blood levels of C-reactive protein (CRP) and interleukin-6 (IL-6) and risk of colorectal cancer
      • 18 studies (8 cohort studies and 10 nested case-control studies) evaluated CRP with 4,706 colorectal cancer cases
      • 6 studies (3 cohort studies and 10 nested case-control studies) evaluated IL-6 with 1,068 colorectal cancer cases
    • every increase in 1 natural log unit of CRP level (in mg/L) associated with
      • increased risk of colorectal cancer overall (relative risk [RR] 1.12, 95% CI 1.05-1.21) in analysis of 18 studies, results limited by significant heterogeneity
      • increased risk of colon cancer (RR 1.13, 95% CI 1.05-1.21) in analysis of 13 studies, results limited by significant heterogeneity
    • no significant difference in risk of rectal cancer with every increase of 1 natural log unit of CRP level (in mg/L) in analysis of 12 studies, results limited by significant heterogeneity
    • no significant difference in risk of colorectal cancer with every increase in 1 natural log unit of IL-6 (in pg/mL) in analysis of 6 studies
    • Reference - Cancer Causes Control 2014 Oct;25(10):1397EBSCOhost Full Text
  • high-dose ursodeoxycholic acid may be associated with increased risk of colorectal neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis
    • based on nested cohort study of small randomized trial
    • 56 adults with ulcerative colitis and primary sclerosing cholangitis were randomized to high-dose ursodeoxycholic acid (28-30 mg/kg/day) vs. placebo
    • follow-up 235 patient-years
    • high-dose ursodeoxycholic acid associated with increased risk of colorectal neoplasia (dysplasia and cancer) compared to placebo (hazard ratio 4.44, 95% CI 1.3-20.1)
    • Reference - Am J Gastroenterol 2011 Sep;106(9):1638EBSCOhost Full Text full-text, commentary can be found in Gastroenterology 2011 Dec;141(6):2267, commentary can be found in Nat Rev Gastroenterol Hepatol 2011 Jul 4;8(7):361
  • bisphosphonate use might be associated with increased risk of colorectal cancer in adults
    • based on pooled analysis of case-control studies
    • pooled analysis of 2 case-control studies with 55,949 adults ≥ 50 years old with primary gastrointestinal cancer were compared to 261,620 matched controls without gastrointestinal cancer in 2 case-control studies
    • 39,141 patients had colorectal cancer and were compared to 183,065 controls
    • approximately 5% of cases and controls in each study had ≥ 1 prescription for bisphosphonates including alendronate, etidronate, ibandronate, and risedronate
    • minimum duration of bisphosphonate prescription was 1 week and > 50% of 14,489 bisphosphonate users had prescriptions for ≥ 20 months
    • bisphosphonate use associated with nonsignificant increased risk of colorectal cancer (adjusted odds ratio 1.07, 95% CI 1-1.14) in analysis of both studies
    • Reference - BMJ 2013 Jan 16;346:f114 full-text, commentary can be found in BMJ 2013 Mar 12;346:f1514
  • organ transplant associated with increased risk of colorectal cancer in cohort study with 175,732 patients with solid organ transplants (JAMA 2011 Nov 2;306(17):1891EBSCOhost Full Text full-text), commentary can be found in JAMA 2012 Feb 15;307(7):663EBSCOhost Full Text
• lifestyle factors
  • tea consumption > 4 cups/day might be associated with increased risk of colon cancer
    • based on pooled analysis of cohort studies
    • pooled analysis of 13 cohort studies evaluating association between risk of colon cancer and coffee, tea, and sugar-sweetened soft drink intake in 731,441 patients
    • 5,604 cases of colon cancer identified
    • compared to nonconsumption
      • consumption of tea > 900 g/day (about four 8-fluid ounce cups) associated with increased risk of colon cancer (adjusted relative risk 1.28, 95% CI 1.02-1.61)
      • no significant differences in risk of colon cancer with coffee consumption > 1,400 g/day (about six 8-fluid ounce cups) or sugar-sweetened soft drink consumption > 550 g/day (about 18 fluid ounces)
    • Reference - J Natl Cancer Inst 2010 Jun 2;102(11):771 full-text, editorial can be found in J Natl Cancer Inst 2010 Jun 2;102(11):749
  • coffee drinking might be associated with increased risk of colorectal cancer in postmenopausal women
    • based on cohort study
    • 83,778 postmenopausal women aged 50-79 years from Women's Health Initiative study were evaluated for relationship between coffee intake and risk of colorectal cancer
    • mean follow-up 12.9 years
    • 1,282 patients developed colorectal cancer
    • compared to coffee nondrinkers
      • moderate coffee drinking (between > 0 cups/day and < 4 cups/day) associated with increased risk of colorectal cancer (adjusted hazard ratio [HR] 1.15, 95% CI 1.02-1.29)
      • high coffee drinking (≥ 4 cups/day) associated with nonsignificantly increased risk of colorectal cancer (adjusted HR 1.14, 95% CI 0.93-1.38)
      • in analysis stratified by colorectal cancer subsites
        • moderate coffee drinking associated with nonsignificantly increased risk of colon cancer (adjusted HR 1.11, 95% CI 0.98-1.27)
        • high coffee drinking associated with nonsignificantly increased risk of colon cancer (adjusted HR 1.17, 95% CI 0.94-1.44)
        • no significant differences in risk of colon, rectal, or rectosigmoid cancer with high or moderate coffee drinking
    • Reference - J Canc Eidemiol 2016;2016:6918431 full-text
  • high intake of dairy products in childhood associated with increased risk of colorectal cancer in cohort study with 4,383 children (Am J Clin Nutr 2007 Dec;86(6):1722EBSCOhost Full Text)
  • suboptimal vitamin D levels may be associated with increased risk of colorectal cancer
    • lower serum 25-hydroxyvitamin D level (25[OH]D) may be associated with increased risk of colorectal cancer
      • based on systematic review of observational studies
      • systematic review evaluating relationship between (25[OH]D) and risk of colorectal cancer and type 2 diabetes mellitus
      • 24 studies evaluated risk of colorectal cancer and 28 studies evaluated risk of type 2 diabetes
      • patients with inflammatory bowel disease excluded in analysis of risk of colorectal cancer
      • comparing highest category to lowest category of serum 25(OH)D, highest category of serum 25(OH)D associated with reduced risk of colorectal cancer (relative risk [RR] 0.62, 95% CI 0.56-0.7) in analysis of 17 studies
      • comparing serum 25(OH)D level at about 20-30 ng/mL to lowest category of 25(OH)D, level at about 20-30 ng/mL associated with reduced risk of colorectal cancer (RR 0.83, 95% CI 0.76-0.9) in analysis of 23 studies, results limited by significant heterogeneity
      • Reference - Int J Environ Res Public Health 2017 Jan 28;14(2)EBSCOhost Full Text full-text
  • low-folate intake or low-serum folate levels
    • dietary folate ≤ 103 mcg/day may be associated with increased risk of colon cancer in adult men
      • based on cohort study
      • 10,011 adults (mean age 53 years in men and 48 years in women, 61% female) from National Health and Nutrition Examination Survey (NHANES) I epidemiologic follow-up study (NHEFS) were evaluated for association between dietary folate levels and risk of colon cancer with 20-year follow-up
      • compared to dietary folate level ≤ 103.3 mcg/day
        • folate > 249 mcg/day associated with decreased risk of colon cancer in men (adjusted relative risk 0.4, 95% CI 0.18-0.88)
        • no significant difference in risk of colon cancer in women
      • Reference - Ann Epidemiol 2001 Jan;11(1):65
    • folate deficiency might be associated with increased colorectal cancer risk in men
      • based on nested case-control study
      • 202 colorectal cancer cases aged 40-84 years were compared to 326 matched controls during 12-year follow-up from Physicians' Health study
      • compared to adequate folate levels, plasma folate levels < 3 mcg/L associated with nonsignificantly increased risk of colorectal cancer (odds ratio 1.78, 95% CI 0.93-3.42) in men
      • Reference - Cancer Res 1997 Mar 15;57(6):1098
    • hyperhomocysteinemia plus folate deficiency may be associated with increased risk for colorectal neoplasia in adults with inflammatory bowel disease
      • based on cohort study
      • 114 adults (mean age 43 years) with inflammatory bowel disease (41 with ulcerative colitis, 73 with Crohn disease) were evaluated for association between folate and homocysteine levels and risk of colorectal neoplasia
      • exclusion criteria included primitive sclerosing cholangitis, and personal or first-degree family history of colorectal cancer or adenomatous polyps
      • 8 patients had colorectal cancer
      • factors associated with dysplasia-associated lesion or masses, or colorectal cancer in univariate analysis
        • red blood cell folate level < 93 mcg/L (210 nmol/L) (p = 0.02)
        • active smoking (p = 0.03)
        • hyperhomocysteinemia (homocysteine level > 15 mcmol/L) (p = 0.003)
        • duration of disease > 10 years (p = 0.006)
        • ulcerative colitis (p = 0.02)
      • in multivariate analysis, increased risk of dysplasia-associated lesion or masses, or colorectal cancer associated
        • with hyperhomocysteinemia with folate deficiency (adjusted odds ratio 16.9, 95% CI 2.3-126.7)
        • nonsignificantly with hyperhomocysteinemia without folate deficiency (adjusted odds ratio 2.5, 95% CI 0.8-18.3)
      • Reference - Inflamm Bowel Dis 2008 Feb;14(2):242
  • lower grip strength associated with increased all cancer-related mortality and colorectal cancer-related mortality
    • based on prospective population-based cohort study
    • 502,293 adults aged 40-69 years in 2007-2010 in United Kingdom were evaluated
    • overall, 2.7% died during mean follow-up 7.1 years
    • grip strength expressed in kg assessed using Jamar hydraulic hand dynamometer
    • mean baseline grip strength 21.7 kg (47.8 lbs) in persons in lowest quarter for strength and 39.6 kg (87.3 lbs) in persons in highest quarter for strength
    • each 5 kg (11.02 lbs) decrease in grip strength associated with increased
      • all cancer-related mortality
        • in women (adjusted hazard ratio [HR] 1.17, 95% CI 1.13-1.21)
        • in men (adjusted HR 1.1, 95% CI 1.07-1.13)
      • colorectal cancer-related mortality
        • in women (adjusted HR 1.17, 95% CI 1.04-1.32)
        • in men (adjusted HR 1.18, 95% CI 1.09-1.27)
    • consistent results for all-cause mortality
    • Reference - BMJ 2018 May 8;361:k1651 full-text

Factors not associated with increased risk

• genetic/familial factors
  • single nucleotide polymorphism rs266729 of ADIPOQ gene may be associated with decreased colorectal cancer risk in 2 case-control studies with 640 cases and 857 controls (JAMA 2008 Oct 1;300(13):1523EBSCOhost Full Text full-text)
• demographic factors
  • menarcheal age not associated with risk of colorectal cancer
    • based on systematic review of observational studies
    • systematic review of 11 cohort and 11 case-control studies evaluating association between menarcheal age and risk of colorectal cancer
    • comparing oldest to youngest categories of menarcheal age, no significant difference in relative risk of colorectal cancer in analysis of 22 studies, results limited by significant heterogeneity
    • similar results in sensitivity analyses evaluating cohort and case-control studies separately
    • Reference - PLoS One 2013;8(6):e65645EBSCOhost Full Text full-text
  • parity not associated with increased risk of colorectal cancer in women
    • based on systematic review of observational studies
    • systematic review of 11 observational studies evaluating parity and risk of colorectal cancer in 973,228 women
    • no significant difference in risk of colorectal cancer comparing
      • ever parity to nulliparity in analysis of 9 studies
      • highest to lowest parity number in analysis of 11 studies
    • Reference - PLoS One 2013;8(9):e75279EBSCOhost Full Text full-text
• medical history and medication or supplementation use
  • nonadvanced adenoma detected at first colonoscopy following positive flexible sigmoidoscopy screening may not be associated with increased 15-year risk of incident colorectal cancer compared to no adenoma (level 2 [mid-level] evidence)
    • based on cohort study
    • 16,162 adults (median age 64 years) having colonoscopy ≤ 1 year after positive flexible sigmoidoscopy screening in Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening trial were assessed
    • 217 patients with colorectal cancer on initial colonoscopy were excluded from analysis
    • on initial colonoscopy
      • 18.1% had advanced adenoma (any adenoma ≥ 1 cm, or with high-grade dysplasia, or villous or tubulovillous histology)
      • 31.8% had nonadvanced adenoma (< 1 cm without advanced histology)
      • 50.1% had no adenoma
    • median follow-up 13 years
    • 15-year incidence of colorectal cancer
      • 2.9% for advanced adenoma (p < 0.001 vs. no adenoma, p < 0.001 vs. nonadvanced adenoma)
      • 1.4% for nonadvanced adenoma (no significant vs. no adenoma)
      • 1.2% for no adenoma
    • 15-year mortality due to colorectal cancer
      • 0.45% for advanced adenoma (p = 0.01 vs. no adenoma)
      • 0.2% for nonadvanced adenoma (not significant vs. no adenoma)
      • 0.16% for no adenoma
    • Reference - JAMA 2018 May 15;319(19):2021EBSCOhost Full Text
  • HIV infection not associated with increased risk of colorectal cancer but might be associated with increased colorectal cancer-specific mortality in adults
    • based on systematic review of observational studies
    • systematic review of 27 retrospective cohort studies evaluating risk for and mortality of colorectal cancer in 1,696,070 adults with HIV infection compared to adults without HIV infection
    • 23 studies with 1,550,017 adults (colorectal cancer in 1,643 patients) and ≥ 7,359,993 person-years follow-up included in meta-analysis
    • comparing adults with HIV infection to adults without HIV infection
      • HIV infection associated with
        • decreased risk of colon cancer (standardized incidence ratio 0.63, 95% CI 0.52-0.75) in analysis of 4 studies
        • nonsignificantly increased colorectal cancer-specific mortality (standardized mortality ratio 2.09, 95% CI 1-4.4) in analysis of 3 studies, results limited by significant heterogeneity
      • no significant differences in risk of colorectal cancer overall, results limited by significant heterogeneity
    • Reference - J Acquir Immune Defic Syndr 2017 Aug 1;75(4):439 full-text
  • constipation does not appear associated with colorectal cancer in higher quality observational studies (level 2 [mid-level] evidence)
    • based on systematic review of observational studies
    • systematic review of 28 studies (8 cross-sectional studies, 3 cohort studies, and 17 case-control studies) evaluating constipation and colorectal cancer
    • comparing colonoscopy findings of 1,497 patients with primary indication of constipation vs. 7,369 patients with lower gastrointestinal symptoms (not constipation) as primary indication in analysis of 8 cross-sectional studies
      • colorectal cancer was found in 5.2% vs. 6.9% of patients
      • constipation associated with reduced likelihood of colorectal cancer (odds ratio 0.56, 95% CI 0.36-0.89); consistent results reported in analysis of 3 higher quality cross-sectional studies
    • comparing 46,068 patients with constipation at baseline vs. 142,970 patients without constipation at baseline in analysis of 3 prospective cohort studies
      • colorectal cancer developed in 302 patients (0.7%) vs. 1,209 patients (0.85%) during follow-up (range 6-12 years) (not significant), analysis limited by significant heterogeneity
      • consistent results in sensitivity analysis defining constipation as 1 stool evacuated every 3 days
    • Reference - Am J Gastroenterol 2013 Jun;108(6):894EBSCOhost Full Text, commentary can be found in Am J Gastroenterol 2013 Dec;108(12):1930EBSCOhost Full Text
  • history of breast cancer not associated with increased risk for colon cancer in cohort study of 227,165 women with first primary invasive breast cancer diagnosed in 1974-1995 from Surveillance Epidemiology and End Results (SEER) database (Lancet 2001 Mar 17;357(9259):837EBSCOhost Full Text), dissenting commentary can be found in Lancet 2001 Jun 23;357(9273):2057EBSCOhost Full Text
  • plasma enterodiol and enterolactone levels not associated with risk of colorectal cancer in adults in nested case-control study with 160 cases and 387 controls (Am J Epidemiol 2008 Mar 15;167(6):734)
  • vitamin D3 supplementation may not be associated with risk of colorectal cancer in elderly women
    • based on Cochrane review of trials with high dropout rates
    • systematic review of 18 randomized trials comparing vitamin D supplementation vs. placebo or no treatment in 50,623 adults (mean age 69 years, 81% female) and reporting cancer incidence
    • follow-up 0.5-7 years
    • vitamin D3 (cholecalciferol) evaluated in 14 trials, 1,25-dihydroxycholecalciferol (calcitriol) in 3 trials, and vitamin D2 (ergocalciferol) in 1 trial
    • most trials included older, community-dwelling women
    • no significant differences in colorectal cancer occurrence comparing vitamin D3 supplementation to placebo or no treatment in analysis of 5 trials with 45,598 adults
    • Reference - Cochrane Database Syst Rev 2014 Jun 23;(6):CD007469
    • DynaMed commentary -- short follow-up periods (0.5-7 years) may limit ability of intervention to affect carcinogenesis as well as ability of investigators to detect cancer
  • use of proton pump inhibitors (PPI) not associated with increased risk of colorectal cancer
    • based on systematic review of observational studies
    • systematic review of 4 case-control studies evaluating PPI use on the risk of colorectal cancer including about 100,000 persons
    • no significant association between PPI use and colorectal cancer risk in analysis of all studies, results limited by significant heterogeneity
    • Reference - J Clin Gastroenterol 2011 Feb;45(2):177
    • DynaMed commentary -- study published in letter to editor section and only gave approximation of number of persons
    • colorectal cancer risk from 2 case-control studies included in systematic review above
      • adjusted odds ratio (OR) for PPI use > 30 pills 1.11 (95% CI 0.97-1.27) in study with 5,589 cases of colorectal cancer compared to 55,890 controls (Gastroenterology 2007 Sep;133(3):755)
      • adjusted OR for PPI use ≥ 5 years 1.1 (95% CI 0.7-1.9) in study with 4,432 cases of colorectal cancer compared to 44,292 controls (Gastroenterology 2007 Sep;133(3):748)
  • statin use not associated with risk of colorectal cancer in cohort study with 423,558 persons (Am J Gastroenterol 2009 Dec;104(12):3015EBSCOhost Full Text), editorial can be found in Am J Gastroenterol 2009 Dec;104(12):3024EBSCOhost Full Text
• lifestyle factors
  • higher energy intake may be associated with decreased risk of colorectal cancer but an increased risk of gastric cancer
    • based on systematic review of observational studies
    • systematic review of 13 prospective cohort studies evaluating association between energy intake and risk of digestive cancers (colorectal, gastric, esophageal, and pancreatic cancers) in 995,577 persons with mean follow-up 11.1 years
    • 5,620 patients had digestive cancers
    • comparing highest to lowest energy intake, highest energy intake associated with
      • decreased risk of all digestive cancers (relative risk [RR] 0.9, 95% CI 0.81-0.98) in analysis of 11 studies
      • decreased risk of colorectal cancer (RR 0.9, 95% CI 0.81-0.99)
      • increased risk of gastric cancer (RR 1.19, 95% CI 1.08-1.31)
    • no significant differences in risk of esophageal and pancreatic cancers
    • each 239 kcal/day increase in energy intake associated with decreased risk of digestive cancers (RR 0.97, 95% CI 0.95-0.99) in analysis of 9 studies
    • Reference - World J Gastroenterol 2012 Dec 28;18(48):7362 full-text
  • total calcium and dairy food intake may be associated with decreased colorectal cancer risk in adult men
    • based on cohort study
    • 45,306 adult men aged 45-79 years were evaluated for association between food intake and risk of colorectal cancer and followed for mean 6.7 years
    • 449 men developed colorectal cancer
    • compared to lowest quartile, highest quartile of total calcium intake associated with decreased risk of colorectal cancer (adjusted relative risk [RR] 0.68, 95% CI 0.51-0.91)
    • compared to ≤ 2 servings/day, ≥ 7 servings/day of total dairy food intake associated with decreased risk of colorectal cancer (adjusted RR 0.46, 95% CI 0.3-0.71)
    • Reference - Am J Clin Nutr 2006 Mar;83(3):667EBSCOhost Full Text, editorial can be found in Am J Clin Nutr 2006 Mar;83(3):527EBSCOhost Full Text
  • dietary intake of calcium and vitamin D may not be associated with colorectal cancer risk in adult women in cohort study with 39,876 women from Women's Health Study (Am J Epidemiol 2005 Apr 15;161(8):755)
  • omega-3 fatty acid intake may not be associated with cancer incidence
    • based on systematic review of observational studies
    • systematic review of 38 prospective cohort studies evaluating relationship between omega-3 fatty acid and risk of 11 different types of cancer in > 700,000 persons with > 3 million person-years total follow-up
    • cancers evaluated included aerodigestive, bladder, breast, colorectal, lung, ovarian, pancreatic, prostate, skin (basal cell carcinoma), and stomach cancers and lymphoma
    • no meta-analysis performed
    • 65 estimates of association between omega-3 fatty acid consumption and cancer were reported, data not pooled due to heterogeneity
    • for colorectal cancer, 1 estimate was for decreased risk and 17 estimates did not find significant association
    • Reference - JAMA 2006 Jan 25;295(4):403EBSCOhost Full Text, correction can be found in JAMA 2006 Apr 26;295(16):1900, commentary can be found in JAMA 2006 Jul 19;296(3):282EBSCOhost Full Text
  • job strain not associated with risk of colorectal cancer
    • based on meta-analysis of individual patient data without systematic review
    • meta-analysis of individual patient data from 12 prospective cohort studies with 116,056 persons aged 17-70 years without cancer at baseline who were followed for median 12 years
    • 5,765 persons (5%) were diagnosed with incident cancer during follow-up including colorectal cancer in 0.5%, lung cancer in 0.3%, breast cancer in 0.9%, and prostate cancer in 0.7%
    • job strain (combination of high demands and low control at work) not associated with overall risk of cancer or colorectal cancer
    • Reference - BMJ 2013 Feb 7;346:f165 full-text
  • caffeine consumption
    • caffeine intake (from coffee or tea or total) not associated with risk of colorectal cancer in adults in pooled analysis of 2 cohort studies with almost 2 million person-years of follow-up (J Natl Cancer Inst 2005 Feb 16;97(4):282 full-text)
    • coffee consumption not associated with risk of colorectal cancer, colon cancer, or rectal cancer in pooled analysis of 2 cohort studies with 106,739 persons (Am J Epidemiol 2006 Apr 1;163(7):638)

Associated conditions

• prevalence of colorectal neoplasm may be elevated in patients with coronary artery disease (CAD)
  • based on cohort study
  • 621 patients had screening colonoscopy after coronary angiography for suspected CAD
    • 206 patients had CAD defined as stenosis > 50% in major coronary artery on angiography
    • 208 patients had suspected CAD with negative angiography
    • 207 patients were matched controls from general population
  • comparing CAD-positive patients vs. CAD-negative patients vs. general population controls
    • prevalence of colorectal neoplasm 34% vs. 18.8% vs. 20.8% (p < 0.001, pairwise comparisons not reported)
    • prevalence of advanced colorectal lesions 18.4% vs. 8.7% vs. 5.8% (p < 0.001, pairwise comparisons not reported)
    • prevalence of cancer 4.4% vs. 0.5% vs. 1.4% (p = 0.02, pairwise comparisons not reported)
  • Reference - JAMA 2007 Sep 26;298(12):1412EBSCOhost Full Text, commentary can be found in Nat Clin Pract Oncol 2008 May;5(5):248

• colorectal carcinoma present in 3.1% of patients with intraductal papillary mucinous neoplasms of pancreas in cohort study with 390 patients (Ann Oncol 2013 Jul;24(7):1907), commentary can be found in Ann Oncol 2013 Aug;24(8):2196
• rectal adenocarcinoma identified in 3 patients (14%) with polymyositis-dermatomyositis in retrospective cohort study of 21 adults aged 65-80 years (J Am Geriatr Soc 1998 Dec;46(12):1584)

Etiology and Pathogenesis

Causes

• accumulation of genetic and epigenetic alterations that activate oncogenes and deactivate tumor suppressor genes, leading to genomic and/or epigenomic instability⁽¹⁾
• current model suggests that genetic changes drive formation of tumor in context of tumor-promoting factors derived from adjacent tissues, which may help explain traditional "proximal" and "distal" colon cancer classification⁽¹⁾

Pathogenesis

• "classic" colorectal cancer formation model⁽¹⁾
  • genetic and environmental factors cause accumulation of genetic and epigenetic mutations, altering stem cell or stem cell-like cells in the base of colon crypts
  • these aberrant crypt foci may then progress to either
    • tubular or tubulovillous adenoma polyps (< 1 cm)
      • tubular or tubulovillous polyps may progress to advanced adenoma (> 1 cm, and/or villous histology) and then eventually to adenocarcinomas
      • only approximately 10% of these polyps progress to adenocarcinoma due to heterogeneous molecular biology in the polyps
      • progression likely driven by about 10-15 years accumulation of genetic and epigenetic mutations, but can be accelerated by chromosome instability (CIN) and microsatellite instability (MSI), such as those found in Lynch syndrome and other genetic syndromes
      • mutations may involve the following genes
        • adenomatous polyposis coli (APC)
        • NRAS/KRAS
        • SMAD family member 4 (SMAD4)
        • tumor protein p53 (TP53)
    • sessile serrated polyps (roughly 5%-10% of polyps), histologically and molecularly distinct from tubular adenomas
      • sessile serrated polyps divided into 3 categories: hyperplastic polyps, sessile serrated adenomas, and traditional serrated adenoma
      • hyperplastic polyps may progress to sessile serrated adenomas, which may then progress to adenocarcinoma
        • alterations in right colon include MSI and CpG Island Methylator Phenotype (CIMP)
        • alterations in left colon include MSI, KRAS mutations, and attenuated form of CIMP
        • other alterations include
          • catenin-beta1 (CTNNB1)
          • BRAF
          • phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit-alpha (PIK3CA)
          • transforming growth factor-beta receptor 2 (TGFBR2)
• mutations seem to cluster in epistatically related groups based in part on signaling pathways affected during carcinogenesis, such as⁽¹⁾
  • WNT signaling, which involves following genes
    • low-density lipoprotein receptor-related protein 5 (LRP5)
    • frizzled class receptor 10 (FZD10)
    • secreted frizzled-related protein (SFRP)
    • family with sequence similarity 123B (FAM123B) (also known as AMER1)
  • mitogen-activated protein kinase (MAPK) signaling, which involves following genes
    • KRAS
    • BRAF
    • NRAS
    • ERBB2
    • ERBB3
  • phosphatidylinositol 3-kinase PI3K signaling, which involves following genes
    • phosphatase and tensin homologue (PTEN)
    • PIK3CA
  • transforming growth factor-beta (TGF-beta) signaling, which involves TGFBR2
  • tp53 signaling
• due to molecular differences in polyps and cancers that may progress from them, the following has been proposed as method of molecular classification of colorectal cancer^(1, 4)
  • CMS1 (MSI immune): hypermutated, MSI, and strong immune activation
  • CMS2 (canonical): epithelial, chromosomally unstable, with marked Wnt and Myc signaling activation
  • CMS3 (metabolic): epithelia, with evident metabolic dysregulation
  • CMS4 (mesenchymal): prominent TGF-beta activation, stromal invasion, and angiogenesis

History and Physical

History

Chief concern (CC)

• primary symptoms include^(1, 6)
  • rectal bleeding without anal symptoms (soreness, discomfort, itching, lumps, or pain)
  • occult blood in stool
  • change in bowel habit to looseness or increased frequency
• other nonspecific symptoms may include^(1, 2)
  • fatigue
  • weight loss
  • generalized or localized abdominal pain
  • symptoms of iron deficiency and anemia, such as shortness of breath and pale appearance

History of present illness (HPI)

• findings reported more frequently during 2 years before diagnosis in 349 patients with colorectal cancer (compared to 1,744 controls) were
  • rectal bleeding
  • weight loss
  • abdominal pain
  • diarrhea
  • constipation
  • abdominal tenderness
  • Reference - Br J Cancer 2005 Aug 22;93(4):399EBSCOhost Full Text full-text
• systematic review of 32 studies (including case-control study above) evaluating clinical features associated with increased risk of colorectal cancer in primary care setting can be found in Can Fam Physician 2014 Aug;60(8):e405EBSCOhost Full Text full-text

Past medical history (PMH)

• ask about history of adenoma, colorectal cancer, and inflammatory bowel disease (Crohn disease, ulcerative colitis)^{(1, 2, 3, 4)}

Family history (FH)

• ask about family history of colorectal cancer, polyps, and other cancers⁽²⁾
• ask about family history of Lynch syndrome, familial adenomatous polyposis, MUTYH-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis syndrome, and serrated polyposis^(1, 3, 4)
• patient-reported family cancer histories for first-degree relatives are accurate for breast and colon cancer
  • based on systematic review of 14 studies comparing patient-reported family histories of cancer with review of relatives' medical records, death certificates, and cancer registries
  • patient-reported family history of colon cancer in first-degree relative had positive likelihood ratio 23 and negative likelihood ratio 0.25
  • Reference - JAMA 2004 Sep 22-29;292(12):1480EBSCOhost Full Text

Physical

Chest

• evaluate women for synchronous breast cancer⁽²⁾

Abdomen

• may present with⁽⁶⁾
  • abdominal mass
  • signs of intestinal obstruction, such as distention or pain
• assess for lymphadenopathy⁽²⁾
• assess for hepatomegaly and ascites⁽²⁾

Rectal

• may present with palpable rectal mass; perform digital rectal exam (ESMO Grade A, Level III) and palpation⁽⁵⁾
• abnormal rectal examination reported to be more frequent during 2 years before diagnosis in 349 colorectal cancer patients compared to 1,744 controls in case-control study (Br J Cancer 2005 Aug 22;93(4):399EBSCOhost Full Text full-text)

• about 10% of adults > 45 years old with new rectal bleeding have colorectal neoplasia
  • based on prospective cohort study
  • 265 adults > 45 years old who reported new rectal bleeding in rural general practice in United Kingdom over 10.25 years were evaluated with rigid sigmoidoscopy plus barium enema (most commonly), flexible sigmoidoscopy, or colonoscopy
  • 15 adults (5.7%) had colorectal cancer and 13 adults (4.9%) had colorectal adenoma, so 10.6% had colorectal neoplasia
  • 2 adults with cancer were < 55 years old, or 3.9% of 561 adults aged 45-54 years
  • Reference - BMJ 2006 Jul 8;333(7558):69 full-text, editorial can be found in BMJ 2006 Jul 8;333(7558):54, commentary can be found in BMJ 2006 Jul 22;333(7560):201

• < 10% of tumors are within reach of examiner's digit on digital rectal exam (Am Fam Physician 2000 Mar 15;61(6):1759EBSCOhost Full Text full-text), editorial can be found in Am Fam Physician 2000 Mar 15;61(6):1621EBSCOhost Full Text full-text

• presentation of colorectal cancer with prolapse or passage of tissue per rectum during vaginal delivery in case report of 3 patients (Obstet Gynecol 2008 Aug;112(2 Pt 2):488)

Performance status scales

• performance status evaluation to aid treatment decisions

  ECOG or WHO Performance Status Scale:

  Grade	Criteria
  0	Fully active, able to carry on all predisease performance without restriction
  1	Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature (such as light house work or office work)
  2	Ambulatory and capable of all self-care, but unable to carry out any work activities; up and about > 50% of waking hours
  3	Capable of only limited self-care, confined to bed or chair > 50% of waking hours
  4	Completely disabled; cannot carry on any self-care; totally confined to bed or chair
  5	Dead
  Abbreviations: ECOG, Eastern Cooperative Oncology Group; WHO, World Health Organization.Reference - Am J Clin Oncol 1982 Dec;5(6):649.

  Karnofsky Performance Status Scale:

  Definitions	Rating	Criteria
  Able to carry on normal activity; no special care needed	100%	Normal, no complaints, no evidence of disease
  	90%	Able to carry on normal activity; minor signs or symptoms of disease
  	80%	Normal activity with effort; some signs or symptoms of disease
  Unable to work; able to live at home and care for most personal needs; varying amount of assistance needed	70%	Cares for self; unable to carry on normal activity or to do active work
  	60%	Requires occasional assistance, but is able to care for most personal needs
  	50%	Requires considerable assistance and frequent medical care
  Unable to care for self; requires equivalent of institutional or hospital care; disease may be progressing rapidly	40%	Disabled; requires special care and assistance
  	30%	Severely disabled; hospital admission is indicated although death not imminent
  	20%	Very sick; hospital admission necessary; active supportive treatment necessary
  	10%	Moribund; fatal processes progressing rapidly
  	0%	Dead
  Reference - J Gerontol 1991 Jul;46(4):M139, Cancer 1994 Apr 15;73(8):2087.

Diagnosis and Staging

• assessment of colorectal cancer should be performed by multidisciplinary team of radiologists, surgeons, radiation oncologists, medical oncologists, and pathologists (ESMO Grade A, Level III for rectal cancer)
• initial testing to establish diagnosis typically includes
  • history and physical examination
  • digital rectal examination for rectal cancer
  • total colonoscopy (NCCN Category 2A; ESMO Grade A, Level III)
  • biopsy for histopathological confirmation (NCCN Category 2A)
• testing for staging typically includes
  • blood tests
    • complete blood count (CBC) (NCCN Category 2A; ESMO Grade A, Level III for rectal cancer)
    • chemistry profile (NCCN Category 2A), especially liver and renal function tests (ESMO Grade A, Level III for rectal cancer)
    • carcinoembryonic antigen (CEA) (NCCN Category 2A; ESMO Grade A, Level III for rectal cancer)
  • imaging studies
    • computed tomography (CT) to define functional status and presence of metastases
      • for rectal cancer, chest, abdominal, and/or pelvic CT (NCCN Category 2A; ESMO Grade A, Level III)
      • for colon cancer, recommendations differ between professional organizations
        • National Comprehensive Cancer Network (NCCN) recommends chest, abdominal, and/or pelvic CT (NCCN Category 2A)
        • European Society of Medical Oncology (ESMO) recommends
          • abdominal CT only (ESMO Grade B, Level V)
          • ESMO recommends against routine chest CT (ESMO Grade D, Level III)
    • magnetic resonance imaging (MRI)
      • to detect peritoneal or pelvic metastases (NCCN Category 2A) and liver metastases (ESMO Grade B, Level IV), in case of doubt in CT
      • in rectal cancer, contrast-enhanced MRI of pelvis
        • useful in locoregional clinical staging and preferred over endorectal ultrasound (NCCN Category 2A)
        • should be performed to guide preoperative treatment and define extent of surgery (NCCN Category 2A; ESMO Grade A, Level III)
    • endorectal ultrasound (ERUS) for early staging of rectal cancer (T1-T2 N0) (NCCN Category 2A)
    • virtual colonoscopy in rectal cancer to exclude synchronous colon tumors (ESMO Grade A, Level III) if total colonoscopy not performed preoperatively because of tumor obstruction
    • for hepatic metastases
      • initial diagnosis should be based on abdominal, pelvic, or chest CT (ESMO Grade B, Level IV)
      • MRI and contrast-enhanced ultrasound can be used in case of doubt in CT (ESMO Grade B, Level IV)
      • positron emission tomography (PET)/CT can be used to select suspected or proven metastatic synchronous adenocarcinoma potentially curable by surgery (NCCN Category 2A)
      • different imaging modalities should be performed stepwise based on need, instead of all at once (ESMO Grade B, Level V)
  • pathology review
  • tumor testing, including mutation testing for microsatellite instability (MSI) or DNA mismatch repair (MMR) to identify Lynch syndrome; also consider genetic testing based on age, personal medical history, and family history of colorectal cancer syndromes such as Lynch syndrome
• see Colorectal cancer diagnosis and staging for details

Management

Management of nonmetastatic colon cancer

• initial assessment
  • for polyp (pedunculated or sessile) with malignant invasion of submucosa, perform the following workup
    • review of pathology to confirm invasive cancer (pT1) (NCCN Category 2A)
    • colonoscopy (NCCN Category 2A), including marking of polyp site during colonoscopy or within 2 weeks of polypectomy (if deemed necessary by the surgeon) (NCCN Category 2A)
    • base management on findings from colonoscopy
  • for possibly resectable nonmetastatic colon cancer, perform following workup
    • review of pathology to confirm colon cancer appropriate for resection, pathologic stage, and lymph node evaluation (NCCN Category 2A)
    • colonoscopy (NCCN Category 2A)
    • complete blood count (CBC), chemistry profile, and carcinoembryonic antigen (CEA) measurement (NCCN Category 2A)
    • chest, abdominal, and/or pelvic computed tomography (CT) (NCCN Category 2A; ESMO Grade B, Level V for abdominal CT) with IV and oral contrast
      • if CT with IV contrast contraindicated or abdominal/pelvic CT inadequate, consider abdominal/pelvic magnetic resonance imaging (MRI) with contrast plus chest CT without contrast
      • European Society of Medical Oncology (ESMO) recommends against routine chest CT (ESMO Grade D, Level III)
  • positron emission tomography (PET)/CT not routinely indicated and only suggested in evaluation of equivocal contrast-enhanced CT finding or when IV contrast strongly contraindicated (NCCN Category 2A)
• initial surgical treatment
  • for initial treatment of malignant polyps
    • after endoscopic polypectomy
      • for single specimen that has been completely removed with favorable histology and clear margins
        • if pedunculated, surveillance (NCCN Category 2A; ESMO Grade B, Level IV for patients with minimal risk of adverse outcome only)
        • if sessile with invasive carcinoma (usually interpreted as having level 4 invasion), consider either
          • surveillance (NCCN Category 2A), with understanding that sessile polyp has greater incidence of adverse outcomes (residual disease, recurrence, mortality, and hematogenous but not lymph node metastasis) than polypoid malignant polyp
          • colectomy (NCCN Category 2A; ESMO Grade B, Level IV for patients with average operative risk) with en bloc removal of regional lymph nodes(NCCN Category 2A)
      • for fragmented specimen, if margin cannot be assessed, or if polyp has unfavorable histology
        • resection in patients with average operative risk and unfavorable histology (ESMO Grade B, Level IV)
        • consider colectomy with en bloc removal of regional lymph nodes (NCCN Category 2A)
      • for stage 0 (Tis, N0, M0) disease, consider segmentary en bloc resection for larger lesions not amenable to local excision
  • for initial treatment of possibly resectable nonmetastatic colon cancer
    • if tumor is nonobstructing
      • perform colectomy with en bloc removal of regional lymph nodes (NCCN Category 2A)
      • follow colectomy with adjuvant therapy as appropriate for pathologic stage (NCCN Category 2A)
    • if tumor is obstructing
      • consider any of following
        • 1-stage colectomy with en bloc removal of regional lymph nodes (NCCN Category 2A)
        • resection with diversion (NCCN Category 2A)
        • diversion (or stent in selected cases to allow decompression of proximal colon) followed by colectomy with en bloc removal of regional lymph nodes (NCCN Category 2A)
      • follow resection with adjuvant therapy as appropriate for pathologic stage (NCCN Category 2A)
    • if clinical T4b
      • consider neoadjuvant chemotherapy with FOLFOX or CAPEOX (NCCN Category 2A)
      • perform colectomy with en bloc removal of regional lymph nodes (NCCN Category 2A)
      • follow resection with adjuvant therapy as appropriate for pathologic stage (NCCN Category 2A)
    • if tumor is locally unresectable or medically inoperable, consider neoadjuvant therapy and evaluation for conversion to resectable disease, then consider following with surgery with or without intraoperative radiation therapy (IORT), if possible (NCCN Category 2A)
    • ESMO recommends initial treatment for stage I (T1-2, N0, M0) through stage III (any T, N1-2, M0) to be wide surgical resection and anastomosis
• adjuvant chemotherapy or chemoradiation therapy based on pathologic stage
  • optimal duration of adjuvant chemotherapy not established
  • for stage 0 (Tis, N0, M0) and stage I (T1-,2 N0, M0), or stage IIA (T3, N0, M0) with microsatellite instability-high (MSI-H) or defective mismatch repair (dMMR), no adjuvant chemotherapy recommended, perform surveillance (NCCN Category 2A)
  • for stage IIA (T3, N0, M0) with MSI-low (MSI-L) or microsatellite-stable (MSS) and no high-risk features, consider any of following
    • enrollment in clinical trial (NCCN Category 2A)
    • surveillance (NCCN Category 2A)
    • capecitabine or 5-fluorouracil (FU) plus leucovorin (NCCN Category 2A)
  • for stage IIA (T3, N0, M0) at high risk, or stage IIB/C (T4, N0, M0), consider any of following
    • adjuvant chemotherapy (ESMO Grade B, Level II), options include
      • capecitabine or FU plus leucovorin (NCCN Category 2A)
      • FOLFOX, CAPEOX, or FLOX (NCCN Category 2A)
    • enrollment in clinical trial (NCCN Category 2A)
    • surveillance (NCCN Category 2A)
  • for stage III (any T, N1-2, M0), consider any of following
    • FOLFOX or CAPEOX are preferred (NCCN Category 1) (preferred)
    • FLOX (NCCN Category 1)
    • capecitabine or FU plus leucovorin (NCCN Category 2A)
    • for T4 with penetration to fixed structure, consider adjuvant chemoradiation therapy (NCCN Category 2A)
• follow-up
  • intensive follow-up required for patients with colon cancer (ESMO Grade A, Level I)
  • for stage I disease, perform colonoscopy at 1 year (NCCN Category 2A)
    • if advanced adenoma (villous polyp, polyp > 1 cm, or high-grade dysplasia) detected, perform repeat colonoscopy in 1 year (NCCN Category 2A)
    • if no advanced adenoma, perform repeat colonoscopy in 3 years, then every 5 years (NCCN Category 2A)
  • for stage II-III or for general follow-up recommendations, perform
    • history, physical, and CEA level measurement every 3-6 months for 2-3 years (NCCN Category 2A for 2 years; ESMO Grade B, Level II for 3 years), then every 6-12 months (NCCN Category 2A; ESMO Grade B, Level II) for 5 years
    • chest/abdominal/pelvic CT with IV and oral contrast every 6-12 months for 3 years in patients at higher risk of recurrence (ESMO Grade B, Level II) or 5 years (NCCN Category 2A; NCCN Category 2B for frequency < 12 months); alternative options include
      • contrast enhanced ultrasound (ESMO Grade C, Level III)
      • abdominal/pelvic MRI with MRI contrast plus noncontrast chest CT if abdominal/pelvic CT not adequate or if CT IV contrast contraindicated (NCCN Category 2A)
    • colonoscopy at 1 year (if no preoperative colonoscopy due to obstruction, perform in 3-6 months) (NCCN Category 2A; ESMO Grade B, Level III)
      • if advanced adenoma, repeat in 1 year (NCCN Category 2A)
      • if no advanced adenoma, repeat in 3-5 years (ESMO Grade B, Level III), or repeat in 3 years, then every 5 years (NCCN Category 2A)
  • PET/CT not routinely suggested for follow-up (NCCN Category 2A)
  • if serial CEA elevation or documented recurrence, perform physical exam, colonoscopy, and chest/abdominal/pelvic CT with contrast (NCCN Category 2A)
    • if negative findings, consider PET/CT scan and reevaluate chest/abdominal/pelvic CT with contrast in 3 months (NCCN Category 2A) until CEA elevation is proven negative or affirmed positive
    • if positive findings, see Management of metastatic colorectal cancer
• see Management of nonmetastatic colon cancer for details

Management of nonmetastatic rectal cancer

• assessment for treatment planning
  • assessment should be done by multidisciplinary team, including team coordinator, radiologists, surgeons, radiation oncologists, medical oncologists, and pathologists (ESMO Grade A, Level III)
  • ask all patients diagnosed with rectal cancer about family history and consider assessment for Lynch Syndrome, familial adenomatous polyposis (FAP), and attenuated FAP (NCCN Category 2A)
  • referral to enterostomal therapist recommended for preoperative marking of ostomy site and patient teaching (NCCN Category 2A)
  • for polyp (pedunculated or sessile) with invasive cancer, perform following workup
    • review of pathology to confirm invasive cancer (pT1) (NCCN Category 2A)
    • colonoscopy (NCCN Category 2A), tattooing of polyp site during colonoscopy or within 2 weeks of polypectomy (if deemed necessary by surgeon) (NCCN Category 2A)
    • plan future management based on findings from colonoscopy
  • for possibly resectable nonmetastatic rectal cancer, perform following workup
    • complete history and physical examination
      • assess performance status to determine operative risk; for patients > 70 years old, perform geriatric assessment or screening for frailty (ESMO Grade C, Level III)
      • palpation (digital rectal exam) for evaluating distance of tumor from anal verge, and for assessing sphincter infiltration
    • biopsy for morphologic verification and review of pathology (NCCN Category 2A)
    • colonoscopy (NCCN Category 2A)
      • rigid rectoscopy and preoperative colonoscopy to terminal ileum required
      • if obstruction present and scope cannot pass the lesion, perform virtual colonoscopy to exclude synchronous colonic tumors
      • if virtual colonoscopy not done, perform completion colonoscopy within 6 months of surgery (ESMO Grade A, Level III)
    • complete blood count (CBC), chemistry profile, liver and renal function tests, and carcinoembryonic antigen (CEA) measurement (NCCN Category 2A; ESMO Grade A, Level III)
    • chest, abdominal, and/or pelvic computed tomography (CT) (NCCN Category 2A; ESMO Grade A, Level III)
      • including IV and oral contrast agent
      • if CT with IV contrast contraindicated, consider abdominal/pelvic magnetic resonance imaging (MRI) with contrast plus chest CT without contrast
    • pelvic MRI with contrast (preferred) and/or endorectal ultrasound (ERUS) (NCCN Category 2A)
      • pelvic MRI most accurate for defining locoregional clinical staging; perform to guide preoperative management and define extent of surgery (ESMO Grade A, Level III)
      • ERUS may be most useful for early cT stages but is less useful for locally advanced disease
• for initial treatment of malignant polyps
  • en bloc resection of polyps recommended for accurate assessment of depth of invasion in resection margin and deepest area (ESMO Grade B, Level II)
  • after endoscopic polypectomy
    • for single specimen that has been completely removed with favorable histology and clear margins (T1 only)
      • if pedunculated, consider surveillance (NCCN Category 2A)
      • if sessile, consider 1 of the following
        • surveillance (NCCN Category 2A), with understanding that sessile polyp has greater incidence of adverse outcomes (residual disease, recurrent disease, mortality, or hematogenous metastasis, but not lymph node metastasis) than polypoid malignant polyp
        • transanal excision, if appropriate (NCCN Category 2A)
        • transabdominal resection (NCCN Category 2A)
    • for fragmented specimen or margin that cannot be assessed or unfavorable histologic features, consider 1 of the following
      • transanal excision, if appropriate (NCCN Category 2A)
      • transabdominal resection (NCCN Category 2A)
    • for very early rectal cancer with low grade (if cT1 N0 submucosal invasion [sm] level 1)
      • local excision (transanal excision) using transanal endoscopic microsurgery (TEM) (ESMO Grade A, Level III)
      • after TEM, if unfavorable histologic features (sm level ≥ 2, grade 3, lymphovascular invasion level 1), perform TME
    • if high-risk histologic features, perform radical surgery and removal of lymph nodes(ESMO Grade A, Level II)
• primary therapy of nonmetastatic rectal cancer
  • for very early rectal cancer, for patients who are poor surgical candidates, consider local radiation therapy, either alone or combined with chemoradiation therapy, with brachytherapy or contact therapy using Papillon technique as an alternative to local surgery (ESMO Grade C, Level III)
  • for early rectal cancer not suitable for local excision, perform TME (ESMO Grade A, Level II)
  • if T1-2, N0 disease, or early disease (based on endorectal ultrasound or MRI), consider 1 of following and follow with adjuvant therapy as appropriate for pathological stage (NCCN Category 2A)
    • transanal excision (if appropriate) (NCCN Category 2A) with TEM if appropriate (after neoadjuvant radiation or chemoradiation therapy if indicated)
    • transabdominal resection (NCCN Category 2A) using TME (ESMO Grade A, Level II)
    • for early high rectal cancer, partial mesorectal excision with a distal margin of at least 5 cm of the mesorectum
  • if T3, N0, any T, N1-2, or T4, and/or locally unresectable or medically inoperable disease (including intermediate, bad, and advanced disease)
    • transabdominal resection (NCCN Category 2A) using TME (ESMO Grade A, Level III for TME) after neoadjuvant therapy with chemoradiation (NCCN Category 1 or NCCN Category 2Adepending on regimens; ESMO Grade A, Level I) or short-course radiation therapy (SCPRT) (NCCN Category 2A; ESMO Grade A, Level I), and follow with adjuvant therapy as appropriate for pathological stage
      • for intermediate disease, if good-quality TME cannot be assured, neoadjuvant therapy is indicated
      • for intermediate, bad, and advanced disease, perform MRI after neoadjuvant therapy to reevaluate the tumor before performing TME (ESMO Grade A, Level I for advanced disease)
    • transabdominal resection after neoadjuvant chemotherapy and primary chemoradiation therapy (NCCN Category 2A), chemoradiation therapy options include
      • capecitabine plus radiation therapy (preferred) (NCCN Category 2A)
      • infusional 5-fluoruracil (FU) plus radiation therapy (preferred) (NCCN Category 2A)
      • bolus FU plus leucovorin plus radiation therapy (NCCN Category 2A)
      • see Management of metastatic colorectal cancer for details
• adjuvant therapy
  • offer adjuvant chemoradiation therapy selectively in patients with high risk of local recurrence if neoadjuvant radiation therapy has not been given, or those with unexpected adverse histopathological features discovered after primary surgery (ESMO Grade A, Level I)
  • consider adjuvant chemotherapy in rectal cancer patients with pathological stage III and high-risk pathological stage II after preoperative chemoradiation therapy or radiation therapy, but evidence suggests more benefit for disease-free survival than overall survival (ESMO Grade C, Level II)
  • adjuvant therapy after transanal excision, based on findings from pathology review (to total 6 months of perioperative therapy)
    • if pT1, NX with high-risk features (positive margins, lymphovascular invasion, poor differentiation, or submucosal 3 invasion), or if pT2, NX, consider 1 of following adjuvant treatments
      • additional surgery with transabdominal resection (NCCN Category 2A) followed by
        • if pT1-2, N0, M0 after surgery, surveillance (NCCN Category 2A)
        • if pT3-T4, N0, M0 or pT1-T4, N1-2 after surgery, 1 of following
          • adjuvant chemotherapy, followed by chemoradiation, and then chemotherapy (NCCN Category 2A)
          • adjuvant chemoradiation, followed by chemotherapy (NCCN Category 2A)
      • chemoradiation (NCCN Category 2A) plus 1 of following treatments
        • if complete response, no therapy but surveillance as appropriate for stage (NCCN Category 2A)
        • additional surgery with transabdominal resection, followed by chemotherapy (NCCN Category 2A)
        • adjuvant chemotherapy (NCCN Category 2A)
  • adjuvant therapy for patients after transabdominal resection, based on findings from pathology review (to total 6 months of perioperative therapy)
    • if pT1-T2, N0, M0, perform surveillance (NCCN Category 2A)
    • if pT3-T4, N0, M0, and no neoadjuvant chemotherapy, consider 1 of following
      • no therapy but surveillance (NCCN Category 2A)
      • adjuvant chemotherapy alone (NCCN Category 2A)
      • adjuvant chemotherapy, followed by chemoradiation, and then chemotherapy (NCCN Category 2A)
      • adjuvant chemoradiation, followed by chemotherapy (NCCN Category 2A)
    • if pT1-T4, N1-2, consider 1 of following
      • adjuvant chemotherapy, followed by chemoradiation, and then chemotherapy (NCCN Category 2A)
      • chemoradiation, followed by chemotherapy (NCCN Category 2A)
  • for locally unresectable or medically inoperable disease, after neoadjuvant therapy and primary treatment with chemoradiation therapy, consider adjuvant transabdominal resection (NCCN Category 2A)
• surveillance
  • perform clinical exam including history, physical, and imaging every 3-6 months for 2 years (NCCN Category 2A; ESMO Grade D, Level V), then every 6 months for 5 years total (NCCN Category 2A)
    • perform completion colonoscopy within 1 year of treatment (if complete colonoscopy not performed at time of workup) (NCCN Category 2A in 3-6 months; ESMO Grade A, Level I within first year)
      • if advanced adenoma (villous polyp, polyp > 1 cm, or high-grade dysplasia) on follow-up colonoscopy, repeat in 1 year (NCCN Category 2A)
      • if no advanced adenoma, repeat in 3 years, then every 5 years (NCCN Category 2A)
      • resect colonic polyps detected on colonoscopy every 5 years until age 75 years (ESMO Grade B, Level I)
    • perform chest/abdominal/pelvic CT every 6-12 months for up to 5 years (NCCN Category 2B for frequency < 12 months; otherwise, NCCN Category 2A ; ESMO Grade B, Level V for ≥ 2 CTs in first 3 years)
    • if no pelvic CT performed, then perform pelvic MRI
    • positron emission tomography (PET)/CT not routinely recommended (NCCN Category 2A), but may be helpful in defining other unrecognized sites in recurrent disease
    • if treated with transanal excision (otherwise not recommended), perform proctoscopy with endoscopic ultrasound or MRI every 3-6 months for 2 years, then every 6 months for 5 years total (NCCN Category 2A)
  • CEA monitoring
    • National Comprehensive Cancer Network (NCCN) recommends for stage III disease (or stage II if patients are potential candidate for aggressive definitive surgery), CEA level measurement every 3-6 months for 2 years, then every 6 months for 5 years total (NCCN Category 2A)
    • European Society for Medical Oncology (ESMO) recommends for patients with average risk, perform CEA level measurement at least every 6 months in first 3 years
  • patients with positive circumferential margins (CRM) may require more proactive surveillance for local recurrence
  • in patients who have received pelvic radiation therapy, monitor for late effects and refer appropriate patients to survivorship clinics
• management of local recurrence
  • if potentially resectable recurrence, consider 1 of the following
    • salvage resection followed by adjuvant chemoradiation (NCCN Category 2A)
    • if radiation therapy not used as initial treatment, neoadjuvant chemoradiation (NCCN Category 2A; ESMO Grade A, Level III) followed by resection (NCCN Category 2A, with intraoperative radiation therapy or brachytherapy if it can be safely delivered)
    • if radiation therapy used previously, reirradiation to lower doses with concurrent chemotherapy (ESMO Grade C, Level IV) followed by resection
    • SCPRT followed by chemotherapy containing fluoropyrimidine or oxaliplatin, and then salvage resection by a specialist team
  • if unresectable recurrence, consider the following palliative options
    • chemotherapy (ESMO Grade C, Level IV) with or without concurrent radiation therapy (ESMO Grade C, Level V) depending on tolerability of patients (NCCN Category 2A)
    • brachytherapy
    • palliative surgical diversion procedures in select patients with reasonable life expectancy
    • appropriate pain management
  • debulking that leads to gross residual cancer (R2 resection) not recommended (NCCN Category 2A)
  • pelvic recurrence reported to cause severe pain and often require opiate and non-opiate pain medications with mucinous discharge and incontinence
• see Management of nonmetastatic rectal cancer for details

Management of metastatic colorectal cancer

• for management of synchronous metastatic disease
  • colon cancer
    • if resectable synchronous liver and/or lung metastases only
      • consider any of
        • synchronous or staged colectomy with surgical resection of liver or lung (preferred) and/or local ablative procedures (NCCN Category 2A), followed by adjuvant chemotherapy
        • neoadjuvant chemotherapy (2- to 3-month course) prior to synchronous or staged colectomy with surgical resection of liver or lung, followed by adjuvant chemotherapy (NCCN Category 2A)
        • colectomy, followed by 2-3 months of chemotherapy as described above, then staged resection of metastatic disease, followed by adjuvant chemotherapy (NCCN Category 2A)
      • hepatic artery infusion with floxuridine (FUDR) with or without 5-fluorouracil (FU) plus leucovorin (NCCN Category 2B) is an optional procedure during liver resection at institutions with experience in both surgical and medical oncology
      • perioperative chemotherapy should not exceed 6 months
    • if unresectable synchronous liver and/or lung metastases⁽³⁾
      • primary treatment
        • systemic chemotherapy with or without targeted therapy (NCCN Category 2A); options include
          • any of FOLFOX, FOLFIRI, or CAPEOX, with or without bevacizumab
          • either FOLFIRI or FOLFOX, with or without panitumumab or cetuximab in patients with wild-type KRAS/NRAS and left-sided tumors
          • FOLFOXIRI with or without bevacizumab
        • consider palliative surgical resection if imminent risk of obstruction, bleeding, perforation, or other significant tumor-related symptoms (NCCN Category 2A)
      • reevaluate patient for conversion to resectable disease every 2 months, if conversion is a reasonable goal (NCCN Category 2A)
      • adjuvant treatment following reevaluation
        • if disease converted to resectable, synchronized, or staged resection of colon cancer and metastases (NCCN Category 2A), followed by either
          • systemic chemotherapy (NCCN Category 2A), with or without targeted therapy (NCCN Category 2B for targeted therapy)
          • observation or shortened chemotherapy course (≤ 6 months total of perioperative therapy preferred) (NCCN Category 2A)
        • if disease remains unresectable, consider systemic chemotherapy (NCCN Category 2A)
    • if synchronous abdominal or peritoneal metastases
      • if nonobstructing, consider systemic chemotherapy (NCCN Category 2A)
      • if colon is obstructed or obstruction is imminent, consider any of colon resection, diverting ostomy, bypass of impending obstruction, or stenting, followed by systemic chemotherapy(NCCN Category 2A)
      • consider complete cytoreductive surgery and/or hyperthermic intraperitoneal chemotherapy (HIPEC) in experienced high-volume centers in selected patients with limited peritoneal metastases having potential of R0 resection (ESMO Grade B, Level III)
  • rectal cancer
    • if resectable synchronous metastases
      • neoadjuvant treatment options include any of (NCCN Category 2A)
        • chemotherapy (2-3 months)
        • chemoradiation
        • short-course radiation therapy (not recommended for T4 tumors)
      • primary treatment
        • after neoadjuvant chemotherapy, options include
          • staged or synchronous resection (preferred), and/or local ablative procedures for metastases and resection of rectal lesion and follow with adjuvant chemoradiation (NCCN Category 2A)
          • chemoradiation or short-course radiation therapy (not recommended for T4 tumors) (NCCN Category 2A) and follow with
            • staged or synchronous resection (preferred), and/or local ablative procedures for metastases and resection of rectal lesion (NCCN Category 2A)
            • optional adjuvant chemotherapy using same regimen as neoadjuvant chemotherapy (6 months of perioperative therapy preferred) (NCCN Category 2A)
        • after neoadjuvant chemoradiation or short-course radiation therapy, consider primary therapy with staged or synchronous resection (preferred), and/or local ablative procedures for metastases and resection of rectal lesion and follow with adjuvant chemotherapy (NCCN Category 2A)
      • perioperative chemotherapy should not exceed 6 months
    • if unresectable (or medically inoperable) synchronous metastases
      • if patient is symptomatic
        • for initial treatment, consider primary treatment with any of (NCCN Category 2A)
          • combination systemic chemotherapy
          • chemoradiation with radiation therapy plus any of infusional IV FU, capecitabine, or bolus FU (if capecitabine or infusional IV FU not tolerable)
          • resection of involved rectal segment
          • diverting ostomy
          • stenting
          • short-course radiation therapy (not recommended for T4 primary tumors)
        • for subsequent treatment, consider systemic chemotherapy (NCCN Category 2A)
      • if patient is asymptomatic, consider systemic chemotherapy (NCCN Category 2A)
• for management of metachronous metastases
  • if resectable metachronous metastases, options include
    • surgical resection (preferred over local ablative procedures) and/or local ablative procedures as primary therapy, followed by
      • adjuvant chemotherapy (6 months perioperative treatment preferred) in patients with no previous chemotherapy (NCCN Category 2A)
      • observation (preferable for patient who previously received oxaliplatin-based therapy) (NCCN Category 2A) or systemic chemotherapy (NCCN Category 2A) with or without targeted therapy (NCCN Category 2B for targeted therapy) in patients who have received prior chemotherapy
    • neoadjuvant chemotherapy (2- to 3-month course) followed by surgical resection (preferred over local ablative procedures) and/or local ablative procedures (NCCN Category 2A) and follow with
      • if no tumor growth during neoadjuvant chemotherapy, consider any of (NCCN Category 2A)
        • restarting neoadjuvant chemotherapy
        • initiating FOLFOX therapy
        • observation
      • if tumor growth during neoadjuvant chemotherapy, consider either of
        • systemic chemotherapy (NCCN Category 2A) with or without targeted therapy (NCCN Category 2B for targeted therapy)
        • observation (NCCN Category 2A)
    • FUDR with or without FU plus leucovorin (NCCN Category 2B) is an optional procedure during liver resection at institutions with experience in both surgical and medical oncology
  • if unresectable metachronous metastases
    • primary treatment
      • in patients who received adjuvant FOLFOX/CAPEOX ≤ 12 months prior, consider chemotherapy and/or targeted therapy (NCCN Category 2A); options include
        • FOLFIRI with or without any of bevacizumab (preferred), ziv-aflibercept, or ramucirumab (NCCN Category 2A)
        • irinotecan with or without any of bevacizumab (preferred), ziv-aflibercept, or ramucirumab (NCCN Category 2A)
        • FOLFIRI plus either cetuximab or panitumumab (wild-type KRAS/NRAS only; response unlikely with BRAF V600E mutation) (NCCN Category 2A)
        • irinotecan plus either cetuximab or panitumumab (wild-type KRAS/NRAS only; response unlikely with BRAF V600E mutation) (NCCN Category 2A)
        • nivolumab or pembrolizumab (deficient mismatch repair [dMMR] or microsatellite instability high [MSI-H] only) (NCCN Category 2A)
      • in patients who received adjuvant FOLFOX/CAPEOX > 12 months prior, FU/leucovorin, capecitabine, or without prior chemotherapy, systemic chemotherapy (NCCN Category 2A)
    • reevaluate patient every 2 months for conversion to resectability if conversion is a reasonable goal (NCCN Category 2A)
      • if metastases become resectable, surgical resection (NCCN Category 2A), followed by adjuvant therapy, including either of
        • systemic chemotherapy (NCCN Category 2A) with or without targeted therapy (NCCN Category 2B for targeted therapy) (6 months of perioperative therapy preferred)
        • observation (NCCN Category 2A)
      • if metastases remain unresectable, systemic chemotherapy (NCCN Category 2A)
• for management of oligometastatic disease
  • systemic chemotherapy is standard of care as initial part of any treatment approach
  • evaluate response to systemic chemotherapy at 6-8 weeks with multidisciplinary team to determine the best treatment strategies depending on localization, therapy goal, and therapy-related morbidity and patient-related factors (ESMO Grade B, Level IV); options include
    • surgery
    • local ablative procedures
  • after surgery or local ablative procedures, consider reintroduction of systemic chemotherapy, but total duration should be ≤ 6 months
  • ablative therapy to eradicate all visible metastatic lesions with noncurative intent should be evaluated and pursued further in suitable patients despite lack of high-quality evidence (ESMO Grade B, Level II)
• specific considerations for limited liver and/or lung metastases
  • for initially resectable disease
    • if technically resectable liver metastasis, primary goal is definitive R0 resection
    • use of perioperative chemotherapy depends on resectability and prognostic criteria
      • if clearly resectable and favorable prognostic criteria, consider resection with or without perioperative chemotherapy (ESMO Grade C, Level I)
      • if technically resectable but unclear or probably unfavorable prognostic criteria
        • consider resection plus perioperative chemotherapy (ESMO Grade B, Level I)
        • addition of targeted therapy not suggested (ESMO Grade E, Level II)
      • if technically resectable and ≥ 1 unfavorable prognostic criteria, consider neoadjuvant chemotherapy prior to resection (ESMO Level V)
      • if resectability and prognostic criteria not clearly defined, including patients with synchronous metastases, consider resection plus perioperative chemotherapy (ESMO Grade B, Level IV)
    • consider adjuvant chemotherapy in patients who have not previously received chemotherapy for metastatic disease regardless of resectability and prognostic criteria (ESMO Level V)
      • but no strong evidence to support use of adjuvant chemotherapy in patients with clearly resectable and favorable prognostic criteria (ESMO Grade C, Level II)
      • adjuvant chemotherapy may be beneficial in patients with technically resectable disease with unclear or probably unfavorable prognostic criteria, or with ≥ 1 unfavorable prognostic criteria (ESMO Grade B, Level III)
    • decision-making should include characteristics and preferences of patients (ESMO Grade B, Level IV)
  • for initially unresectable disease
    • for patients able to withstand intensive therapy
      • if conversion to resectable disease possible
        • cytoreduction is goal, and conversion therapy regimen leading to high response rate and/or large tumor reduction recommended (ESMO Grade A, Level II)
          • if wild-type RAS, options include (ESMO Grade A, Level II for all options)
            • doublet chemotherapy plus anti-epidermal growth factor receptor (anti-EGFR) antibody recommended (preferred)
            • FOLFOXIRI plus bevacizumab may be considered (second choice)
            • doublet chemotherapy plus bevacizumab may be considered (third choice)
          • if mutated RAS, bevacizumab plus either doublet chemotherapy or FOLFOXIRI recommended (ESMO Grade A, Level II)
        • reevaluation of response every 2 months
          • if evidence of tumor shrinkage at first reevaluation
            • definitive R0 resection and/or local ablation techniques recommended to achieve no evidence of disease (NED)
            • if surgery and/or local ablation techniques not suitable, consider continuing first-line therapy (conversion therapy) with appropriate targeted agents depending on RAS and BRAF mutation status
          • if no evidence of tumor shrinkage at first reevaluation, changing of cytotoxic doublet chemotherapy suggested to maximize chance of resection
          • if disease progression, change to with second-line therapy
          • consider alternative chemotherapy regimens for toxicity concerns
      • if aggressive biology (impending clinical threat or organ dysfunction) and/or risk of developing or existing severe symptoms, even though conversion to resectable disease not possible
        • consider intensive management with cytoreduction as goal
        • reevaluation of response every 2 months
        • management should not be changed without tumor progression or major toxicity
      • if conversion to resectable disease not possible
        • consider intensive management with disease control as goal
        • reevaluation of response every 2-3 months
          • if good response or disease control, consider maintenance therapy with fluoropyrimidine plus bevacizumab as preferred option
          • if disease progression or toxicity, change to second-line therapy
    • for patients who may be unfit or are unfit for intensive therapy and who have unresectable disease that is impossible to convert to resectable disease
      • for patients who may be unfit, consider palliative first-line and maintenance therapy
      • for patients who are unfit, offer best support palliative care
      • see Systemic chemotherapy for metastatic colorectal cancer for additional information
• see Management of metastatic colorectal cancer for details

Management of malignant large bowel obstruction

• no enteral feeding if complete obstruction
• hydration > 1,000 mL/day might be associated with less nausea (level 2 [mid-level] evidence)
• medications to relieve symptoms
  • octreotide (Sandostatin) 0.2-0.9 mg/day by continuous subcutaneous infusion appears more effective than hyoscine butylbromide for relieving gastrointestinal (GI) symptoms in malignant bowel obstruction (level 2 [mid-level] evidence)
  • steroids might reduce symptoms but evidence inconclusive (level 2 [mid-level] evidence)
  • anticholinergic agents and/or antiemetics may also be helpful (level 3 [lacking direct] evidence)
• surgery
  • primary resection and anastomosis is preferred option for uncomplicated malignant left-sided bowel obstruction
  • no conclusive evidence favoring any individual surgical strategy over another for acute malignant left-sided colonic obstruction due to colorectal cancer (level 2 [mid-level] evidence)
  • enhanced recovery pathways associated with reduced hospital stay and 30-day morbidity following colorectal surgery (level 2 [mid-level] evidence)
• self-expanding metallic stents may be palliative or used as bridge to surgery
  • may be effective in overcoming left-sided malignant colorectal obstructions (level 2 [mid-level] evidence)
  • stenting may be associated with lower short-term morbidity and mortality than open surgery (level 2 [mid-level] evidence)
• decompression may be appropriate for inoperable obstruction
  • nasogastric tube decompression may be temporary measure
  • gastrostomy may allow longer decompression
  • decompression via colorectal tube reported to be effective for acute malignant colorectal obstruction (level 3 [lacking direct] evidence)
• endoscopic laser ablative therapy reported to be effective for palliation of symptoms (level 3 [lacking direct] evidence)
• see Malignant large bowel obstruction for details

Complications and Prognosis

Complications

• complications from untreated colorectal cancer may include
  • malignant large bowel obstruction
  • malnutrition (Nutr Hosp 2013 Mar-Apr;28(2):412EBSCOhost Full Text)
  • gastrointestinal bleeding⁽⁶⁾
  • bowel perforation⁽²⁾
  • 14 cases of needle tract colorectal metastases reported following fine needle aspiration biopsy of liver metastases (BMJ 2004 Feb 28;328(7438):507 full-text), commentary can be found in BMJ 2004 Jul 31;329(7460):290, BMJ 2004 Oct 30;329(7473):1045
  • colorectal cancer treatment associated with erectile dysfunction in case series of 28 patients (BMJ 2011 Oct 18;343:d5824 full-text), editorial can be found in BMJ 2011 Oct 18;343:d6366
• complications of metastatic colorectal cancer⁽¹⁾
  • cachexia
  • loss of appetite
  • anemia
  • liver failure
  • biliary obstruction
  • impaired pulmonary function
• complications of treatment for colorectal cancer may include^(1, 4)
  • complications of surgery
    • leakage of anastomosis at suture-line of intestinal loops after tumor removal
    • wound dehiscence
    • abdominal scar herniation
  • complications of chemotherapy
    • diarrhea
    • neutropenia
  • complications of targeted therapy
    • papulopustular rash
    • paronychia
    • skin atrophy
    • alopecia
    • bleeding
    • arterial thromboembolic events
    • impaired wound healing
    • hypertension
    • proteinuria
  • complications of treatment of rectal cancer
    • fecal incontinence
    • increased number of stools
    • erectile dysfunction in men
    • dyspareunia in women
    • from radiation therapy
      • vaginal stenosis in women
      • infertility risks in both men and women
      • pelvic floor problems
      • testicular failure following neoadjuvant radiation therapy in prospective cohort study of 168 adults with stage I-III rectal cancer or prostate cancer (Ann Surg 2018 Feb;267(2):326)
• cardiovascular complications
  • older patients with colorectal cancer appear to be at increased risk of developing cardiovascular disease or heart failure
    • based on cohort study
    • 72,408 patients > 65 years old with incident stage I-III colorectal cancer and 72,408 matched controls without cancer were followed for median 8 years
    • median age at diagnosis of colorectal cancer was 78 years
    • 10-year cumulative incidence comparing patients with colorectal cancer vs. controls
      • 57.4% vs. 22% (p < 0.001) for new-onset cardiovascular disease including stroke and myocardial infarction
      • 54.5% vs. 18% (p < 0.001) for new-onset heart failure
    • precancer diabetes or hypertension in patients receiving chemotherapy associated with increased likelihood of cardiovascular morbidity (p < 0.001 for each)
    • Reference - J Clin Oncol 2018 Feb 20;36(6):609EBSCOhost Full Text

Prognosis

• colorectal cancer is fourth leading cause of cancer deaths worldwide
• colorectal cancer is third leading cause of cancer deaths in United States
• 5-year relative survival rates for patients with colorectal cancer in United States from 2006 to 2012
  • 65% with disease at all stages
  • 90% with localized disease
  • 71% with regional disease
  • 14% with distant stage disease
• medical factors that may affect prognosis include
  • tumor and microenvironment characteristics, such as
    • tumor grade
    • poor tumor differentiation (negative for prognosis)
    • extranodal tumor deposits (negative for prognosis)
    • number of involved lymph nodes (worse prognosis for increased number)
    • lymphovascular, extramural vascular, or perineural invasion (negative for prognosis)
    • lymphoid inflammatory response
    • positive resection margins (negative for prognosis)
    • bowel obstruction and perforation (negative for prognosis)
  • some medications, including statins and metformin
  • medical comorbidities, such as preexisting inflammatory bowel disease, and obesity, metabolic syndrome, and/or diabetes
  • performance status and quality of life
• demographic factors, such as age of onset and family history
• lifestyle factors that may affect prognosis include
  • dietary factors, such as prediagnostic and postdiagnostic intake of milk and red and processed meats
  • smoking status
  • physical activity
• predictive biomarkers for prognosis include
  • genetic markers, such as BRAF mutation, microsatellite instability, and chromosome 18q deletion
  • other serum and histologic and genetic biomarkers, including
    • pretreatment serum levels of carcinoembryonic antigen (CEA) and/or carbohydrate 19-9 (CA 19-9) (negative for prognosis if elevated)
    • CD133 expression
• genetic expression profiles for prognostication include
  • 13-gene classifier (ColoGuideEx) helps stratify 5-year relapse-free survival in patients with stage II colorectal cancer (level 1 [likely reliable] evidence)
  • 18-gene signature (ColoPrint) helps predict 5-year relapse-free survival in patients with stage I-III colorectal cancer (level 3 [lacking direct] evidence)
  • 634-gene signature may predict recurrence ≤ 5 years after surgery in adults with stage II colon cancer (level 2 [mid-level] evidence)
• See Colorectal cancer prognostication for details

Prevention and Screening

Prevention

• dietary considerations
  • greater consumption of the following foods associated with reduced risk of colorectal cancer
    • some vegetables and fruits (level 2 [mid-level] evidence), including total flavonols from fruit and vegetables (level 2 [mid-level] evidence)
    • nonfermented milk (level 2 [mid-level] evidence)
    • fish (level 2 [mid-level] evidence)
  • vitamins and minerals
    • use of specific vitamins and minerals associated with reduced risk of colorectal cancer
      • multivitamins (level 2 [mid-level] evidence)
      • vitamin B6 (level 2 [mid-level] evidence)
      • calcium in general population (level 2 [mid-level] evidence), but not when used in combination with vitamin D in women (level 2 [mid-level] evidence)
      • magnesium for rectal cancer in women (level 2 [mid-level] evidence)
      • zinc (level 2 [mid-level] evidence)
    • inconsistent evidence to determine if folic acid supplementation associated with reduced risk of colorectal cancer
  • increased dietary fiber intake associated with reduced risk of colorectal cancer in general population (level 2 [mid-level] evidence), but does not appear to reduce risk of colorectal cancer in adult women (level 2 [mid-level] evidence)
  • dietary intervention advising increased consumption of fruits and vegetables and reduction of dietary fat intake to < 20% of calories may not reduce incidence of invasive colorectal cancer in postmenopausal women (level 2 [mid-level] evidence)
  • vegetarian diet (especially pescovegetarian) associated with reduced risk of colorectal cancer in adults (level 2 [mid-level] evidence)
• physical activity associated with reduced risk of colon cancer (level 2 [mid-level] evidence)
• medications
  • aspirin use
    • associated with reduced risk of colorectal cancer (level 2 [mid-level] evidence)
    • in adults aged 50-59 years, start low-dose aspirin use if ≥ 10% ten-year cardiovascular disease (CVD) risk, not at increased risk for bleeding, life expectancy ≥ 10 years, and willing to take low-dose aspirin daily for ≥ 10 years (USPSTF Grade B recommendation)
    • in adults aged 60-69 years, decision to start low-dose aspirin should be on individual basis if ≥ 10% ten-year CVD risk (USPSTF Grade C recommendation)
    • in adults < 50 years old or ≥ 70 years old, current evidence is insufficient to assess balance of benefits and harms of starting aspirin use (USPSTF Grade I recommendation)
  • hormone replacement therapy associated with reduced risk of colorectal cancer in women (level 2 [mid-level] evidence)
  • metformin use associated with reduced risk of colorectal cancer in patients with type 2 diabetes (level 2 [mid-level] evidence)
  • statin use associated with reduced risk of colorectal cancer (level 2 [mid-level] evidence)
• polypectomy associated with reduced risk of distal colorectal cancer (level 2 [mid-level] evidence)
• see Colorectal cancer prevention for details

Screening

• specifics of formal recommendations for screening for colorectal cancer vary but most include
  • beginning to screen average-risk adults starting at age
    • 50 years, or considering initiation at age ≥ 45 years
    • 40-45 years in African American adults
    • 40 years in Alaska Natives
  • recommended screening options from multiple guideline groups (American Cancer Society, United States (US) Multi-Society Task Force, American College of Physicians, US Preventative Services Task Force, Canadian Task Force on Preventative Health) include
    • fecal immunochemical test (FIT) or high-sensitivity fecal occult blood testing (FOBT) every year
    • multi-target stool DNA test every 3 years
    • sigmoidoscopy or computed tomography colonography every 5 years
    • colonoscopy every 10 years
• see Colorectal cancer screening for details

Quality Improvement

Physician Quality Reporting System Quality Measures

• 72. Colon Cancer: Chemotherapy for AJCC Stage III Colon Cancer Patients
  • Percentage of patients aged 18-80 years with AJCC Stage III colon cancer who are referred for adjuvant chemotherapy, prescribed adjuvant chemotherapy, or have previously received adjuvant chemotherapy within the 12-month reporting period

• 100. Colorectal Cancer Resection Pathology Reporting: pT Category (Primary Tumor) and pN Category (Regional Lymph Nodes) with Histologic Grade
  • Percentage of colon and rectum cancer resection pathology reports that include the pT category (primary tumor), the pN category (regional lymph nodes) and the histologic grade

• 156. Oncology: Radiation Dose Limits to Normal Tissues
  • Percentage of patients, regardless of age, with a diagnosis of breast, rectal, pancreatic or lung cancer receiving 3D conformal radiation therapy who had documentation in medical record that radiation dose limits to normal tissues were established prior to the initiation of a course of 3D conformal radiation for a minimum of two tissues

• 185. Colonoscopy Interval for Patients with a History of Adenomatous Polyps – Avoidance of Inappropriate Use
  • Percentage of patients ≥ 18 years old receiving a surveillance colonoscopy, with a history of a prior adenomatous polyp(s) in previous colonoscopy findings, who had an interval of ≥ 3 years since their last colonoscopy

• 320. Appropriate Follow-Up Interval for Normal Colonoscopy in Average Risk Patients
  • Percentage of patients aged 50-75 years receiving a screening colonoscopy without biopsy or polypectomy who had a recommended follow-up interval of at least 10 years for repeat colonoscopy documented in their colonoscopy report

• 343. Screening Colonoscopy Adenoma Detection Rate Measure
  • Percentage of patients ≥ 50 years old with ≥ 1 conventional adenoma or colorectal cancer detected during screening colonoscopy

• see Physician Quality Reporting System Quality Measures for additional information

Choosing Wisely

• Society of Surgical Oncology recommends against
  • obtaining routine blood work other than a serial carcinoembryonic antigen (CEA) level during surveillance for colorectal cancer
  • performing routine positron emission tomography/computed tomography (PET/CT) in the initial staging of localized colon or rectal cancer or as part of routine surveillance for patients who have been curatively treated for colon or rectal cancer
  • Reference - Choosing Wisely 2016 Jul 12

Choosing Wisely Canada

• Canadian Oncology Societies recommend against performing routine colonoscopic surveillance every year in patients following their colon cancer surgery, but instead recommend basing frequency on the findings of the prior colonoscopy and corresponding guidelines (Choosing Wisely Canada 2014 Oct 29)

Quality indicators

• AHRQ Evidence Report 2006 May:138 PDF
• 21 quality indicators for care of colon carcinoma in vulnerable elders can be found in J Am Geriatr Soc 2007 Oct;55 Suppl 2:S277

Guidelines and Resources

Guidelines

International guidelines

• international consensus guideline on clinical target volume delineation in rectal cancer can be found in Radiother Oncol 2016 Aug;120(2):195
• World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) recommendations on diet, nutrition, physical activity and colorectal cancer can be found at WCRF/AICR 2017 PDF

United States guidelines

• American Gastroenterology Association (AGA) position statement on diagnosis and management of colorectal neoplasia in inflammatory bowel disease can be found in Gastroenterology 2010 Feb;138(2):738

• National Comprehensive Cancer Network (NCCN) guidelines on
  • genetic/familial high-risk assessment: colorectal can be found at NCCN website (free registration required)
  • colorectal cancer screening can be found at NCCN website (free registration required)
  • colon cancer can be found at NCCN website (free registration required)
  • rectal cancer can be found at NCCN website (free registration required)

• American Society of Colon and Rectal Surgeons (ASCRS)
  • practice guideline on surveillance of patients after curative treatment of colon and rectal cancer can be found in Dis Colon Rectum 2015 Aug;58(8):713
  • practice parameter on management of colon cancer can be found in Dis Colon Rectum 2012 Aug;55(8):831
  • practice parameter on management of rectal cancer can be found in Dis Colon Rectum 2013 May;56(5):535
  • practice guideline on surveillance of patients after curative treatment of colon and rectal cancer can be found in Dis Colon Rectum 2015 Aug;58(8):713

• American College of Radiology (ACR) Appropriateness Criteria for
  • pretreatment staging of colorectal cancer can be found at ACR 2016 PDF
  • local excision in rectal cancer can be found at ACR 2014 PDF
  • metastatic rectal cancer at presentation can be found at ACR 2014 PDF
  • resectable rectal cancer can be found at ACR 2012 PDF
  • recurrent rectal cancer can be found at ACR 2014 PDF

• American College of Gastroenterology (ACG) guidelines on colorectal cancer screening 2009 (corrected) can be found in Am J Gastroenterol 2009 Mar;104(3):739EBSCOhost Full Text PDF, correction can be found in Am J Gastroenterol 2009 Jun;104(6):1613, commentary can be found in Am J Gastroenterol 2009 Oct;104(10):2626EBSCOhost Full Text, Am J Gastroenterol 2009 Oct;104(10):2626EBSCOhost Full Text, Am J Gastroenterol 2009 Oct;104(10):2627EBSCOhost Full Text

• American Society of Clinical Oncology (ASCO) clinical practice guideline on follow-up care, surveillance protocol, and secondary prevention measures for survivors of colorectal cancer can be found in J Clin Oncol 2013 Dec 10;31(35):4465EBSCOhost Full Text full-text

• colonoscopy and endoscopy
  • American Cancer Society/United States Multi-Society Task Force on Colorectal Cancer (ACS/USMSTFCC) guidelines on
    • colonoscopy surveillance after cancer resection can be found in Gastroenterology 2016 Mar;150(3):758 and Gastrointest Endosc 2016 Mar;83(3):489
    • colonoscopy surveillance after polypectomy can be found in Gastroenterology 2012 Sep;143(3):844, commentary can be found in Gastroenterology 2013 Apr;144(4):e21
  • American Society for Gastrointestinal Endoscopy (ASGE) guidelines on
    • role of endoscopy in staging and management of colorectal cancer can be found in Gastrointest Endosc 2013 Jul;78(1):8, correction can be found in Gastrointest Endosc 2013 Sep;78(3):559
    • modifications in endoscopic practice for elderly can be found in Gastrointest Endosc 2013 Jul;78(1):1, correction can be found in Gastrointest Endosc 2013 Sep;78(3):559

• United States Multi-Society Task Force on Colorectal Cancer (USMSTFCC) guideline on
  • colorectal cancer screening can be found in Am J Gastroenterol 2017 Jul;112(7):1016 or at ACG 2017
  • colonoscopy surveillance after polypectomy can be found in Gastroenterology 2012 Sep;143(3):844
  • colonoscopy surveillance after colorectal cancer resection can be found in Gastroenterology 2016 Mar;150(3):758 and Gastrointest Endosc 2016 Mar;83(3):489
• United States Preventive Services Task Force (USPSTF) recommendations on
  • colorectal cancer screening can be found in JAMA 2016 Jun 21;315(23):2564EBSCOhost Full Text
  • aspirin use to prevent cardiovascular disease and colorectal cancer can be found in Ann Intern Med 2016 Jun 21;164(12):836EBSCOhost Full Text

United Kingdom guidelines

• National Institute of Care Excellence (NICE) guidance on
  • diagnosis and management of colorectal cancer can be found at NICE 2011 Jun:CG131 PDF, addendum can be found at NICE 2014 Dec PDF, summary can be found in BMJ 2011 Nov 9;343:d6751
  • bevacizumab in combination with oxaliplatin and either fluorouracil plus folinic acid or capecitabine for treatment of metastatic colorectal cancer can be found at NICE 2010 Dec:TA212 PDF
  • cetuximab, bevacizumab, and panitumumab for the treatment of metastatic colorectal cancer after first-line chemotherapy can be found at NICE 2012 Jan: TA242 PDF
  • cetuximab and panitumumab for previously untreated metastatic colorectal cancer can be found at NICE 2017 Mar:TA439 PDF
  • trifluridine-tipiracil for second-line treatment of metastatic colorectal cancer can be found at NICE 2016 Aug:TA405 PDF
  • recognition and referral for suspected cancer can be found at NICE 2015 June:NG12 PDF
• Association of Coloproctology of Great Britain and Ireland (ACPGBI)
  • Association of Coloproctology of Great Britain and Ireland (ACPGBI) guideline on management of colorectal cancer can be found at ACPGBI 2007 PDF
  • Association of Coloproctology of Great Britain and Ireland (ACPGBI) position statement on management of malignant colorectal polyp can be found in Colorectal Dis 2013 Aug;15 Suppl 2:1, commentary can be found in Colorectal Dis 2014 Jan;16(1):67

• Scottish Intercollegiate Guidelines Network (SIGN) national clinical guideline on diagnosis and management of colorectal cancer can be found at SIGN 2016 Aug PDF

Canadian guidelines

• Cancer Care Ontario (CCO) guideline on screening for Lynch syndrome by immunohistochemistry, BRAF mutations analysis, and MLH1 promoter methylation analysis for patients in Ontario with colorectal or endometrial cancers can be found at CCO 2015 Sep

• Cancer Care Ontario (CCO) Program in Evidence-Based Care guideline on
  • adjuvant systemic chemotherapy for stage II and III colon cancer following complete resection can be found at CCO 2015 Aug
  • optimization of preoperative assessment in patients diagnosed with rectal cancer can be found at CCO 2014 Jan
  • preoperative or postoperative therapy for management of patients with stage II or III rectal cancer can be found at CCO 2013 Nov

• Cancer Care Ontario (CCO) Program in Evidence-Based Care guidelines on
  • continuous vs. intermittent chemotherapy strategies in inoperable, advanced colorectal cancer can be found at CCO 2014 Jan
  • strategies of sequential therapies in unresectable, metastatic colorectal cancer treated with palliative intent can be found at CCO 2014 Jan
  • positron emission tomography (PET) imaging in colorectal cancer can be found at CCO 2010 Nov
  • role of liver resection in colorectal cancer metastases can be found at CCO 2012 Jun
  • referral of patients with suspected colorectal cancer by family physicians and other primary care providers can be found at CCO 2017 Apr
  • follow-up care, surveillance protocol, and secondary prevention measures for survivors of colorectal cancer can be found at CCO 2016 Mar
  • use of leucovorin (combined with 5-fluoruracil) in treatment of any stage colorectal cancer can be found at CCO 2016 Feb
• Gastrointestinal Cancer Disease Site Group evidence-based guideline recommendations on use of positron emission tomography imaging in colorectal cancer can be found in Clin Oncol (R Coll Radiol) 2012 May;24(4):232
• Gastrointestinal Cancer Disease Site Group practice guideline on preoperative or postoperative therapy for stage II or III rectal cancer can be found in Clin Oncol (R Coll Radiol) 2010 May;22(4):265

• British Columbia Medical Association (BCMA) guideline on follow-up of colorectal polyps or cancer can be found at BCMA 2013 Jan 16 PDF

European guidelines

• National Board of Health and Welfare (NBHW [Socialstyrelsen]) guideline on colon and rectal cancer can be found at NBHW 2014 Apr PDF [Swedish]

• S3 Leitlinie Kolorektales Karzinom finden Sie unter AWMF 2017 PDF [Deutsch]

• European Society for Medical Oncology/European Society of Surgical Oncology/European Society of Therapeutic Radiation Oncology (ESMO/ESSO/ESTRO) guideline on multidisciplinary management of rectal cancer can be found in Cancer Radiother 2012 Dec;16(8):711 [French]

• European Society for Medical Oncology (ESMO) clinical practice guideline on diagnosis, treatment, and follow-up of rectal cancer can be found in Ann Oncol 2017 Jul 1;28(suppl‗4):iv22

• European Society for Medical Oncology (ESMO) clinical practice guideline on diagnosis, treatment, and follow-up of early colon cancer can be found in Ann Oncol 2013 Oct;24 Suppl 6:vi64

• European Society for Medical Oncology (ESMO)
  • clinical practice guideline on diagnosis, treatment, and follow-up of metastatic colorectal cancer can be found in Ann Oncol 2014 Sep;25 Suppl 3:iii1
  • clinical practice guideline on familial risk of colorectal cancer can be found in Ann Oncol 2013 Oct;24 Suppl 6:vi73
  • consensus guidelines on management of patients with metastatic colorectal cancer can be found in Ann Oncol 2016 Aug;27(8):1386

• Gastroenterology Association of Spain (Asociación Española de Gastroenterología) guideline on prevention of colorectal cancer can be found in Gastroenterol Hepatol 2009 Dec;32(10):717.e1[Spanish]
• Dutch Gastrointestinal Tumors Working Group (Landelijke werkgroep Gastro Intestinale Tumoren [LWGT]) guideline on colorectal carcinoma can be found at LWGT 2014 [Dutch]
• Dutch Association of Clinical Genetics (Vereniging van Klinische Genetica Nederland [VKGN]) guideline on hereditary colon cancer can be found at VKGN 2015 PDF [Dutch]
• Dutch Quality Institute for Healthcare (Kwaliteitsinstituut voor de Gezondheidszorg [CBO]) expert guideline on follow-up to polypectomy can be found at CBO 2002 PDF [Dutch]

• Haute Autorité de Santé conseils pour cancer colo-rectal se trouvent sur le site Haute Autorité de Santé 2008 Feb [French]

• Haute Autorité de Santé/Institut National du Cancer (HAS/INCA) conseils sur cancérologie digestive: pratiques chirurgicales se trouvent sur le site Haute Autorité de Santé 2009 Feb [French] ou à Institut National du Cancer 2009 Feb [French]

• German S3 consensus guideline on colorectal carcinoma can be found in Z Gastroenterol 2010 Jan;48(1):65 [German]
• German S3 consensus on management of polyps, neoadjuvant therapy, and treatment of metastases can be found in Dtsch Arztebl Int 2009 Dec;106(51-52):843EBSCOhost Full Text full-text

• Gruppo Italiano Patologi Apparato Digerente (Italian Group of Gastrointestinal Pathologists [GIPAD]) recommendations on colorectal tumors: histology report can be found in Dig Liver Dis 2011 Mar;43 Suppl 4:S344

Asian guidelines

• Japanese Society for Cancer of the Colon and Rectum (JSCCR) 2016 guideline on treatment of colorectal cancer can be found in Int J Clin Oncol 2018 Feb;23(1):1 full-text

Australian and New Zealand guidelines

• Cancer Council Australia (CCA) clinical practice guideline on surveillance colonoscopy in adenoma follow-up following curative resection of colorectal cancer and for cancer surveillance in inflammatory bowel disease can be found at CCA 2011 Dec PDF

Middle Eastern guidelines

• National Comprehensive Cancer Network (NCCN) guideline on colon cancer modified for Middle East and North Africa region can be found in J Natl Compr Canc Netw 2010 Jul;8 Suppl 3:S22

Review articles

• reviews of colorectal cancer can be found in
  • Nat Rev Dis Primers 2015 Nov 5;1:15065 full-text
  • Lancet 2014 Apr 26;383(9927):1490
  • Lancet 2010 Mar 20;375(9719):1030, commentary can be found in Lancet 2010 Jul 31;376(9738):331
  • Mayo Clin Proc 2007 Jan;82(1):114
  • Lancet 2005 Jan 8;365(9454):153EBSCOhost Full Text
• reviews of colon cancer can be found in
  • BMJ 2007 Oct 6;335(7622):715 full-text, commentary can be found in BMJ 2007 Nov 10;335(7627):953
  • Aust Fam Physician 2006 Apr;35(4):192 full-text, commentary can be found in Aust Fam Physician 2006 Aug;35(8):569
  • Adv Stud Med 2006 Jan;6(1):30 PDF
• review of Lynch syndrome-associated colorectal cancer can be found in N Engl J Med 2018 Aug 23;379(8):764
• review of genomic and oncoproteomic advances in detection and treatment of colorectal cancer can be found in World J Surg Oncol 2009 Apr 1;7:36 full-text
• Canadian Agency for Drugs and Technologies in Health (CADTH) Technology Overview on clinical effectiveness of positron emission tomography (PET) in oncology can be found at CADTH 2010 Dec PDF
• review of preoperative neoadjuvant therapy for curable rectal cancer can be found in Colorectal Dis 2009 Mar;11(3):245
• review of laparoscopic surgery for abdominal cancer can be found in J Am Coll Surg 2010 Sep;211(3):412 full-text, commentary can be found in J Am Coll Surg 2011 Feb;212(2):269
• review of chemopreventive effect of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) on colorectal cancer and other cancers can be found in Lancet Oncol 2009 May;10(5):501
• review of effect of statin therapy on colorectal cancer can be found in Gut 2010 Nov;59(11):1572
• review of systemic therapy for colorectal cancer can be found in N Engl J Med 2005 Feb 3;352(5):476, commentary can be found in N Engl J Med 2005 Apr 28;352(17):1820
• review of multidisciplinary management of early-stage rectal cancer can be found in J Natl Compr Canc Netw 2012 Dec 1;10(12):1577
• review of how to order and interpret serum tumor markers can be found in BMJ 2009 Sep 22;339:b3527, correction can be found in BMJ. 2009;339:b4079
• review of care of cancer survivors can be found in Am Fam Physician 2005 Feb 15;71(4):699EBSCOhost Full Text full-text, commentary can be found in Am Fam Physician 2005 Nov 1;72(9):1658EBSCOhost Full Text
• review of nutrients and foods in colorectal cancer prevention can be found in Gastroenterology 2015 May;148(6):1244 full-text
• review of peritoneal carcinomatosis can be found in World J Surg Oncol 2009 Jan 8;7(1):5 full-text
• case report of colonic carcinoma presenting as repeated episodes of Enterobacter septicemia during remission induction of acute myeloblastic leukemia can be found in BMJ 2009 Nov 2;339:b4027
• case presentation of adenocarcinoma of cecum with metastases to regional lymph nodes and peritoneum can be found in N Engl J Med 2010 Jun 24;362(25):2411 full-text
• case presentation of recurrence of colorectal adenocarcinoma after open surgery can be found in World J Surg Oncol 2008 Jan 17;6:5 full-text

MEDLINE search

• to search MEDLINE for (Colon carcinoma or Rectal cancer) with targeted search (Clinical Queries), click therapy, diagnosis, or prognosis
• to search MEDLINE for (Colon carcinoma) with targeted search (Clinical Queries), click therapy, diagnosis, or prognosis
• to search MEDLINE for (Rectal cancer) with targeted search (Clinical Queries), click therapy, diagnosis, or prognosis

Patient Decision Aids

• clinician and patient decision aids from University of Sydney for
  • screening for bowel cancer for men aged 55-64 years PDF
  • screening for bowel cancer for women aged 55-64 years PDF

ICD Codes

ICD-10 codes

• C18 malignant neoplasm of colon
  • C18.0 caecum
  • C18.1 appendix
  • C18.2 ascending colon
  • C18.3 hepatic flexure
  • C18.4 transverse colon
  • C18.5 splenic flexure
  • C18.6 descending colon
  • C18.7 sigmoid colon
  • C18.8 overlapping lesion of colon
  • C18.9 colon, unspecified
• C19 malignant neoplasm of rectosigmoid junction
• C20 malignant neoplasm of rectum
• C21.8 overlapping lesion of rectum, anus and anal canal
• C78.7 secondary malignant neoplasm of liver

References

General references used

• 1. Kuipers EJ, Grady WM, Lieberman D, et al. Colorectal cancer. Nat Rev Dis Primers. 2015 Nov 5;1:15065 full-text
• 2. Labianca R, Nordlinger B, Beretta GD, et al. Early colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013 Oct;24 Suppl 6:vi64-72
• 3. Benson AP, Venook AB, Cederquist L, et al. Colon Cancer. Version 2.2017. In: National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines). NCCN 2017 Mar from NCCN website (free registration required)
• 4. Benson AP, Venook AB, Cederquist L, et al. Rectal Cancer. Version 3.2017. In: National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines). NCCN 2017 Mar from NCCN website (free registration required)
• 5. Glynne-Jones R, Wyrwicz L, Tiret E, et al. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017 Jul 1;28(suppl‗4):iv22-iv40
• 6. Scottish Intercollegiate Guidelines Network (SIGN). Diagnosis and Management of colorectal cancer: a national clinical guideline. SIGN 2011 Dec:126 PDF
• 7. Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016 Aug;27(8):1386-422, commentary can be found in Ann Oncol 2017 Jun 1;28(6):1399

Recommendation grading systems used

• World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) criteria for grading evidence
  • Convincing - strong evidence justifies goals and recommendations designed to reduce the incidence of cancer, highly unlikely to be modified in the foreseeable future as new evidence accumulates
  • Probable - strong evidence to support a probable causal relationship, generally justifies goals and recommendations designed to reduce the incidence of cancer
  • Suggestive - evidence may be too limited or have methodological flaws to create a convincing causal judgement but suggests a direction of effect and consistent direction
  • No conclusion - evidence so limited that no firm conclusion can be made
  • Substantial effect on risk unlikely - strong evidence to give confidence that an exposure (food, physical activity) is unlikely to have an effect
  • Reference - WCRF/AICR recommendations on diet, nutrition, physical activity and colorectal cancer (WCRF/AICR 2017 PDF)

• National Comprehensive Cancer Network (NCCN) categories of evidence and consensus
  • Category 1 - based on high-level evidence, there is uniform NCCN consensus that the intervention is appropriate
  • Category 2A - based on lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate
  • Category 2B - based on lower-level evidence, there is NCCN consensus that the intervention is appropriate
  • Category 3 - based on any level of evidence, there is major NCCN disagreement that the intervention is appropriate
  • Reference - NCCN Categories of Evidence and Consensus

• European Society for Medical Oncology (ESMO)
  • levels of evidence
    • Level I - evidence obtained from ≥ 1 randomized trial of good methodological quality with low potential for bias or meta-analyses of multiple, well-designed, controlled studies without heterogeneity
    • Level II - evidence obtained from small or large randomized trials with suspicion of bias (lower methodological quality) or meta-analyses of lower quality trials or trials with heterogeneity
    • Level III - evidence obtained from prospective cohort studies
    • Level IV - evidence obtained from retrospective cohort studies or case-control studies
    • Level V - evidence obtained from studies without control group, case reports, or expert opinions
  • grades of recommendation
    • Grade A - strong evidence for efficacy with substantial clinical benefit (strongly recommended)
    • Grade B - strong or moderate evidence for efficacy but with limited clinical benefit (generally recommended)
    • Grade C - insufficient evidence for efficacy or benefit which does not outweigh risk or disadvantages (recommended as optional)
    • Grade D - moderate evidence against efficacy or for adverse outcome (generally not recommended)
    • Grade E - strong evidence against efficacy or for adverse outcome (never recommended)
  • References
    • ESMO clinical practice guideline on diagnosis, adjuvant treatment, and follow-up for early colon cancer (Ann Oncol 2013 Oct;24 Suppl 6:vi64)
    • ESMO clinical practice guideline on diagnosis, treatment, and follow-up for rectal cancer (Ann Oncol 2013 Oct;24 Suppl 6:vi81)
    • ESMO clinical practice guideline on treatment for advanced colorectal cancer (Ann Oncol 2010 May;21 Suppl 5:v93)

• United States Preventive Services Task Force (USPSTF) grades of recommendation (after July 2012)
  • Grade A - USPSTF recommends the service with high certainty of substantial net benefit
  • Grade B - USPSTF recommends the service with high certainty of moderate net benefit or moderate certainty of moderate-to-substantial net benefit
  • Grade C - USPSTF recommends selectively offering or providing the service (based on professional judgment and patient preference) with at least moderate certainty of small net benefit
  • Grade D - USPSTF recommends against providing the service with moderate-to-high certainty of no net benefit or harms outweighing benefits
  • Grade I - insufficient evidence to assess balance of benefits and harms
  • Reference - USPSTF Grade Definitions

Synthesized Recommendation Grading System for DynaMed Plus

• DynaMed systematically monitors clinical evidence to continuously provide a synthesis of the most valid relevant evidence to support clinical decision-making (see 7-Step Evidence-Based Methodology).
• Guideline recommendations summarized in the body of a DynaMed topic are provided with the recommendation grading system used in the original guideline(s), and allow DynaMed users to quickly see where guidelines agree and where guidelines differ from each other and from the current evidence.
• In DynaMed Plus (DMP), we synthesize the current evidence, current guidelines from leading authorities, and clinical expertise to provide recommendations to support clinical decision-making in the Overview & Recommendations section.
• We use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to classify synthesized recommendations as Strong or Weak.
  • Strong recommendations are used when, based on the available evidence, clinicians (without conflicts of interest) consistently have a high degree of confidence that the desirable consequences (health benefits, decreased costs and burdens) outweigh the undesirable consequences (harms, costs, burdens).
  • Weak recommendations are used when, based on the available evidence, clinicians believe that desirable and undesirable consequences are finely balanced, or appreciable uncertainty exists about the magnitude of expected consequences (benefits and harms). Weak recommendations are used when clinicians disagree in judgments of relative benefit and harm, or have limited confidence in their judgments. Weak recommendations are also used when the range of patient values and preferences suggests that informed patients are likely to make different choices.
• DynaMed Plus (DMP) synthesized recommendations (in the Overview & Recommendations section) are determined with a systematic methodology:
  • Recommendations are initially drafted by clinical editors (including ≥ 1 with methodological expertise and ≥ 1 with content domain expertise) aware of the best current evidence for benefits and harms, and the recommendations from guidelines.
  • Recommendations are phrased to match the strength of recommendation. Strong recommendations use "should do" phrasing, or phrasing implying an expectation to perform the recommended action for most patients. Weak recommendations use "consider" or "suggested" phrasing.
  • Recommendations are explicitly labeled as Strong recommendations or Weak recommendations when a qualified group has explicitly deliberated on making such a recommendation. Group deliberation may occur during guideline development. When group deliberation occurs through DynaMed-initiated groups:
    • Clinical questions will be formulated using the PICO (Population, Intervention, Comparison, Outcome) framework for all outcomes of interest specific to the recommendation to be developed.
    • Systematic searches will be conducted for any clinical questions where systematic searches were not already completed through DynaMed content development.
    • Evidence will be summarized for recommendation panel review including for each outcome, the relative importance of the outcome, the estimated effects comparing intervention and comparison, the sample size, and the overall quality rating for the body of evidence.
    • Recommendation panel members will be selected to include at least 3 members that together have sufficient clinical expertise for the subject(s) pertinent to the recommendation, methodological expertise for the evidence being considered, and experience with guideline development.
    • All recommendation panel members must disclose any potential conflicts of interest (professional, intellectual, and financial), and will not be included for the specific panel if a significant conflict exists for the recommendation in question.
    • Panel members will make Strong recommendations if and only if there is consistent agreement in a high confidence in the likelihood that desirable consequences outweigh undesirable consequences across the majority of expected patient values and preferences. Panel members will make Weak recommendationsif there is limited confidence (or inconsistent assessment or dissenting opinions) that desirable consequences outweigh undesirable consequences across the majority of expected patient values and preferences. No recommendation will be made if there is insufficient confidence to make a recommendation.
    • All steps in this process (including evidence summaries which were shared with the panel, and identification of panel members) will be transparent and accessible in support of the recommendation.
  • Recommendations are verified by ≥ 1 editor with methodological expertise, not involved in recommendation drafting or development, with explicit confirmation that Strong recommendations are adequately supported.
  • Recommendations are published only after consensus is established with agreement in phrasing and strength of recommendation by all editors.
  • If consensus cannot be reached then the recommendation can be published with a notation of "dissenting commentary" and the dissenting commentary is included in the topic details.
  • If recommendations are questioned during peer review or post publication by a qualified individual, or reevaluation is warranted based on new information detected through systematic literature surveillance, the recommendation is subject to additional internal review.

DynaMed Editorial Process

• DynaMed topics are created and maintained by the DynaMed Editorial Team and Process.
• All editorial team members and reviewers have declared that they have no financial or other competing interests related to this topic, unless otherwise indicated.
• DynaMed provides Practice-Changing DynaMed Updates, with support from our partners, McMaster University and F1000.

Special acknowledgements

• Yoo-Joung Ko, MD, MMS, MSc (Assistant Professor of Medicine, University of Toronto; Director of Medical Oncology Postgraduate Education, Sunnybrook Health Sciences Centre; Ontario, Canada)
• Dr. Ko declares relevant financial relationships with Taiho (Speaker's Bureau), Shire, and Eisai (Advisory Board/Committee).

• Zbys Fedorowicz, MSc, DPH, BDS, LDSRCS (Director of Bahrain Branch of the United Kingdom Cochrane Center, The Cochrane Collaboration; Awali, Bahrain)
• Dr. Fedorowicz declares no relevant financial conflicts of interest.

• William Aird, MD (Deputy Editor of Hematology, Endocrinology, and Nephrology; Professor of Medicine, Harvard Medical School; Massachusetts, United States)
• Dr. Aird declares no relevant financial conflicts of interest.

Choosing Wisely Canada acknowledges dissemination of their recommendations through DynaMed Plus to reach the point of clinical decision-making.

On behalf of the American College of Physicians Barbara Turner, MD, MSEd, MACP, ACP Deputy Editor, Clinical Decision Resource, as part of the ACP-EBSCO Health collaboration, managed the ACP peer review of the Overview and Recommendations section and related clinical content in this topic. David S. Weinberg, MD, MSc (Chief Medical Officer, Fox Chase International and Temple University Health System; Professor of Medicine, Temple University Medical School; Chairman, Department of Medicine, Professor of Medicine and Senior Member, Divisions of Population and Medical Science, and Director, Gastroenterology Section, Fox Chase Cancer Center; Pennsylvania, United States), served as the ACP Topic Reviewer to help ensure the validity and clinical relevance of DynaMed Plus internal medicine topics. Dr. Weinberg declares no relevant financial conflicts of interest.

• DynaMed Plus topics are written and edited through the collaborative efforts of the above individuals. Deputy Editors, Section Editors, and Topic Editors are active in clinical or academic medical practice. Recommendations Editors are actively involved in development and/or evaluation of guidelines.

• Editorial Team role definitions

  Topic Editors define the scope and focus of each topic by formulating a set of clinical questions and suggesting important guidelines, clinical trials, and other data to be addressed within each topic. Topic Editors also serve as consultants for the internal DynaMed Plus Editorial Team during the writing and editing process, and review the final topic drafts prior to publication.

  Section Editors have similar responsibilities to Topic Editors but have a broader role that includes the review of multiple topics, oversight of Topic Editors, and systematic surveillance of the medical literature.

  Recommendations Editors provide explicit review of DynaMed Plus Overview and Recommendations sections to ensure that all recommendations are sound, supported, and evidence-based. This process is described in "Synthesized Recommendation Grading."

  Deputy Editors are employees of DynaMed and oversee DynaMed Plus internal publishing groups. Each is responsible for all content published within that group, including supervising topic development at all stages of the writing and editing process, final review of all topics prior to publication, and direction of an internal team.

How to cite

National Library of Medicine, or "Vancouver style" (International Committee of Medical Journal Editors):