Colorectal CancerDavid Glenn Weismiller, MD, ScM, FAAFP

Department of Family and Community MedicineUniversity of Nevada, Las Vegas School of Medicine

Disclosure Statement• Dr. Weismiller has nothing to disclose.

The AAFP has selected all faculty appearing in this program. It is the policy of the AAFP that all CME planning committees, faculty, authors, editors, and staff disclose relationships with commercial entities upon nomination or invitation of participation. Disclosure documents are reviewed for potential conflicts of interest and, if identified, they are resolved prior to confirmation of participation. Only those participants who had no conflict of interest or who agreed to an identified resolution process prior to their participation were involved in this CME activity.

Learning Objectives 1. Discuss the epidemiology of colorectal cancer

(CRC)2. Define current CRC screening guidelines and

review screening recommendations by organization

3. Discuss the strengths and limitations of current data for the use of chemoprevention for CRC

Cancer of Large Intestine• Most frequent internal neoplasm in the US

– 5%-6% lifetime risk (1 in 17)– More common in Western nations– Equal frequency in men and women– African Americans and Caucasians equally

affected• African Americans have a higher mortality

CA Cancer J Clin, 2016. 66(1): p. 7-30. World J Gastrointest Oncol, 2016. 8(12): p. 826-834. JAMA, 2016. 315(23): p. 2564-75. Cancer Epidemiol Biomarkers Prev, 2012. 21(6): p. 895-904.

Colorectal Cancer (CRC)• Third most common cause of cancer and cancer-

related deaths in the US.• Most CRCs arise from adenomatous polyps

(APs) or serrated polyps (SPs) as a result of sporadic mutations or DNA mismatch repair.

• CRC screening reduces mortality by removing APs and SPs or by early detection of CRC.

• Only 60% of Americans meet the recommendations for completing screening.

Colorectal Cancer (CRC)

Source: Emmanuelm@en.wikipedia

• Histology– 95% Adenocarcinoma

• Progression from adenoma (adenomatous polyp) to carcinoma – may take 10 years

• Polyps – < 1 cm: < 1% chance of CA– 1-2 cm: 10%−20% chance of CA– > 2 cm: 30%−50% likelihood– Detecting and removing polyps early CAN PREVENT much colon cancer.

CRC Screening = Prevention + Early Detection

Early detection ® decreased mortality

Prevention (polyp removal) ® decreased incidence CRC

Aspirin to Prevent CVD and Colorectal Cancer Population Recommendation Evidence

Rating Adults aged 50-59 years with a > 10% 10-year CVD risk

Initiate low-dose aspirin use for the primary prevention of CVD and CRC in adults aged 50-59 years who have a 10% or greater 10-year CVD risk, are NOT at increased risk for bleeding, have a life-expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years.

B

Adults aged 60-69 years with a > 10% 10-years CVD risk

Decision to initiate low-dose aspirin use for the primary prevention of CVD and CRC in adults aged 60 to 69 years who have a 10% or greater 10-year CVD risk should be an individual one. Persons who are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years are more likely to benefit. Persons who place a higher value on the potential benefits than the potential harms may choose to initiate low-dose aspirin.

C

8

Aspirin to Prevent CVD and Colorectal Cancer

Population Recommendation Evidence Rating

Adults younger than 50 years

Current evidence is insufficient to assess the balance of benefits and harms of initiating aspirin use for the primary prevention of CVD and CRC in adults younger than 50 years.

I

Adults aged 70 years or older

Current evidence is insufficient to assess the balance of benefits and harms of initiating aspirin use for the primary prevention of CVD and CRC in adults aged 70 years or older.

I

9

Risk Factors• Non-modifiable

o Family or personal history of CRC or advanced adenomas

o Personal history of IBDo Personal history of

hereditary polyposis syndromes

• Modifiableo Smokingo Obesityo Inactivityo Heavy Alcohol Useo Red meat

consumption ( 500 mg/week)

CA Cancer J Clin. 2014;64(1):9-29.Gastroenterol Clin North Am. 2002;31(4):925-943.

Diagnosis of Cancer of the Large Intestine• Endoscopy

– Flexible sigmoidoscopy– Colonoscopy

• Imaging– Barium enema– CT– Rectal ultrasound

• Symptoms: Variable and nonspecific– Rectal bleeding– Lower abdominal pain– Change in bowel habits

• Physical findings– Abdominal mass– Enlarged liver

• Lab– Stool for occult blood

1. A 54-year-old male sees you for a health maintenance visit. He inquires about the options for colorectal cancer screening. He has not had any screening tests performed in the past and has no personal or family history of colon cancer. You explain to him that there are several alternatives, but according to the U.S. Preventive Services Task Force, recommendations regarding the optimal screening intervals vary by test. He opts for fecal occult blood testing. You recommend he repeat this test at which one of the following intervals?

A. YearlyB. Every 3 yearsC. Every 5 yearsD. Every 10 years

Recommendation of the USPSTF on Screening for CRCJune, 2016

• Screening tests – equally acceptable• 2016 recommendation focuses on BEING SCREENED as opposed to screening

test to be used

Population(AdultAge) Recommendation50-75* Screenwithhighsensitivityfecaloccultbloodtesting

(FOBT),sigmoidoscopy, orcolonoscopy(GRADEA)76-85 Donotscreenroutinely(GRADEC); individualdecision,

takingintoaccountthepatient’soverallhealthandpriorscreeninghistory.Adultsinthisagegroupwhohaveneverbeenscreenedforcolorectalcanceraremorelikelytobenefit.

>85 Donotscreen

Ann Intern Med. 2008;149(9):627-637.*AmericanCollegeofGastroenterologyrecommendsstartingatage45inblacks

Stool-Based Testshttp://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/colorectal-cancer-screening2

Screening Method

Frequency Evidence of Efficacy Other Considerations

gFOBT Every year RCTs with mortality end points:High-sensitivity versions (eg, Hemoccult SENSA) have superior test performance characteristics than older tests (eg, Hemoccult II)

Does not require bowel preparation, anesthesia, or transportation to and from the screening examination (test is performed at home)

FIT Every year Test characteristic studies:Improved accuracy compared with gFOBTCan be done with a single specimen

Does not require bowel preparation, anesthesia, or transportation to and from the screening examination (test is performed at home)

FIT-DNA Every 1 or 3 y Test characteristic studies:Specificity is lower than for FIT, resulting in more false-positive results, more diagnostic colonoscopies, and more associated adverse events per screening testImproved sensitivity compared with FIT per single screening test

There is insufficient evidence about appropriate longitudinal follow-up of abnormal findings after a negative diagnostic colonoscopy; may potentially lead to overly intensive surveillance due to provider and patient concerns over the genetic component of the test

Direct Visualization Tests http://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/colorectal-cancer-screening2

Screening Method

Frequency Evidence of Efficacy Other Considerations

Colonoscopy Every 10 y Prospective cohort study with mortality end point

Requires less frequent screening. Screening and diagnostic followup of positive results can be performed during the same examination.

CTcolonography

Every 5 y Test characteristic studies: There is insufficient evidence about the potential harms of associated extracolonic findings, which are common

Flexiblesigmoidoscopy

Every 5 y RCTs with mortality end points:Modeling suggests it provides less benefit than when combined with FIT or compared with other strategies

Test availability has declined in the United States

Flexible sigmoidoscopywith FIT

Flexible sigmoidoscopyevery 10 y plus FIT every year

RCT with mortality end point (subgroup analysis)

Test availability has declined in the United StatesPotentially attractive option for patients who want endoscopic screening but want to limit exposure to colonoscopy

USPSTFCOLORECTALCANCERSCREENING

USPSTFCOLORECTALCANCERSCREENING

Colonoscopy Screening Recommendations Based on Risk Factors

Risk Factor Age to Initiate Screening Interval if normal (years)

Single first-degree relative with CRC or an advanced adenoma diagnosed at >60 years of age

50 years (may start at 45 years in blacks) 10

Single first-degree relative with CRC or an advanced adenoma diagnosed at <60 years of age

40 years or 10 years younger than affected relative’s age when diagnosed, whichever is earlier

5

Two first-degree relatives CRC or an advanced adenoma diagnosed at any age

40 years or 10 years youngerthan the youngest affected relative’s age when diagnosed, whichever is earlier

5

Am Fam Physician. 2015;91(2):93-100.

* An advanced adenoma is defined as an adenoma that is 10 mm or larger, has villous elements, or has high-grade dysplasia.

AGA

• Do not repeat colorectal cancer screening (by any method) for 10 years after a high-quality colonoscopy that does not detect neoplasia.

CRC Screening in Individuals at Increased Risk

• Individuals at increased risk for CRC require more frequent or earlier testing.

• This includes those with personal or family history of advanced adenomas or CRC, personal history of inflammatory bowel disease (IBD), and genetic polyposis syndromes.

• Screening/surveillance modality is usually colonoscopy.

Barriers to Screening Individuals at Increased Risk

• Confusing guidelines• Uncertainty regarding genetic syndromes• Non-standardized recommendations, e.g.

each genetic syndrome has slightly different recommendations

Barriersto

Practice

2. One week after a complete and adequate baseline screening colonoscopy, a 51-year-old female with no history of previous health problems visits you to review the pathology report on the biopsy specimen obtained from the solitary 8-mm polyp discovered in her sigmoid colon. The report confirms that this was a hyperplastic polyp. Her family history is negative for colon cancer. Which one of the following is the most appropriate interval for follow-up colonoscopy in this patient?

A. 1 yearB. 3 yearsC. 5 yearsD. 10 years

PolypsPolyp Risk Follow-upAdenomatous• Tubular adenoma

(most common)• Tubulovillous

adenoma• Villous adenoma

Malignant potential4.8% malignant transformation rate

19% malignant transformation rate38.4% malignant transformation rate

See next slide

Hyperplastic(50% of polyps found)

No increased risk for CRC Routine surveillance guidelines

Serrated Principle precursor of hypermethylated gene cancers; 20-30% of CRCs from this pathway; difficult to detect during colonoscopy as flat and indiscrete

See next slide

Br J Surg. 2002;89 (7):845-860.Gastroenterology. 1990;98(2):371-379.

Gastroenterology. 2012;143(3):844-857.Gastroenterology. 2010;139(5):1497-1502.

Guidelines for Follow-up Surveillance Colonoscopy

Initial Colonoscopy Findings Follow-up Interval

Normal – No polyps or normal biopsy results 10 yearsHyperplastic polyps – small (<10mm) hyperplastic polyps in rectum or sigmoid 10 yearsLow-risk polyps• 1 or 2 small (<10mm) tubular adenomas• Small sessile serrated polyp (<10mm) without dysplasia

5-10 years5 years

High-risk polyps• 3-10 tubular adenomas• Tubular adenoma or serrated polyp > 10mm• Adenoma with villous features or high-grade dysplasia• Sessile serrated polyp with cytologic dysplasia• Traditional serrated adenoma

3 years

Am Fam Physician. 2015;91(2):93-100.

AGA

• Do not repeat colonoscopy for at least five years for patients who have one or two small (<1cm) adenomatous polyps, without high-grade dysplasia or villous histology, completely removed via a high-quality colonoscopy.

Gastroenterology, November 2015:149(6).

Algorithm for CRC Screening Based on Family History

Relative Risk for the Association Between Family History of Colorectal Cancer and Risk According to Age of FDR

Gastroenterology, 2015:149(6): 1321-1322.Gastroenterology, 2015:149(6): 1438-1445.

Gastroenterology, November 2015:149(6).

Algorithm for CRC Screening Based on Family History

Am J Gastroenterology, 2015;110:236-242.

Cancer Type Screening Recommendations

Colon • Colonoscopy every 1-2 yrs, beginning at age 10-12 years• Screening can be delayed to late teenage years in families with

attenuated FAP• Prophylactic colectomy when polyps become unmanageable• If remaining rectum or ileal pouch, screen every 6 months to 2

yearsUpper GI tract • EGD every 1-3 years starting at age 20-25 yearsOther • Annual physical examination including exam of thyroid and thyroid

ultrasound• No data to support routine screening for other related cancers

Cancer Screening in Individuals with FAP

Cumulative Risks of Colorectal Cancer in Hereditary Colorectal Cancer Syndromes

Am J Gastroenterol. 2015;110(2):223-262;

Summary: FAP• >/= 100 colorectal adenomas• APC gene mutation, AD inheritance pattern• Average age symptomatic presentation: 36 years of age• Average age cancer diagnosis: 39 years of age• Sigmoidoscopy starting at 10-12 years of age, then q1-2 yrs until

polyps found• If colectomy is delayed more than 1 year after polyps are found,

then perform annual colonoscopy • EGD starting at 25-30 years of age• Annual thyroid ultrasound Am J Gastroenterology, 2015;110:236-242.

HNPCC (Lynch Syndrome)• May be defined clinically or by presence of 1 of 5 DNA

mismatch repair genes• AD, Mutation of DNA mismatch repair genes: hmsh2,

hmsh1, hmsh6, hpms2• Prevalence is unknown, but estimated to be 1/440• Average age of CRC diagnosis, 45 years• Lifetime risk of development of CRC is 80%

Gastroenterology 1999;116:1453-1456

Journal of Medical Genetics, 2007: (44)

• Annual surveillance colonoscopy should begin between ages 20-25 years.

• FDRs of patients with HNPCC that develop CRC should undergo screening colonoscopy every 1-2 years starting at age 25.

• Surveillance should continue until age 75.• There is no evidence supporting screening for extra-

colonic cancers at this time.

Summary: Guidelines for the Clinical Management of Lynch Syndrome

Ulcerative ColitisLink with Colon Cancer

• 2.8-15x as likely to develop colon cancer if there is history of moderate or extensive involvement of the colon

• Colonoscopy q 2-5 years* [SOR: C]– Initiated 10 years after UC is diagnosed– Interval based on findings

• Kornbluth A, Sachar DB. Practice Parameters Committee of the ACG. Ulcerative colitis practice guidelines in adults. Am J Gastroenterol. 2010;105(3):501-523.

• Adams SM, Bornemann PH: Ulcerative colitis. Am Fam Physician 2013;87(10):699-705.• Ford AC, Moayyedi P, Hanauer SB: Ulcerative colitis. BMJ 2013;346:f432.

Cumulative Risk of UC-Associated CRC

Alimentary Pharmacology and Therapeutics, 2003:149(6). World J Gastroenterol. 2014; 20(29): 9872–9881.

• Risk of CRC increases with early age at IBD diagnosis, longer duration of symptoms, extent of disease

• 0.5-1.0% annually after 8-10 years, 5-10% after 20 years, 12-20% after 30 years

• Screening colonoscopy 8-10 years following onset of symptoms (NOT diagnosis)

• Surveillance colonoscopy should begin within 1-2 years thereafter

• Following 2 negative exams, the next surveillance examination may be performed in 1-3 years until IBD has been present for 20 years

• After 20 years, surveillance should continue every 1-2 years

Summary: CRC screening and Surveillance in IBD

Inflamm Bowel Dis 2005;11:314–321.

Treatment of Cancer of the Large Intestine

• Surgical excision with 5 cm margin • Clearing colonoscopy at time of diagnosis; thereafter, q 3-5

years• 40%-50% of patients have long-term survival after

resection. • Chemotherapy with 5-FU produces partial tumor remission

in 15%-20%• New agents: Irinotecan and oxaliplatin• Radiation therapy useful for symptomatic metastases

Key RecommendationsCRC Screening

Recommendation SORColorectal cancer screening should begin at 50 years of age in average-risk individuals A

The American College of Gastroenterology recommends that colorectal cancer screening begin at 45 years of age in black patients C

Average-risk patients with normal findings on colonoscopy should have repeat colonoscopy in 10 years C

Patients with small, distal hyperplastic polyps are considered to have a normal colonoscopy result and should have repeat colonoscopy in 10 years C

Repeat surveillance colonoscopy in 5 to 10 years for low-risk polyps CRepeat surveillance colonoscopy in 3 years for high-risk polyps C

Best Practice Recommendations• Individuals with a first-degree relative with either CRC or

adenomatous polyp diagnosed <60 years of age should be advised to start screening colonoscopy at 40 years of age or 10 years younger than the earliest diagnoses in their family, whichever comes first (SOR C).

• Individuals with Adenomatous Polyposis Syndromes should begin colonoscopy between 10-20 and repeat every 1 to 2 years (SOR C).

Best Practice Recommendations• Screening colonoscopy should begin 8-10 years after the

onset of symptoms in individuals with CD with colonic involvement and UC and repeated every 1 to 3 years (SOR C).

• In individuals with HNPCC, colonoscopy should begin at age 25 and be repeated every 3 years (SOR C).

Thank you!

Answers1. A2. D

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clinical screening for familial adenomatous polyposis. Gut. 1999;44:698-703.2. Byers T et al. American Cancer Society guidelines for screening and surveillance for

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familial adenomatous polyposis. Gastroenterology. 1998;114:893-901.4. Imperiale et al. Risk of advanced proximal neoplasm in asymptomatic adults for

colorectal cancer. N Engl J Med. 2000;343:169-174.5. Kornbluth A and Sachar DB. Ulcerative colitis practice guidelines in adults. AJG.

1997;92(2):204-211.6. Leiberman et al. Use of colonoscopy to screen asymptomatic adults for colorectal

cancer. N Engl J Med. 2000;343:162-168.

References7. Rockey DC et al. Relative frequency of upper gastrointestinal and colonic lesions in

patients with positive fecal occult-blood test. N Engl J Med. 1998;339:153-159.8. Sharma VK and Howden CW. Colorectal cancer screening: How are we doing and

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Guidelines for Colorectal Cancer Screening 2008. Am J Gastroenterol online: http://www.medicine.nevada.edu/residency/lasvegas/internalmed/documents/coloncaGuideline.pdf

10. National Cancer Institute. Red meat consumption; Last Updated: March 2015. Available from: http://progressreport.cancer.gov/prevention/red_meat