Clinical Practice Guideline

for

COLORECTAL CANCER

Developed for the

Aerospace Medical Association

by their constituent organization

American Society of Aerospace Medicine Specialists

Overview: Colorectal cancer (CRC), the fourth most common cancer in the US with about 153,760 new cases in 2007 with about 52,000 expected deaths; it is the second leading cause of cancer death. There is a 5.5% lifetime risk of developing CRC in the US with African Americans having the highest age-adjusted CRC incidence and mortality rate. The racial disparity in incidence and mortality may be due to significant differences in the screening in different US populations. The overall 5-year survival in the US has dramatically improved in past decades and is now approximately 65%³. It is a disease of older people with 90% of US cases occurring after age 50 with both incidence and mortality rates higher in men than in women.

Most colorectal cancers are adenocarcinomas and arise from existing adenomatous polyps. Hereditary syndromes account for fewer than 10% of cases. Other than increasing age and male gender, predictors of increased CRC risk are alcohol use, smoking and increased body mass index. It was speculated for many years that an increase in fiber in the diet helped to protect people from CRC. A recent large pooled analysis of several studies has shown that high dietary fiber is not associated with a reduced risk of CRC. Unlike some other cancers, tumor size is not as critical as are depth of invasion and nodal status in determining disease prognosis.

Colonic adenomas are the precursors to almost all colorectal cancers and are found in up to 40% of all persons by the age of 60. As most colonic polyps are adenomas and more than 90% of adenomas probably do not progress to CRC, it is not currently possible to reliably identify those polyps that will progress. Oncologists have recognized that a larger polyp size and more advanced histologic features are more predictive of progressing to invasive cancer and are now using the term “advanced adenoma” to refer to adenomas larger than 1 cm and have some advanced histologic features (tubolovillous, villous or high-grade dysplasia). There is also consensus that most subcentimeter polyps are not adenomatous and only a small fraction of all adenomas are advanced which has led to much discussion to more selective alternatives to universal polypectomy.

Current screening recommendations are for all Americans to have an initial screening starting at age 50. Options for screening from the US Multisociety Task Force on Colorectal Cancer include: (1) annual fecal occult blood test, (2) flexible sigmoidoscopy every five years, (3) combination of (1) and (2) above, (4) colonoscopy every ten years, and (5) air contrast barium enema very five years. This has led to the reduced mortality for CRC seen in most US populations. If there were polyps removed via sigmoidoscopy or colonoscopy that showed evidence of an advanced adenoma, then the recommendation would be to repeat the test in three years. Screening should begin at age 40 for those with a first degree relative with colon cancer and the interval is every 5 years if that first degree relative was less than 60 when diagnosed (the American College of Gastroenterology treats history of cancer and adenomas the same for the purpose of screening initiation and intervals). A recent analysis of screening intervals concluded that persons previously screening with colonoscopy without evidence of colorectal neoplasia, the 5-year risk of CRC is extremely low. The study did not go out to ten years, but the findings were not inconsistent with the rationale for a ten-year interval in those screened negative. There has been some shift on how to best screen individuals. There is now advocacy for computed tomographic colonography (CTC) rather than beginning with colonoscopy, but the US Preventative Task Force did not endorse CTC for screening. There is a small, but real risk of colonic perforation with colonoscopy and none with CTC. It has also been shown that both methodologies result in similar detection rates for advanced neoplasia. Detection of polyps smaller than one centimeter is not as high with CTC.

The disease is often insidious in development and common symptoms are fatigue, anemia, altered bowel function and weight loss. The most common acute surgical problem is bowel obstruction. About 5% of CRC patients will have a synchronous cancer and the liver is the most common site for a synchronous metastasis^.

Staging of Colorectal Cancer

Table 1. American Joint Committee on Cancer (AJCC) Colon Cancer Staging System

Stage (T)	Primary Tumor (T)
TX	Primary Tumor cannot be assessed
T0	No evidence of primary tumor
Tis	Carcinoma in situ: intraepithelial or invasion of lamina propria
T1	Tumor invades submucosa
T2	Tumor invades muscularis propria
T3	Tumor invades through the muscularis propria into the subserosa, or into non-peritonealized pericolic or perirectal tissues
T4	Tumor directly invades other organs or structures, and/or perforates visceral peritoneum
	Regional Lymph Nodes
NX	Regional lymph nodes not assessed
N0	No regional lymph node metastasis
N1	Metastasis in 1 to 3 regional lymph nodes
N2	Metastasis in 4 or more regional lymph nodes
	Distant Metastasis
MX	Distant metastasis cannot be assessed
M0	No distant metastasis
M1	Distant metastasis

Table 2. Stage Grouping for Colorectal Cancer

Stage	Primary Tumor (T)	Regional Lymph Nodes (N)	Distant Metastasis (M)	Dukes	MAC
0	Tis	N0	M0	-	-
I	T1	N0	M0	A	A
	T2	N0	M0	A	B1
IIA	T3	N0	M0	B	B2
IIB	T4	N0	M0	B	B3
IIIA	T1-T2	N1	M0	C	C1
IIIB	T3-T4	N1	M0	C	C2/C3
IIIC	Any T	N2	M0	C	C1/C2/C3
IV	Any T	Any N	M1	-	D

Surgery is the cornerstone of therapy for CRC and 70 to 80 percent of patients with tumors can be resected with curative intent. Among patients who have undergone resection for localized disease, the five-year survival rate is 90%. The survival rate decreases to 65% when metastasis to regional lymph nodes is present. Most recurrences occur within three years, and 90% occurs within five years. The most common sites of recurrence are the liver, the local site, the abdomen and the lung. Prospective studies have demonstrated that the use of chemotherapy in patients with metastatic disease prolongs survival and enhances quality of life in comparison to palliative care alone. Fluorouracil has been the backbone of therapy for CRC for many years. It is normally administered with leucovorin, a reduced folate, which enhances the effectiveness of the fluorouracil. Newer agents are now being used in advanced disease states and the most promising protocol now utilizes fluorouracil, leucovorin and oxaliplatin in a regimen known as FOLFOX, which has quickly become the standard of care for chemotherapy for CRC. The use of oxaliplatin and a similar agent, irinotecan, has significantly prolonged median survival by several months. Adjuvant radiation therapy is frequently used for treatment of rectal cancer, and is considered for cases in which resection of T3 and T4 lesions leaves potentially positive resection margins. Also, the treatment of choice for any metastatic lesion if possible is surgery. Chemotherapy is used in conjunction, but resection of liver, lung, or any recurrent lesion is the standard and no patient should be offered chemotherapy without the consideration for resection. Chemotherapy alone will not cure any patient; up to 50% of patients with liver metastasis are long term survivors post surgical resection.

There has been much debate over the years on how best to follow patients post-treatment for CRC. After it has been concluded that the colon is free of cancer and polyps, colonoscopy is recommended every three to five years in most patients. Physician visits with targeted exams are recommended every 3 to 6 months for the first three years with decreased frequency thereafter for 2 years. There is also consensus that patients be tested every 3 to 6 months for up to 5 years with a carcinoembryonic-antigen test, as most recurrences will first be detected wit this lab. A recent UK study has shown that more intensive follow-up (as outlined above) is cost-effective and results in improved survival with absolute survival effects of 7-9%.

Aeromedical Concerns: Of significant concern with CRC is the potential for sudden incapacitation as the initial presentation; emergent obstruction or perforation. Chronic anemia presents more insidiously and can cause in-flight problems if undetected. CRC has a late age onset and slow progression, thereby removing most USAF aviators from the high risk window. Regular screening may decrease late presentations; however this screening begins at an age outside the majority of our aviators.

Once diagnosed and treated, the potential for recurrence becomes an important health and aeromedical concern. It has been shown that 80 to 90 percent of all recurrences following curative resection occur within the first 2-3 years and that 95% occur within five years. The five-year survival point can be used as a reliable mark of cure as most CRC recurrences do so within the first five postoperative years. The presence of colostomy or ileostomy is not compatible with military aviation.

Medical Work-up: The aviator needs to have a complete history, work-up to include colonoscopy (or CTC), pathology, stage, treatment, surveillance plan and activity level. The exam needs to be inclusive of abdominal and rectal exams as well as all imaging studies. Reports from a gastroenterologist and the treating surgeon are important. Labs of importance are serial CBCs and carcinoembryonic antigen tests. Military members may require a tumor board as well as a medical board to determine worldwide deployability.

Aeromedical Disposition:

Air Force: Colorectal cancer is disqualifying for all classes of flying in the US Air Force. In the US Air Force, waiver can be considered in trained aircrew as early as six months after treatment is completed if they are considered in remission. For untrained aircrew, they must be five years post-treatment and in remission.

Army: Colorectal cancer is considered disqualifying in AR 40-501 Standards of Medical Fitness. This condition is discussed in the Colorectal Cancer Army Policy Letter which articulates similar aeromedical concerns as the USAF. Waiver can be considered if all gross tumor is removed at surgery, adjuvant therapy has been completed, all side effects of therapy have resolved, and no evidence of tumor is detected in post-therapy evaluation. For cases where nodes are involved, waiver may be considered 2 years after completion of therapy. Patients with metastasis, residual disease, or treatment-related side-effects will not normally be considered for waiver. Optimal follow-up is unclear and is tailored to the aircrew member; but the following is required: 1) History and physical (with rectal exam and occult blood testing), CEA, (and, for patients with anastamosis in the pelvis, sigmoidoscopy) every 3 months for 3 years, then every 6 months for 2 years. 2) Postero-anterior and lateral chest x-ray every year. 3) Annual colonoscopy for 3 years, then every 3 to 5 years thereafter, if first three are normal. Discovered abnormalities will result in immediate grounding and referral to appropriate subspecialty physicians.

Navy: Waiver can be considered after successful resection of the tumor and completion of any adjuvant chemotherapy. It is suggested to wait 2 years before requesting initial waiver recommendation.

Civilian: In civil aviation if a colon tumor is totally resected an airman can be returned to flying status as soon as their physician releases them from care. If the individual is to receive adjuvant therapy, they are not allowed to return to flying until it has been completed and there is no evidence of side effects. Tumors that have metastasized to local lymph nodes or distantly are required to wait for at least one year before reconsidering them for medical certification. Colostomy and ileostomy are permitted in the civil aviation environment. If on pathology evaluation the tumor has extended into or through the muscularis of the bowel wall requires the airman to have a MRI of the brain and repeat this study each of the five-years they are observed. Civilian airmen are required to provide yearly status reports to the Aeromedical Certification Division for five years. These conditions require an Authorization for Special Issuance.

Clinically, the individual should be disease-free and fully recovered from all treatments. Surgical and Oncologic consultations are also required. Required studies include: liver function tests and scan or CT/MRI scan, colonoscopy or adequate air contrast barium enema, and serum carcinoembryonic antigen (CEA) measurement. The possibility of co-existing malignancy and asynchronous lesions must also be considered. Colonoscopy is generally recommended, and a part of the ongoing follow-up.

Waiver Experience:

Air Force: Query of AIMWTS revealed a total of 14 submitted cases of colorectal cancer. There were no cases for those applying for pilot training. Of the fourteen cases, three were disqualified for an acceptance rate of 79%.

Army: The Aeromedical Epidemiological Data Repository (AEDR) catalogs all Army flight physicals since 1960. There have been approximately 160,000 individual aircrew entered in this database. During this period of time, there have been 12 cases of colorectal cancer of all types discovered. Of those, 8 were retained.

Navy: Precise statistics are not available at this time.

Civilian: A search of airmen currently issued with colon cancer revealed 140 first-, 165 second, and 663 third-class.

ICD9 Codes for Colorectal Cancer
153.0	Malignant neoplasm of hepatic flexure
153.1	Malignant neoplasm of transverse colon
153.2	Malignant neoplasm of descending colon
153.4	Malignant neoplasm of cecum
153.6	Malignant neoplasm of ascending colon
153.7	Malignant neoplasm of splenic flexure
153.8	Malignant neoplasm of other specified sites of large intestine
153.9	Malignant neoplasm of colon, unspecified
154.0	Malignant neoplasm of rectosigmoid junction
154.1	Malignant neoplasm of rectum
154.8	Malignant neoplasm of other sites of rectum, rectosigmoid junction, & anus

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References:

Compton C, Hawk E, Grochow L, et al. Colon Cancer. Ch. 81 in Abeloff’s Clinical Oncology, 4^th ed. Churchill Livingstone, 2008.

Jerant AF, Fenton JJ, and Franks P. Determinants of Racial/Ethnic Colorectal Cancer Screening Disparities. Arch Intern Med. 2008;168(12):1317-24.

Golfinopoulos V, Sanlanti G, and Ioannidis JPA. Survival and disease-progression benefits with treatment regimens for advanced colorectal cancer: a meta-analysis. Lancet Oncol. 2007; 8:989-911.

Driver JA, Gaziano JM, Gelber RP, et al. Development of a Risk Score for Colorectal Cancer in Men. Am J Med. 2007;120:257-63.

Park Y, Hunter DJ, Spiegelman D, et al. Dietary Fiber Intake and Risk of Colorectal Cancer. JAMA. 2005;294:2849-57.

Levine JS and Ahnen DJ. Adenomatous Polyps of the Colon. N Eng J Med. 2006;355:2551-57.

Kim DH, Pickhardt PJ, Taylor AJ, et al. CT Colonoscopy for the Detection of Advanced Neoplasia. N Eng J Med. 2007;357:1403-12.

Walsh JME and Terdiman JP. Colorectal Cancer Screening. JAMA. 2003;289:1288-96.

Imperiale TF, Glowinski EA, Lin-Cooper C, et al. Five-Year Risk of Colorectal Neoplasia after Negative Screening Colonoscopy. J Eng J Med. 2008;359:1218-24.

Singh H, Turner D, Xue L, et al. Risk of Developing Colorectal Cancer Following a Negative Colonoscopy Examination. JAMA. 2006;295:2366-73.

Engstrom PF, Arnoletti Jp, Benson AB, et al. Colon Cancer. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology; V.3.2008. Accessed on 17 Nov 2008 at http://www.nccn.org/professionals/physician_gls/PDF/colon.pdf

Pfister DG, Benson AB and Somerfield MR. Surveillance Strategies after Curative Treatment of Colorectal Cancer. N Eng J Med. 2004;350:2375-82.

Meyerhardt JA and Mayer RJ. Systemic Therapy for Colorectal Cancer. N Eng J Med. 2005;352:476-87.

Ohlsson B. Intensive follow-up for colorectal cancer is cost-effective. Evidence-based Healthcare (2004)8, 186-87.

Prepared by Dr. Dan Van Syoc

Date: September 26, 2010