Laboratory Studies
Routine laboratory studies should include a complete blood count (CBC); serum chemistries, including liver and kidney function tests; and a carcinoembryonic antigen (CEA) test. A cancer antigen (CA) 19-9 assay, if available, may also be useful to monitor the disease.
Screening CBC may demonstrate a hypochromic, microcytic anemia, suggesting iron deficiency. The combined presence of vitamin B12 or folate deficiency may result in a normocytic or macrocytic anemia. All men and postmenopausal women with iron deficiency anemia require a GI evaluation.
Liver function tests are usually part of the preoperative workup. The results are often normal, even in patients with metastases to the liver.
Perform a CEA test in all patients with rectal cancer. A baseline level is obtained before surgery and a follow-up level is obtained after surgery. If a previously normalized CEA begins to rise in the postoperative period, this suggests possible recurrence. A CEA level higher than 100 ng/mL usually indicates metastatic disease and warrants a thorough investigation. The steps of the workup are outlined in Figure 1.
Fecal immunochemical tests appear to be accurate for detecting colorectal cancer. In a meta-analysis that examined 8 different brands of fecal immunochemical tests (FITs), Lee and colleagues found that FITs had high accuracy, high specificity, and moderately high sensitivity for the detection of colorectal cancers. [35, 36] The meta-analysis, which included 19 studies with sample sizes ranging from 80 to 27,860, showed that FITs had sensitivity of 0.79, specificity of 0.94, a positive likelihood ratio of 13.10, and a negative likelihood ratio of 0.23. The overall diagnostic accuracy of FITs was 95%.
Screening for Colon and Rectal Cancer
The process of malignant transformation from adenoma to carcinoma takes several years. The purpose of screening is to eradicate potential cancers while they are still in the benign stage of the adenoma-carcinoma sequence. Screening also increases the likelihood of discovering existing cancers while they are still in the early stage.
Screening techniques
Screening techniques include the following:
-
Guaiac-based fecal occult blood test (FOBT): Perform FOBT yearly by testing 2 samples from each of 3 consecutive stools. If any of the 6 sample findings is positive, recommend that the patient have the entire colon studied via colonoscopy or flexible sigmoidoscopy. FOBT has significant false-positive and false-negative rates.
-
Stool DNA screening (SDNA): SDNA screening is done using polymerase chain reaction of sloughed mucosal cells in stool. This test evaluates for genetic alterations that lead to the cancer formation. Compared with no testing, SDNA testing is cost effective and has high sensitivity for invasive cancer.
-
Fecal immunochemical test (FIT): Fecal immunochemical testing uses a monoclonal antibody assay to identify human hemoglobin. This test is more specific for lower GI tract lesions. The presence of the globin molecule is indicative of bleeding in the colon and rectum because the globin molecule is broken down during passage through the upper GI tract. This test is probably the wave of the future in fecal occult blood testing and may serve as screening in certain populations. FIT has comparable sensitivity for the detection of proximal and distal advanced neoplasia. [37]
-
Rigid proctoscopy: Rigid proctosigmoidoscopy can be performed without an anesthetic, allows direct visualization of the lesion, and provides an estimation of the size of the lesion and degree of obstruction. This procedure is used to obtain biopsies of the lesion, assess ulceration, and determine the degree of fixation. Rigid proctoscopy has proved to be a highly reproducible method of determining the level of rectal cancer and does not depend on the operator and on the technique. Therefore, it gives an accurate measurement of the distance of the lesion from the anal verge; the latter is critical in deciding which operation is appropriate. The anal verge should be used as preferred landmark because the lowest edge of the rectal cancer and the anal verge can be visualized simultaneously during rigid proctoscopy evaluation. In conclusion, the level of rectal cancer must be confirmed by rigid proctoscopy. [38]
-
Flexible sigmoidoscopy (FSIG): Perform this test every 5 years. Biopsy any lesions identified, and perform a full colonoscopy. With flexible sigmoidoscopy, lesions beyond the reach of the sigmoidoscope may be missed. FSIG introduces significant variability for the level of rectal cancer and level of rectum itself. Therefore, FSIG should not be used to determine the level of the rectal cancer. [38] Screening with flexible sigmoidoscopy is associated with significant decreases in the incidence of colorectal cancer (in both the distal and proximal colon) and in colorectal cancer mortality (distal colon only). [39]
-
Combined glucose-based FOBT and flexible sigmoidoscopy: Theoretically, the combination of these two tests may overcome the limitations of each test.
-
Double-contrast barium enema (DCBE): Although barium enema is the traditional diagnostic test for colonic polyps and cancer, the United States Preventive Services Task Force (USPSTF) did not consider barium enema in its 2008 update of colorectal cancer screening recommendations. The USPSTF noted that barium enema has substantially lower sensitivity than modern test strategies and has not been studied in trials of screening trials; its use as a screening test for colorectal cancer is declining. [40]
-
CT colonography (CTC): Virtual colonoscopy (CTC) was introduced in 1994. After bowel preparation, the thin-cut axial colonic images are gathered in both prone and supine positions with high-speed helical CT scanner. Then, the images are reconstituted into a 3-dimensional replica of the entire colon and rectum. This provides a good visualization of the entire colon, including the antegrade and retrograde views of the flexures and haustral folds. Because this is a diagnostic study, patients with positive findings should undergo colonoscopic evaluation the same day.
-
Fiberoptic flexible colonoscopy (FFC): FFC is recommended every 5-10 years. Colonoscopy allows full visualization of the colon and excision and biopsy of any lesions. The likelihood is extremely low that a new lesion could develop and progress to malignancy between examinations.
Average-risk screening
People who are asymptomatic, younger than 50 years, and have no other risk factors are considered at average risk for developing colorectal cancer. Screening of the average-risk population should begin at age 50 years and end at age 75 years. [40] Indications for screening in patients at average risk for colon and rectal cancer include the following:
-
No symptoms and age 50-75 years
-
No symptoms, but requesting screening
-
Change in bowel habits
-
Rectal and anal bleeding
-
Unclear abdominal pain
-
Unclear iron deficiency anemia
A French study found that even in patients with no personal or family history of colorectal polyps or cancer, starting colonoscopy screening at age 45 instead of age 50 can be valuable. In a prospective study that included 6027 consecutive screening colonoscopies, Karsenti et al found that for the 515 patients age 45 to 49 years, the average polyp detection rate was 26% and the average neoplasia detection rate was nearly 4%. By comparison, for the 4438 patients older than 50 years, the average polyp detection rate exceeded 35% and the average neoplasia detection rate exceeded 5%. Both rates were markedly lower in the 1076 study patients age 44 years and younger. [41]
The US Multi-Society Task Force on Colorectal Cancer (USMSTF) has endorsed various cost-effective screening regimens. Screening options for the detection of adenomatous polyps and cancer for asymptomatic adults 50 years and older include FSIG every 5 years, colonoscopy every 10 years, DCBE every 5 years, or CTC every 5 years. Testing options that primarily detect cancer in asymptomatic adults 50 years and older include annual glucose-based FOBT with high test sensitivity for cancer; annual FIT with high test sensitivity for cancer; or SDNA with high test sensitivity for cancer, although the optimal interval for SDNA is uncertain.
Each screening test has unique advantages. They have been shown to be cost-effective and have associated risks and limitations. Ultimately, patient preferences and availability of testing resources guide the selection of screening tests.
The main disadvantage of the structural tests is their requirement for bowel preparation. The primary advantage of structural tests is that they can detect polyps as well as cancer. Conscious sedation is usually used for colonoscopy. FSIG is uncomfortable, and screening benefit is limited to sigmoid colon and rectum. Risks for colonoscopy, DCBE, and CTC may rarely include perforation; colonoscopy may also be associated with bleeding. Positive findings on FSIG, DCBE, and CTC usually result in referral for colonoscopy.
The advantages of the stool tests are that they are noninvasive, do not require bowel preparation, can be done in the privacy of the patient's home, and are more readily available to patients without adequate insurance coverage or local resources.
In the United States, colon and rectal cancer screening rates have been averaging between 50% and 60%. Brounts and colleagues studied colorectal cancer screening in the Military Healthcare System. In this study, overall screening rates were lower in minority groups than in whites. Also, overall lower screening rates were identified in patients younger than 65 years. Although ethnicity-related, gender-related, and age-related disparities were observed, screening rates were improved in this equal-access health care system when compared with national averages. [42]
Screening of high-risk patients
A patient's family history or personal history may indicate increased risk for colorectal cancer. Patients at high risk for colon and rectal cancer due to family history who should be included in surveillance programs include those with the following:
-
Family history of colon and rectal cancer
-
First-degree relative with adenoma aged younger than 60 years
-
Genetic cancer syndromes
-
Hereditary nonpolyposis colorectal cancer (HNPCC)
-
Familial adenomatous polyposis (FAP)
Patients at high risk for colon and rectal cancer due to personal history who should be included in surveillance programs includes the following:
-
Personal history of inflammatory bowel disease (IBD)
-
Personal history of adenomas
-
Personal history of colon or rectal cancer
Screening recommendations by risk factor are as follows:
-
First-degree relative affected: Offer family members the same screening tests as the general population; however, begin the screening at age 40 years rather than age 50 years. These people often undergo colonoscopy as their initial screening test, particularly if the relative was diagnosed with cancer at a young age.
-
Family history of FAP: Genetic counseling and genetic testing are recommended to determine whether the person is a gene carrier. Current tests are approximately 80% accurate. In the remaining 20%, the mutation cannot be identified. Genetic testing is useful only if the test result is positive or if the test is a true negative (ie, mutation present in other family members are not identified in the patient being tested). Flexible sigmoidoscopy should be offered to known gene carriers and persons with an indeterminate carrier status every year to look for polyps. When polyposis develops, consider colectomy.
-
Family history of HNPCC: Genetic counseling and genetic testing should be offered to individuals whose family histories meet the Amsterdam criteria (see Causes, above). Patients with documented HNPCC should undergo colonoscopy every 1-2 years when 20-40 years of age and every year when older than 40 years. Since these cancers tend to be located on the right side of the colon, flexible sigmoidoscopy is not recommended.
-
Personal history of adenomatous polyps: Patients who have adenomatous polyps removed during colonoscopy should have a repeat examination at 1 to 3 years. If the findings of this examination are normal, follow up at 5 years.
-
Personal history of colorectal cancer: Patients who have colorectal cancer and undergo resection for cure should have a repeat colonoscopy after 1 year. If this examination reveals no abnormalities, follow up at 3 years. In the absence of disease, perform colonoscopy every 5 years thereafter.
-
Personal history of IBD: Surveillance colonoscopy is performed to look for dysplasia as a marker for colorectal cancer in patients with long-standing IBD. These patients should undergo colonoscopy every 1-2 years after 8 years of diffuse disease or after 15 years of localized disease. Random biopsies are performed at specific intervals throughout the colon and rectum. Colectomy is recommended when dysplasia is present.
Histologic Findings
Histopathologic features such as poor differentiation, lymphovascular and/or perineural invasion, T4 tumor stage, and clinical findings such as obstruction or perforation, and elevated preoperative CEA levels are all associated with increased recurrence rates and worse survival.
Staging
Dukes Classification
In 1932, Cuthbert E. Dukes, a pathologist at St. Mark Hospital in England, introduced a staging system for rectal cancer. His system divided tumor classification into three stages, as follows:
-
Those limited to the rectal wall (Dukes A)
-
Those that extend through the rectal wall into extra-rectal tissue (Dukes B)
-
Those with metastases to regional lymph nodes (Dukes C).
This system was modified by others to include subdivisions of stages B and C, as follows:
-
Stage B was divided into B1 (tumor penetration into muscularis propria) and B2 (tumor penetration through muscularis propria).
-
Stage C was divided into C1 (tumor limited to the rectal wall with nodal involvement) and C2 (tumor penetrating through the rectal wall with nodal involvement).
-
Stage D was added to indicate distant metastases
Tumor, Node, Metastasis (TNM) System
This system was introduced in 1954 by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (IUAC). The TNM system is a universal staging system for all solid cancers that is based on clinical and pathologic information. Each category is independent.
Neither the Dukes nor the TNM system includes prognostic information such as histologic grade, vascular or perineural invasion, or tumor DNA ploidy. TNM staging of rectal cancer correlates well with 5-year survival rates of patients with rectal cancer (see the TNM stage–dependent 5-year survival rate for rectal carcinomas).
TNM classification for cancer of the colon and rectum (AJCC)
Primary tumor (T) includes the following:
-
TX - Primary tumor cannot be assessed or depth of penetration not specified
-
T0 - No evidence of primary tumor
-
Tis - Carcinoma in situ (mucosal); intraepithelial or invasion of the 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 tissue
-
T4 - Tumor directly invades other organs or structures and/or perforates the visceral peritoneum
Regional lymph nodes (N) include the following:
-
NX - Regional lymph nodes cannot be assessed
-
N0 - No regional lymph node metastasis
-
N1 - Metastasis in 1-3 pericolic or perirectal lymph nodes
-
N2 - Metastasis in 4 or more pericolic or perirectal lymph nodes
-
N3 - Metastasis in any lymph node along the course of a named vascular trunk
Distant metastasis (M) include the following:
-
MX - Presence of metastasis cannot be assessed
-
M0 - No distant metastasis
-
M1 - Distant metastasis
Table 1. Comparison of AJCC Definition of TNM Staging System to Dukes Classification. (Open Table in a new window)
Rectal Cancer Stages |
TNM Staging |
Duke Staging |
5-Year Survival |
|
Stage I |
T1-2 N0 M0 |
A |
>90% |
|
Stage II |
A |
T3 N0 M0 |
B |
60%-85% |
B |
T4 N0 M0 |
60%-85% |
||
Stage III |
A |
T1-2 N1 M0 |
C |
55%-60% |
B |
T3-4 N1 M0 |
35%-42% |
||
C |
T1-4 N2 M0 |
25%-27% |
||
Stage IV |
T1-4 N0-2 M1 |
5%-7% |
||
The TNM stage–dependent 5-year survival rate for rectal carcinomas is as follows:
-
Stage I - 90%
-
Stage II - 60-85%
-
Stage III - 27-60%
-
Stage IV - 5-7%
-
Diagnostics. Staging and workup of rectal cancer patients.
-
Staging and treatment. Rectal cancer treatment algorithm (surgery followed by adjuvant chemotherapy and radiotherapy). Initial stages are Endorectal ultrasound staging (uT).
Tables
Rectal Cancer Stages |
TNM Staging |
Duke Staging |
5-Year Survival |
|
Stage I |
T1-2 N0 M0 |
A |
>90% |
|
Stage II |
A |
T3 N0 M0 |
B |
60%-85% |
B |
T4 N0 M0 |
60%-85% |
||
Stage III |
A |
T1-2 N1 M0 |
C |
55%-60% |
B |
T3-4 N1 M0 |
35%-42% |
||
C |
T1-4 N2 M0 |
25%-27% |
||
Stage IV |
T1-4 N0-2 M1 |
5%-7% |
||
Resection Margins |
Proximal Resection Margin |
Distal Resection Margin |
Ideal Margins |
5 cm or more |
2 cm or more |
Minimally acceptable margins |
5 cm or more |
0.5-1 cm |
Regimen |
Frequency |
Schedule |
FOLFOX |
Every 2 weeks |
Oxaliplatin 85 mg/m2 day 1 Leucovorin 200 mg/m2 day 1 5-Fluorouracil (5-FU) 400 mg/m2 IV bolus day 1 and 2 5-FU 600 mg/m2 IV infusion day 1 and 2 (22 hours) |
FOLFOX 4 |
Every 2 weeks (Four cycles) |
Oxaliplatin 85 mg/m2 day 1 Leucovorin 200 mg/m2 day 1 5-FU 400 mg/m2 IV bolus day 1 and 2 5-FU 2400 mg/m2 IV infusion day 1 (46 hours) |
mFOLFOX 6 |
Every 2 weeks (Four cycles) |
Oxaliplatin 85 mg/m2 day 1 Leucovorin 400 mg/m2 day 1 5-FU 400 mg/m2 IV bolus day 1 and 2 5-FU 1200 mg/m2 IV infusion day 2 days |
CapeOx |
Every 3 weeks |
Oxaliplatin 130 mg/m2 day 1 Capecitabine 1000 mg/m2 PO BID for 14 days |
FOLFIRI |
Every 2 weeks |
Irinotecan 165 mg/m2 day 1 Leucovorin 200 mg/m2 day 1 5-FU 400 mg/m2 IV bolus day 1 and 2 5-FU 600 mg/m2 IV infusion day 1 and 2 (22 hours) |
FOLFOXIRI |
Every 2 weeks |
Irinotecan 180 mg/m2 day 1 Oxaliplatin 85 mg/m2 day 1 Leucovorin 200 mg/m2 day 1 5-FU 3200 mg/m2 IV infusion day 1 and 2 (48 hours) |
Bevacizumab |
Every 2 weeks with chemotherapy |
5-10 mg/kg IV |
Cetuximab |
With chemotherapy |
400 mg/m2 IV day 1, then 250 mg/m2 IV weekly |
Parameter |
Organization |
|||
ESMO (2013) [110] |
ASCO (2013) [109] |
NCCN (2019) [1] |
ASCRS (2015) [111] |
|
History and physical exam |
Every 3-6 mo for 3 y, then every 6 -12 mo at 4 and 5 y |
Every 3-6 mo for 3 y, then every 6 mo to 5 y |
Every 3-6 mo for 2 y, then every 6 mo to 5 y |
Every 3-6 mo for 2 y, then every 6 mo to 5 y |
CEA |
Every 3-6 mo for 3 y, then every 6 -12 mo at 4 and 5 y |
Every 3 mo for 3 y* |
Every 3-6 mo for 2 y, then every 6 mo to 5 y |
Every 3-6 mo for 2 y, then every 6 mo to 5 y |
Chest CT* |
Every 6-12 mo for first 3 y |
Every 1 y for 3 y |
Every 6-12 mo to 5 y |
Every 1 y for 5 y |
Colonoscopy** |
At y 1 after surgery, and every 3-5 y thereafter |
At 1 y, then every 5 y, dictated by the findings on the previous colonoscopy |
At 1 y, 3 y, and 5 y if negative |
At y 1 after surgery, and every 3-5 y dictated by the findings on the first postoperative examination. |
Abdominal CT* |
Every 6-12 mo for first 3 y |
Every 1 y for 3 y |
Every 6-12 mo to 5 y |
Every 1 y for 5 y |
ESMO = European Society of Medical Oncology; ASCO = American Society of Clinical Oncology; NCCN = National Comprehensive Cancer Network; American Society of Colon and Rectal Surgeons = ASCRS CEA = carcinoembryonic antigen; CT = computed tomography * For patients at high risk for recurrence (eg, lymphatic or venous invasion, or poorly differentiated tumors). **Colonoscopy should be performed 3-6 mo postoperatively if preoperative colonoscopy was not done, due to an obstructing lesion; otherwise, colonoscopy in 1 y; if abnormal, repeat in 1 year; if no advanced adenoma (ie, villous polyp, polyp >1 cm, or high-grade dysplasia), repeat in 3 y, then every 5 y. |
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