(1)
Harvard Radiation Oncology Program, Boston, MA, USA
(2)
Brigham and Women’s Hospital and Dana-Farber Cancer Institute, Boston, MA, USA
(3)
Massachusetts General Hospital, Boston, MA, USA
13.1 Epidemiology and Risk Factors
13.1.1 Epidemiology
Colorectal cancer (CRC) is the third most commonly diagnosed cancer and third leading cause of death among men and women in the United States [1].
Estimated 134,490 new cases of large bowel cancer diagnosed annually in the United States, including about 95,270 colon and 39,220 rectal cancers [2].
The lifetime risk of developing CRC is about 1 in 20 (5 %).
Death rate from CRC has been dropping in both men and women for more than 20 years, secondary to screening and improvements in treatment. There are currently more than one million survivors of CRC in the United States [1].
Approximately 2/3 of CRCs occur in the colon and 1/3 occur in the rectum.
13.1.2 Risk Factors
Approximately 75 % of CRCs are sporadic, whereas 15–20 % occur in those with a positive family history or a personal history of polyps.
The etiology of CRC appears to be multifactorial (Table 13.1).
Age
Diet
Low socioeconomic status
Likely confounded by unhealthy behaviors.
Cigarette smoking
Sedentary lifestyle
Alcohol consumption
African-Americans often diagnosed at a younger age, associated with a higher mortality [7].
Personal or family history
Having a single first-degree relative with CRC increases the risk about twofold over that of the general population [8].
Inflammatory bowel disease (IBD)
Prior abdominal radiation (RT) (typically from childhood cancer)
Protective factors
Physical activity
Diet high in fiber
Vitamin B6
Calcium/vitamin D
Fish consumption
Aspirin and NSAIDS [9]
Inherited cancer syndromes and genetics
Hereditary nonpolyposis CRC (HNPCC) or Lynch syndrome
Autosomal dominant disorder; defects in mismatch repair genes.
Increased risk of CRC as well as endometrial, ovarian, stomach, small bowel, hepatobiliary, brain, and renal pelvis cancers.
Familial adenomatous polyposis (FAP)
Symptoms appear around age 16; CRC occurs in 90 % of untreated individuals by age 45.
Autosomal dominant inheritance.
Mutations in the APC gene lead to multiple polyp formation.
MYH is involved in oxidative DNA damage repair; mutation causes an autosomal recessive form of FAP.
Table 13.1
Risk factors of colorectal cancer
Inherited colon cancer syndromes (5 %)
Family history of polyps or colorectal cancer (15 %)
Inflammatory bowel disease
Sporadic (75 %)
Hereditary nonpolyposis colorectal cancer (HNPCC), Lynch syndrome: defect in mismatch repair (MMR) genes
Personal history: large (>1 cm) adenomatous polyps or polyps with villous or tubulovillous histology (3.5–6.5 RR) [52]
Ulcerative colitis: increased risk begins 8–10 years after diagnosis of pancolitis; 15–20 years for colitis limited to left colon [53]
Low socioeconomic status, confounded by associated unhealthy behaviors (e.g., high-fat diet)
Familial adenomatous polyposis (FAP): APC gene
Twofold risk if first-degree relative with colorectal cancer [8]
Crohn’s disease: less data
Age, incidence increases after age 40 (90 % cases after age 50)
African Americans: younger age, higher mortality
13.1.3 Screening
Screening recommendations (per US Preventive Services Task Force 2008 [10]).
For those age ≥50, no family history of CRC, no personal history of prior polyps, asymptomatic:
Colonoscopy every 10 years OR
Flexible sigmoidoscopy every 5 years with fecal occult blood test every 3 years OR
Annual fecal occult blood testing
High-risk individuals
Diagnosis in first-degree relative: colonoscopy at age 40 or 10 years before earliest familial diagnosis.
IBD: colonoscopy every 1–2 years, initiate 8 years after symptom onset.
FAP: APC gene testing, early screening (age 10–12), annual colonoscopy, colectomy near time of initial diagnosis.
HNPCC: colonoscopy every 1–2 years, initiate at age 20 or 2–5 years prior to the earliest age of CRC diagnosis in the family.
13.2 Anatomy
Rectum is ~ 15 cm long; subdivided into three parts based on distance from the anal verge.
Upper 1/3 (12–16 cm)
Middle 1/3 (6–12 cm)
Lower 1/3 (<6 cm)
Anterior peritoneal reflection represents the point below which the rectum exits the peritoneal cavity and becomes a retroperitoneal structure.
Below this, there is a mesorectal resection margin encompassing the rectum, with a layer of visceral fascia enclosing both the rectum and mesorectum.
Lymphatics
Lymphatic drainage passes along the superior hemorrhoidal arterial trunk toward inferior mesenteric artery.
Venous drainage
Upper rectum ➔ to inferior mesenteric vein via superior hemorrhoidal vein ➔ portal system
Lower rectum ➔ to internal iliac veins and inferior vena cava
13.3 Clinical Presentation
Asymptomatic individualsfound on routine screening
Symptomatic individuals
Common symptoms include gross red blood in stools and change in bowel habits such as constipation, diarrhea, or reduction of stool caliber. Iron deficiency anemia may also be found on laboratory evaluation.
Hemorrhoidal bleeding is a diagnosis of exclusion.
13.3.1 Workup
History ➔ include family history of CRC or polyps.
Physical examination ➔ focus on digital rectal examination, which can assess tumor size, ulceration, and fixation to surrounding structures. Can also determine distance from anal verge and evaluate sphincter function.
Labs: CBC to assess for anemia, carcinoembryonic antigen (CEA) level.
Full colonoscopy + biopsy.
Local staging
Endorectal ultrasound can be used to assess tumor extension and T stage or pelvic MRI for extent of primary tumor, distance to the mesorectal fascia, and lymph node involvement.
Distant staging
Computed tomography of chest/abdomen/pelvis.
13.4 Staging
AJCC staging (7th edition) [11] (Table 13.2)
Primary tumor (T)
Lymph nodes (N)
Metastases (M): CRC most frequently metastasizes to the liver, lung, or peritoneum.
Liver metastases are most frequently associated with upper rectal tumors which have venous drainage directly to portal system.
Lung metastases are associated with lower rectal tumors which have venous drainage directly to IVC.
Primary tumor (T)
Tx
Primary tumor cannot be assessed
Tis
Carcinoma in situ: intraepithelial or invasion of the lamina propria
T1
Tumor invades submucosa
T2
Tumor invades muscularis propria
T3
Tumor invades through the muscularis propria into pericolorectal tissues
T4a
Tumor penetrates to the surface of the visceral peritoneum
T4b
Tumor directly invades or is adherent to other organs or structures
Regional lymph nodes (N)
N1
Metastasis in 1–3 regional lymph nodes
N1a: 1 regional node
N1b: 2–3 regional nodes
N1c: tumor deposit(s) in subserosa, mesentery, or perirectal tissue without lymph node involvement
N2
Metastasis in ≥4 regional lymph nodes
N2a: 4–6 regional nodes
N2b: 7 or more regional nodes
Metastasis (M)
M1
Distant metastasis
M1a: Metastasis confined to one organ or site
M2a: Metastasis in more than one organ/site or the peritoneum
Stage I
T1-T2 N0
Stage II
Stage IIA: T3 N0
Stage IIB: T4aN0
Stage IIC: T4bN0
Stage III
Stage IIIA: T1-T2N1 or N1c, T1N2a
Stage IIIB: T3-T4aN1 or N1c, T2-T3N2a, T1-T2N2b
Stage IIIC: T4aN2a, T3-T4aN2b, T4bN1-T2
Stage IV: metastatic disease
Stage IVA: Any T, Any N, M1a
Stage IVB: Any T, Any N, M1b
13.5 Prognostic Factors
T stage
The local extent of disease (depth of penetration) independently predicts for survival.
N stage
The number of involved lymph nodes is a strong predictor for outcome.
Degree of lymph node (LN) dissection.
Total number of lymph nodes resected during surgery has been suggested to influence prognosis [12].
LN ratio
This has been suggested as a means to incorporate involved nodes and total number resected for prognostication.
Lymphovascular invasion
Both venous and lymphatic invasion represent independent adverse factors.
Perineural invasion
Obstruction/perforation
Several studies suggest that clinical obstruction or gross perforation at the time of diagnosis portends worse outcomes; this may be due to aggressive histology necessitating the need for emergency surgery.
Oncologic resection
Relates to outcomes
R0: complete tumor resection with all margins histologically negative
R1: incomplete tumor resection with microscopic surgical resection margin involvement
R2: incomplete tumor resection with gross residual tumor that was not resected
Circumferential margin status
Refers to the surgically dissected nonperitonealized surface of the specimen, any aspect of the colorectum that is not covered by a serosal layer of mesothelial cells and that must be dissected from the retroperitoneum.
For mid- and distal rectal cancers that are entirely subperitoneal in location, the entire external surface of the specimen is considered a CRM.
The CRM status is an important prognostic factor for local and distant recurrence.
Preoperative CEA
CEA levels ≥5 ng/mL may have an adverse impact on survival.
Response to neoadjuvant therapy
Tumor downstaging as detected by pathologic examination of the resected specimen is associated with better prognosis as compared to patients with residual tumor, especially nodal disease.
Molecular biology (as below)
13.6 Molecular Biology
KRAS
KRAS mutations in codon 12 or 13 are identified in 12–75 % of tumors. They are associated with poor prognosis in some studies, but not all [13, 14]. This may be due to different mutations within the gene that may exert different influences.
Activating mutations in KRAS results in constitutive activation of the Ras-Raf-ERK pathway, resulting in resistance to anti-EGFR therapy.
BRAF
RAF-activating mutations, specifically V600E, occur in less than 10 % of sporadic colorectal cancers and are a negative prognostic factor. Data are mixed as to whether BRAF mutations also confer resistance to anti-EGFR therapy [15].
MSI
Mutations in mismatch repair (MMR) genes are found in Lynch syndrome and 15–20 % of sporadic colon cancer.
Tumors with deficient MMR result in a high number of DNA replication errors and high levels of DNA MSI (microsatellite instability). Tumors that are MSI high are associated with longer survival than MSI-low or microsatellite-stable tumors.
18q deletions
Allelic loss of a region on the long arm of chromosome 18 commonly occurs in CRC.
Evidence suggests an association between 18q loss and an inferior prognosis in patients with node-negative and node-positive disease [16].
13.7 Genetics
The Cancer Genome Atlas (TCGA) published its genomic profile of colorectal cancer after sequencing 224 samples [17].
16 % of colorectal cancers were found to be hypermutated.
Three-quarters had expected high microsatellite instability.
Colon and rectal cancers were found to have similar patterns of genomic mutations.
Frequent mutations were found in the expected APC, TP53, SMAD4, PIK3CA, and KRAS. Mutations were also found in ARID1A, SOX9, and FAM123B.
Copy number alterations include amplifications of ERBB2 and IGF2.
Chromosomal translocations included the fusion of NAV2 and TCF7L1.
Tumors from the right (ascending) colon were more likely to be hypermethylated and to have higher rates of mutation compared to other CRCs.
Mutations frequently target MAPK and PI3K pathways but less frequently receptor tyrosine kinases.
13.8 Treatment Paradigms
For treatment recommendations, it important to distinguish between colon and rectal cancer.
Colon cancer ➔ role for RT is poorly defined.
Risk of local recurrence in colon cancer is <5 %; the issue is distant metastatic disease.
Retrospective studies suggest the use of adjuvant radiation in select high-risk patients:
Massachusetts General Hospital (MGH) series found that RT for T4 tumors with extension into adjacent structures led to favorable local control and recurrence-free survival rates [18].
Mayo Clinic series utilizing adjuvant RT in 27 patients with locally advanced tumors demonstrated improved local control [19].
Follow-up series from MGH found favorable long-term outcomes in 152 patients with T4 or residual disease with the use of adjuvant RT.
79 patients with T4 node-negative disease and 44 patients with node-positive disease demonstrated a 10-year local control rate of 88 % and a recurrence-free survival of 58 % [20].
Intergroup 0130: Prospective, randomized trial evaluating the utility of adjuvant chemoradiation (chemoRT) compared to adjuvant chemotherapy alone in T3N1 or T3N2 colon cancers [21].
Overall 5-year survival was 62 % for the chemotherapy patients compared to 58 % for chemoRT patients (p>0.50). 5-year disease-free survival (DFS) was 51 % for both groups, and toxicity (grade ≥3) occurred in 42 % of chemotherapy alone patients vs 54 % of chemoRT patients (p = 0.04).
Limitations included the absence of radiation quality control and central pathologic review, as well as the inclusion of patients with T3 tumors in whom the benefit may be less than with T4 tumors.
This remains the only prospective phase III trial to utilize radiation in colon cancer.
At this time, adjuvant radiation is typically reserved for patients with markedly increased risk of local recurrence, i.e., those with positive margins and/or gross residual disease.
What makes rectal cancer different?
Local recurrence for rectal cancer is typically 25–50 %. Surgery for rectal cancer is much more difficult than for colon cancer, as the pelvis is narrow.
How to decrease local recurrence rates in rectal cancer?
Better surgery (see “TME” below), nodal dissection
Addition of adjuvant treatment, including chemotherapy and RT
13.9 Multidisciplinary Treatment
13.9.1 Stage I (T1N0, T2N0): Surgery
Optimal surgical approach depends on size, stage, and location of the primary tumor.
Local excisions for early stage and superficial tumors without clinical lymph node involvement are primarily performed by conventional transanal excision (TAE) and transanal endoscopic microsurgery (TEM).
The concern regarding perirectal lymph node involvement in rectal cancer is not insignificant.
As tumor stage increases, the incidence of perirectal nodal involvement increases.
Lymph node involvement seen in:
Histologic grade and vascular involvement are also independent predictors of nodal involvement with one study revealing a 29–50 % risk of perirectal nodal disease for patients with T1 and T2 tumors showing poorly differentiated histology or lymphatic/blood vessel invasion [24].
Complete mesocolic resection is recommended to obtain adequate lymph nodes for staging.
Procedure dependent on location of the primary colorectal tumor.
For rectal cancer, total mesorectal excision (TME) is recommended.
Involves sharp dissection of the avascular plane between the mesorectal visceral lining and the pelvic parietal fascia. Hence, a TME not only removes the primary tumor but also the draining lymph nodes, providing optimal clearance of proximal, distal, and radial margins.Related posts:
Basics of Chemotherapy
Primary Liver Cancer: Background and Clinical Evidence
Stereotactic Body Radiation Therapy for Liver Metastases: Radiation Therapy Planning
Pancreatic Cancer: Background and Clinical Evidence
Rectal and Colon Cancer: Radiation Therapy Planning
Gastric Cancer: Radiation Therapy Planning
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
