NEOPLASMS OF THE SMALL AND LARGE INTESTINE
Neoplasms of the Small Intestine
The small intestine accounts for the majority of the length (≈75%) and absorptive surface (≈90%) of the gastrointestinal (GI) tract. Nonetheless, it is a rare site for the development of neoplastic disease, because only 1 to 2% of primary GI tumours originate in the duodenum, jejunum, or ileum. In fact, half of all small bowel neoplasms represent metastatic disease from other sites, particularly elsewhere in the GI tract. Although small bowel malignancies constitute less than 0.5% of all cancers, the incidence of small bowel tumours (especially carcinoids) has increased dramatically over the last several decades, which may possibly be a reflection of better diagnostic techniques. Overall, the mean age at diagnosis of a small bowel tumour is about 67 years (younger for those with sarcomas and lymphomas); neoplasms are more common in males, and they occur more frequently in African Americans than whites.
Adenocarcinomas, arising from mucosal glands, were formerly the most frequent primary small bowel tumour. They now constitute 25 to 33% of small bowel neoplasms, including benign growths, and 40% of all malignant tumours. Adenocarcinomas most commonly arise in the duodenum (65% of all small intestinal adenocarcinomas), even though the duodenum represents only a tiny fraction of the length of the small bowel. They occur less commonly in the jejunum and least commonly in the ileum. The majority are well or moderately differentiated.
Small bowel carcinoids, which derive from enterochromaffin cells in the crypts of Lieberkühn, are now the most common small bowel tumours, accounting for up to 44% of malignancies. They tend to be quite well differentiated. In contrast to glandular tumours, small intestinal carcinoids tend to arise in the distal ileum, and up to 30% are multifocal. Other small bowel neuroendocrine tumours are occasionally seen, including biochemically active neoplasms such as gastrinomas and somatostatinomas. Very rarely, high-grade true small-cell carcinomas occur.
Malignant connective tissue tumours account for 10 to 17% of small bowel neoplasms. Gastrointestinal stromal tumours (GISTs), which derive from the interstitial cells of Cajal or a common precursor, account for approximately 85% of these neoplasms. GISTs, like adenocarcinomas, disproportionately arise in the duodenum, and the small bowel itself is the second most common primary site for these mesenchymal neoplasms (33% derive from small bowel). Morphologically, GISTs often resemble leiomyosarcomas, but they can be differentiated by the expression of the Kit protein (CD117). Other small bowel sarcomas, such as true leiomyosarcomas, are seen more rarely.
Primary GI lymphomas are the most common extranodal lymphomatous variation, and the small intestine is the second most common GI site for such tumours. Lymphomas account for approximately 8% of small bowel neoplasms. The ileum, rich in submucosal lymphoid follicles, is the most common small bowel site. Tumors may be low or higher grade and can arise from precursor B or T lymphocytes. The overwhelming majority are non-Hodgkin tumours. Lymphomas involving the small bowel may also be a manifestation of true systemic disease.
Malignant melanoma can develop as a primary mucosal small bowel tumour, probably arising from schwannian neuroblasts associated with GI innervation. In addition, the small bowel is the most common GI site for melanoma metastases.
Finally, a variety of common benign tumours may originate in the small bowel, including adenomas, leiomyomas, and lipomas. Desmoids (most often seen in patients with familial adenomatous polyposis [FAP]), hamartomas, and haemangiomas are relatively rare. Benign growths are more common in the distal small intestine.
The small intestine can be involved with advanced cancers from other sites through direct invasion, extension of peritoneal metastases, or hematogenous spread. As noted, the small bowel is the most common GI site for melanoma metastases; involvement is also fairly common with ovarian, breast, lung, and other GI neoplasms.
Inflammatory bowel disease and some environmental factors (e.g., salt-cured foods, alcohol) predispose to small bowel adenocarcinomas. Data regarding tobacco exposure and obesity are conflicting. Additionally, many of the polyposis syndromes are associated with small bowel neoplasms. Most notably, FAP (see later) is associated with adenomas and carcinomas of the duodenum and jejunum, but especially in the ampullary and periampullary region. At least 90% of FAP patients develop duodenal adenomas, and up to 10% develop cancer. The risk of cancer is related to the number of polyps, their size and histologic type, and the presence of high-grade dysplasia. Patients with FAP should undergo regular screening for duodenal neoplasia with both forward- and side-viewing endoscopes beginning around the time of colectomy and repeated at 1- to 5-year intervals, depending on the presence and degree of duodenal polyposis. Patients with MUTYH -associated polyposis likewise develop duodenal neoplasia and should undergo screening. Patients with hereditary nonpolyposis colon cancer (HNPCC) are also at increased risk for small intestine adenocarcinoma, which may be the first manifestation of their disease. HNPCC-associated small bowel cancer may present at a young age (median, 39 years) and occurs with decreasing frequency from the duodenum to the ileum, with about 50% of occurrences in the duodenum. Screening may be considered beginning at age 30. Patients with sprue are at increased risk for small bowel lymphomas, and they have an almost 35-fold increased risk for developing adenocarcinomas.
The most common presenting symptom of small bowel tumours is abdominal pain, especially for those that are true cancers. Weight loss, nausea, GI bleeding, and symptoms related to perforation are less common. Approximately 25% of patients have GI obstruction, and duodenal periampullary tumours can lead to obstructive jaundice. Most malignancies are symptomatic, whereas benign tumours may be asymptomatic in up to half of patients. Carcinoid tumours in the small bowel are often asymptomatic, although in the setting of advanced disease, they may secrete bioactive amines, leading to flushing, diarrhoea, wheezing, and eventually symptoms of right heart failure (related to valvular fibrosis). This occurs more commonly with tumours originating in the jejunum and ileum. Benign tumours tend to be found incidentally, although intraluminal growth may eventually cause symptoms of obstruction, and some may grow large enough to ulcerate and bleed.
The physical examination in patients with small bowel tumours is often unremarkable, although a palpable mass and, in more advanced cases, ascites may be present. As discussed earlier, patients with periampullary neoplasms may be jaundiced and/or icteric. Obstructive signs such as hyperperistalsis may be present, and patients with lymphoma may also have splenomegaly or other signs of systemic involvement, such as lymphadenopathy. Laboratory findings may include iron deficiency anaemia or increased hepatic enzymes (the latter is especially common in those with liver metastases or biliary obstruction). Serum levels of the carcinoembryonic antigen (CEA) tumour marker may be elevated in small bowel adenocarcinoma, especially in advanced cases, but it is neither sensitive nor specific enough for routine diagnostic use. Patients with neuroendocrine tumours may demonstrate elevated levels of serotonin, chromogranin A, tumour-specific bioactive amines (e.g., gastrin), or urinary 5-hydroxyindoleacetic acid. Variants of intestinal lymphomas may show heavy chain immunoglobulin A fragments in serum and urine.
Proper imaging is crucial for both diagnosis and staging of small bowel neoplasms, but no one method is clearly the best. Standard radiographic techniques of value include upper GI with small bowel follow-through (helpful in demonstrating both masses and potential mucosal defects), angiography (which may show a site of bleeding or tumour blush with specific neoplasms), and computed tomography (CT) or magnetic resonance imaging (MRI) enteroclysis (double-contrast studies are both sensitive and specific for small bowel masses). Transabdominal ultrasound and standard CT may indicate a primary mass as well as metastases; MRI appears to be superior to CT in detecting and characterizing liver metastases.
Primary neuroendocrine tumours and their metastases are often apparent on indium-111 octreotide scanning. A wide variety of histologies may have uptake on positron emission tomography (PET) scanning. PET does not yet have a well-defined role in the diagnosis of most small bowel malignancies, although PET scans are useful in those with GISTs, to monitor response to systemic therapy (see later). Plain films rarely are specific enough to lead to a diagnosis, but they may demonstrate intestinal obstruction.
Capsule endoscopy uses a wireless endoscopic device that allows minimally invasive imaging of the small intestine. The system consists of the capsule camera—a swallowable, self-contained, battery-operated device that transmits two images per second—a receiver worn on the patient’s belt, and a computerized work station for downloading and viewing the images. The primary indications for capsule endoscopy are the evaluation of obscure GI bleeding and Crohn disease. Tumors are found in about 2 to 3% of patients undergoing capsule endoscopy for obscure GI bleeding, and they may be more common in younger patients. Tumors detected include lymphoma, adenocarcinoma, metastatic disease, carcinoid tumour, and GIST. Capsule endoscopy has also been used to assess the small intestines of patients with FAP and Peutz-Jeghers syndrome (PJS), although its clinical utility for routine screening of these patients has not been established.
Deep enteroscopy describes a group of related techniques to facilitate deep intubation of the small bowel with long endoscopes. The small bowel may be examined antegrade (through the mouth) or retrograde (through the colon), allowing the majority of the small bowel to be examined. Although more invasive than capsule endoscopy, deep enteroscopy has a similar diagnostic yield but allows for tissue sampling (biopsy) and therapy including polypectomy and control of bleeding.
Patients with FAP, MUTYH polyposis, PJS, and probably HNPCC require regular surveillance of the small intestine, with specific recommendations as noted earlier. Patients with sporadic small intestine adenomas and possibly carcinoid tumours should undergo colonoscopy because they are at increased risk for colonic neoplasia. No specific guidelines exist for following patients with resected small bowel adenocarcinomas.
The staging systems for small bowel tumours vary by histology. Adenocarcinomas and, more recently, neuroendocrine cancers and GISTs are staged using different classifications within the American Joint Committee on Cancer’s TNM malignant tumours system. Intestinal non-Hodgkin lymphomas, whether primary or part of a systemic process, are staged in accordance with a modified Ann Arbor system originally used in Hodgkin disease.
In general, surgical excision is the treatment of choice for most localized small bowel tumours. The extent of excision necessary depends on the tumour’s location and histology. Adenocarcinomas involving the first and second portions of the duodenum require pancreaticoduodenectomy, whereas those in the more distal small intestine may be treated with segmental or wide local resection, including regional lymph nodes. Low-grade neuroendocrine tumours should be managed with en bloc resection, again including regional nodes. GISTs, which very rarely spread to regional nodes, may be treated with excision without lymphadenectomy (except in cases with gross involvement of nodes). Primary surgery for lymphomas may be offered for low-stage malignancies and may also be required for complications of disease (e.g., intussusception). Local management of benign small bowel tumours varies from observation (incidentally discovered lipomas) to endoscopic polypectomy (small adenomas) to pancreaticoduodenectomy (periampullary villous adenomas).
The need for and types of adjuvant therapy vary as well. Fully resected benign tumours require no additional therapy. Adenocarcinomas are often treated according to the principles developed for colorectal cancer, with some experts advocating fluoropyrimidine-based systemic chemotherapy, at least for patients with nodal involvement. Older retrospective studies demonstrated no benefit from adjuvant systemic therapy, but its use has still increased almost three-fold over the last two decades. Chemoradiotherapy has occasionally been recommended for those with more locally advanced duodenal adenocarcinomas. So far, no randomized trials have proven either strategy offers any advantage. Fully excised well- to moderately differentiated neuroendocrine cancers do not require adjuvant therapy. Postoperative imatinib mesylate treatment clearly postpones the recurrence of high-risk GISTs (Grade A); a survival benefit has been demonstrated for those with gastric and nongastric primaries. Questions remain regarding dose and ideal duration of therapy. There is no defined role for the postoperative treatment of other mesenchymal tumours. Lymphomas treated with excision alone have high rates of recurrence, and systemic chemotherapy is advocated for high-grade variants; some experts also recommend chemotherapy for low-grade subtypes.
Patients with advanced small bowel adenocarcinomas are often treated with systemic chemotherapy regimens known to be effective against cancers of similar histology originating in the colon. However, the data supporting any specific regimen are scant and are not derived from randomized trials. Approximately 90% of patients with incurable GISTs have durable disease control when treated with the tyrosine kinase inhibitor imatinib mesylate, and the median survival for patients with metastatic disease has recently improved from approximately 18 months to 5 years.
Patients with small bowel lymphomas may be treated with chemotherapy that is effective in similar tumours originating outside the GI tract.
Patients with small bowel adenocarcinomas generally do worse than those with similarly staged colonic glandular tumours. Also, patients with duodenal primaries may have poorer outcomes than those with more distal small bowel cancers. In general, 5-year survival rates range from 4% for those with metastases to 80% for those with very early disease confined to the small bowel wall. Five-year survival in patients with small bowel carcinoids exceeds 50%. In the pre-imatinib era, patients with surgically resected small bowel GISTs had recurrence rates ranging to 90% or higher, depending on the tumour’s size, precise location, and mitotic rates; those with more distal tumours had a worse prognosis than those with duodenal primaries. Patients with recurrences almost invariably died within 2 years because salvage surgery and systemic chemotherapy were ineffective. True life expectancy in the era of postoperative imatinib use is unknown, but the median survival of patients with advanced GISTs likely exceeds 5 years. Small intestinal lymphomas have 5-year survival rates surpassing 60%, although this is highly variable and depends on the histologic subtype.
Neoplasms of the Large Intestine
Colorectal cancer (CRC) is the third most common cancer in the United States. Disease that has spread beyond regional lymph nodes is, for the most part, incurable, and CRC in general remains the second leading cause of neoplastic death. The lifetime risk of developing CRC for the average individual is about 1 in 18 to 20.
Almost three quarters of large bowel cancers arise proximally (i.e., are of colonic origin). Although CRC is primarily a disease of the elderly (median age ≈ 73 years), about 10% of cases occur in those aged 50 or younger. CRC incidence and mortality have decreased overall recently, although the incidence has been increasing in the young. Incidence rates for right-sided cancers have also been decreasing, possibly but not solely owing to effective distal large bowel screening with flexible sigmoidoscopy. CRC is slightly more common in men than in women and in African Americans than in whites. Men develop CRC an average of 5 to 10 years earlier than women; similarly, large bowel cancers seem to arise an average of 5 to 10 years earlier in African Americans than in whites. Significant geographic variation in incidence occurs, probably based more on environmental factors than on genetic ones, as suggested by migration studies.
Between 96 and 98% of CRCs are adenocarcinomas. Rarely seen histologies include neuroendocrine cancers, epidermoid carcinomas, lymphomas, and sarcomas (including GISTs). Composites, particularly adenocarcinomas with neuroendocrine differentiation, are frequently encountered.
Adenocarcinomas derive from colonic columnar glandular epithelium in the colorectal mucosal lining. They are equally common in males and females and are most frequently reported in the sigmoid colon. Adenocarcinomas most commonly present at a localized or regional (nodal) stage. About two thirds are of moderate grade. The majority are nonmucinous, although the mucinous phenotype constitutes up to one fifth of all CRCs. Another variant is the true signet ring carcinoma, identified by large quantities of single tumour cells with nuclear displacement by intracytoplasmic mucin. Data are controversial as to whether mucinous tumours have a worse prognosis, whereas signet ring histology is clearly associated with advanced disease and/or worse outcome.
Neuroendocrine cancers can have a variety of histologies ranging from bland, well-differentiated carcinoids to high-grade small-cell carcinomas. True carcinoids are the second most common histologic colorectal subtype. They are more common in nonwhites and make up the vast majority of nonadenocarcinoma epithelial cancers. Distal bowel carcinoids are hormonally inactive. Noncarcinoid neuroendocrine cancers tend to be high grade and commonly present with hepatic and other distant metastases.
Epidermoid carcinomas are rare overall but still account for up to one fourth of CRCs. Most are squamous cell subtypes. They are more common in women and Hispanic patients. Epidermoid carcinomas are located in the rectum more than 90% of the time, and they are usually moderately or poorly differentiated. Interestingly, they commonly present as localized cancers, regardless of their degree of differentiation.
Medullary carcinomas, which are more often right-sided and seen in older female patients, tend to have a lower incidence of lymph node involvement. The majority exhibit microsatellite instability, and they tend to have a relatively better prognosis.
Primary colorectal lymphomas are fairly rare, constituting 10 to 20% of all GI lymphomas but less than 1% of CRCs. They are much more common in males and in the elderly. The cecum is the most common site of origin. Tumors are usually of B-cell origin.
Sarcomas of the large bowel have no gender or racial predilections. More than 50% have been classified as leiomyosarcomas, and they are most commonly found in the rectum. Sarcomas are usually diagnosed at a localized stage, regardless of grade, although about 40% are actually poorly differentiated. Kaposi sarcomas and GISTs are other sarcoma histologies found in the large bowel; many of the distal tumours called “leiomyosarcomas” in older registries were likely true GISTs.
Predisposing conditions for colonic neoplasia include age (discussed previously), gender, race, inflammatory bowel disease, family history, and defined inherited syndromes. Defined genetic cancer syndromes, however, account for only a small percentage of CRCs (see later). Patients with first-degree relatives who also have colon neoplasia (adenomas or carcinomas) are commonly seen. Individuals with a first-degree relative with CRC face a 2- to 3-fold increased risk for malignancy, and this risk rises to 5- or 6-fold if two first-degree relatives are affected. Patients whose relatives have adenomas face a 1.8-fold increased risk for CRC, and this rises to 2.6 if the relative is younger than 60 years.
Patients with ulcerative colitis and Crohn disease are at increased risk for CRC in proportion to the amount of bowel involved and the duration of illness. 2For example, adenocarcinoma of the colon is 10 to 20 times more common in persons with ulcerative colitis than in the general population. Between 2 and 4% of all patients with long-term ulcerative colitis develop this malignancy, and the cumulative incidence over a 25-year period is approximately 12%. Overall, the incidence of colorectal adenocarcinoma is 60% higher in persons with inflammatory bowel disease than in the general population and has been stable over time. Patients with both ulcerative colitis and primary sclerosing cholangitis seem to be at even greater risk. For those with Crohn colitis, patients with extensive disease involving more than one third of the colon are at increased risk (six- to eight-fold), similar to those with ulcerative colitis. Isolated proctitis is not a risk factor. Patients with ulcerative colitis or extensive Crohn disease should undergo screening colonoscopy every 1 to 2 years beginning 8 to 10 years after disease onset. At colonoscopy, a dye spray may be used to identify suspicious areas, and multiple biopsies (at least 32 for pan-colitis) are obtained with targeting of suspicious lesions. The purpose of this is to identify the presence of dysplasia. The presence of high-grade dysplasia, any dysplasia in a mass or lesion that cannot be excised endoscopically, or multifocal low-grade dysplasia should prompt colectomy.
Patients who have had ureterocolostomy and those with acromegaly are also at increased risk. Case-control studies suggest that obesity, low physical activity, smoking, excessive alcohol, high-fat diet, and lack of dietary fibre increase the CRC risk. Patients with Streptococcus bovis bacteraemia or endocarditis have increased rates of CRC and should undergo colonoscopy.
Several defined dominant and recessive genetic conditions have been identified that convey an increased risk of CRC. These include FAP, HNPCC, MUTYH -associated polyposis, PJS, juvenile polyposis, PTEN hamartoma syndrome, and Cronkhite-Canada syndrome.
GENERAL FEATURES OF INHERITED COLORECTAL CANCER SYNDROMES
|SYNDROME||POLYP HISTOLOGY||POLYP DISTRIBUTION||AGE OF ONSET||RISK OF COLON CANCER||GENETIC LESION||CLINICAL MANIFESTATIONS||ASSOCIATED LESIONS|
|Familial adenomatous polyposis||Adenoma||Large intestine, duodenum||16 yr (range, 8-34 yr)||100%||5q (APC gene)||Rectal bleeding, abdominal pain, bowel obstruction||Desmoids, CHRPE|
|Peutz-Jeghers syndrome||Hamartoma||Large and small intestine||First decade||Slightly above average||19p(STK11)||Possible rectal bleeding, abdominal pain, intussusception||Or cutaneous melanin pigment spots, other tumours|
|MUTYH -associated polyposis||Adenoma||Large intestine, duodenum||45-50 yr (range, 13-60 yr)||75% (range, 50-100%)||1p (MUTYH gene)||Rectal bleeding, abdominal pain, bowel obstruction||CHRPE, osteomas|
|Juvenile polyposis||Hamartoma (rarely adenoma)||Large and small intestine||First decade||≈9%||PTEN ,SMAD4 ,BMPR1||Possible rectal bleeding, abdominal pain, intussusception||Pulmonary AVMs|
|Hereditary nonpolyposis colon cancer||Adenoma||Large intestine||40 yr (range, 18-65 yr)||30%||Mismatch repair genes *||Rectal bleeding, abdominal pain, bowel obstruction||Other tumours (e.g., ovary, uterus, pancreas, stomach)|
AVM = arteriovenous malformation; CHRPE = congenital hypertrophy of the retinal pigment epithelium.
* Including hMSH2 , hMSH3 , hMSH6 , hMLH1 , hPMS1 , and hPMS2 .
FAP is an autosomal dominant condition characterized by the development of hundreds to thousands of adenomatous polyps and CRC by age 40. Estimates of disease prevalence are 1 in 8000 to 15,000 births.
FAP is inherited as an autosomal dominant disease with incomplete penetrance. It has been mapped to the adenomatous polyposis coli (APC) gene located on the long arm of chromosome 5 (5q21). APC is a tumour suppressor gene that is a critical regulator of intestinal epithelial cell growth. Inherited mutations generally result in a truncated gene product. Patients with the familial syndrome inherit one mutant copy of APC; when a loss-of-function mutation develops in the other APC allele, mucosal epithelial cell growth is no longer controlled normally, and polyps develop. Variable phenotypes can be partly attributed to differences in the location of the APC mutation, with attenuated FAP being seen in mutations at the 5′ and 3′ ends of the gene.
Adenomas begin to appear early in the second decade of life, and GI symptoms begin to appear in the third or fourth decade. Polyps are distributed relatively evenly throughout the colon, although a slight predominance has been noted in the distal colon. Almost all patients with FAP develop frank colorectal carcinoma by age 40 years if the condition is left untreated. Gastric polyps (mostly nonadenomatous) occur in 30 to 100% of patients, and duodenal adenomas are found in 45 to 90%. Periampullary duodenal cancer develops in approximately 10% of cases. Small bowel lesions that are distal to the duodenum rarely progress to malignancy. In attenuated FAP, fewer than 100 colonic adenomas develop, there is a right colon predominance, and cancer develops approximately 10 years later. Genetic testing may identify the mutation in up to 85% of affected individuals and is useful for family screening.
The primary treatment option in FAP patients is total proctocolectomy with conventional ileostomy or ileoanal (pouch) anastomosis. Individuals with APC mutations and those with no identified mutation but clinical FAP in their families should be screened with annual sigmoidoscopy beginning at age 10 to 12 years. In families with known APC mutations, individuals who test negative do not require heightened surveillance but should undergo routine risk screening. FAP patients should be screened for duodenal polyposis with upper endoscopy beginning at age 20, with subsequent surveillance depending on polyp burden and histology. Cyclooxygenase-2 inhibition with sulindac or celecoxib may be considered in patients with small bowel adenomas or adenomas in the remnant rectum. Eicosapentaenoic acid supplementation has also been shown to decrease polyps in the remnant rectum.
Gardner syndrome is a phenotypic subtype of FAP that is also caused by mutations in the APC gene. It is distinguished by the presence of extraintestinal manifestations, including osteomas (particularly mandibular), soft tissue tumours (including lipomas, sebaceous cysts, and fibrosarcomas), supernumerary teeth, desmoid tumours, mesenteric fibromatosis, and congenital hypertrophy of the retinal pigment epithelium. The phenotypic differences between Gardner syndrome and FAP appear to result from variations in the location of the APC mutation, the presence of modifying genes, and environmental factors. Adenomatous polyps in Gardner syndrome have the same malignant potential as those found in FAP, and CRC screening and treatment recommendations are the same.
A hallmark of Turcot syndrome is the combination of colorectal polyposis and malignant diseases of the central nervous system. Mutations in the APC gene account for two thirds of cases, and the remaining one third result from mutations in the DNA mismatch repair genes that are also mutated in HNPCC. Central nervous system manifestations include medulloblastomas, glioblastomas, and ependymomas.
HNPCC, also known as Lynch syndrome, is the most common hereditary CRC syndrome and accounts for approximately 2% of all cases of CRC. It is an autosomal dominant trait and is highly penetrant. Clinically, HNPCC has been defined by the presence of all three of the following: (1) three or more relatives with histologically verified HNPCC-associated cancer (CRC or cancer of the endometrium, small bowel, ureter, or renal pelvis), one of whom is a first-degree relative of the other two, in the absence of FAP; (2) CRC involving at least two generations; and (3) one or more family members with cancer diagnosed before age 50.
HNPCC is caused by loss-of-function germline mutations in a set of genes involved in the repair of DNA base pair mismatches that occur during DNA replication (also known as the mutation mismatch repair system).
The median age for diagnosis of HNPCC is the mid-40s. Although several adenomas may be present, the diffuse polyposis characteristic of FAP is not found. Colonic neoplasia has a right-sided predominance (proximal to the splenic flexure). Although the cancers tend to be poorly differentiated, they generally have a better prognosis than similar sporadic CRCs. Synchronous and metachronous CRC is common. Patients with HNPCC are also at high risk for other malignant diseases, especially endometrial carcinoma, as well as cancers of the ovary, stomach, small bowel, hepatobiliary tract, ureter, and pancreas. The Muir-Torre syndrome variant is associated with cutaneous lesions and visceral malignancies. Screening for HNPCC may begin with testing of the tumour for microsatellite instability, performing immunohistochemical staining for products of mismatch repair genes (including hMSH2 , hMSH6 , hMLH1 , and hPMS2). A positive screen does not definitely indicate HNPCC, because up to 15% of sporadic tumours may have these features; this should be followed with germline testing.
Persons potentially affected with HNPCC should undergo a colonoscopy every 2 years beginning at age 21 and annually beginning at age 40. Patients with CRC or large adenomas should undergo subtotal colectomy. Women in HNPCC-affected families should have pelvic examinations every 1 to 3 years beginning at age 18; annual pelvic examinations, transvaginal ultrasonography, and endometrial biopsy have been recommended beginning at age 25. Prophylactic total abdominal hysterectomy with bilateral salpingo-oophorectomy may also be considered at the time of colectomy. Chemoprophylaxis with aspirin 600 mg daily may be considered; one randomized controlled trial did show benefit.
MUTYH -associated polyposis is a recently described autosomal recessive syndrome caused by mutations in the MUTYH gene (also called MYH [mutY homologue]). It is characterized by colonic polyposis and a high rate of CRC. Approximately 0.4% to 0.7% of CRC patients are homozygous for MUTYH mutations.
MUTYH -associated polyposis is caused by a biallelic inherited defect in the MUTYH gene located on chromosome 1p. Inherited as an autosomal recessive trait, this leads to defects in base excision repair and acquired mutations of the APC gene and other genes, such as KRAS . This results in adenoma formation and the subsequent development of adenocarcinoma.
Phenotypically, affected patients are similar to those with attenuated FAP. Patients have five to hundreds of adenomas. Multiple hyperplastic polyps and serrated adenomas may also be seen. The onset is later than in classic FAP, with cancers more likely to be right sided and to occur at age 45 to 50. Associated extracolonic features include gastroduodenal polyps, duodenal carcinoma, breast and ovarian cancer in female carriers, bladder cancer, skin cancer, congenital hypertrophy of the retinal pigment epithelium, and osteoma. Monoallelic carriers do not appear to have an increased cancer risk.
The diagnosis is suggested by the presence of colonic polyposis in the absence of FAP, or when there appears to be recessive inheritance. In these cases, genetic testing for MUTYH gene mutations should be considered. Whether heterozygote carriers are at increased risk has not been established, but screening similar to that for individuals with first-degree relatives with CRC may be advisable (i.e., colonoscopy at age 40 and then every 5 years).
Patients with numerous polyps should undergo colectomy. Patients with mild disease and a relatively small number of polyps may be considered for colonoscopy with polypectomy and regular surveillance. Colonoscopy should be performed beginning at age 18 to 20 and repeated every 1 to 2 years. Regular endoscopic surveillance for duodenal polyps should also be performed beginning at age 25 to 30.
PJS is an intestinal hamartomatous polyposis of the upper and lower GI tract that is associated with characteristic mucocutaneous pigmentation. The average age at diagnosis is in the mid-20s. PHS predisposes to both intestinal and extraintestinal malignancies.
PJS is a rare autosomal dominant syndrome with high penetrance. The prevalence is between 1 in 8300 and 1 in 29,000. The gene responsible for the syndrome is the serine-threonine kinase (STK11) gene located on chromosome 19p; a mutation in STK11 is found in approximately 60% of patients with this syndrome. The hamartomatous polyps in PJS are located predominantly in the small intestine (64 to 96%), stomach (24 to 49%), and colon (60%). Histologically, these polyps are benign; they are unique in that a layer of muscle that extends into the submucosa or muscularis propria may surround the glandular tissue. Adenomatous and hyperplastic polyps may also be found.
The most common symptoms are small bowel intussusception, obstruction, and GI bleeding that may require surgery and may be recurrent. PJS is associated with an increased risk of cancer, with an estimated 47% of patients developing a malignancy by age 65. The most common cancers are those of the small intestine, stomach, colon, pancreas, testes, breast, ovary, cervix, and uterus. More than 95% of patients have a characteristic pattern of melanin spots on the lips, buccal mucosa, and skin. Because genetic testing is not widely available, first-degree relatives should be screened beginning at birth with an annual history, physical examination, and evaluation for melanotic spots, precocious puberty, and testicular tumours.
Standard medical care for patients with PJS involves an annual physical examination that includes evaluation of the breasts, abdomen, pelvis, and testes, as well as a complete blood cell count. Surveillance for cancer includes small bowel radiography every 2 years, esophagogastroduodenoscopy and colonoscopy every 2 years, and endoscopic ultrasound of the pancreas every 1 to 2 years. For women, annual Pap smear, transvaginal ultrasound, CA125, and mammography are recommended. Polyps larger than 1 cm should be removed endoscopically. Laparotomy and resection are recommended for recurrent or persistent small intestinal intussusception, obstruction, or intestinal bleeding.
Familial juvenile (non-neoplastic, hamartomatous) polyposis is a rare (<1 in 100,000 births) syndrome characterized by 10 or more non-neoplastic hamartomatous polyps throughout the GI tract, or any number of polyps in a patient with a family history of juvenile polyposis. The syndrome is inherited in an autosomal dominant manner with high penetrance and is caused by mutations in the SMAD4 , PTEN , or BMPR1A gene. The hamartomas are histologically distinct from the polyps seen in PJS. Patients generally present with rectal bleeding, anaemia, abdominal pain, or intestinal obstruction in childhood or early adolescence. Extraintestinal symptoms include pulmonary arteriovenous malformations in some probands. The risk of malignancy in juvenile polyposis is reportedly as high as 20% and occurs in adulthood (median age, 37 years). Affected individuals should undergo regular colonoscopic surveillance. Patients with numerous, large, or high-grade dysplastic polyps may be considered for subtotal colectomy. Family members should be screened with colonoscopy every 3 to 5 years beginning at age 12 to 15 until age 40.
PTEN hamartoma syndrome is a rare autosomal dominant syndrome consisting of multiple hamartomatous polyps of the skin and mucous membranes, including GI polyps, facial tricholemmomas, oral papillomas, and keratoses of the hands and feet. It was previously referred to as Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome. The causative genetic lesion has been mapped to the PTEN tumour suppressor gene. The rate of associated malignancy is high, particularly in the thyroid, breast, and reproductive organs. The polyps in PTEN hamartoma syndrome are benign. The incidence of CRC is approximately 10 times higher than in the general population.
Cronkhite-Canada syndrome is a rare, sporadic, acquired condition characterized by multiple hamartomatous polyps throughout the GI tract, along with alopecia, dermal pigmentation, and atrophy of the nail beds. Symptoms include diarrhoea, protein-losing enteropathy, GI bleeding, intussusception, and rectal prolapse. It carries a poor prognosis, with 5-year mortality rates as high as 55%. Patients are at risk for gastric and CRC, and endoscopic surveillance has been recommended.
Recently, several new syndromes have been identified that predispose to CRC. In the serrated polyposis syndrome, affected individuals have multiple (≥5), large (at least 2 ≥ 10 mm), serrated adenomas, affected family members, and an increased CRC risk. Patients with defects in the epithelial cell adhesion molecule (EPCAM) gene have the phenotypic features of Lynch syndrome without mutations of the mismatch repair genes. Germline defects in the POLE and POLD1 genes leads to DNA proofreading errors, polyposis, and/or CRC. The hereditary mixed polyposis syndrome is an autosomal dominant condition causing polyps of multiple and mixed morphologies and CRC; the causative genetic defect (a duplication spanning the 3′ end of the SCG5gene and a region upstream of the GREM1 locus) has recently been discovered.
Non-neoplastic polyps account for approximately half of all mucosal polyps detected in the large bowel of average-risk individuals older than age 50 years. These polyps, which are also termed nonadenomatous polyps , can be subcategorized into hyperplastic, inflammatory, lymphoid, and juvenile polyps. Most non-neoplastic polyps are hyperplastic polyps that arise as a result of abnormal maturation of the mucosal epithelial cells; these polyps are usually small in diameter and are found predominantly in the distal sigmoid colon and rectum. Hyperplastic polyps are not malignant and are not thought to be associated with any measurable increase in malignant potential. Patients with inflammatory bowel disease may develop inflammatory pseudopolyps, which may require biopsy or removal to distinguish them from neoplastic polyps. Lymphoid polyps are regions of the mucosa that contain exaggerated intramucosal lymphoid tissue. Juvenile polyps usually develop in the rectum of children younger than 5 years and are termed hamartomatous because they are focal malformations that resemble tumours but are caused by abnormal development of the lamina propria; these polyps require no therapy unless they cause symptoms (e.g., obstruction, severe bleeding) or are part of a genetic syndrome.
A polyp is defined as a grossly visible mass of epithelial cells that protrudes from the mucosal surface into the lumen of the intestine. A polyp may be sessile, flat, or pedunculated when it is attached by a stalk. Polyps are classified as either non-neoplastic or neoplastic (adenomatous). Polyps may rarely cause symptoms such as bleeding, prolapse, or obstruction. Neoplastic polyps have the potential to become malignant.
Adenomatous polyps (or adenomas) are neoplastic polyps with malignant potential. They are benign glandular tumours that exhibit either low- or high-grade dysplasia under microscopy. Their anatomic distribution parallels that of colorectal adenocarcinoma. Adenomatous polyps manifest in a range of sizes and may be sessile, flat, or pedunculated in morphology. They are believed to be the precursor lesion to colorectal adenocarcinoma, a process that occurs along the adenoma-carcinoma sequence. Evidence supporting the adenoma-carcinoma sequence comes from several sources. Patients with genetic conditions that predispose to adenoma formation (e.g., FAP) develop cancer at high rates. Animal studies in which adenomas are induced by either carcinogens or genetic manipulation show carcinoma formation. Correlative evidence includes the observations that the epidemiology is similar for adenomas and carcinomas, that both lesions are more common in the same anatomic locations, and that adenomatous tissue can often be found in small adenocarcinomas. Intervention studies have shown that the removal of adenomatous polyps leads to a significant decrease in the risk for CRC.
Adenomatous polyps are relatively common, particularly in elderly populations. Among healthy screening populations older than 50 years, adenomas are found in more than 15% of women and 25% of men. The prevalence of adenomas tends to be high in regions of the world where CRC is common. The importance of genetic risk factors is clear in the hereditary polyposis syndromes, and sporadic adenomas have a familial component; for example, individuals with a positive first-degree family history have a four-fold greater risk of developing adenomatous polyps. African Americans in the United States have an increased risk for developing adenomas and carcinomas relative to whites; the risk in Asian and Hispanic individuals is similar to that in whites.
The layer of epithelial cells lining the surface of the normal large bowel undergoes continuous self-renewal, with a turnover period of 3 to 8 days. Undifferentiated stem cells located at the base of invaginated crypts give rise to cells that migrate toward the lumen as they differentiate further into specialized enterocytes; these cells are subsequently removed by apoptosis, by extrusion, or by phagocytes underlying the epithelial layer. The development of adenomatous polyps is associated with a sequence-specific accumulation of genetic lesions that cause an imbalance between epithelial cell proliferation and cell death. As a result, cells accumulate at the luminal surface, where they remain undifferentiated and continue to undergo cell division, eventually leading to the abnormal development of a mass of adenomatous tissue.
Adenomas are classified into three main histologic subtypes: tubular adenomas, villous adenomas, and tubulovillous adenomas. Tubular adenomas account for 70 to 85% of all adenomas removed at colonoscopy. They are often small and pedunculated, and they consist of dysplastic tubular glands that divide and branch out from the mucosal surface; they rarely contain concomitant high-grade dysplasia or carcinoma. In contrast, villous adenomas (<5% of all adenomas) are generally large and sessile and are composed of strands of dysplastic epithelium that project, finger-like, into the lumen of the gut; they have a much higher prevalence of high-grade dysplasia or carcinoma. Tubulovillous adenomas (10 to 25% of all adenomas) have a mixture of tubular and villous architecture. Advanced adenomas are defined as those that measure 1 cm or greater or have any villous histology or high-grade dysplasia. Patients with advanced adenomas or multiple adenomas (three or more) are at much greater risk for synchronous (developing simultaneously) or metachronous (developing after a time interval) CRC.
Patients with adenomatous polyps generally remain asymptomatic, but they may present with an asymptomatic positive stool occult blood test or with evident haematochezia. The lifetime incidence of additional adenomas in a patient with one known adenoma is 30 to 50%. Fewer than 5% of all adenomas eventually develop into carcinomas. Two critical factors that determine the likelihood of an adenoma developing into an invasive lesion are the size of the polyp and the grade of dysplasia. For polyps less than 1 cm, the risk for carcinoma is 1 to 3%; polyps between 1 and 2 cm have a 10% risk of becoming cancerous; and more than 40% of polyps greater than 2 cm progress to an invasive lesion. All adenomatous polyps contain some degree of dysplasia, but they can be further categorized as low- or high-grade to indicate the degree of dysplasia and the corresponding risk for invasive carcinoma. High-grade dysplasia is associated with a 27% rate of eventual transformation into carcinoma.
Adenomatous polyps in the colon and rectum can be diagnosed by endoscopy, barium radiography, or CT scanning (CT colography or virtual colonoscopy). Colonoscopy is the preferred method for diagnosing adenomas because of its high accuracy and the ability to immediately biopsy and resect most polyps. Barium enema, as assessed in the National Polyp Study, missed 52% of polyps measuring 1 cm or more. CT colography has good sensitivity for detecting large (>1 cm) polyps (>85%) and for detecting cancers (96%), but it is less sensitive and specific for smaller polyps. CT colography requires bowel preparation, exposes the patient to ionizing radiation, and cannot remove polyps. Colonoscopy may miss 6 to 12% of large (≥1 cm) polyps and 5% of cancers. Of note is that nonpolypoid (flat and depressed) colorectal neoplasms are found in about 9% of asymptomatic and symptomatic adults on colonoscopy and are more likely to contain a carcinoma than are polypoid lesions; these lesions may not be visible on barium radiography or CT.
Flexible sigmoidoscopy, which is often used to screen asymptomatic persons at average risk for colorectal adenocarcinoma, detects 50 to 60% of all polyps and cancers. Generally, patients who have polyps detected by barium radiography, CT colography, or flexible sigmoidoscopy should undergo colonoscopy to remove the lesion and search for additional polyps. In one study in which patients with polyps discovered by flexible sigmoidoscopy underwent subsequent colonoscopy, there was an 80% reduction in the incidence of CRC.
Sessile serrated adenomas/polyps (SSA/P) are a recently recognized neoplastic lesion with malignant potential. In the past, these have been confused with large, benign, hyperplastic polyps. SSA/P are characterized microscopically as having a disorganized and distorted crypt growth pattern. SSA/P are sessile or flat, may be difficult to distinguish on endoscopy and have a right colon predominance. The risk of progression to cancer is at least as high as for conventional adenomas. Pathogenesis is via hypermethylation of CpG islands (“CIMP-high”) and MLH1 , and have BRAF mutations, leading to polyps and tumours with microsatellite instability. Traditional serrated adenomas are a rare subtype that are histologically distinct from SSA/P and have a high prevalence of high-grade dysplasia and carcinoma in situ.
The goal of treatment for neoplastic polyps is to remove or destroy the lesion during endoscopy. This recommendation is based on overwhelming evidence that endoscopic polypectomy reduces the subsequent incidence and mortality of CRC. Pedunculated adenomas are generally removed by snare polypectomy, with subsequent submission of the tissue for pathologic analysis. Piecemeal snare resection may be required to remove sessile polyps. Surgical resection of a polyp is indicated when endoscopic resection of an advanced adenoma is not possible. The biopsied polyp must be evaluated histologically to determine the presence or absence of carcinoma; if a malignant lesion is found, its histologic grade, vascular and lymphatic involvement, and proximity to the margin of resection should be determined. Unfavourable histopathologic factors that should prompt surgical resection include poorly differentiated histology, vascular invasion, lymphatic invasion, and incomplete endoscopic resection. Malignant pedunculated polyps with cancer confined to the submucosa, with no evidence of unfavourable histologic features, can be definitively treated with endoscopic resection, without the need for surgical resection. Whether similar malignant sessile polyps can be managed nonoperatively is controversial. In these cases, the risk of surgery versus the risk of recurrence or lymphatic metastases needs to be balanced.
Patients who have undergone resection of an adenomatous or sessile serrated polyp are at increased risk for the subsequent development of adenoma and colorectal adenocarcinoma. This risk is influenced by the size, histology, and number of adenomas, and the surveillance intervals differ. Low-risk patients—those with only 1 or 2 small tubular adenomas—should undergo colonoscopy in 5 to 10 years. Patients with multiple (>2) adenomas, large (≥1 cm) adenomas, or adenomas with villous or high-grade histology should undergo colonoscopy in 3 years. Patients with numerous (>10) adenomas should undergo colonoscopy within 3 years. Patients who have had polypectomy of a large (≥2 cm) adenoma or an adenoma that had to be removed in pieces (piecemeal resection) should undergo colonoscopy within 6 months to evaluate the completeness of the resection. Patients with sessile serrated polyps smaller than 10 mm without dysplasia should undergo surveillance colonoscopy at 5 years. Patients with sessile serrated polyps 10 mm or larger, high-grade dysplasia, or a traditional serrated adenoma should undergo colonoscopy at 3 years.
COLONOSCOPY SURVEILLANCE INTERVALS
|MOST ADVANCED FINDING||INTERVAL|
|No polyps or small (<10 mm) hyperplastic polyps||10 yr|
|1-2 adenomas, <1 cm||5-10 yr|
|3-10 adenomas or adenoma with villous features, ≥1 cm, or with high-grade dysplasia||3 yr|
|>10 adenomas||<3 yr|
|Sessile adenoma ≥ 2 cm, piecemeal excision||2-6 mo|
|<10 mm, no dysplasia||5 yr|
|≥10 mm or dysplasia||3 yr|
Colorectal cancer is caused by the accumulation of multiple genetic lesions over time. Except for hypermutated tumours, colon and rectal primaries have similar patterns of alterations. Both the tissue architecture and the cellular genotype change as the disease progresses. Three distinct molecular pathways have been recognized: chromosomal instability, microsatellite instability, and CpG island methylator phenotype (CIMP). These pathways are not mutually exclusive, and tumours may exhibit features of more than one.
The chromosomal instability pathway is the most common, accounting for up to 70% of sporadic CRC. The most common gene mutations are in the APC gene (a tumour suppressor gene) and KRAS (a proto-oncogene involved in the transduction of mitogenic signals across cell membranes). Germline mutations in APC are the cause of FAP. Chromosomal instability leads to aneuploidy (imbalance in chromosome number), genomic amplifications, and loss of heterozygosity where cells have only one allele of a gene owing to the loss of individual chromosomes during mitosis. Additional important affected genes include the mutated in colon cancer (MCC) gene (a tumour suppressor gene), p53 (a regulator of the cell cycle), VEGF, MYC, MET, LYN, PTEN, and others. Many of the genetic changes affect the Wnt signalling pathway, which appears to be important for initiation and progression of CRC.
The microsatellite instability (MSI) pathway is caused by defects in DNA mismatch repair. Microsatellites are short, repeating nucleotide sequences that are prone to errors owing to their repetitive nature. MSI-high tumours have genetic defects in the mismatch repair genes, especially MLH1 , MSH2 , MSH6 , and PMS2 . Germline mutations in these genes are the cause of HNPCC (Lynch syndrome). Hypermethylation silencing of MLH1 also results in MSI-high cancers. MSI-high tumours are more common in the right colon, in women, and have a lymphocytic infiltration and poor differentiation. They are associated with improved survival, despite being less responsive to some chemotherapeutic agents such as 5-fluorouracil.
In the CIMP pathway, hypermethylation of DNA promoter regions leads to gene silencing, and silencing of tumour suppressor genes leads to carcinogenesis. In colorectal carcinogenesis, these include APC , MCC , MLH1 , MGMT , and others. CIMP-high tumours are often poorly differentiated with mucinous or signet ring morphology, are MSI-high, and have BRAF mutations. The sessile serrated adenoma is likely the precursor lesion.
The majority of patients with CRC present with symptoms; these may be emergent. Common symptoms related to primary disease include rectal bleeding with or without manifestations of anaemia, abdominal pain, and change in bowel function. Patients with systemic disease may exhibit anorexia, weight loss, and symptoms related to hepatic dysfunction, such as jaundice, icterus, and ascites (the last may also be seen with peritoneal metastases). Symptoms vary depending on the primary site. Proximal lesions are more likely to present with bleeding and associated symptoms; more distal disease has a higher risk of obstruction and perforation. Rectal cancers can also manifest with tenesmus and changes in stool calibre. They involve sacral nerve plexi, causing significant neuropathic pain. Patients with PJS or Gardner syndrome may exhibit extraintestinal manifestations. Patients with Streptococcus bovis bacteraemia or endocarditis are at increased risk of harbouring CRC and should undergo colonoscopy.
The history, physical examination, and judicious use of both laboratory and radiologic tests are important in diagnosing CRC. The history should include the possibility of prior CRC or adenomatous polyps, inflammatory bowel disease, and family history of colonic neoplasia. On physical examination, extraintestinal lesions characteristic of PJS or Gardner syndrome may be noticed. Metastatic disease may be suggested by enlargement of left supraclavicular lymph nodes (Virchow’s nodes) or the liver, or by the presence of an umbilical mass (Sister Mary Joseph’s node) or ascites. The digital rectal examination may reveal a distal rectal cancer or spread of the tumour to the rectal shelf or pelvis (Blumer’s shelf). The stool shows evidence of frank or occult blood in 40 to 80% of advanced cases. Iron deficiency anaemia or an elevation in liver enzymes may aid in the diagnosis. The CEA level may be elevated, but it cannot be relied on for diagnosis, owing to inadequate sensitivity.
Methods for diagnosing CRC are similar to those used to detect adenomatous polyps. Colonoscopy is the procedure of choice for all patients who have occult blood in their stools, unexplained iron deficiency anaemia, or signs and symptoms suggestive of CRC. Colonoscopy is more accurate than barium radiographic studies for the detection of colorectal neoplasms of all sizes and has the advantage of enabling the clinician to detect synchronous cancers and to obtain tissue for histologic analysis.
Additionally, accurate local staging of rectal cancers is paramount. Endoscopic ultrasound combines high-frequency ultrasonography with videoendoscopy. It is superior to CT and allows an accurate determination of the degree of invasion and detection and sampling of enlarged lymph nodes. Endoscopic ultrasound is also highly sensitive for the detection of rectal cancer recurrence after local resection or low anterior resection. MRI using either endorectal or phased array coils can also provide accurate local staging of rectal cancer. Local staging of nonrectal large bowel cancer is generally not performed preoperatively, because this information is not used to guide therapy.
Many expert consensus guidelines now recommend CT scans of the abdomen and pelvis for CRC patients because advanced liver metastases would preclude resection of an asymptomatic primary. Chest imaging with plain films or CT is recommended as well. PET scans have specific uses in defined cases of CRC, such as precluding additional systemic disease before resection of a solitary metastatic site. They may also be used to further describe abnormalities seen on CT. However, there is no role for PET in the routine work-up. Plain abdominal films are mostly useful in diagnosing obstruction.
The purpose of screening is to reduce CRC-related mortality by removing the precursor adenomas and detecting prevalent cancers at earlier, more curable stages. The long latency between adenoma development and subsequent cancer, on the order of 10 to 20 years, makes CRC a preventable disease through colonoscopy with polypectomy. It is an age-associated disease, and most patients should begin screening at age 50. There is a range of options for average-risk individuals. These can be divided into two categories: stool tests, which include tests for occult blood and abnormal DNA, and structural tests, which include colonoscopy, flexible sigmoidoscopy, CT colography, and double-contrast barium enema. Stool tests are best suited for detecting prevalent cancers (and some advanced adenomas), whereas structural tests detect both cancers and adenomas. In a randomized trial of asymptomatic adults 50 to 69 years of age, one-time colonoscopy and faecal immunochemical testing were equally good at finding prevalent colon cancer, but more adenomas were identified by colonoscopy. These tests may be used alone or in combination. Current multisociety guidelines recognize the multiple screening options but encourage the use of structural tests that have the ability to both detect and prevent CRC. For example, the American College of Physicians recommends that clinicians screen for CRC in average-risk adults starting at age 50, and in high-risk adults starting at age 40 (or 10 years younger than the age at which the youngest affected relative was diagnosed with CRC), using a stool-based test, flexible sigmoidoscopy, or optical colonoscopy in patients who are at average risk, but optical colonoscopy in patients who are at high risk. Clinicians should stop screening for CRC in adults older than 75 years or in adults with a life expectancy of less than 10 years.
OPTIONS FOR COLORECTAL NEOPLASIA SCREENING *
|TESTS THAT DETECT ADENOMATOUS POLYPS OR CANCER|
|Colonoscopy||Every 10 yr|
|Flexible sigmoidoscopy †||Every 5 yr|
|CT colography †||Every 5 yr|
|Double-contrast barium enema †||Every 5 yr|
|TESTS THAT DETECT PRIMARILY CANCER †|
|Faecal occult blood tests|
|High-sensitivity guaiac-based faecal occult blood test||Annually|
|Faecal immunochemical test||Annually|
|Stool DNA||Interval uncertain|
CT = computed tomography.
* Beginning at age 50 for average-risk individuals.
† Positive test should prompt full colonoscopy.
Tests for faecal occult blood detect haemoglobin in the stool from bleeding tumours. These tests are either guaiac based or immunochemical based. The guaiac tests detect blood in stool through the pseudoperoxidase activity of heme or haemoglobin. The immunochemical tests react with human globin and are therefore more specific. Guaiac testing consists of collecting two samples from three consecutive stools. To improve test accuracy, individuals undergoing guaiac testing are instructed to avoid aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), vitamin C, red meat, poultry, fish, and some vegetables. Three large prospective randomized trials demonstrated that guaiac-based testing decreased CRC mortality by 15 to 33%, and this benefit appears to persist for 30 years. One large U.S. study also showed a 20% decrease in CRC incidence, attributed to the relatively higher rates of colonoscopy in the study group. Guaiac-based tests have sensitivities for cancer from 35 to 80%. Immunochemical-based tests do not rely on a peroxidase reaction and therefore may have fewer false positives and false negatives. They are done essentially the same way as the traditional guaiac, but they do not require the dietary restrictions of guaiac-based tests and only one stool specimen is collected. The immunochemical tests have better adherence, find 2.5 times as many cancers and advanced adenomas as guaiac-based tests, and are now the preferred faecal occult blood test for screening. Faecal occult blood tests are repeated annually, and any positive test should prompt colonoscopy.
Stool DNA tests rely on the observation that both adenomas and carcinomas contain altered DNA, and this DNA is shed in the stool. Tests contain a multiple marker panel designed to detect exfoliated DNA markers. Collection kits are designed to facilitate stool collection (at least 30 g) and mailing. First-generation stool DNA tests had better sensitivity for CRC (52%) than a guaiac-based test (unrehydrated Hemoccult II; 13% sensitivity) but poor sensitivity for advanced adenomas (15%). Next-generation stool DNA testing with an updated marker panel can identify about 90% of patients with CRC and about 40% of patients with advanced adenomas, with an 87% specificity. Stool DNA testing is more expensive than faecal occult blood testing, and the optimal screening interval has not been defined.
Flexible sigmoidoscopy is capable of examining the distal 60 cm of the colon, or roughly the splenic flexure to the rectum. It can be done with minimal bowel preparation, does not require sedation, and can be performed by primary care providers, nurses, or physician’s assistants. Flexible sigmoidoscopy can detect distal cancers or polyps as well as colonoscopy can. The detection of an adenoma should prompt referral for full colonoscopy, owing to the high prevalence of synchronous neoplasia in the unexamined proximal colon. In one randomized trial, a single flexible sigmoidoscopy performed once between ages 55 to 64 years reduced CRC incidence by 23% and mortality by 31%. In another randomized trial, screening with flexible sigmoidoscopy led to a significant 29% decrease in CRC incidence in both the distal and proximal colon, and a significant 50% decrease in mortality from cancers of the distal colon only. In a third trial, CRC incidence was reduced by 20% and death by 12%. Sigmoidoscopy should be repeated every 5 years and may be combined with yearly faecal occult blood testing.
Colonoscopy allows complete examination of the colon as well as adenoma removal, and thus cancer prevention. In the United States, it is generally done under sedation after an oral bowel preparation, and by physicians with specific training in colonoscopy and polypectomy. Large cohort studies have found an up to 1% cancer rate, 5 to 10% advanced adenoma rate (size > 10 mm, villous histology, or high-grade dysplasia), and at least 20% with 1 or more adenomas. Major complication rates are less than 0.5%, with more than half due to polypectomy. There are no direct randomized studies assessing the efficacy of colonoscopy for screening, although there is a large amount of indirect evidence. Colonoscopy is generally used as the gold standard in assessing other screening methods. In a large randomized Minnesota study of faecal occult blood testing, a decrease in cancer incidence was observed that could be explained only by the use of colonoscopy and polypectomy at a higher rate in the screened population. Randomized and case-control studies of sigmoidoscopy demonstrate a CRC mortality benefit that should also apply to colonoscopy. The National Polyp Study, which followed patients after polypectomy, found that the incidence of CRC was reduced 76 to 90% compared to three reference populations. In another study of patients who had adenomas detected and removed by colonoscopy, the risk of death from CRC at 16 years was only 50% of what was expected in the general population, with most of the reduced incidence found among patients who had low-risk adenomas removed. The efficacy of colonoscopy is influenced by the quality of the exam, with the most important quality markers being the cecal intubation rate (indicating a complete exam) and the adenoma or polyp removal rate. Studies have demonstrated superior CRC prevention when the colonoscopy is performed by a physician with a high adenoma or polyp removal rate. Physician experience and specialty are also important, with gastroenterologists preventing more CRC than other specialties. If the initial screening colonoscopy is normal, further screening can be deferred for 10 years.
Double-contrast barium enema evaluates the entire colon by coating the mucosal surface with high-density barium and insufflating with air via a rectal tube. Multiple radiographs are obtained while varying the patient’s position under fluoroscopy. It requires a colon preparation and exposes the patient to a small amount of ionizing radiation. There are no studies of double-contrast barium enema as a screening test. It is 85 to 97% sensitive for colon cancer, but its sensitivity for detecting large adenomas is only 48 to 73%. It should be repeated every 5 years. The finding of a polyp larger than 5 mm should prompt colonoscopy.
CT colography (also known as virtual colonoscopy) uses multidetector CT technology to obtain two- and three-dimensional images of the entire colon. It requires an adequate colon preparation and gaseous distention of the bowel using a rectal tube. Tagging of residual stool with barium or iodinated contrast material is frequently used. CT scanning is performed with the patient in the supine and prone positions. No studies have been done to evaluate the efficacy of CT colography in decreasing CRC incidence or mortality. CT colography has been compared with standard colonoscopy for the detection of neoplasia in screening populations. The sensitivity of CT colography for large (≥10 mm) polyps is 85 to 92%, with a specificity of 83 to 86%. For polyps 5 mm or larger, CT colography is about 65% sensitive and 89% specific. Sensitivity for CRC (96%) is similar to that of colonoscopy. Laxative-free CT colography is accurate in detecting adenomas 10 mm or larger but less so for smaller lesions. Although the optimal interval for testing has not been established, it is recommended that CT colography screening begin at age 50; if negative, it should be repeated at 5-year intervals. If a polyp larger than 5 mm is found, colonoscopy should be performed.
Accurate staging of CRC is of the utmost importance in determining both prognosis and the most relevant and effective therapy. The versions of the TNM classification system for large bowel cancers used by the American Joint Committee on Cancer and the International Union Against Cancer are identical. Differing from many solid tumours (although not those of other GI origin, except for anal cancer), CRCs are not staged according to size. Stage I cancers penetrate into but not through the bowel wall (T1–2N0M0), whereas stage II cancers penetrate through the wall and can involve nearby organs without spreading to regional lymph nodes. About 40% of patients present with stage I or II disease in the United States. Stage III cancers involve regional lymph nodes and constitute about 40% of presenting cases. Stage IV colorectal tumours (distant metastasis or metastases) commonly involve liver, lung, distant nodes, and peritoneum, with about 20% of patients presenting with this stage. Rectal primaries, because of early access to the systemic circulation, may involve the lungs without liver metastases; this pattern of spread is distinctly unusual in proximal large bowel cancers.
STAGING FOR COLORECTAL ADENOCARCINOMAS
|IVA||Any T||Any N||M1a|
|IVB||Any T||Any N||M1b|
Tis = in situ; T1 = submucosa; T2 = muscularis propria; T3 = subserosa, pericolorectal tissues; T4a = visceral peritoneum; T4b = other structures.
N1a = 1 regional node; N1b = 2-3 regional nodes; N1c = satellite(s) without regional nodes; N2a = 4-6 regional nodes; N2b = ≥7 regional nodes.
M1a = 1 organ; M1b = >1 organ, peritoneum.
The prognosis for patients with CRC depends primarily on stage. Five-year survival for patients with proximal (colonic) adenocarcinomas ranges from a low of 6 to 8% for those with metastatic disease to approximately 95% for those with stage I resected tumours. Corresponding rates for rectal cancers are similar to slightly inferior overall, ranging from 4 to 72%. Besides TNM stage, additional factors that are prognostic for poorer outcomes in patients undergoing potentially curative resection include signet ring histologic subtype (see preceding discussion under Pathobiology), lymphovascular and perineural invasion, absence of host lymphoid response, presence of clinical obstruction preoperatively, high preoperative serum levels of the CEA tumour marker, positive margins, high tumour grade, and microsatellite-stable disease. Differing from many solid tumours originating outside the GI tract, CRCs do not have different prognoses based on size.
Genetic factors are important as well, even in the metastatic setting. Patients with tumours harbouring BRAF mutations appear to have a worse outcome. KRAS mutations were formerly thought to be prognostic but now appear to be only predictive for lack of benefit from certain types of systemic therapy.
NSAIDs, including aspirin, are believed to reduce adenoma formation and inhibit colon cancer development by inhibiting cyclooxygenase and subsequent prostaglandin generation. Prostaglandins (e.g., E 2 ) promote cell proliferation and tumour growth. The NSAIDs sulindac and celecoxib cause regression of existing adenomas and inhibit the formation of new adenomas in patients with FAP. Epidemiologic studies have shown decreased CRC rates in regular users of NSAIDs. Randomized trials of aspirin have shown 20 to 40% reductions in adenoma recurrence. A secondary analysis combining data from four European vascular event prevention trials reported up to a 70% reduction in the incidence of CRC when at least 75 mg of aspirin daily was continued for 5 or more years. However, the 4 individual studies and two large American trials (Women’s Health Trial, Physicians Health Study) did not find an aspirin benefit. Calcium supplementation (1200 mg/day) was shown to decrease the rate of metachronous adenomas by 20%. However, the large Women’s Health Trial (36,000 participants) found that calcium (1000 mg) plus vitamin D (400 IU) had no effect in reducing CRC incidence. Currently, the routine use of aspirin and calcium for CRC prevention is not recommended, but it may be considered on an individual basis.
Epidemiologic studies have reported correlations between CRC and obesity, smoking, inactivity, excessive alcohol use, and diets high in fat and low in fruits, vegetables, and fibre. These observations suggest that lifestyle modifications may decrease CRC risk. Unfortunately, three randomized intervention trials of modest dietary changes (10% less fat, 25 to 75% more fibre, 50% more fruits and vegetables) found no significant reductions in adenomas or CRC over 3 to 8 years of follow-up. Fish consumption is inversely associated with CRC incidence, and eicosapentaenoic acid supplementation decreases polyp burden in FAP.
Resection is the primary treatment modality for patients with regionally confined CRC. Highly selected patients with metastatic disease may also undergo surgery with curative intent. The goal of curative surgery for colonic adenocarcinoma is margin-negative elimination of the tumour, plus en bloc removal of the primary feeding arterial vessel and corresponding lymphatics for that segment of bowel. A minimum of 12 lymph nodes should be retrieved for microscopic examination to assure staging accuracy. Synchronous colon cancers may be removed individually or with subtotal colectomy, and tumours adherent to adjacent structures should be resected en bloc. Prophylactic oophorectomy is no longer recommended, but women with one ovary grossly involved with cancer should undergo bilateral oophorectomy because of the relatively high risk of involvement of the other side. Laparoscopic resection is currently thought to be as effective as open resection and requires a modestly shorter recovery time. Very preliminary data suggest elderly patients undergoing a laparoscopic procedure have a lower chance of being discharged to a nursing home (as opposed to their own residences) than those treated with standard resection.
In general, surgical considerations for rectal primaries are similar. Total mesorectal excision (en bloc removal of the lymphovascular and fatty envelope surrounding the rectum) is recommended for distal cancers, whereas tumour-specific mesorectal excision (en bloc removal of the mesorectum 5 cm distal to the tumour) should suffice for upper rectal tumours. Local transanal excision is acceptable for selected low rectal cancers thought to have minimal risk of nodal involvement. Selection criteria include the following: T1 disease, size less than 3 cm, low grade (well differentiated), location within 8 cm of the anal verge, no lymphovascular invasion, and less than one third circumferential. The wide spectrum of symptoms that occur in most patients after resection and reconstruction of the rectum, ranging from increased bowel frequency to faecal incontinence or evacuatory dysfunction, has been termed anterior resection syndrome.
Resection of the primary formerly was recommended for patients presenting with synchronous CRC and unresectable metastases, regardless of whether the primary caused symptoms. This practice pattern obviously had the potential to delay systemic treatment in patients who were markedly more likely to die from their metastases before suffering significant complications from the intact large bowel tumour. Recent data suggest that stage IV patients with an asymptomatic primary tumour can safely begin systemic therapy without undergoing surgery, with only a small chance of developing serious complications requiring urgent operative interaction. Patients with rectal primaries may be at slightly higher risk for developing complications than those with tumours originating in the proximal large bowel.
Obstructing tumours that can be fully removed should be resected, with bowel anastomosis usually being acceptable in this setting. Proximal diversion alone, especially in the setting of very locally advanced unresectable cancer, may be necessary; if the primary tumour responds to the point where it can later be removed, resection followed by ostomy closure is reasonable. Endoscopic stenting may be useful to relieve acute obstruction. Perforated bowel is usually resected, with the choice of anastomosis, with or without diversion, depending on a number of factors, including degree of faecal contamination and general health of the patient.
Radiation therapy may be used as curative or palliative treatment of large bowel cancers. In general, it is employed much more commonly in treating rectal versus colonic primaries. Single-institution trials have shown that irradiation improves local control following resection of high-risk proximal large bowel (colonic) cancers, but these findings were not confirmed in a randomized intergroup trial that closed early owing to slow accrual. Current recommendations for adjuvant radiation to the tumour bed following colon cancer resection include positive margins and localized perforation. Some authorities also advocate its use in colon cancers at particularly high risk of local recurrence (T4, T3N1-2 tumours in the ascending or descending colon), but that recommendation is not universally accepted. Irradiation may still play a role in treating colon cancer metastases to bone, brain, liver, and lung, as well as in cases of bleeding, obstruction, and locally advanced unresectable disease.
A major use for radiation in the definitive treatment of large bowel adenocarcinoma involves perioperative therapy for resectable rectal cancer. It is also commonly employed with chemotherapy for unresectable locally advanced invasive tumours, which occasionally may downsize and be surgically removed after therapy. As with colon primaries, irradiation may be used to palliate bleeding, obstruction, or selected metastases from rectal cancers.
The backbone of CRC treatment in both the adjuvant and metastatic settings is a fluorinated pyrimidine. The most commonly used drug is 5-fluorouracil (5-FU), although oral prodrugs are increasingly being used. 5-FU targets the enzyme thymidylate synthase, inhibiting DNA synthesis and/or repair. It also may be incorporated into RNA, interfering with further processing. Although not particularly effective as a single agent (see later), 5-FU’s efficacy can be enhanced by changing its means of administration (prolonging infusion) and by administering it with a variety of biochemical modulators, most commonly leucovorin. Other chemotherapeutic agents commonly used in treating advanced CRC include irinotecan, a topoisomerase I inhibitor, and oxaliplatin, a later-generation platin that forms bulky DNA adducts that inhibit replication. Recent effective biologics include agents targeting vascular endothelial growth factor (bevacizumab) or circulating VEGF (aflibercept), the epidermal growth factor receptor (cetuximab, panitumumab), or a combination of the VEGF and various tyrosine kinase receptors (regorafenib).
Patients with resected stage I colon cancers have a high cure rate, and this cannot easily be improved on with systemic therapy. Stage II patients have a higher chance of relapse (event-free survival ≈ 76% at 3 years), and systemic therapy with 5-FU and leucovorin improved that figure by about 3% for an unselected group of node-negative patients. Patients harbouring highly microsatellite-unstable tumours have a better prognosis in general but may actually have worse outcomes with 5-FU treatment, although that is controversial. Treatment of stage II patients remains controversial in general: some experts suggest that the proportional benefit of systemic therapy is as great as it is in stage III disease, while others point out the low absolute magnitude of benefit and do not advocate its use. Risk stratification using molecular markers has been attempted but has not been demonstrated to have predictive capabilities, with the exception of microsatellite instability and its described resistance to fluoropyrimidines. Some clinical categories of stage II disease are believed to be at particularly high risk for recurrence (e.g., obstruction). These patients usually receive postoperative chemotherapy, often with regimens commonly prescribed for patients with stage III cancer. Radiation has been tested in patients thought to be at higher-than-average risk of local relapse (T4 tumours), but its use is not standard. Other drugs useful in metastatic disease and resected node-positive patients (specifically oxaliplatin) are not routinely recommended nor used in those with stage II cancers.
Five-year disease-free survival for patients with stage III colon cancer ranges from 45 to 85%, depending on substage. Barring significant comorbidities or other confounding factors, all patients with node-positive disease receive adjuvant systemic therapy. Combinations of 5-FU and oxaliplatin (usually FOLFOX [fluorouracil, leucovorin, oxaliplatin]) clearly improve long-term survival rates and represent standard care. Regimens containing irinotecan and biologics (bevacizumab, cetuximab) are highly effective in the treatment of advanced disease (see later), but oddly they do not clearly benefit patients when they are given in the postoperative setting. Patients who are not candidates for combination chemotherapy may be offered capecitabine, an oral prodrug activated to 5-FU in sequential enzymatic steps. Capecitabine has also been combined effectively and relatively safely with oxaliplatin for adjuvant use. An important outstanding question regarding adjuvant chemotherapy is whether a shorter duration (3 months vs. the standard 6) might be equally effective, as suggested in one small randomized trial.
Therapeutic considerations are slightly different for patients with primary rectal adenocarcinomas, owing to the difficulty of achieving negative circumferential (radial) margins. Specifically, the risk of local recurrence is much more significant. Adjuvant chemotherapy for rectal cancer is still controversial. In general, rectal cancer patients undergoing standard resection for stage I tumours do not receive additional treatment. However, higher-risk patients (T2 disease, T1 with poorly differentiated histology, perineural or lymphovascular invasion, or close margins) treated with local excision should receive postoperative pelvic irradiation with or without 5-FU chemotherapy, or they should return to the operating room for total mesorectal excision. Irradiation is standard for those with stage II and III rectal adenocarcinomas to decrease local relapse rates, increase the chance of sphincter preservation (when used in selected preoperative settings for low-lying cancers), and possibly improve survival. The major considerations are timing (pre- or postoperative use), course (short or long), and whether to combine it with fluoropyrimidine-based chemotherapy. Short-course (5-day) preoperative irradiation without chemotherapy may be considered and used if tumour downsizing is not necessary. When short-course radiation is used, patients still require postoperative systemic therapy with either a fluoropyrimidine alone (stage II) or a fluoropyrimidine-oxaliplatin combination regimen (node-positive disease). Long-course irradiation (≈5.5 weeks) is particularly important when tumour response is necessary to make surgery easier or more feasible. It is usually combined with continuous-infusion 5-FU or capecitabine, and it can be given pre- or postoperatively (if the patient did not receive preoperative short-course radiation). Including oxaliplatin preoperatively does not improve results and is not recommended independent of a clinical trial, owing to its higher toxicity profile. Oxaliplatin may be used postoperatively if the pathology specimen demonstrates nodal involvement. With long-course irradiation, preoperative (compared with postoperative) treatment is less toxic and may offer improved local control. However, it requires accurate preoperative staging (to avoid treating patients who might have stage I disease). Highly selected rectal cancer patients thought to be at low risk of local recurrence (T3N0 or T1-2N1) may receive total mesorectal excision plus best systemic therapy without irradiation, usually postoperatively.
Metastatic disease is treated identically, regardless of the site of origin (colon vs. rectum). Patients with incurable metastatic CRC have a median survival of approximately 6 months with best supportive care alone; however, incremental gains made through the adoption of new systemic therapies have extended that time to nearly 2 years or more. For example, treatment with single-agent fluoropyrimidines leads to median survival in the 10- to 13-month range; adding one more effective chemotherapy drug (either irinotecan or oxaliplatin) affords survival of about 15 to 20 months, and adding both drugs to 5-FU has been reported to extend life to 23 months. Interestingly, long-term results seem to be similar regardless of which drug (oxaliplatin or irinotecan) is added to 5-FU first (although the toxicity pattern varies, depending on which drug is given), or even regardless of whether 5-FU is used first and combination chemotherapy is used subsequently, as long as patients are eventually exposed to all active agents.
Additional improvements have arisen through the development of drugs that are more convenient and/or less toxic than standard agents, although they may not be more effective. Capecitabine, an oral prodrug activated to 5-FU in three sequential enzymatic steps, can be substituted for that agent alone and in combination with oxaliplatin (although patients still need intravenous access for the latter drug).
Recent breakthroughs have mostly been related to use of biologic agents. Drugs used successfully to date include several monoclonal antibodies and one oral tyrosine kinase inhibitor. Bevacizumab is a humanized monoclonal antibody directed against vascular endothelial growth factor, an important mediator of angiogenesis. Bevacizumab has little single-agent activity against CRC, but it improves the interval without progression when added to irinotecan- or oxaliplatin-containing chemotherapy. Bevacizumab with FOLFOX or FOLFIRI (fluorouracil, leucovorin, irinotecan) now represents first-line treatment for patients with advanced large bowel cancer in the United States, and many oncologists continue its use along with second-line fluoropyrimidine-based chemotherapy. Aflibercept, or VEGF trap, is a fusion protein with VEGF-binding portions from VEGFR and the Fc portion of IgG1. It prevents VEGF-A and B from binding to receptors. A second-line trial after oxaliplatin failure showed aflibercept with irinotecan- and fluoropyrimidine-based chemotherapy (FOLFIRI), improves survival over chemotherapy with placebo. It is unknown whether it is better to continue bevacizumab versus switching to aflibercept in the setting of second-line therapy.
The epidermal growth factor receptor (EGFR) is another important target in advanced CRC. Cetuximab and panitumumab are monoclonal antibodies (chimeric and human, respectively) directed against the EGFR. They have single-agent activity against CRCs, and both may be combined with irinotecan-based chemotherapy to improve progression-free survival. Panitumumab also improves progression-free survival front-line when combined with oxaliplatin-containing chemotherapy. Although both agents appear effective in front-line or later use, efficacy is restricted to patients whose tumours harbour wild-type KRAS.
Regorafenib is an oral inhibitor of angiogenic (VEGFR-1, -2, -3, and TIE-2), stromal (PDGFR-B, FGFR), and oncogenic (KIT, RET, BRAF) tyrosine kinases. It has activity in advanced CRC, improving progression-free and overall survival after failure of standard therapies.
Complete resection of hepatic or pulmonary metastases may result in long-term survival and is the standard of care for selected patients with CRC. The majority of data exist for hepatic metastasectomy. Actuarial 5-year survival rates have been in the 25 to 60% range. However, relapse after 5 years still occurs, suggesting that this percentage does not reflect the number actually cured with surgery. That figure, calculated from 10-year survival rates, is probably between 17 and 25%, which still compares quite favourably with the survival rate for patients with CRC metastatic to the liver who do not undergo surgery. The role of preoperative systemic therapy in potentially resectable patients remains controversial; if used, a fluoropyrimidine with either oxaliplatin or irinotecan +/− panitumumab (for wild-type KRAS ) or irinotecan-based chemotherapy +/− cetuximab (for wild-type KRAS ), or triple chemotherapy with a fluoropyrimidine, oxaliplatin, and irinotecan may be employed. In those undergoing metastasectomy, many experts advocate 6 months of postoperative fluoropyrimidine-based chemotherapy, often with oxaliplatin. Importantly, bevacizumab can impair wound healing, and most experts avoid its use in the immediate perioperative period.
Small liver metastases that are not resectable because of anatomic location or in a frail patient unable to undergo hepatic resection may be treated with radio frequency ablation, which uses alternating electric current to generate heat, destroying malignant cells through protein coagulation. Although it has never been directly compared with resection in a randomized trial, radio frequency ablation appears to offer inferior local control of disease. Some advocate the placement of a hepatic artery pump to infuse fluoropyrimidine-based chemotherapy to treat unresectable liver-predominant metastases. Other techniques useful in noncolorectal liver-based tumours (e.g., hepatocellular carcinoma), such as chemoembolization, have no proven role for large bowel liver metastases.
Surveillance should be undertaken in patients fit enough to undergo metastasectomy or systemic therapy for recurrent CRC. The American Society of Clinical Oncology recommends annual CT of the chest and abdomen for 3 years following resection of high-risk primary tumours, with pelvic CT added in cases of rectal origin. Colonoscopy should also be done at 3 years and then every 5 years, with flexible proctosigmoidoscopy offered to rectal cancer patients who have not received irradiation. Physical examinations should be performed every 3 to 6 months for 3 years, then biannually for at least 2 more years. CEA levels should be checked every 3 months for at least 3 years, although the benefits for improving outcome are uncertain.
Colorectal cancer remains a significant problem despite the fact that most cases can be prevented. Large gains have been made in terms of overall survival, but the vast majority of patients with advanced disease still succumb to their malignancy. Minimal tailoring can currently be offered to patients (e.g., selecting a chemotherapeutic agent based on toxicity or not using an anti-EGFR antibody in those with KRAS -mutated tumours); the dream of truly individualized therapy remains elusive but is under active study.