SeminarColorectal cancer
Section snippets
Pathogenesis
Most large bowel cancers arise within pre-existing adenomatous polyps or adenomas. These lesions are common. True incidence is difficult to calculate in symptom-free and unselected populations, but necropsy studies have shown a prevalence of about 35% in Europe and the USA, with lower rates (10–15%) in Asia and Africa. Adenomas are classified by histological architecture as tubular, tubulovillous, or villous. Villous change is associated with a higher malignant potential, as are large (up to
Molecular biology and genetics
Relative colorectal cancer risk is defined by genetic predisposition and environmental factors, including a diet low in fibre, vegetables, and folate, and high in fat, red meat, and alcohol, sedentary occupation, and cigarette smoking.
Recognition of the genetic component of colorectal cancer is growing. Mutations are present as inherited germline defects or arise in somatic cells secondary to environmental insult. There are two main inherited predisposition syndromes: familial adenomatous
Sporadic colorectal cancer
Vogelstein and colleagues3 have proposed a multistep model for the genetic events in the progression of sporadic colorectal cancer. Colorectal cancer occurs mainly in the elderly, which is consistent with the theory that a cell must accumulate a combination of four or five defects, including mutational activation of oncogenes and inactivation of tumour-suppressor genes, to undergo full malignant transformation. If one or more of these defects are present at birth as germline abnormalities,
FAP
FAP is an autosomal dominant disorder in which multiple adenomatous polyps develop in the colon during the second and third decades of life. These polyps are histologically identical to those preceding sporadic colorectal cancer, and, although individually each has little risk of malignant transformation, the numbers (reaching thousands in some patients) mean that the risk of colorectal cancer is almost 100% by age 40 years.4
The gene that causes FAP (the adenomatous polyposis coli [APC] gene)
HNPCC
HNPCC describes an autosomal dominant predisposition to colorectal cancer that lacks the excess polyposis seen in FAP. The disorder is thought to account for up to 6% of colorectal cancer cases. HNPCC is classified into two Lynch syndromes, and an international group has defined a set of diagnostic criteria—the Amsterdam criteria10, 11 (panel). Clinical features of HNPCC include an association with other tumours (endometrium, ovary, hepatobiliary tract, skin), a predilection for the right side
Screening and prevention
The premises underlying any cancer screening programme include a sensitive and specific screening assay and a likelihood that early detection of disease will result in more patients being seen who can be cured by surgical intervention. Patients at increased risk of colorectal cancer cannot be defined by family history. Molecular genetic studies looking for relevant germline mutations could elucidate relative risk for patients, in particular families (for example in families with FAP the
Faecal occult blood tests
The faecal occult blood test is a cheap investigation and causes the patient little discomfort. There are several types of test, including immunological and haemporphyrin assays, but the most commonly used is the Haemoccult test. Filter paper impregnated with guiac undergoes phenolic oxidation in the presence of haemoglobin in the stool after the addition of hydrogen peroxide. The test detects 10 mL of blood loss per day in 67% of patients and more than 20 mL blood loss per day in 80–90% of
Flexible sigmoidoscopy
Flexible sigmoidoscopy is quick and simple and gives high sensitivity and specificity but has the disadvantage that only 65% of adenomas and early cancers can be visualised because of limited access. Results from two case-control studies are, however, promising. Newcomb25 reviewed medical records of 66 patients with colorectal cancer and 196 controls. Individuals who had undergone a single assessment by sigmoidoscopy had lower mortality risks from cancers of the rectum and distal colon than
Colonoscopy
The disadvantage of flexible sigmoidoscopy is that only the distal 65 cm of the colon can be examined. This limitation may not, however, be critical, since evidence suggests that distal adenomas have a higher potential than proximal adenomas for malignant progression. Adenomas found on sigmoidoscopy could select patients for more extensive investigation (barium enema or colonoscopy). The alternative primary intervention is full colonoscopy. Although this procedure can decrease mortality by up
Heterogeneity between surgeons
Surgeons have played an important historical part in establishing clinical audit for postoperative morbidity and mortality. Despite this role, there is substantial variability between surgeons in the outcomes they achieve. A review of patients in Scotland managed by 13 surgeons, none of whom had a special interest in surgery for colorectal cancer, showed adjusted hazard ratios for all patients of 0·59-1·61.29 Similar variability was seen for outcome data from a series of more than 3000 patients
Surgery for colonic tumours
The colon and rectum are anatomically distinct and present different difficulties to the surgeon. The principles of radical surgical resection for colonic tumours have generally remained unchanged in the past few decades. The procedure involves ligation of the major vascular pedicle, obtaining tumour-free margins, and resection of any contiguous involved organ. Ligation of the vascular pedicle enables wide excision of lymph nodes draining the tumour, which is helpful in histopathological
Surgery for rectal cancer
Resection margins and surgical technique are especially important in determining outcome for rectal tumours compared with colon tumours, since anatomical constraints make surgery to remove tumours more complicated.
Williams and colleagues31 reported that only three of 50 patients undergoing abdominoperineal resection had involved lymph nodes distal to the gross tumour within the mesorectum. Despite this finding, MacFarlane and colleagues32 advocate complete excision of the mesorectum for rectal
The role of the pathologist
Pathological investigation of resected samples provides essential prognostic information that facilitates treatment decisions, such as the offer of adjuvant chemotherapy. The Dukes and Astler-Collins staging systems are widely used, but there is increasing international uptake of the tumour node metastisis (TNM) system. Additional factors that one would expect to be reported routinely in the pathology report include tumour grade, evidence of vascular invasion or lymphocyte infiltration, and the
Follow-up for colorectal cancer
There is continuing debate on the best method of follow-up for patients with colorectal cancer and current practices vary widely from single clinical surveillance to repeat laparotomy. This variety is of importance, since between 3% and 10% of patients have been estimated to be eligible for potentially curative surgery if relapse is detected at an early stage. However, randomised trials show no survival advantage for patients who are followed up intensively, such as by regular ultrasound,
Chemotherapy and radiotherapy
The anatomical differences between colon and rectal cancer and the ease of surgical intervention determine the pattern of recurrence, which defines the most appropriate adjuvant and relapse treatments. About 50% of recurrences of rectal cancer occur in the pelvis and are, therefore, amenable to local radiotherapy. By contrast, relapse of colon cancer is generally at distant sites-liver, lungs, and bone-and systemic chemotherapy seems more appropriate.
Chemotherapy
Fluorouracil has been the mainstay of chemotherapy for colorectal cancer for four decades. It is a prodrug which is converted intracellularly to various metabolites that inhibit synthesis of thymidine, DNA, and RNA (figure 2). Insights into its molecular pharmacology have led to several strategies to modulate its cytotoxic effects. The most important is coadministration with folinic acid, which increases the degree of inhibition of thymidylate synthase, depletes cellular thymidine, and induces
Systemic chemotherapy for advanced disease
Five randomised controlled trials of fluorouracil-based chemotherapy compared with the best supportive care in advanced colorectal cancer showed consistently better survival (by 3–6 months) and equal or better quality of life with early active treatment before symptoms occurred (figure 3).36 The overall benefits of chemotherapy are probably underestimated because of the high crossover to chemotherapy from the control groups when symptoms occurred (60% in the Nordic Study Group).
Many
Hepatic arterial chemotherapy for metastatic disease
Regional chemotherapy depends on the premises that most cytotoxic agents have steep dose-response curves and that high drug concentrations can be generated within a target organ (eg, liver) or body cavity (eg, peritoneum) because of differential drug clearance. Up to 20% of patients who relapse after an apparently curative resection of colorectal cancer present with disease macroscopically confined to the liver, which suggests that hepatic arterial chemotherapy could be a useful treatment.
Adjuvant chemotherapy
Despite 80% of patients with colon cancer having complete macroscopic clearance of their disease by resection, 50% of these patients develop recurrence, presumably because of disseminated micrometastases present at the time of surgery. Adjuvant chemotherapy is used to eradicate these circulating cancer cells before they become established and refractory to intervention. The Intergroup trial38 tested adjuvant chemotherapy after surgery with stage B colorectal cancer compared with surgery
Rectal cancer and radiotherapy
In advanced rectal cancer, radiotherapy can improve pain, staunch haemorrhage, and lessen tenesmus. In patients with inoperable local advanced disease, radiotherapy can convert 35–75% to resectability.44 Radiotherapy has been assessed as an adjuvant therapy. In the largest trial of radiotherapy before surgery (the Swedish Rectal Cancer Trial45), administration of 25 Gy over five fractions produced a relative decrease in local recurrence rate of 61% and an improvement in overall survival (58 vs
Cytotoxic agents
Raltitrexed is a quinazoline antifolate that directly inhibits thymidylate synthase. It gains entry to cells via the reduced folate carrier system and is polyglutamated to a potent, long-life inhibitor of thymidylate synthase. Raltitrexed administered by intravenous bolus (3 mg/m2) every 3 weeks has been compared with bolus fluorouracil and folinic acid (daily for 5 days every 4 weeks) in three randomised trials, including about 1500 patients with advanced colorectal cancer. Tumour response
Immunotherapy
Colorectal cancer has never been a very obvious target for immunotherapeutic intervention. Many cytokines have been tested and found to be inactive. Riethmuller and colleagues59 did a randomised study of a murine monoclonal antibody, which binds a tumour-specific cellsurface glycoprotein (17-1a), compared with a control as an adjuvant therapy in 189 patients with stage C colorectal cancer. Survival was significantly lengthened in the antibody-treated group (5-year survival rates 51 vs 36%,
Gene therapy
Cancer gene therapy encompasses many genetic manipulation strategies, including insertion of genes encoding cytokines, expression of tumour-suppressor genes to inhibit proliferation, and insertion of genes such as p53 that might lead to sensitisation to conventional cytotoxic therapy. Phase I trials have been completed of adenoviruses used to deliver the tumour-supressor p53 gene by hepatic arterial infusion.62 The virus was well tolerated and will enter Phase II trials in combination with
Biological agents
There are several innovative therapies in preclinical and early clinical development for colorectal cancer that are based on understanding of molecular and cellular carcinogenic events. These therapies include small-molecular-weight inhibitors of the K-ras oncogene, which have an antiproliferative effect by prevention of posttranslational modification of the mutant protien. Agents used include potent inhibitors of the matrix metalloproteinase enzymes essential for tumour invasion and metastasis
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