Colorectal cancer

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Chapter 17 COLORECTAL CANCER

• Colorectal cancer is a major health concern with more than one million new cases yearly, and an overall mortality rate of 50% worldwide.

• Surgery is the primary and definitive curative intervention.

• Adjuvant chemotherapy, following curative surgery, is essential in stage III.

• The new standard of adjuvant care is fluorouracil, folinic acid and oxaliplatin for 6 months.

• Combination chemotherapy with biological agents (bevacizumab) is the gold standard in advanced disease.

• Long-term survival for patients with resectable liver and lung metastasis is 30%–40%.

• Combination chemoradiotherapy is mandatory in patients with rectal cancer, preferably prior to surgery.

RISK FACTORS

Environmental and genetic factors can increase the likelihood of developing colorectal cancer (CRC) (Table 17.1). Although inherited susceptibility most strikingly increases the risk, the majority of CRCs are sporadic. Age is a very important risk factor. It rarely occurs before the age of 40, and the incidence begins to increase significantly in the sixth decade, with the highest rate between 65 and 75 years. The incidence rate is higher in industrialised regions, higher in African American than in whites, and it is nearly equal for males and females (M:F ratio1.3:1.0 for rectal tumours).

TABLE 17.1 Risk factors for colorectal cancer (CRC)

Risk factor	Examples	Risk
Genetic disorders	Familial adenomatous polyposis	I
	Hereditary non-polyposis colorectal cancer	I
	Peutz-Jeghers syndrome	I
	Hyperplastic polyposis	I
	Cowden’s syndrome	I
	Juvenile polyposis syndrome	I
Personal history of CRC or adenoma		I
Family history of CRC or adenoma		I
Inflammatory bowel disease	Ulcerative colitis, Crohn’s disease	I
Medications	NSAIDs, aspirin, calcium, vitamin D, statins, hormone replacement therapy (in postmenopausal women)	D
Endocrine disorders	Diabetes mellitus	I
	Insulin resistance	I
	Acromegaly	I
	Obesity	I
	Gastrin	I
Surgical interventions	Cholecystectomy	I
Surgical interventions	Ureterocolic anastomoses	I
Environmental factors	Smoking	I
	Moderate physical activity	D
	Healthy diet (low calorie, rich in fruits and vegetables with low animal products)	D
	Alcohol (moderate and high amount)	I

D = decrease risk for CRC; I = increase risk for CRC; NSAIDs = non-steroidal antiinflammatory drugs.

SYMPTOMS

The majority of patients will present with change in the regular bowel habits, rectal bleeding (rarely melaena) and/or iron deficiency anaemia, abdominal pain, or a combination.

Symptoms may vary according to the site of the tumour. Approximately 25% of the patients have metastatic disease at the time of diagnosis. The most common metastatic sites are the regional lymph nodes, liver, lungs and peritoneum. Ovaries, adrenals, bone, skin and brain may be involved as well. Patients may present with signs or symptoms in any of these organs.

Patients who are symptomatic at the time of diagnosis have a somewhat worse prognosis.

Intestinal obstruction or colonic perforation carries a poor prognosis regardless of the stage of the tumour.

GENETICS

Cancers are all caused by abnormalities in genes, although most cancers are not caused by inherited genetic disorders. Cancer is the result of complex interactions between the fingerprints of the genome and interaction with the environment. For most cancers, the wide variations seen among different national groups appear to be explained almost entirely by environmental factors with familial factors playing a minor role. The exception to this is malignancy in the colon where genetics is much more important. CRC follows three major patterns:

• Sporadic—no family history. This type accounts for about 75% of the cases, and it is most common in subjects older than 50 years. Age, dietary and environmental factors are the most important known risk factors.

• Familial predisposition to CRC. This accounts for about 20% of the cases. Although there is a clear family history of CRC, the pattern is not consistent with any of the inherited syndromes described below. The relative risk for a single affected first-degree relative is 1.7. The risk is further increased if more relatives have CRC, or if affected relatives were diagnosed before 55 years of age.

• Inherited polyposis syndromes—5% of cases are due to these syndromes. This type includes familial adenomatous polyposis (FAP), hereditary non-polyposis colorectal cancer (HNPCC), hamartomatous polyposis syndromes (e.g. Peutz-Jeghers, juvenile polyposis), hyperplastic polyposis and Cowden’s syndrome. These conditions are associated with a very high risk of developing CRC (as well as other tumours outside the gastrointestinal tract), and the genetic mutations underlying many of them have been identified (Table 17.2).

TABLE 17.2 Inherited polyposis syndromes

MULTI-STEP MODEL OF CRC

Specific genetic mutations

The APC (adenomatous polyposis coli) gene on chromosome 5 is the most critical gene in the early development of CRC. Somatic mutations in both alleles are present in 80% of sporadic CRCs. Most sporadic CRCs with wild-type APC have mutations in other genes of the Wnt signalling pathway, mostly in β-catenin.

The K-ras oncogene is found in up to 50% of sporadic adenomas and CRC. It encodes a family of G-proteins that regulate cellular signal transduction by acting as a one-way switch for the transmission of extra-cellular growth signals to the nucleus. Once mutations occur, they leave the ras in a constitutively active state that leads to a continuous growth stimulus.

The p53 gene located on chromosome 17p is the most commonly mutated gene in human cancer. It serves as the guardian of the genome. It is particularly critical when cells are under stress. Normally, cells arrest their growth in response to DNA damaging agents by induction or activation of p53. Once activated, p53 induces a variety of growth-limiting responses, including cell cycle arrest (to facilitate DNA repair), apoptosis, senescence and differentiation. In about 50%–70% of CRCs, p53 inactivation occurs by a mutation of one allele followed by loss of heterozygosity (LOH), as a late event in the transition from large adenoma into CRC. Patients who harbour p53 mutations have worse outcomes and shorter survival.

There are three candidate tumour suppressor genes on chromosome 18q. DCC (deleted in colon cancer), SMAD4 and SMAD2 genes were identified through studies of allelic loss. One copy of 18q was lost in 73% of sporadic CRC, and in 47% of advanced adenomas. For patients in stage II with DCC gene the prognosis is similar to that of patients with advanced stage III disease. The practical importance of this knowledge may be the identification of a subgroup of patients with stage II disease who may benefit from adjuvant chemotherapy.

Mismatch repair genes

Mismatch repair genes are the hallmark of HNPCC, but are also found in 15% of sporadic CRC. They are involved in correcting base mismatches and small insertions or deletions that occur during DNA replication. MSH2 and MLH1 are the most important ones followed by MSH6, MSH3, PMS1 and PMS2. The prognosis in this setting is better and the response to chemotherapy is less favourable.

Cyclo-oxygenase 2 upregulation

Cyclo-oxygenase 2 (COX 2) is upregulated in 40%–50% of adenomas and in 85% of CRC cells. Overexpression of COX-2 plays a key role in the multi-step process of CRC. Inhibition of COX 2 may play an important role in preventing CRC. The protective effect of non-steroidal antiinflammatory drugs (NSAIDs), which are COX 2 inhibitors, has been demonstrated in epidemiological studies.

DIAGNOSIS

• CRC may be suspected based on one or more of the previously described symptoms, most commonly a change in bowel habit.

• The patient may be asymptomatic and CRC may be discovered by routine screening of average and high-risk subjects.

• Colonoscopy is the single best diagnostic test.

• If malignant obstruction precludes a full colonoscopy preoperatively, virtual colonoscopy or single-contrast barium enema should be performed. If none is possible, complete evaluation of the colon should be carried out 3–6 months after surgery.

• Distant metastases should be carefully investigated by chest X-ray, or computerised tomography (CT) and abdominal CT with contrast material. Positron-emission tomography (PET)-CT is the most sensitive method to detect metastasis, when there is a high level of suspicion for metastasis.

• Obtain carcinoembryonic antigen (CEA) levels before initiating any therapy. Elevated CEA is a poor prognostic factor after treatment. It is used for surveillance, and an elevated level is usually a sign of recurrence. It has low sensitivity and specificity, and should not be used for screening.

Laboratory findings

• The complete blood count (CBC) may reveal iron deficiency anaemia.

• Alkaline phosphatase can be elevated in case of liver or bone metastasis.

• Liver function tests may be normal if only a few liver metastases are present.

Pathology

• Adenocarcinoma occurs in 90%–95% of the cases of CRC.

• There are two separate and distinct major pathways leading to CRC: the chromosomal instability pathway (80%–85%), and the microsatellite instability pathway (15%–20%), which is implicated in HNPCC.

• Two important variants are mucinous adenocarcinoma with a variable amount of extracellular mucus, and signet-ring cell, which contains large portions of intracellular mucin with peripheral displacement of the nucleus.

• Rare types include squamous cell, carcinoid, adenosquamous, lymphoma, sarcoma and undifferentiated carcinomas.

Staging and prognosis

• The Dukes’ staging system is still mostly used around the world, though the AJCC/TNM staging system is the preferred staging system in some countries (Table 17.3).

• Pathological stage is the single most important prognostic factor.

• Histological grade is not a major prognostic variable. Nevertheless, 5 years survival is better for grades I and II than for grades III or IV.

• Other adverse prognostic factors include: bowel obstruction, perforation, chromosome 18q allelic loss, high level of thymidylate synthase (TS) and mutations in p53.

TABLE 17.3 Different staging systems in colorectal cancer

THERAPY

The development of interdisciplinary diagnostic and therapeutic strategies has led to a moderate decline in mortality (2% per year). This is attributed to increased public and professional awareness, assimilation of recommended life style modification, screening and removal of polyps, better surgical techniques, better staging and use of adjuvant chemotherapy. Surgery will cure 50% of patients. More than 40% of the diagnosed patients will develop metastatic disease. Survival is directly related to the extent of disease at the time of diagnosis. If metastasis has occurred to distant sites, the 5-year survival rate is 5%–7%, but it increases to >90% when the cancer is diagnosed early. Long-term survival for patients with resectable liver and lung metastasis can be as high as 30%–40% with aggressive and novel therapy. Early detection of this surgically curable disease and preventive interventions (e.g. polypectomy) is the single best modality. There is now compelling evidence that colon screening of asymptomatic, average risk individuals over 50 years of age can reduce CRC mortality by 15%–90%, depending on the screening programme (see Chapter 18).

Surgical management

Colectomy

Surgery is the primary and definite curative intervention. It consists of an en bloc resection of the intestinal segment containing the tumour along with adjacent mesentery, pericolic fat and the draining lymph nodes. A margin of 2–5 cm on either side of normal lower bowel is needed. The adequate number of lymph nodes that should be examined is at least 13. Sentinel lymph node biopsy aims to map lymph nodes that are most likely to contain metastatic disease. Even though it has gained popularity in breast cancer, it is rarely used in CRC. Type and extent of surgical resection depend on the location of the tumour. If the tumour is adherent to, or invades, another organ, an en bloc excision should be tried. Total abdominal colectomy with ileo-anal/rectal anastomosis is mandatory in FAP patients. Subtotal colectomy is usually recommended in HNPCC. Generally in the setting of obstructing or perforating tumour, a proximal protective colostomy is performed, followed by a second surgery after 4–8 weeks to establish colon continuity.

Laparoscopic colectomy

Laparoscopic colectomy is emerging as a novel and promising technology, although it is still considered investigational. In a large randomised study, quality of life, the rate of intraoperative complications, re-operation, 30-day mortality and hospital readmission were very similar between the two groups. The only advantages of laparoscopy were slightly shorter hospital stay and less use of postoperative pain medication that were needed with laparoscopy.

Adjuvant therapy

Fluorouracil

Has been used since 1957 and remains the primary chemotherapeutic agent, with a response rate of 10%–12%. In 1990, an NIH consensus panel recommended adjuvant fluorouracil based chemotherapy in all stage III CRC. This was based on a large study in which fluorouracil and levamisole (an anthelmintic and immunostimulant agent), given for 12 months, achieved a 41% reduction in the relapse rate and a 33% decrease in mortality. Similarly, combining fluorouracil with folinic acid (calcium folinate) was shown to be effective as adjuvant therapy in stage III disease, and selected stage II cases. Fluorouracil and levamisole (given for 12 months) was as effective as fluorouracil and folinic acid (for 6 months), but more toxic. Consequently, the latter combination became the standard of care.

Capecitabine

An oral fluoropyrimidine that is converted by thymidine phosphorylase to active fluorouracil in the tumour tissue. It was shown to be as effective as fluorouracil, but less toxic, as an adjuvant therapy and in metastatic disease. Two major unique side effects are hand and foot syndrome and nonsignificant hyperbilirubinaemia.

Oxaliplatin

Acts synergistically with fluorouracil, even in fluorouracil-refractory disease. The addition of oxaliplatin to fluorouracil and folinic acid appears to have a better outcome as adjuvant therapies in stage III. The new standard of adjuvant care is fluorouracil, folinic acid and oxaliplatin for 6 months. Fluorouracil is given in a continuous infusion or in a short drip. Oxaliplatin has a unique neurotoxicity—laryngopharyngeal dysaesthesia, cold hypersensitivity and cumulative, partially reversible peripheral neuropathy. Nausea, vomiting and myelotoxicity are also common.

Irinotecan

Survival advantage had been shown as a second-line therapy for metastatic disease. Two forms of diarrhoea have been reported: early onset, which should be treated with atropine, and delayed onset (on days 3–5), requiring close monitoring and aggressive therapy (high dose loperamide, 4 mg initially and then 2 mg every 2 hours until diarrhoea stops for at least 12 hours). Neutropenia, alopecia, nausea and vomiting are also common. Adding irinotecan to folinic acid and fluorouracil failed to show an advantage in the adjuvant setting.

New biological agents

Cetuximab

A chimeric IgG monoclonal antibody that blocks epidermal growth factor receptor (EGFR) associating with its ligand, thus inhibiting the downstream signal transduction and preventing cell growth, differentiation and metastasis. It causes a typical acne-like rash, which is associated with a positive response.

Bevacizumab

A recombinant humanised vascular endothelial growth factor (VEGF) monoclonal antibody that blocks angiogenesis. Major toxicity includes proteinuria, hypertension, arterial thrombosis and intestinal perforation.

Addition of these new biological agents to oxaliplatin-based regimens is now being evaluated in the adjuvant setting.

Treatment of advanced disease

A combination of fluorouracil and folinic acid in continuous infusion, with irinotecan or oxaliplatin and bevacizumab is the most novel standard of care in first-line therapy. It confers a median survival of 20–24 months in metastatic disease. Oxaliplatin- or irinotecan-based chemotherapy can be given as second-line treatment. Cetuximab is active as third-line treatment in combination with irinotecan in irinotecan-resistant patients.

Treatment of rectal cancer

In contrast to colon cancer, 15%–20% of rectal tumours recur locally. Local recurrence can involve pelvic organs and bony structures, nerves and soft tissue. Radiotherapy has shown a protective, dose response curve, for preventing local recurrence in the rectum. Pelvic irradiation to the tumour bed and the pelvic lymph nodes is an integral component of the treatment in stages II and III.

Traditionally, postoperative radiotherapy was the gold standard in the USA, while the preoperative approach was preferred in Europe.

Currently, the most promising regimen worldwide is preoperative radiotherapy combined with fluorouracil in a continuous infusion (during radiation) 5 times a week for 6 weeks. This preoperative approach is advantageous since it improves compliance, pelvic recurrence, sphincter preservation and is associated with fewer radiation associated side effects to the small intestine.

Surgery is recommended following chemoradiotherapy.

Fluorouracil and folinic acid are given for an additional 4 months after successful surgery.

In cases when surgery was performed first, postoperative treatment includes fluorouracil (continuous infusion or bolus) during pelvic irradiation followed by four cycles of maintenance fluorouracil and folinic acid.

SUMMARY

Colorectal cancer (CRC) is a widespread and lethal disease in the Western world. It is the third most common malignancy after lung and breast cancer in women, and after lung and prostate in men. Approximately 75% of new cases occur among individuals at average risk. Adenocarcinomas account for 95% of cases, and synchronous adenocarcinoma can be found in 8%. Tumours of the proximal colon are now more common. CRC carcinogenesis is composed of a series of events that gradually (i.e. over 10–15 years) leads to transition from normal appearing mucosa, through adenoma (the pre-malignant lesion) into frank adenocarcinomas.

FURTHER READING

American Joint Committee on Cancer. Manual for staging of cancer, colon and rectum, 6th edn. New York: Springer-Verlag; 2002.

Kwak EL, Chung DC. Hereditary colorectal cancer syndromes: an overview. Clin Colorectal Cancer. 2007;6:340-344.

Levine JS, Ahnen DJ. Clinical practice. Adenomatous polyps of the colon. N Engl J Med. 2006;355:2551-2557.

Pfister DG, Benson AB3rd, Somerfield MR. Clinical practice: surveillance strategies after curative treatment of colorectal cancer. N Engl J Med. 2004;350:2375-2382.

Smith RA, Cokkinides V, Eyre HJ. American Cancer Society guidelines for the early detection of cancer 2004. CA Cancer J Clin. 2004;54:41-52.

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