Clinical Review: Colorectal cancer

Contributed by Dr Rob Glynne-Jones, consultant clinical oncologist at Mount Vernon Hospital and Watford and Barnet General Hospitals, Hertfordshire, and Bowel Cancer UK expert medical adviser to Bowel Cancer UK.

Around 37,000 patients in the UK were diagnosed with CRC in 2006
Around 37,000 patients in the UK were diagnosed with CRC in 2006

Section 1: Epidemiology and aetiology
Colorectal cancer (CRC) remains the third most common cancer, and the second largest cause of cancer-related death.

More than 37,000 patients in the UK were diagnosed with CRC in 2006, and about 14,000 died of the disease. The lifetime risk of developing CRC appears to be around one in 60 in men and one in 20 in women.1

Risk factors
The average age of diagnosis is in the 65-70 age group. Environmental, lifestyle and genetic risk factors include consumption of large amounts of processed meat, poor nutrition, obesity, lack of physical activity, increasing age, inflammatory bowel conditions and recognised genetic susceptibilities. The regular use of aspirin,2 COX-2 inhibitors, HRT and statins are proposed to have protective or preventive effects.

Inherited syndromes
In 3-10 per cent the cancer relates to two well-recognised inherited autosomal dominant CRC syndromes - familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC).

In addition, individuals with a strong family history of colon cancer or pelvic malignancies despite the absence of any recognised genetic mutation also appear to be at increased risk of developing CRC.

FAP is caused by a mutation in the tumour-suppressor adenomatous polyposis coli gene. FAP is characterised by the development of multiple colorectal adenomatous polyps (typically before the age of 20-30 years).

The lifetime risk of CRC for FAP patients has been reported to be close to 100 per cent.

In contrast, HNPCC is caused by germline mutations in tumour suppressor mismatch repair genes known as micro-satellite instability (MSI).

MSI entails a problem in DNA repair involving a series of copying errors, because of dysfunctional mismatch repair genes, and may be inherited or arise as a genetic mutation in individuals without a family history of CRC.

Section 2: Making the diagnosis
The symptoms of CRC may mimic other less serious non-malignant pathologies including irritable bowel syndrome, haemorrhoids, diverticular disease, constipation and coeliac disease.

Common symptoms include unexplained anaemia with or without evidence of rectal bleeding, a persistent change in bowel habit lasting more than six weeks, urgency and increased frequency of defecation, tenesmus, production of mucus, abdominal pain or a mass, and perianal symptoms, for example pain on defecation.

Symptoms of metastatic disease often include reduced appetite and weight loss.

Screening
In the UK, the bowel cancer screening programme utilises faecal occult blood analysis, which, if positive, triggers other investigations including a colonoscopy.3 The screening programme targets 60-69-year-olds, although this is wider in Scotland (50-74 years).

Faecal occult blood is a crude but effective test. More than four million tests have been sent out, but uptake is patchy.4 Early evidence suggests that with screening, patients present at an earlier stage and there are less emergency cases.

Colonoscopy
Colonoscopy allows both direct visualisation of the inside surface of the bowel, and allows removal of any polyps for histology. Polyps larger than 10mm carry a much higher risk of being malignant. Colonoscopy also carries a small defined morbidity and mortality.

Around one in 1,000 patients will experience a perforation and in a small proportion of these, it will be fatal.

Modern staging with ultrasound, CT scanning and PET scanning offers better resolution and superior information than in the past. Currently, MRI has gained a wider role in rectal cancer in predicting the likelihood of the surgeon failing to achieve a curative resection.

Computed tomography
Multidetector CT chest, abdomen and pelvis using oral and IV contrast can assess liver and lung metastases and whether lymph nodes are involved.

CT colonography is more or less comparable to colonoscopy both in detecting the larger adenomas (10mm or greater), but likewise it may miss some small adenomas. It has been evaluated against colonoscopy in the British Special Interest Group in Gastrointestinal and Abdominal Radiology trial.5

Transrectal ultrasound
Transrectal ultrasound is particularly useful for small early tumours in the rectum. It is useful in addition to MRI in the confirmation of early T1 and T2 tumours, which are under consideration for local, non-radical resection or brachytherapy.

MRI
MRI is useful in defining both tumour and node stages in rectal cancer.6 The tumour anatomy appears as a raised disc with rolled edges.

MRI can ascertain a clear or threatened circumferential resection margin. Tongues of tumour extending superiorly along the course of the draining mesorectal veins constitutes macroscopic venous invasion and is visualised on MRI, which predicts the development of liver metastases.

Section 3: Managing the condition
Advances in radiation planning and delivery and new effective cytotoxic drugs, such as oxaliplatin and irinotecan, give greater scope for dealing with unresectable rectal cancer and the potential for controlling distant micrometastases.

Surgery
Significant improvements in local control and overall survival were achieved after it was recognised how important the radial margin or circumferential resection margin are. This has led to improvements for patients with resectable rectal cancer.

Chemotherapy
The cytotoxic antimetabolite chemotherapy agent 5-fluorouracil (5FU) remains the mainstay of treatment for patients with CRC.

5FU is usually given with folinic acid (FA), which helps to increase its activity, or as an infusion, which reduces side-effects. There are also oral alternatives available (capecitabine and tegafur plus uracil).

Either 5FU or capecitabine are commonly combined with the other cytotoxic drugs which have activity in CRC (oxaliplatin and irinotecan).

There are also two effective targeted therapies which represent novel biological agents targeting either angiogenesis (bevacizumab) or the epidermal growth factor receptor (cetuximab). Cetuximab appears to be effective on its own without chemotherapy.7

Adjuvant 5FU chemotherapy, and the addition of oxaliplatin to 5FU-based chemotherapy have shown a significant benefit in patients with stage III (involved lymph nodes) colon cancer and decrease the risk of recurrence.8

Radiotherapy
Local recurrence gives rise to intractable pain and intestinal obstruction, and a very poor quality of life. There are three adjuvant radiation approaches used to prevent recurrence: short course pre-operative radiotherapy; long course pre-operative chemoradiation; and postoperative chemoradiation.

In the UK, chemoradiation is usually selected for patients in whom pre-operative MRI suggests that the circumferential margin is threatened, and the surgeon will be unable to perform a curative resection.

Because of the higher incidence of circumferential resection margin involvement following abdominoperineal resection some have suggested that all patients undergoing abdominoperineal resection should be considered for preoperative radiotherapy. However, local recurrence may occur even following an uninvolved circumferential resection margin, because of lymphatic spread from the distal rectum to lymph nodes on the pelvic sidewall.

In contrast, systemic chemotherapy with 5FU (or capecitabine), oxaliplatin and irinotecan are being used to treat metastatic disease, or potential micro-metastases in preoperative and in the postoperative adjuvant setting - both sequentially, and in rectal cancer concurrently, with radiotherapy.

The use of radiotherapy as a definitive treatment is limited by the tolerance of structures, such as bladder and small bowel, but doses of 100Gy or more can be delivered to a small volume (small early tumours) with high rates of local control without risk of unacceptable late complications. These techniques should be confined to specialists with considerable expertise.

TEMS
Transanal endoscopic microsurgery (TEMS) uses a 40mm diameter operating scope with stereoscopic views allowing the safe removal of small localised rectal tumours.

The UK has 21 centres, which register patients via a national TEMS database. Recent reports on the database show 454 cases of rectal cancer with 35-month follow up, with morbidity and mortality rates of 17.2 per cent and 1.5 per cent, respectively.

Section 4: Prognosis
The initial stage strongly predicts prognosis. A number of staging systems exist but commonly in the UK we use the Dukes staging system, and the tumour, node, metastasis staging system (see box, right).

Recurrence
Following resection of the primary tumour, some patients will develop recurrence.

It may be local or distant (spread to other organs). Local relapse is a common problem for rectal cancer, however rates are lower for colon cancer patients. The risk of distant relapse increases with Dukes stage.

A small number of patients can have these removed, but the prognosis for patients following distant recurrence is usually poor. Avoiding relapse is key in the adjuvant treatment of CRC.

Metastases
Despite dramatic advances in the treatment of advanced disease, including the incorporation of oxaliplatin and irinotecan into first-line regimens, triplets of chemotherapy, and the more recent selected integrated use of targeted monoclonal antibodies, the five-year survival rates from chemotherapy for patients with advanced colorectal cancer remain less than 10 per cent.

Resection offers the only realistic hope for cure in terms of a 30 per cent five-year survival, although this depends on the number, location and extent of metastases.

However, further recurrence after resection will occur in almost 75 per cent of the patients - predominantly within the first two years after surgery, and usually located in the liver.

Until recently, the classic contraindications for resection of CRC liver metastases have been: more than four metastases, disease outside the liver, a potential resection margin of <1cm, the presence of comorbid disease and an incomplete resection.

Nowadays, the volume of the remaining liver after resection is considered critical.

Palliative chemotherapy
NICE recommends infusional 5FU/FA, alone or in combination with irinotecan or oxaliplatin as first-line treatment options for the management of advanced CRC.

There is evidence that giving all three cytotoxic drugs is better than two, so the optimal treatment sequence would be 5FU/FA plus oxaliplatin followed on progression by 5FU/FA plus irinotecan, or vice-versa. Treatment options are guided by patient preferences, tolerability of adverse events and fitness.

Follow-up
Follow-up of patients after surgery usually comprises regular clinic visits, carcinoembryonic antigen (CEA) tests, CT and colonoscopy. Commonly, patients undergo a clinical review, CEA test and a CT at six-monthly intervals for the first two years, which is gradually extended for five years.

Patients also undergo a colonoscopy three to five years after surgery, which is repeated until the patient is 75.

CRC is one of the few cancers where lifestyle changes impact on outcome.

All patients should be encouraged to lead a healthier life with a well-balanced diet, plenty of exercise and to give up smoking.

Tumour, node, metastasis classification

TNM classification of colorectal cancer
T - Primary tumour (T)

TX: Primary tumour cannot be assessed

T0: No evidence of primary tumour

Tis: Carcinoma in situ

T1: Tumour invades submucosa

T2: Tumour invades muscularis propria

T3: Tumour invades through muscularis propria into subserosa, or into non-peritonealised pericolic or perirectal tissues

Optional expansions of T3

  • PT3a minimal invasion <1mm beyond="" the="" border="" of="" muscularis="" propria="" li="">
  • PT3b slight invasion >1mm beyond the border of the muscularis propria
  • PT3c moderate invasion >5-15mm beyond the border of the muscularis propria
  • PT3d extensive invasion >15mm beyond the border of the muscularis propria
  • PT4 tumour directly invades other organs or structures (T4a), and/or perforates visceral peritoneum (T4b)

N - Regional lymph nodes (N)
NX: Regional lymph nodes cannot be assessed

N0: No regional lymph node metastasis

N1: Metastasis in one to three regional lymph nodes

N2: Metastasis in four or more regional lymph nodes

M - Distant metastasis (M)
MX: Presence of distant metastasis cannot be assessed

M0: No distant metastasis

M1: Distant metastasis

Source: UICC TNM Staging, 6th edition, 2002

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Resources
1. Bowel Cancer. Cancer Research UK 2009. www.cancerhelp.org.uk

2. Chan AT, Ogino S, Fuchs CS. Aspirin use and survival after diagnosis of colorectal cancer. JAMA 2009; 302(6): 649-58.

3. Weller D, Coleman D, Robertson R et al. The UK colorectal cancer screening pilot: results of the second round of screening in England. Br J Cancer 2007; 97: 1601-5.

4. Damery S, Clifford S, Wilson S. Colorectal cancer screening using the faecal occult blood test (FOBt): A survey of GP attitudes and practices in the UK. BMC Fam Pract 2010; 11(1): 20.

5. Halligan S, Lilford RJ, WardleJ et al. Design of a multicentre randomised trial to evaluate CT colonography vs colonoscopy or barium enema for diagnosis of colonic cancer in older symptomatic patients: the British Special Interest Group in Gastrointestinal and Abdominal Radiology study. Trials 2007; 8: 32.

6. MERCURY Study Group. Extramural depth of tumour invasion at thin section MR in patients with rectal cancer. Results of the MERCURY Study. Radiology 2007; 243: 132-9.

7. Karapetis CS, Khambata-Ford S, Jonker DJ et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008; 359(17): 1757-65.

8. Andre T, Boni C, Navarro M et al. Improved overall survival with oxaliplatin, fluorouracil and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 2009; 27(19): 3109-16.

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