1.d.i. Rationale for screening for colorectal cancer

In common with other cancers such as breast and cervix, colorectal cancer is suited to the institution of a screening programme:

· it is a major health problem (1.b.i. Demographics)

· there is a lengthy precancerous stage i.e. the adenomatous polyp.

· intervention at an earlier stage affects morbidity and mortality²⁴⁷.

· modalities are available to detect polyps.

· the cost of screening is not prohibitive

1.d.ii. Screening methods for colorectal cancers and adenomas

At least 75% of colorectal cancers arise in persons who have no known family history⁴². As such the screening of high risk families, while potentially valuable to the individuals, is unlikely to have a major impact on the overall incidence or mortality. Therefore, population based screening is recommended as the way forward ¹⁰.

There are several methods by which the population might be screened:

· Symptom questionnaire

· Faecal Occult Blood Testing (FOBT)

· Barium enema

· Colonoscopy

· Flexible sigmoidoscopy

· New advances e.g. K-ras stool testing

Symptom Questionnaire

Bowel symptoms are very common and can be an indicator of many general medical conditions (e.g. thyrotoxicosis), large bowel pathology (e.g. colitis) or functional bowel disorders (e.g. irritable bowel syndrome). As such, one cannot define a high risk group for further intervention through symptomatology alone and the addition of a symptom questionnaire to other screening modalities increases costs with little return²⁴⁸.

Faecal Occult Blood Testing (FOBT)

FOBT is mainly aimed at the detection of early asymptomatic cancers. The premise is that such cancers bleed and the detection of these small amounts of blood define a high risk group who undergo further intervention (colonoscopy)^247,249,250. The main advantages of FOBT screening is that it is non-invasive, easily performed without the need for bowel preparation, can be performed on transported specimens and of low cost. The main disadvantages, however, are low sensitivity, because 40% of cancers and 80% of adenomas are missed by the test^251,252, and the late stage in the disease at which lesions bleed, leading to a short lead-time and a requirement for frequent testing.

Barium Enema

Traditionally before the advent of fibre-optic technology, imaging of the colon was performed using a barium enema. It has been shown however that the sensitivity for even quite large colonic lesions can be quite low and the examination requires full bowel preparation and is poorly accepted by patients.

Colonoscopy

Initially, colonoscopy may appear to be the best method for screening for colorectal adenomas and cancers. The sensitivity for even small polyps as small as 5mm is high so that neoplasia is detected at an early stage. Also, lesions can be removed at the time of screening so colonoscopy can be both diagnostic and therapeutic.

There are however disadvantages to colonoscopic screening:

· full bowel preparation is required. This normally involves stimulant or osmotic laxatives (e.g. Picolax or Klean prep). Recommendations include a low fibre diet for several days prior to commencement of preparation which itself starts the day before the examination.

· the majority of colonoscopic examinations are carried out with sedation. This excludes the subject from driving to and from the hospital, prevents the adequate discussion of results on the day and can be distressing both from the anxiety of not being fully conscious but also the hangover effects that are reported.

· complication rates including perforation are reported as being approximately 1 in 2,000 and a mortality of 1 in 5,000²⁵³. Though this may be acceptable in clinical practice in symptomatic patients, it would represent an obstacle to the acceptance of the population to be screened.

· the overall compliance is lower or comparable to flexible sigmoidoscopic screening^253,254.

· colonoscopy requires considerable training, skill and experience. At present, as colonoscopy becomes the investigation of choice for colonic disorders over barium enema, there is a relative shortage of colonoscopists. A trend that seems set to continue and would increase in magnitude should screening be introduced.

· colonoscopy is the most expensive of the potential screening tools.

Flexible Sigmoidoscopy

Flexible sigmoidoscopy has advantages over colonoscopy in that:

· bowel preparation can be undertaken with a phosphate enema that gives good results, is quick and easy to be self-administered at home and is acceptable.

· sedation is not normally required

· there is a very low complication rate including perforation

· it is associated with 70% acceptance rate²⁵⁵

· it can be performed by non-medical personnel thus reducing the logistic problem of requiring more endoscopists

· it is relatively cheap

However, flexible sigmoidoscopy does not allow visualisation of the proximal bowel. A 60cm sigmoidoscope, however, can be passed in most cases to the junction of the sigmoid and descending colon below which 60% of colorectal cancers are located.

New Advances

Screening for stool markers that are more accurate than occult blood would substantially improve sensitivity. There is great interest in looking for the DNA alterations that occur in the formation of polyps and cancers in cells exfoliated from neoplasms. Early investigations targeting single mutations, usually K-ras that is present in less than half of all colorectal neoplasms, show that mutations in tumour can be detected in stools from the same patients^256-258. Colorectal neoplasms however are genetically heterogeneous and no one mutation has been found to be universally expressed. It is likely that an approach of investigating multiple mutations commonly expressed would improve diagnostic yield. Ahlquist et al. demonstrated sensitivities of 91% for colorectal cancer and 82% for adenomas >1cm using a multi-target assay that assessed 15 mutations commonly seen in colorectal neoplasia²⁵⁹.

1.d.iii. Rationale for flexible sigmoidoscopy screening - FlexiScope Trial

The FlexiScope trial is a multicentre randomised controlled trial looking at the efficacy of a single flexible sigmoidoscopy and polypectomy as required at between the ages of 55 and 64 years in preventing colorectal cancer. It is funded by the Imperial Cancer Research Fund and the Medical Research Council and has completed the screening phase of 40,000 people. The rationale for the protocol is detailed in the Lancet paper by Atkin et al.¹⁰ a brief summary is given below.

Polpypectomy

The benefit of polypectomy at reducing the incidence of colorectal cancer has been demonstrated^260-264 but until the FlexiScope trial, which will not report for at least 5 years, there has not been a well-designed randomised controlled trial looking at the efficacy of flexible sigmoidoscopy in the prevention of death from colorectal cancer.

Gilbertsen et al.²⁶⁰ followed up over 21,000 subjects after rigid sigmoidoscopy and polypectomy for a mean of 4 years with those having polyps removed undergoing annual surveillance. In this time, 13 rectal cancers were diagnosed compared with 90 cancer that might have been expected concluding an 85% reduction in incidence by polypectomy.

A smaller case-control study by Newcomb et al.²⁶³ found a reduction in the incidence of colorectal cancer of 80% after examinations done mostly by flexible sigmoidoscopy.

Single Examination at age 55

Atkin et el.²⁶⁴ investigated the long term risks of rectal cancer following sigmoidoscopy in 1618 men and women who had adenomas removed via the sigmoidoscope up to 30 years previously. Only 14 (0.9%) developed rectal cancers compared to the estimated 80 cancers expected and 11 of these had had incomplete removal of their adenomas. So only 3 rectal cancers developed after complete adenoma removal and all of them were diagnosed 17 or more years after the procedure.

The conclusion therefore was that if all adenomas detected at sigmoidoscopy are removed completely the risk of rectal cancer may be very low for many years after²⁶⁵.

There remains some uncertainty as to the ideal age at which screening should take place. In keeping with the lead time for mutation of an adenoma to carcinoma^13,16, adenoma prevalence increases markedly after the age of 50 and appears to plateau at the age of 60.

Screening at an older age (>60) would have advantages in adenoma pick up rate and greater reassurance of a negative test, but would miss the 7% of cancers occurring in the 55 -59 age group. It was decided to include the age range 55 - 64 to try and determine the best age for screening to take place.