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Colorectal Cancer – An Ideal Tumour to Screen?

Saturday, July 1st, 2000
Dr Peter A Bampton MBBS, FRACP, Department of Gastroenterology, Flinders Medical Centre, Bedford Park, South Australia



Introduction

The three most common internal malignancies in westernised populations are breast, lung and colorectal cancer. Colorectal cancer is increasingly becoming more common relative to these cancers, in part because of efforts to reduce smoking and the consequent reduction in the incidence of lung cancer, but mainly due to the ageing population. Colorectal cancer becomes more common with age and it is currently estimated that in Australia there will be a 20% increase in the incidence of colorectal cancer in the five years from 1996 to 2001 and a further 17% increase in the following five years.  1  

The biology of colorectal cancer, however, suggests that it might be suitable for screening. Colorectal cancer develops in a predictable sequence, with the initial manifestation being the formation of a colonic polyp, which may go on to develop into carcinoma. This polyp-carcinoma sequence takes 10 years, suggesting a long window of opportunity in which a tumour could be removed in its "pre-malignant’ phase.  2   Indeed, in patients who have had a polypectomy, the subsequent risk of colorectal cancer is reduced by over 75%.  3  

The ability of any community screening programme to change the burden of disease in terms of its mortality and morbidity rates depends upon four factors. These can be summarised as:

  1. the availability of a screening test that has adequate sensitivity to detect the target disease
  2. the test’s accessibility to the population to be screened
  3. the test procedure’s acceptability to the screening population - in order to guarantee an appropriate level of participation
  4. whether the benefits of the screening programme are worth the cost, ie, cost-effectiveness.  4  

This brief review will demonstrate how screening for colorectal cancer using faecal occult blood (FOB) testing fulfils each of these criteria.



Availability of a Sensitive Screening Test

The use of a FOB test to detect an asymptomatic colorectal cancer was first described by Greegor.  5   Three randomised controlled trials have now demonstrated that FOB testing reduces colorectal cancer mortality.  6  ,   7  ,   8   The Minnesota trial was the first to be reported. It demonstrated a 33% reduction in mortality from colorectal cancer after the institution of annual FOB testing.  6   Biennial testing was used in the two European trials, which showed a 15-18% reduction in mortality.  7  ,   8   The improved survival rates resulted from the detection of colorectal cancer in an earlier stage, hence improving the chance of surgical cure. However, prolonged follow-up in the patients screened in the Minnesota trial revealed lower incidence of colorectal cancer as well as a reduced mortality from the disease. This was presumably due to the early detection, through FOB testing, of colonic polyps and their subsequent removal by colonoscopy.  9  

These studies used guaiac-based FOB testing. In the Minnesota trial, when slide rehydration was introduced, the rate of positive results increased from 2.4% to 9.8%. This improved the sensitivity of the test from 80% to 92%, however, this occurred at the expense of a decline in specificity from 98% to 90%.6 This decline led to the perception that FOB testing was bedevilled by an overly high false positive rate. The European studies were performed without rehydration and had a rate of positive results of 1.1 and 2%.

An alternative to guaiac-based testing is immunochemical testing, which detects only the human heme rather than detecting peroxidase activity, which can be subject to dietary interference. This latter test has a higher specificity and sensitivity, based on data from patients with known cancers but there has been no large scale randomised trials with long-term follow up examining its performance in the screening situation.  10  

Nevertheless, there is no doubt that FOB testing will reduce the rate of mortality from colorectal cancer. It is possible that flexible sigmoidoscopy might have a further effect on colorectal cancer mortality rates by detecting polyps and enabling their removal, leading in turn to a decrease in the incidence of colorectal cancer. There have been two case controlled studies which suggest that flexible sigmoidoscopy significantly reduces the mortality rate from distal colorectal cancer  11  ,   12   and it would seem logical to combine FOB testing with periodic flexible sigmoidoscopy. In one study, the addition of flexible sigmoidoscopy to FOB testing did increase the detection rate for cancer. However, this benefit was partially offset as the introduction of flexible sigmoidoscopy reduced patient compliance.  13   An alternative would be to screen using flexible sigmoidoscopy alone. Prospective studies to determine whether this approach is feasible are currently enrolling patients.  14  

The Barium enema has been proposed as a tool for colorectal cancer screening, being advocated as an alternative to colonoscopy both as a screening modality per se and as a follow up to positive FOB tests. However, this method has proved less sensitive than colonoscopy in detecting colonic polyps in post-polypectomy surveillance studies.  15   As a procedure, it is less well tolerated by patients being tested than is colonoscopy with adequate sedation.  16   Alternatively, colonoscopy at five or 10 yearly intervals has been proposed as a method of mass screening. However, participation rates in trials of this approach have been so poor that any increased sensitivity of the colonoscopy over FOB testing is negated by the poor participation rate.  17  ,   18  

Currently, therefore, there is good evidence to suggest that FOB testing is an appropriate screening modality for colorectal cancer. Intermittent barium enema is unlikely to be of value;  19   intermittent colonoscopy is a possible alternative if participation rates can be increased, and only if there are the personnel and infrastructure to support this approach.



Accessibility of the Screening Test

FOB testing is an ideal screening test as it is cheap and relatively easy to read. It is unique in that it is the only screening test which the screenee performs themselves. High participation rates have been achieved in the trial setting.  6  ,   7  ,   8   The alternative screening modalities of sigmoidoscopy, barium enema and colonoscopy are more resource intensive and do not attract participation as easily as FOB testing. Flexible sigmoidoscopy can be performed on unsedated participants by trained endoscopy nurses and, thus, be made more accessible, but requires disinfection procedures and availability of flexible instruments. Few countries would have the personnel or resources to support mass colonoscopic screening.  1  

A positive FOB result does necessitate a subsequent colonoscopy, but a positive result increases the likelihood that the screenee has colorectal cancer by 30 times, ie, it is far better to reserve the resource intensive test (colonoscopy) for patients who will achieve maximum benefit of this test.



Acceptability of the Screening Test

Controlled trials of FOB testing would suggest that high participation rates can be achieved (up to 70% even with second round screening).  6  ,   7  ,   8   The addition of flexible sigmoidoscopy to the FOB screening regimen would significantly reduce compliance In one study it decreased from 66% to 35%, although there was evidence that despite this reduction, sensitivity actually increased.  13   Australian trials have suggested that participation rates in flexible sigmoidoscopy trials can reach 40%,  1   and the most recent UK sigmoidoscopy trial had an initial screening round participation of 71% of eligible subjects.  14  

Colonoscopy remains a less acceptable approach to individuals, as demonstrated by the poor participation rates in the trials performed to date.  20   However, a "one off" colonoscopy may not be an unreasonable approach and may be easier to achieve than repeated FOB testing - compliance has been shown to decrease with each round of FOB testing. Given that, with physician counselling, patients with a positive FOB have an 81% participation rate in their follow-up colonoscopy,  6   it may be possible to improve participation in colonoscopy-based population screening programmes. If a participation rate of 44% could be achieved, then it could be expected to reduce colorectal cancer mortality by 35% - ie, a favourable result compared with the initial FOB trials. Studies are currently underway examining the feasibility of this approach.  18  



Cost-effectiveness

Screening programmes must be cost-effective to justify their introduction into the competition for health funds. A commonly used US benchmark for acceptable cost is US$40,000 per year of life gained, based on the annual cost of maintaining a patient with end-stage renal disease alive on dialysis. Renal dialysis was explicitly legislated as a covered Medicare benefit for all Americans with renal failure and this figure is therefore used as the upper limit the US congress would reasonably expect to spend for a year of life gained.  21  

The cost-effectiveness of a screening strategy is a function of the natural history of the disease, the sensitivity and specificity of the testing used and the flow-on costs of a positive result as well as the risks and costs of the tests used. A number of different models have been used to examine the cost-effectiveness of different strategies. The most detailed modelling performed suggests that annual FOB testing and flexible sigmoidoscopy every five years will gain 6.28 years of life per 100,000 people screened (a cost of US$13.639 per year of life saved). This is on the assumption of a 5-year pre-cancerous phase. If a 10-year pre-cancerous phase is assumed, then the cost per year of life saved drops further to US$11,652  22  . Other cost modelling has supported the use of the barium enema, but was based on data which over-estimated the sensitivity of this test and is, therefore, flawed.  23   Another analysis of five different cost strategies, found FOB testing alone to be the most cost-effective, although adding five-yearly, flexible sigmoidoscopy did not add excessively to this cost. Indeed, this study was the first to examine the cost of not screening, and it was concluded that, as the cost of colonoscopy decreases and the cost of colorectal cancer care increases, it will soon cost more not to screen than to screen.  24   In the European trials of FOB testing, analysis suggested a cost of US$5,400-$9,650 per life year saved.  25  

There is some evidence that 10 yearly colonoscopy after an initial colonoscopy at 50 is perhaps the most cost-effective approach, although this assumes a reasonable degree of participation. It would appear that, given the lack of precision over some of the assumptions inherent in the models described and the consequent broad range in confidence bounds, two broad conclusions can be drawn.  26   First, the cost-effectiveness of each approach (FOB; barium enema; colonoscopy) is similar. Secondly, FOB compares well with colonoscopy as a screening modality and, until the issues of population participation and resource availability for colonoscopic-based screening programmes are resolved, it remains the preferred option. Barium-enema-based screening is unlikely to be a competitive option, especially with recent data suggesting it has quite poor sensitivity for significant adenomas and cancers in the screening population.  15  



The Implementation of a FOB-based Screening Programme

It seems likely from the level 1 evidence provided by the Minnesota and European trials  6  ,   7  ,   8   that a FOB-based screening programme for colorectal cancer would improve survival from colorectal cancer and is a feasible choice. The extent to which it achieves this improved survival, however, depends upon its implementation.

There are five vital elements in the successful implementation of a screening programme. These are the initial approach to the population, the registration of the screenees with the programme, the successful application of the screening tool, a method that ensures that abnormal results are followed up and the continuation of the programme (ie, re-screening).  27  


The Initial Approach and Application of the Screening Tool

In Germany, Japan and the US, FOB testing is available free of charge, but there is no structured screening programme. In the US there has been a significant amount of publicity and media support for colorectal cancer screening, with a resultant participation rate in the US of up to 50% in 1998.  28   This is a greater participation rate than has been achieved with similar free availability in Germany and Japan, where there has been less mass promotion. However, the screenees are predominantly white and bettereducated, suggesting that the approach is missing significant segments of the US population.  1  ,   28  


Follow-up of the Positive Result

In these three countries, whilst there has been an attempt to approach the population to offer the test, the lack of registration of screenees and lack of follow up of the positive result has reduced the benefit of the screening programs.  1  ,   29   There has been no reduction in mortality from colorectal cancer in Germany and Japan. In the US, when screened positive individuals were reviewed, they were often not followed up with appropriate investigation by the primary physcian.  29  


Continuation of Screening

Emphasis of the continuation of screening is important, especially in a FOB-based screening approach, which would require repeat testing at one to two yearly intervals. Whilst trials have shown that participation in second round screening decreases compared with the initial round, participation can still be maintained at reasonable levels.  6  ,   7  ,   8   Nevertheless, this does require a pro-active approach, and it would not be unreasonable to assume that participation in second round screening would fall significantly if there were no mechanism by which first round screenees could be reminded that their next test was due.



Conclusions

Colorectal cancer has a natural history that lends itself to intervention through screening, and there is a variety of suitably sensitive and specific screening tests available. These tests achieve a mortality reduction with an acceptable cost per year of life saved. The most accessible and affordable, currently, is FOB testing. The challenge is to devise a process whereby a FOB-based screening programme can be applied to the general population in a manner which maximises participation, appropriate follow-up and continuation with subsequent rounds of screening. These process issues are the next critical step in colorectal cancer screening. Pilot studies have commenced in the United Kingdom  30   and Australia  1   to address them. The question for colorectal cancer screening is no longer why, but how and when.



References

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  2. Hamilton SR. Pathology and biology of colorectal cancer. In Young GP, Rozen P, Levin B. Prevention and early detection of colorectal cancer. London: WB Saunders Company Ltd; 1996. p. 3–21
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