Evaluation of Flexible Sigmoidoscopy Screening as an Adjunct to the National FOBT Screening Programme in Scotland
Condition: Colorectal Cancer; Colorectal Adenoma
MeSH terms: Adenoma
Study type: Interventional

Summary: 
      Guaiac faecal occult blood testing (gFOBT) consistently demonstrates reductions in deaths
      from colorectal cancer of around 16% and gFOBT screening is now routine in all four countries
      of the United Kingdom. However, gFOBT has significant limitations and is associated with a
      substantial interval cancer rate in the region of 50 %, indicating a severe deficiency in
      sensitivity for cancer. Additionally, as the majority of colorectal cancers arise from
      pre-existing adenomas, it is important for colorectal screening programmes to detect adenomas
      in order to reduce the incidence of the disease as well as the associated mortality. Although
      gFOBT does detect some adenomas, most randomised trials have not demonstrated a reduction in
      colorectal cancer incidence. Also, FOBT screening tends to under-detect cancers in women and
      it is relatively insensitive for rectal cancer when compared with colon cancer.

      Single flexible sigmoidoscopy (FS), between the ages of 55 and 65 years, has been shown to
      bring about a significant reduction in colorectal cancer mortality. In addition, and most
      importantly, after a period of four years a significant reduction in colorectal cancer
      incidence was observed. FS does not suffer from low specificity since false positives do not
      occur, and there is independent evidence that it is more sensitive than a single gFOBT. In
      addition, FS is ideally suited to detecting rectal cancers and adenomas, and it is unlikely
      that there would be a gender difference in the sensitivity.

      Single FS has not been compared with biennial FOBT and there is no information regarding the
      utility of FS in a population that has already been exposed to FOBT screening. It is
      hypothesised that offering a combination of gFOBT and FS would provide an enhanced screening
      algorithm that would be associated with better outcomes than gFOBT alone. In order to test
      this hypothesis a randomised evaluation pilot study of FS screening integrated into the
      current gFOBT Screening Programme, will be carried out in those around age 60, as this
      appears to be the age at which adenoma prevalence peaks.
    

Detailed description: 
      Screening for colorectal cancer is now being introduced in many countries worldwide, but
      there is still considerable uncertainty as to the ideal modality. Population based trials of
      guaiac faecal occult blood testing (gFOBT) have consistently demonstrated significant
      reductions in disease specific mortalities and three randomised population based trials of
      biennial gFOBT have demonstrated reductions in deaths from colorectal cancer of around 16%.
      As a result of these trials, a demonstration pilot was performed in the United Kingdom which
      has led to the introduction of gFOBT screening in all four countries of the United Kingdom.

      However, gFOBT has significant limitations. It is clear that this form of screening is
      associated with a substantial interval cancer rate in the region of 50 %, indicating a severe
      deficiency in sensitivity for cancer. Furthermore, as it is now well established that the
      majority of colorectal cancers arise from pre-existing adenomas, it is important for any
      colorectal screening programme to detect adenomas in order to reduce the incidence of the
      disease as well as the associated mortality. Although gFOBT does detect some adenomas, the
      randomised studies have not demonstrated a reduction in colorectal cancer incidence with the
      exception of the Minnesota Study that used rehydrated gFOBT resulting in a high positivity
      rate and a large number of colonoscopies. It should be borne in mind however, that the newer
      faecal immunochemical tests (FIT), which, unlike gFOBT, are specific for human haemoglobin,
      perform better in terms of both cancer and adenoma detection.

      It is also of interest that recent scrutiny of the interval cancer data from the Scottish
      demonstration pilot has clearly demonstrated that gFOBT screening tends to under-detect
      cancers in women when compared with men. In addition, it is relatively insensitive for rectal
      cancer when compared with colon cancer. Analysis of quantitative FIT data in our laboratory
      as part of an evaluation of FIT as a first line test in Scotland, has shown that the mean
      faecal haemoglobin concentration in women is lower than that in men, and that the cutoff
      value required for women to give a 2% positivity rate (similar to that achieved by the gFOBT
      currently in use in the UK) is less than half that for men. Thus, for gender at least, FIT
      will have the same limitations as gFOBT.

      In a recent randomised trial carried out in 14 UK centres, a single flexible sigmoidoscopy
      (FS) between the ages of 55 and 65 years has been shown to bring about a significant
      reduction in colorectal cancer mortality. In addition, and most importantly, after a period
      of four years a significant reduction in colorectal cancer incidence was observed, presumably
      as a result of the routine removal of adenomas at FS. Interestingly, the reduction in
      incidence was restricted to left-sided cancers despite the fact that total colonoscopy was
      carried out in all those with a significant index lesion found at FS (5% of the screened
      population). FS does not suffer from low specificity since false positives do not occur, and
      there is independent evidence that it is more sensitive than a single gFOBT or FIT. In
      addition, FS is ideally suited to detecting rectal cancers and adenomas, and it is unlikely
      that there would be a gender difference in the sensitivity.

      This landmark study (henceforth referred to as the "UK FS trial") was, however, an efficacy
      study since it was carried out in a population who had already indicated an interest in
      participating and, as a result, the uptake in those randomised to FS was an impressive 71%.
      This, however, leaves significant questions surrounding the introduction of FS screening, as
      it is not clear how it would perform as a population screening tool. Extrapolation of the
      results of the FS trial to the general population would suggest an uptake in the region of
      around 30% and although it is not clear what the uptake of FS would be in the Scottish
      population, data from the Glasgow centre that participated in the FS indicate a likely uptake
      of 24%. This compares with an overall uptake of around 60% in the current Scottish Bowel
      Screening Programme based on gFOBT.

      A population based randomised trial of FS from Norway achieved a participation rate of 67%
      but a randomised study from The Netherlands achieved an uptake of 32.4% for FS compared with
      49.5% and 61.5% for gFOBT and FIT respectively. In addition, there is evidence that
      participants perceive the personal burden of FS to be greater than that of either type of
      faecal testing. On the other hand, a study from Italy found a similar participation rate or
      FIT and FS, although both were low at 32% of those invited. Two small studies conducted in
      the London area observed an uptake of screening FS of around 50% but a similar study carried
      out in Tayside, Scotland achieved an uptake of only 24%. It is not clear why there should be
      such discrepancies in uptake of FS, but both cultural issues and differences in levels of
      deprivation are likely to be important.

      The randomised study from The Netherlands demonstrated that the diagnostic yield of advanced
      neoplasia (cancers and significant adenomas) per 100 invitees was greater for FS than for
      either of the faecal tests suggesting that the overall performance of FS may be better than
      faecal testing despite a lower participation rate. This introduces an important ethical
      dimension; namely, whether or not it is acceptable to use a population screening tool that
      reaches a relatively small proportion of the population rather than a test that is associated
      with a higher participation rate but has an overall poorer performance in terms of disease
      detection. This is further complicated by the adverse effect of deprivation on uptake of
      screening. It is known that, in Scotland, the difference in uptake of gFOBT population
      screening between the most deprived and the least deprived quintile is around 20%. The effect
      of deprivation on uptake of FS population screening is not known, although in the UK FS trial
      there was a 16% difference in intention to participate and a 20% difference in actual uptake
      in those invited between the most and least deprived quartiles in Glasgow.

      In a recent re-appraisal of the options for colorectal cancer screening commissioned by the
      UK National Screening Committee, and based on the UK FS trial, data from the first two rounds
      of the English Bowel Screening Programme and data on the sensitivity and specificity of FIT,
      modelling has suggested that a single FS would perform better than biennial gFOBT and that FS
      at age 62 results in the greatest reduction in CRC incidence, CRC mortality and CRC treatment
      costs, whereas FS at age 54 results in the greatest gain in life years and QALYs. In addition
      it was suggested that biennial FIT may outperform both biennial gFOBT and one off FS.

      As result, FS screening has been introduced into England for all at the age of 55. Thus it is
      offered 5 years before gFOBT screening starts, as this is offered between the ages of 60 and
      74. In Scotland, however, the age range for gFOBT screening is 50 to 74, and the main issue
      surrounding the introduction of FS screening in Scotland is that there is no information
      regarding the utility of FS in a population that has already been exposed to FOBT screening.

      Nevertheless, given the high degree of efficacy of FS screening, particularly in terms of
      disease prevention via adenoma detection, and the relatively higher participation associated
      with gFOBT screening and its potential to detect proximal cancers, it is hypothesised that
      offering a combination of both approaches would provide an enhanced screening algorithm that
      would be associated with better outcomes than either modality alone. In order to test this
      hypothesis and answer some key unresolved questions around FS, it is necessary to carry out a
      pilot of FS screening integrated into the current faecal test-based Scottish Screening
      Programme, and to maximise the information from this pilot it is proposed to carry it out as
      a random evaluation. It is also proposed that FS is offered at around the age of 60, as this
      appears to be the age at which adenoma prevalence peaks, and therefore the age at which
      adenoma detection and removal is likely to confer the maximum benefit. There is also evidence
      from the gFOBT pilot that 80% of interval cancers are diagnosed over the age of 60.

      As the Scottish Bowel Screening Programme offers gFOBT from the age of 50, and as screening
      started in Grampian, Tayside and Fife in 2000 as part of the UK demonstration screening
      pilot, carrying out a study in these areas will demonstrate whether or not FS adds value to a
      mature biennial FOBT screening programme. Further evaluation in Greater Glasgow will test FS
      in a challenging Health Board with areas of high urban deprivation.

      We will seek to establish the value and feasibility of flexible sigmoidoscopy in populations
      which have been exposed to gFOBT screening for colorectal cancer.

      In this way it will be possible to estimate the added value of adding FS to the FOBT
      programme. This will inform the structure of the Scottish Bowel Screening Programme and
      provide information that will have international implications.

      It will also be possible to estimate the practicalities of introducing flexible sigmoidoscopy
      into the Scottish population against a background of ongoing gFOBT screening.
    

Intervention name(s): Flexible Sigmoidoscopy; Fecal occult blood test
Intervention type(s): Procedure; Other
Intervention description(s): Examination of the rectal and distal colon by means of a flexible endoscope; Test for hemoglobin in faeces
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Prevention