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Cola

People randomized to this arm are offered flexible sigmoidoscopy in addition to FOBT at the age of 60.

People in this are offered fecal occult blood testing only.

Examination of the rectal and distal colon by means of a flexible endoscope

Flexible Sigmoidoscopy

Fecal occult blood test

Robert JC Steele, MD

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.

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.

Evaluation of Flexible Sigmoidoscopy Screening as an Adjunct to the National FOBT Screening Programme in Scotland

Evaluation of Flexible Sigmoidoscopy Screening as an Adjunct to the National FOBT Screening Programme in Scotland - A Random Evaluation

Pathology report of lesion removed at flexible sigmoidoscopy or subsequent colonoscopy

Record of whether or not the flexible sigmoidoscopy had been carried out

University of Dundee

Professor of Surgery

Digestive System Diseases

Rectal Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Intestinal Diseases

Rectal Diseases

Central Nervous System Depressants

Anesthetics

Subjects will come to the OR and undergo a flexible sigmoidoscopy after induction of anesthesia and receive separate endoscopic injections of Spot (up to 5 cc), 99mTc-sulfur colloid (up to 0.5 mCi), and Indocyanine green (ICG) (1 ml). Patient will undergo the standard transanal endoscopic surgery (TES) to remove the rectal neoplasm, exposing the lymph node basin. The sentinel node(s) will be identified using a combination of the gamma probe and fluorescence imaging endoscopically, dissected out, and removed through a transanal approach.

Radiotracer injection around the rectal tumor for SLN mapping with gamma probe

Endoscopic injection of 99mTc-sulfur colloid

Dye injection around the rectal tumor for SLN mapping with NIR imaging.

Endoscopic injection of ICG

Dye injection for tattooing rectal tumor prior to surgical resection.

Endoscopic injection of Spot

Flexible sigmoidoscopy prior to surgery to facilitate endoscopic injections of radiotracer and dyes.

Flexible sigmoidoscopy

Endoscopic near infrared (NIR) imaging of ICG and detection of radiotracer with gamma probe after standard removal of rectal neoplasm.

Endoscopic NIR imaging and gamma probe

Surgical removal of identified lymph nodes in the rectum.

Dissection of sentinel lymph node(s)

Amy Harrigan, BS, CCRC

Amy Harrigan

Traci L Hedrick, MD, MS

Traci Hedrick, MD

The purpose of this study is to develop a technique that allows physicians to identify the first lymph nodes draining from a rectal tumor (the sentinel lymph nodes). Currently, there is no technique used to find these lymph nodes in the rectum during surgery and therefore many patients with rectal cancer need to undergo a total rectal resection. Dyes, tracers, imaging and a gamma probe will be used in this study during a standard minimally invasive transanal endoscopic surgery (TES) to try to locate these lymph nodes. If surgeons are able to locate these lymph nodes they will be removed during surgery. If the technique is successfully developed as a result of this research, it could help patients in the future with early stage rectal cancer by allowing doctors to see if their cancer has spread to the lymph nodes of the rectum without having to undergo a total rectal resection. These patients would then be able to undergo a TES combined with a lymph node dissection to gain more knowledge about the stage of their disease. This knowledge would then be used to determine if and what further treatment is necessary for the patient's rectal cancer.

Sentinel Lymph Node Mapping in Rectal Cancer

Novel Sentinel Lymph Node Mapping Technique in Early Stage Rectal Cancer

Data from the first 6 eligible patients will be used to verify feasibility. For this phase, the data need to support a detection rate of at least 50% for the procedure to be considered feasible to move forward with the 2nd phase. The proposed SLNm technique will be declared 'feasible' if at least one SLN is identified per patient. Identification of the SLN in three consecutive patients would provide 80% confidence of successful identification more than 50% of the time. A total sample of size of 6 patients would allow for three refinements in technique if necessary to establish feasibility.

2nd Phase: Sample size is set at 16 eligible patients. For this study, continued investigation of the proposed technique would be of interest if 70-100% of the SLNs are detected. If at least on SLN is detected in 14 of 16 patients, an observed rate of 87.5%, then the lower limit of a one-sided 90% confidence interval is 70%. Thus, detection of at least one SLN in 14 or more patients out of 16 assessed would provide strong preliminary data for the technique (i.e. SLN is detected in at least 70% of patients). If it's assumed, on average, 1.5 SLN could be identified and excised per patient, then with 24 possible SLN, the estimated rate of SLN positive for disease would have an expected half width (or precision of the estimate) of 12-14%.

University of Virginia

Assistant Professor of Surgery

Colonic Diseases

Personally-tailored educational software program

Anthony F Jerant, MD

The purpose of this study is to determine whether a newly developed educational software program is effective in increasing patients' confidence in their ability to undergo colon cancer screening. If the software is effective in this regard, the study will also determine if increased confidence to undergo screening leads to more people being screened and to people feeling as though their decision about screening was informed.

Background: Interactive multimedia computer programs (IMCPs) show promise for facilitating informed patient decisions. However, it is unclear whether IMCPs can activate patients by delivering personally tailored information to bolster self-efficacy, a key mediator of health behavior. It is also unclear whether IMCPs might be employed to lessen disparities in care experienced by less educated people by tailoring self-efficacy enhancing information to educational level and compensating for provider biases in communication. Finally, the optimal way to deploy IMPCs in primary care (e.g. before versus following an office visit) remains unclear. Aims/Hypotheses: We will compare changes in colorectal cancer (CRC) screening self-efficacy, intention, uptake, and informed decision making resulting from an IMCP providing personally tailored information (to subject educational level and self-efficacy) intended to boost self-efficacy with changes resulting from a non-tailored control IMCP. We hypothesize both the intervention and control condition will result in increases in CRC screening self-efficacy, but increases will be significantly greater in the intervention group. We also hypothesize both the intervention and control condition will increase CRC screening intention, uptake, and informed decision making, but increases will be greater in the intervention group and will be mediated by self-efficacy enhancement. Methods: Pilot randomized controlled trial (RCT) of 2 groups, comparing a PCN office visit-linked, tailored (to subject self-efficacy) IMCP software program plus mailed reminders versus a non-tailored CRC screening IMCP software program plus mailed reminders (control). Screening methods targeted will be fecal occult blood testing, flexible sigmoidoscopy, colonoscopy, and computed tomographic virtual colonoscopy. Primary outcomes will be CRC screening self-efficacy, intention, uptake, and informed decision making. Implications: Our pilot is powered to detect a significant effect on CRC screening self-efficacy but not other outcomes; however, by conducting it as we would a future and larger RCT, we will determine protocol feasibility. If our hypotheses are confirmed, it would imply cancer screening IMCPs should be focused on enhancing self-efficacy. Since self-efficacy is a mediator of many patient and health care provider behaviors, it would also imply that similar IMCPs could be developed to support a host of patient and professional education efforts.

Study of Using Computerized Education to Increase Patients' Confidence in Their Ability to Be Screened for Colon Cancer

Randomized Controlled Trial of Software-Based Enhancement of Colorectal Cancer Screening Self-Efficacy

University of California, Davis

Symptoms and General Pathology

Colitis

Colitis, Ulcerative

Ulcer

Colonic Neoplasms

All subjects who are undergoing a standard of care colonoscopy for flexible sigmoidoscopy and have a history of UC and agree to participate will be in the main study group.

Partial wave spectroscopy (PWS)has been developed to allow scientists to learn about any changes to the cells that may indicate a risk of developing colon cancer.

PWS Testing

David T Rubin, MD

The purpose of this study is to study samples of rectal mucosa (the moist lining of the rectum) using a new light scattering technology, called partial wave spectroscopy (PWS) in patients who will undergo a standard of care colonoscopy or a flexible sigmoidoscopy and have a history of ulcerative colitis (UC).

The purpose of this study is to study samples of rectal mucosa (the moist lining of the rectum) using a new light scattering technology, called partial wave spectroscopy (PWS)in patients who will undergo a colonoscopy or a flexible sigmoidoscopy and have a history of ulcerative colitis (UC). PWS has been recently developed to allow scientists to learn about any changes to the cells that may indicate a risk of developing colon cancer. We believe that the PWS test will more accurately detect the risk of colon cancer.

A sample of rectal mucosa will be collected during the subject's standard of care colonoscopy or flexible sigmoidoscopy.

Partial Wave Spectroscopic Detection of Colon Cancer Risk

Samples will be collected and then shipped to Northwestern University for analysis using PWS. This is to assess accuracy of detecting the risk for colon cancer.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Evaluation of Flexible Sigmoidoscopy Screening as an Adjunct to the National FOBT Screening Programme in Scotland	NCT02560194	Colorectal Canc... Colorectal Aden...	Flexible Sigmoi... Fecal occult bl...	59 Years - 61 Years	University of Dundee
Sentinel Lymph Node Mapping in Rectal Cancer	NCT02869152	Rectal Neoplasm...	Endoscopic inje... Endoscopic inje... Endoscopic inje... Flexible sigmoi... Endoscopic NIR ... Dissection of s...	18 Years -	University of Virginia
Study of Using Computerized Education to Increase Patients' Confidence in Their Ability to Be Screened for Colon Cancer	NCT00273585	Colorectal Canc...	Personally-tail...	50 Years -	University of California, Davis
Partial Wave Spectroscopic Detection of Colon Cancer Risk	NCT01095432	Ulcerative Coli... Colon Cancer	PWS Testing	18 Years -	University of Chicago

Spots Global Cancer Trial Database for flexible sigmoidoscopy