Editorials
`
`issue. It will take into account the service contribution
`provided by the doctors within structured training pro›
`grammes, guidance from the Department of Health on
`the recruitment of doctors, equal opportunities legisla›
`tion and policy, the arrangements for registration with
`the General Medical Council, and current immigration
`regulations. Options to be considered by the panel
`include a wholesale revision of the Overseas Doctors
`Training Scheme and the criteria for direct placement
`and possibly limiting direct placement
`to certain
`specific training placements or stopping it completely.
`There is anecdotal evidence that a number of over›
`seas doctors successfully complete the examination of
`the professional and linguistic assessment board but
`find it difficult to get training grade posts afterwards. In
`some cases doctors have waited for more than a year
`despite applying for many jobs. The supply of training
`placements for overseas doctors has been outstripped
`by the demand. Training opportunities in the NHS can
`meet the needs of overseas doctors, which include
`basic and higher specialist training and preparation for
`examinations. Improvements in managing and deliver›
`ing training are needed to maximise the training
`opportunities;
`these improvements could include
`offering an induction course about
`the NHS and
`specific training placements and assessing the doctor’s
`training needs and agreeing objectives. Immigration
`regulations allow overseas doctors to stay in the United
`Kingdom to complete postgraduate training to the
`standard of the Certificate of Completion of Satisfac›
`
`tory Training. This certificate is granted by the Special›
`ist Training Authority of the Medical Royal Colleges
`and confirms that the doctor has completed specialist
`training.
`While we await the recommendations of the review
`panel, overseas doctors who are considering travelling
`to the United Kingdom for training must be given
`appropriate information from British embassies and
`consulates, from the British Council, and from the
`GMC. The information must clearly state that success
`in the professional and linguistic assessment board
`examination does not guarantee employment in the
`NHS, and that there is competition for placements in
`training grades. Overseas doctors should be warned, as
`those who train in the United Kingdom should also be,
`that in certain specialties gaining a training post at a
`higher specialist level is intensely competitive.
`Christopher Welsh regional postgraduate dean
`NHS Executive Trent, Sheffield S10 3TH
`(chris.welsh@doh.gsi.gov.uk)
`
`1 Sridhar MK. What is the future for overseas graduates? BMJ 2000;320:
`307.
`2 Richards T. The Overseas Doctors Training Scheme: failing expectations.
`BMJ 1994;308;1627›31.
`3 Mick SS, Pfalher MN. Review and synthesis of the literature on foreign medical
`graduates/international medical graduates, 1980›1994: report to the Bureau of
`Health Professions, Health Resources and Services Administration, US
`Department of Health and Human Services. Rockville, MD: DHSS, 1995.
`4 Department of Health. NHS hospital, public health medicine and community
`health service medical and dental workforce census: England at 30 September
`1999. London: DoH, 1999.
`
`Molecular stool screening for colorectal cancer
`Using DNA markers may be beneficial, but large scale evaluation is needed
`
`Colorectal cancer is the most common fatal
`
`malignancy among non›smokers in North
`America and Europe. Better tools are needed
`to improve the accuracy, compliance rates, safety, and
`affordability of screening. Stool testing has several
`important advantages over structural screening meth›
`ods and warrants more investigation. Stool testing is
`non›invasive, avoids unpleasant cathartic preparation,
`can be performed on transported specimens without
`people having to visit their physicians, and, unlike sig›
`moidoscopy, reflects the state of the full length of the
`colorectum. Screening for stool markers that are more
`accurate than occult blood could substantially improve
`screening outcomes, and there is a strong biological
`rationale for targeting the DNA alterations that are
`exfoliated from neoplasms.
`Faecal occult blood testing, used to screen for color›
`ectal cancer for nearly three decades, continues to be the
`most widely used tool. Although controlled trials have
`shown that is of significant benefit, deaths from colorec›
`tal cancer have only been reduced by 15›33% after
`10›14 years, and it has had no real impact on reducing
`the cumulative incidence of cancer.1–3 These outcomes
`are consistent with a tool that misses many early stage
`cancers and most premalignant adenomas.
`Because neoplasms that could be caught by screen›
`ing often do not bleed and occult bleeding from trivial
`sites is common, faecal occult blood is an inherently
`
`insensitive and non›specific marker. When compared
`with endoscopy, faecal occult blood tests detect < 30%
`of cancers and < 12% of
`large adenomas.4 The
`specificity of the faecal occult blood test averages about
`95% (range 88›98%); this translates into an average false
`positive rate of 5%, the equivalent of an unnecessary
`colonoscopy on 1 in every 20 people screened.4
`Non›specificity increases the costs of screening pro›
`grammes and morbidity from diagnostic interventions.
`These limitations of faecal occult blood tests are biologi›
`cally inescapable and cannot be remedied by techno›
`logical advances in measuring faecal occult blood.
`DNA is an intriguing alternative marker in the stool
`for reasons that are, theoretically, compelling. Firstly,
`DNA is released into the faecal stream continuously via
`exfoliation rather than intermittently via bleeding, which
`could enhance sensitivity and obviate the need for mul›
`tiple stool tests during each screening. Secondly, DNA
`comes from the neoplasm itself rather than from the cir›
`culation, which could improve specificity. Thirdly,
`colonocyte exfoliation from cancers is quantitatively
`much greater than from normal mucosa.5 6 Fourthly, the
`well characterised genetic alterations in colorectal
`neoplasms serve as potential targets for assays.7 Fifthly,
`DNA seems to be stable during faecal transit and
`storage. Sixthly, proscriptions on diet and medications
`would probably be unnecessary with this test. Finally,
`sensitive laboratory techniques allow minute amounts of
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`DNA to be detected; recovered faecal DNA can be
`amplified more than a billion›fold by polymerase chain
`reaction before it is measured.
`Early investigations targeting single mutations, usu›
`ally K›ras, show that mutations in tumours can be
`detected in stools from the same patients.8–10 Since
`colorectal neoplasms are genetically heterogeneous,
`however, no one mutation has been identified that is
`universally expressed. Mutant K›ras, for example, is
`present in less than half of all colorectal neoplasms;
`this would restrict the maximum sensitivity of this test
`for colorectal cancer to less than 50% if it was used as
`the sole marker for screening in a stool assay.8–10 Also,
`since mutant K›ras may arise from non›neoplastic
`sources, such as pancreatic hyperplasia, this marker
`may lack specificity. Multiple DNA alterations should
`be targeted to achieve high rates of detection, and each
`component marker must be specific for a neoplasm to
`avoid false positive results.
`Data from pilot projects suggest that the diagnostic
`yield improves when a stool assay with multiple targets
`is directed at a spectrum of DNA alterations commonly
`expressed by cancers.11 The assay used in the pilot
`study included 15 mutational “hot spots” on K›ras, p53,
`and APC genes; BAT›26, a microsatellite instability
`marker (a genomic alteration present in 15›20% of
`colon cancers), and long (non›apoptotic) DNA. Using
`one stool per patient, which was tested blind, DNA
`alterations were detected in 20 of 22 (91%) patients
`with colorectal cancer, 9 of 11 (82%) patients with
`adenomas > 1 cm, and 2 of 28 (7%) controls who had
`had normal colonoscopies. When K›ras was dropped
`from the assay, sensitivity for cancer was unaffected but
`it fell to 73% for large adenomas and specificity rose to
`100%. Larger studies are clearly indicated to corrobo›
`rate these early outcomes.
`Preliminary data suggest that components of this
`assay panel may also detect cancers that occur above
`the colon, including in the lung, at sensitivities compa›
`rable to those for colorectal neoplasia.12
`Thus, stool screening with DNA markers could
`have benefits beyond detecting colorectal neoplasms: it
`may be useful in controlling other cancers as well. It
`will be important to evaluate the implications of these
`
`Editorials
`
`findings using screening algorithms and evaluations of
`overall cost effectiveness.
`Assay methods are labour intensive and must be
`streamlined for large scale testing, but exciting technolo›
`gies are emerging to make this possible. While it is too
`early to know for certain, molecular markers may im›
`prove the effectiveness and efficiency of stool screening.
`David A Ahlquist professor of medicine
`Division of Gastroenterology and Hepatology, Mayo Clinic E›19,
`Rochester, MN 55905, USA (ahlquist.david@mayo.edu)
`
`DAA has been given partial research support (to help with
`supplies and assay costs) through a grant from EXACT Labora›
`tories, which developed the multitarget assay system discussed
`in this editorial.
`
`1 Mandel JS, Bond JH, Church TR, Snover DC, Bradley GM, Schuman LM,
`et al. Reducing mortality from colorectal cancer by screening for fecal
`occult blood. Minnesota colon cancer study. N Engl J Med 1993;328:
`1365›71.
`2 Hardcastle JD, Chamberlain JO, Robinson MN, Moss SM, Amar SS, Bal›
`four TW, et al. Ramdomised controlled trial of faecal›occult blood
`screening for colorectal cancer. Lancet 1996;348:1472›7.
`3 Kronborg O, Fenger C, Olsen J, Jorgensen OD, Sondergaard O.
`Randomized study of screening for colorectal cancer with fecal›occult
`blood test. Lancet 1996;348:1467›71.
`4 Ahlquist DA. Fecal occult blood testing for colorectal cancer: can we
`afford to do this? Gastroenterol Clin N Am 1997;26:41›55.
`5 Ahlquist DA, Harrington JJ, Burgart LJ, Roche PC. Morphometric analy›
`sis of the “mucocellular layer” overlying colorectal cancer and normal
`mucosa: relevance to exfoliated stool screening markers. Hum Pathol
`2000;31:51›7.
`6 Loktionov A, O’Neill IK, Silvester KR, Cummings JH, Middleton SJ,
`Miller R. Quantitation of DNA from exfoliated colonocytes isolated from
`human stool surface as a novel noninvasive screening test for colorectal
`cancer. Clin Cancer Res 1998;4:337›42.
`7 Boland CR, Sato J, Saito K, Carethers JM, Marra G, Laghi L, et al. Genetic
`instability and chromosomal aberrations in colorectal cancer: A review of
`current models. Cancer Detect Prev 1998;22:377›82.
`8 Sidransky D, Tokino T, Hamilton SR, Kinzler KW, Levin B, Frost P, et al.
`Identification of ras oncogene mutations in the stool of patients with cur›
`able colorectal tumors. Science 1992;256:102›5.
`9 Eguchi S, Kohara N, Komuta K, Kanematsu T. Mutations of the p53 gene
`in stool of patients with resectable colorectal cancer. Cancer 1996;77:
`1707›10.
`10 Villa E, Dugani A, Rebecchi AM, Vignoli A, Grottola A, Buttafoco P, et al.
`Identification of subjects at risk for colorectal carcinoma through a test
`stool. Gastroenterology
`based
`on K›ras
`determination in the
`1996;110:1346›53.
`11 Ahlquist DA, Skoletsky JE, Boynton KA, Harrington JJ, Mahoney DW,
`Pierceall WE, et al. Colorectal cancer screening by detection of altered
`human DNA in stool: feasibility of a multitarget assay system. Gastroenter›
`ology (in press).
`12 Ahlquist DA, Cameron AJ, Jett J, Pearson RK, de Groen PC, Edell E, et al.
`Universal detection of aerodigestive cancers by assay of nonapoptotic
`human DNA in stool [abstract]. Gastroenterology 2000;188:A855.
`
`Which clinical studies provide the best evidence?
`The best RCT still trumps the best observational study
`
`Acommon question in clinical consultations is:
`
`“For this person, what are the likely effects of
`one treatment compared with another?” The
`central tenet of evidence based medicine is that this
`task is achieved by using the best evidence combined
`with consideration of that person’s individual needs.1 A
`further question then arises: “What
`is
`the best
`evidence?” Two recent studies in the New England
`Journal of Medicine have caused uproar in the research
`community by finding no difference in estimates of
`treatment effects between randomised controlled trials
`and non›randomised trials.
`The randomised controlled trial and, especially,
`systematic reviews of
`several of
`these trials are
`
`traditionally the gold standards for judging the benefits
`of treatments, mainly because it is conceptually easier
`to attribute any observed effect to the treatments being
`compared. The role of non›randomised (observa›
`tional) studies in evaluating treatments is contentious:
`deliberate choice of the treatment for each person
`implies that observed outcomes may be caused by dif›
`ferences among people being given the two treat›
`ments, rather than the treatments alone. Unrecognised
`confounding factors can always interfere with attempts
`to correct for identified differences between groups.
`These considerations have supported a hierarchy
`of evidence, with randomised controlled trials and
`derivatives at the top, controlled observational studies
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