ColoreCtal CanCer
`
`Colorectal cancer: prevention
`and early diagnosis
`
`Victoria White
`richard Miller
`
`Abstract
`Colorectal cancer (CrC) is a curable disease; over 90% of patients who
`have surgical resection of a Dukes’ a tumour will still be alive after 5 years.
`this is direct evidence that an early diagnosis will reduce mortality from
`CrC. Despite this, CrC is the second most important cause of cancer-related
`deaths in the UK. the discrepancy suggests that outcomes can be improved
`by a better understanding of the causes of the disease and its early detec-
`tion and treatment. In this article, prevention and early diagnosis are dis-
`cussed. the important associations of CrC with diet, obesity and exercise are
`considered, as well as the benefits of patient education and continued aca-
`demic research into these areas. Screening for CrC using faecal occult blood
`test (FoBt) is examined in detail and surveillance programmes for hereditary
`non-polyposis colorectal cancer, familial adenomatous polyposis and other
`high-risk patients are reviewed. Finally, the impact of the ‘two-week wait’ rule
`introduced by the ‘nHS Cancer Plan 2000’ is analysed, and proposals made
`on how to maximize its purpose to detect CrC as early as possible.
`
`Keywords colorectal cancer; ePIC; familial adenomatous polyposis;
` hereditary non-polyposis colorectal cancer; patient education; screening;
`surveillance
`
`
`Colorectal cancer (CRC) is a major cause of cancer morbidity in
`the UK, and in 2002 there were 34,889 new cases and 16,000
`deaths from the disease.1 After lung cancer, it is the second most
`important cause of cancer-related deaths.1
`
`Pathogenesis
`
`The pathogenesis of CRC is well understood in terms of the
`‘­adenoma–carcinoma sequence’. This describes the progression
`of CRC as an accumulation of mutations in key genes, for exam-
`ple, tumour suppressor genes such as the adenomatous polypo-
`sis coli (APC) and TP53 genes, and in proto-oncogenes such as
`K-ras. In macroscopic terms, these molecular changes contribute
`to the development of polypoid lesions and, later, invasive car-
`cinoma. In polyps, the normal architecture of colonic crypts is
`disrupted by disturbances in the sequence of basal proliferation,
`
`Victoria White MRCS is a Research Clinician at the MRC Cancer Cell Unit,
`Hutchison/MRC Research Centre, Cambridge, UK. Competing interests:
`none declared.
`
`Richard Miller MS FRCS is a Consultant Colorectal Surgeon at the
`Cambridge Colorectal Unit, Addenbrooke’s Hospital, Cambridge
`University Hospitals NHS Foundation Trust, Cambridge, UK. Competing
`interests: none declared.
`
`migration and differentiation. Many individuals have polyps, but
`it is estimated that only 5% will develop invasive cancer. Preven-
`tion of colorectal cancer, therefore, depends on early elimination
`of these polyps and/or the factors that predispose the colonic
`epithelium to become transformed.
`
`Aetiology
`
`Eighty-five per cent of CRC cases fall into the category of ‘­sporadic’
`disease, where the primary cause of polyp formation is unknown.
`The remaining 15% of cases are accounted for by less common
`causes of CRC, for example familial CRC (i.e. where one first-degree
`relative aged <45 years old is affected by CRC or there are two
`affected first-degree relatives), dominantly inherited CRC syndromes
`and inflammatory bowel disease (IBD). In the latter two groups, the
`molecular events of polyp formation are understood. The heredi-
`tary CRC syndromes (e.g. hereditary non-polyposis colorectal can-
`cer (HNPCC), familial adenomatous polyposis (FAP), Peutz-Jegher
`syndrome, and juvenile polyposis) have germline mutations that
`predispose the epithelium to develop multiple polyps. A germline
`mutation of APC is responsible for the colorectal polyps that develop
`in FAP, whereas mutations in mismatch repair genes which usually
`detect, excise and replace any inadvertent nucleotide mismatches
`during DNA replication, result in HNPCC. Compared with the
`large number of polyps in FAP, there are markedly fewer polyps in
`HNPCC. The HNPCC polyps are predominantly located in the right
`colon but their rate of transformation is high compared with FAP
`(see Figure 1). In IBD such as ulcerative colitis and colonic Crohn’s,
`the predisposition to CRC arises from the increased proliferation of
`colonic epithelium during inflammatory episodes.
`Polyp formation in sporadic disease is not well understood,
`consequently, numerous studies on external factors such as diet,
`obesity and other lifestyle parameters have been, and are being,
`undertaken to identify causal relationships with CRC. Some of
`these studies are discussed below and are an important source of
`evidence-based preventative measures.
`
`Prevention
`
`Diet
`In the 1960s, Burkitt proposed that ‘­the relationship between diet
`and bowel disease’ should be investigated. His hypothesis was
`
`Figure 1 Macroscopic view of a polyposis seen in familial adenomatous
`polyposis. reprinted with kind permission from Dr Mark arends,
`Consultant Histopathologist, addenbrooke’s Hospital, Cambridge, UK.
`
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`ColoreCtal CanCer
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`that low-fibre diets slowed colonic transit and thereby increased
`the opportunity of carcinogens, generated by bacterial activity on
`faecal constituents, to exert their effect on the colonic epithelium.
`The effect of diet (as well as metabolic, genetic and environmen-
`tal factors) on the development of cancer is now being explored
`in the European Prospective Investigation into Cancer and Nutri-
`tion (EPIC) study. EPIC is the world’s largest prospective study
`and involves over half a million people recruited from 23 different
`regions of 10 European countries. The advantage of obtaining data
`from multiple regions is that a clearer relationship between differ-
`ent dietary habits and the development of cancer may be seen.2
`The first completed data sets have now been analysed from the
`ongoing EPIC study; these show that dietary patterns are regional
`and that diet does have an impact on the development of CRC. For
`example, it has been demonstrated that dietary fibre is likely to be
`protective against colorectal cancer; comparison between the low-
`est daily fibre intake of 12 g and the highest intake of 30 g, showed
`a 40% reduction in the risk for CRC after calibration.3 The source
`of fibre was not significant.3 As a result, it has been suggested that
`about eight portions of fruit and vegetables and the equivalent of
`five slices of wholemeal bread should be eaten if the benefits of
`dietary fibre are to be realized.2 Linked studies have also shown
`that a high intake of red or processed meat is associated with a 35%
`increase in colorectal cancer if more than 160 g are consumed per
`day (2 or more portions) when compared to less than one portion
`per week.4 In contrast, a high fish consumption of 80 g or more is
`protective.4 The increased risk of CRC with a high consumption of
`red and processed meat may be related to the association of these
`foodstuffs with increased amounts of N-nitrosocompounds in the
`faeces. These compounds bind to the epithelial DNA and may act
`as mutagens to initiate the adenoma–carcinoma sequence.
`Some studies have not demonstrated that a high fibre diet
`reduces the risk of CRC,5 therefore, continuing investigations are
`still necessary to confirm the findings and to identify any other
`dietary factors that might contribute to the risk of developing CRC.
`
`Obesity and exercise
`There is accumulating epidemiological evidence that central
`obesity is a risk factor for CRC. The biological mechanisms still
`need to be elucidated, but hyperinsulinaemia appears to play a
`role. With further research, it may emerge that weight loss is
`an important preventative measure against CRC as it is against
`endometrial cancer, heart disease and type II diabetes.
`Regular exercise also protects against CRC. Furthermore, there
`is evidence that CRC patients have an absolute improvement of
`14% in their five-year survival if they had active lifestyles before
`presenting with symptoms of CRC.6 An active patient is defined
`as someone who exercises vigorously for 20 minutes at least once
`a week or participates in weekly general health and fitness.6
`
`Alcohol and smoking
`The link between alcohol and CRC remains equivocal. Some
`evidence suggests that there is a dose–risk relationship which
`is particularly pertinent to rectal cancer. However, the evidence
`for tobacco is slightly stronger; rectal cancer, rather than colon
`cancer, is related to smoking even after adjustment for alcohol.7
`This epidemiological evidence is also supported by other stud-
`ies which have shown that smokers have a higher incidence of
`colorectal polyps.
`
`Chemoprevention
`Non-steroidal anti-inflammatory drugs (NSAIDs) may inhibit
`progression and development of CRC. A recent Cochrane meta-
`analysis analysed four randomized controlled trials which com-
`pared aspirin with a placebo in ‘­average’-risk populations.8 No
`significant reduction in the incidence of adenomas was noted in
`the primary prevention trial, but data from the three secondary
`prevention trials showed a statistically significant reduction in
`the recurrence of sporadic adenomas in the ‘­treatment’ groups.
`The overall results (which included trials treating FAP patients
`with aspirin) showed a trend in favour of treating with aspirin
`to prevent colorectal adenomas.8 However, the largest trials pre-
`selected patients for aspirin tolerance, and therefore the risks
`of gastrointestinal bleeding and haemorrhagic stroke must be
`weighed against the benefit of treatment.
`
`Patient education
`Symptoms of CRC include a change in bowel habit (particularly
`loose stools for more than six weeks) and rectal bleeding (char-
`acteristically, dark blood which may or may not be mixed with
`stool). Bright red rectal blood in the absence of other anal dis-
`ease (e.g. haemorrhoids, tags and fissures) is also a high-risk
`symptom. Efforts to educate patients about the importance of
`these symptoms, together with information about screening pro-
`grammes, are likely to lead to earlier patient presentation, par-
`ticularly as there is evidence that patients do ignore symptoms
`(for years in some cases), and express fears about unpleasant
`examinations and not wanting ‘­to waste the doctor’s time’.
`
`Early diagnosis through screening
`
`There is evidence that polypectomy reduces the incidence of
`CRC.9,10 Population screening for premalignant or early disease
`in the form of polypoid lesions is, therefore, likely to reduce the
`incidence of sporadic CRC in the longer term. For an average-
`risk individual (e.g. no family or personal history of CRC), the
`lifetime cumulative incidence of CRC is 6%,11 but the risk of
`developing sporadic CRC doubles every 10 years after 40 years
`of age.11 To achieve the maximum benefits of a screening test,
`it should be undertaken when the patient is most likely to have
`pre-invasive or very early invasive disease. Since the average age
`of patients who receive a diagnosis of adenomatous polyps is
`around 60 years old, the Department of Health guidelines in the
`UK advise that biennial screening should be offered to everyone
`between 60 and 69 years old (http://www.cancerscreening.nhs.
`uk/bowel/index.html). Initial screening will be performed using
`the faecal occult blood test (FOBT). Patients with positive tests
`will be offered colonoscopy in quality-assured centres.
`
`Faecal occult blood test
`The principle behind FOBT is that polyps and malignant
`lesions bleed, and blood from these lesions is shed into the
`faecal stream and the peroxidase activity of haem is detected
`by the guaiac impregnated test cards. However, not all colonic
`lesions bleed, and the principal criticism of FOBT is its low
`sensitivity and inadequate specificity which can translate into
`high levels of false-negative and false-positive rates respec-
`tively (see Table 1 for definitions). Estimates of the sensitivity
`for CRC range from 12.9%12 to 50%,13 and for large adenomas,
`
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`Definitions of sensitivity and specificity
`
`Sensitivity
` • Definition: probability of a positive test when the disease is
`present
` • application: if the test has a high sensitivity, it will identify
`patients with the disease, and therefore a negative result
`indicates that the patient does not have the disease
` Specificity
` • Definition: probability of a negative test when the disease is
`absent
` • application: if the test has a high specificity, a negative result
`identifies people who do not have the disease, and therefore
`a positive result indicates that the patient has the disease
`
`Table 1
`
`sensitivity estimates are as low as 12%.12 The specificity
`of FOBT is usually around 95%, which results in a 5% false-
`positive rate. In some clinical settings this may be acceptable,
`but in a national screening programme this means unneces-
`sary colonoscopies for 1 in 20 of the people screened by FOBT.
`If, as expected, thousands of individuals take up the FOBT
`screening, the 1 in 20 unnecessary colonoscopies may lead to
`significant patient risk and financial burdens for patients and
`health services.
`
`Surveillance following adenoma removal
`
`Despite the criticisms, FOBT is still a viable screening test;
`it is non-invasive and cheap, but more importantly it reduces
`mortality from CRC. Several trials have independently shown a
`significant reduction in mortality from CRC in the individuals
`randomized to receive FOBT.13–15 In the FOB-tested groups, the
`reduction in mortality was 15–18%13,15 for biennial screening and
`33% for annual screening.14 Furthermore, 18 years of follow-up
`from the Minnesota trial has demonstrated a significant reduc-
`tion in the incidence of CRC in patients randomized to FOBT.
`
`CRC prevention through the surveillance of screened patients
`with early disease
`The number of patients diagnosed with adenomas and early
`CRC will inevitably increase as a screening programme becomes
`established. These patients need regular follow-up or surveil-
`lance because of their increased risk of recurrent adenomas. The
`interval between surveillance colonoscopies is timed to balance
`the risk of repeat colonoscopies against the need to diagnose and
`treat any further neoplasia and/or CRC before it causes signifi-
`cant morbidity. Initially a 3-year interval was proposed based
`on the data from the US National Polyp Study, but further stud-
`ies have modified this recommendation. It has been shown that
`if adenomas are found, the number and size of the adenomas
`often predict the polyp findings at subsequent follow-up colono-
`scopies. As a result, patients can be risk-stratified according to
`the number and size of the adenomas that are found at initial
`colonoscopy.16 At the next follow-up, the patient is re-stratified
`according to the new colonoscopic findings.16 A summary of the
`stratification process is illustrated in Figure 2.
`
`Low risk
`1–2 adenomas
`AND
`both small (<1 cm)
`
`≥
`
`A
`
`No surveillance
`or 5 year*
`
`Baseline colonoscopy
`
`Intermediate risk
`3–4 small adenomas
`OR
`at least one ≥1 cm
`
`B
`
`3 year
`
`High risk
`≥5 small adenomas
`OR
`≥3 at least one ≥1 cm
`
`C
`
`1 year
`
`Findings at follow-up
`
`Findings at follow-up
`
`Findings at follow-up
`
`Cease
`
`follow-up
`No adenomas
`A
`Low risk adenomas
`Intermediate risk adenomas B
`High risk adenomas
`C
`
`1 negative exam
`2 consecutive
`negative exams
`Low or intermediate
`risk adenomas
`High risk adenomas
`
`B
`Cease
`follow-up
`B
`
`C
`
`Reproduced with kind permission from Atkin WS, Saunders BP. Gut 2002; 51(Suppl 5): V6−9.16
`
`Negative, low or
`intermediate risk adenomas
`High risk adenomas
`
`B
`
`C
`
`*Other considerations
`Age, comorbidity, family history, accuracy
`and completeness of examination
`
`Figure 2
`
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`Prevention through surveillance of patients at above-average
`risk of CRC
`For patients with a higher risk of CRC compared to the general
`population (e.g. inherited CRC syndromes and IBD), early detec-
`tion of CRC depends on appropriate surveillance programmes.
`Strong evidence (Level II) has shown that surveillance of HNPCC
`patients reduces both the incidence of CRC and the risk of mor-
`tality from CRC17 associated with this syndrome. Furthermore,
`surveillance frequency for HNPCC is based on the early age of
`presentation with the disease (median age 40–45 years) and the
`likelihood that progression from adenoma to invasive carcinoma
`is more rapid than sporadic CRC – sometimes within three years
`of a clear colonoscopy. In contrast to HNPCC, the disease profiles
`and risks for FAP, IBD and familial CRC are all different, and
`therefore different surveillance guidelines are required.18–20 These
`guidelines are summarized in Table 2, but they remain flexible
`and practice standards will evolve as new data are published.
`
`Prevention and early diagnosis through UK Government
`initiatives
`
`The ‘­NHS Cancer Plan’, introduced to reform cancer services,
`directed that, by 2005, the time from GP referral to treatment
`for all cancers should be a maximum of 62 days. The initiative
`
` introduced the two-week wait rule (TWR) and the ‘­two-week
`wait clinics’. An implicit benefit of the rule is the earlier diag-
`nosis and treatment of CRC and, therefore, better survival rates
`for patients. However, although 99.5% of patients referred via
`the TWR are seen within the specified time, a recent study has
`shown that less than 25% of CRC cases were diagnosed through
`these clinics.21 Most CRC patients still present through the emer-
`gency services and other routes (e.g. general medical or surgical
`outpatients). This suggests that for most CRC patients the TWR
`has had little impact. To optimize the benefits of the TWR, fac-
`tors that inhibit its efficiency need to be explored. The reasons
`for delays are multiple and include patient, primary and second-
`ary care factors. In the primary care setting, early referral via
`the TWR is available for patients with ‘­at risk’ symptoms/signs,
`but delays still exist where, for example, the doctor gets ‘­locked’
`into the wrong diagnosis or makes a routine referral because
`TWR criteria are either not met or not included.22 In practice,
`therefore, it may be necessary for all patients with suspicious
`symptoms, not just those who meet TWR criteria, to have rapid
`investigation. This could be via GP direct access colonoscopy
`or the ‘­direct to test’ approach where a consultant receives a
`referral and arranges investigation prior to a clinic visit. Clearly
`this would require a significant improvement in colonoscopy
`services, especially since hospital waiting times, particularly for
`
`Summary of the guidelines on colonic surveillance programmes for patients at increased risk of CRC
`
`Disease
`
`Risk
`
`Colonic surveillance/surgery (guidelines)
`
`HnPCC18
`
`FaP18
`
`80% for CrC (13–
`20% for gastric
`cancer and ≥40%
`for endometrial
`cancer)
`CrC almost
`certain without
`prophylactic
`surgery
`
`Familial
`CrC20
`
`1:6 if two affected
`first-degree
`relatives, 1:10 if
`one <45 years old
`
`IBD19
`
`CrC24
`
`5–8% after 20
`years 18% after
`30 years
`50% recurrence
`
` (i) Biennial colonosopy from 20–25 years old, or 5 years before the age of diagnosis of the youngest
`affected relative. Continue until 75 years old. If CrC diagnosed: surgical resection and prophylactic surgery
`(high risk of metachronous CrC)
` (ii) If documented mismatch repair gene mutation: consider prophylactic surgery with endoscopic surveillance
`if the rectum is retained because the risk of rectal cancer is 3% every 3 years for the first 12 years
` (i) If patient is from a FaP family, but there is no documented mutation: annual flexible sigmoidoscopy
`(F/S) from puberty until 30 years old. attenuated forms of the disease exist, therefore F/S every 3–5 years
`from 30–60 years of age
` (ii) If documented aPC mutation or ≥100 adenomatous polyps: prophylactic surgery. If the rectum is
`retained, annual endoscopic review (risk of cancer in the retained rectal stump is 12–29%)
`total colonic evaluation either after first consultation on family history or between 35–40 years old
`(whichever is later) to identify patients with adenomas/CrC. If no adenoma/CrC at first colonoscopy, repeat
`surveillance at 55 years old
`If no adenomas at 55 years of age, patients’ degree of risk is probably equivalent to that of the general
`population
` (i) First surveillance colonoscopy 8–10 years after the onset of disease; surveillance every three years for
`next 10 years
` (ii) biennial colonoscopy for patients with a 20–30-year history, and annual colonoscopy if >30 years’ history
`80% of recurrences within 2 years, therefore close follow-up in this period. Ct, Cea and patient symptoms
`are the principal means of detecting recurrence. Current guidelines suggest liver imaging for asymptomatic
`patients at least once within 2 years of resection. CrC patients are predisposed to further adenomas and
`metachronous cancers, therefore surveillance colonoscopy, repeated every 3 to 5 years depending on local
`guidelines, is recommended.
`
`For HnPCC and FaP, families are advised also to register with the regional Clinical Genetics Centre.
`HnPCC, hereditary non-polyposis colorectal cancer; FaP, familial adenomatous polyposis; aPC, adenomatous polyposis coli; CrC, colorectal cancer; IBD, inflamma-
`tory bowel disease; Cea, carcinoembryonic antigen.
`
`Table 2
`
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`colonoscopy and CT scans, are significant in many units. The
`common factor to improve the efficiency of the TWR is rapid
`access to high-quality colonoscopy, the current gold-standard
`investigation.
`
`Prevention and early diagnosis – the future
`
`Screening promises to improve the detection of early CRC and
` ultimately contribute to its prevention. However, FOBT as a
`single test is currently limited because of its low sensitivity and
` inadequate specificity, but if complemented by another non-
`invasive test, sensitivity could be significantly improved. Various
`potential ‘­complementary’ non-invasive tests are currently being
`developed, such as faecal DNA tests and molecular tests on isolated
`colonocytes.23 However, the availability of these tests for clinical
`investigation is still in the future. Consequently, continuing patient
`education about lifestyle, symptoms of CRC and screening, as well
`as promoting and funding initiatives to expedite diagnosis, staging
`and treatment of CRC, are vital to help prevent the mortality and
`◆
` morbidity associated with the disease.
`
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