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Scottish Intercollegiate Guidelines Network2

VIEWS: 56 PAGES: 51

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Scottish Intercollegiate Guidelines Network




 67         Management of Colorectal Cancer
            A national clinical guideline




                             1     Introduction                                           1
                             2     Prevention and screening                               3
                             3     The impact of colorectal cancer on
                                   patients and their families                            8
                             4     Genetics                                              10
                             5     Primary care and referral                             13
                             6     Diagnosis                                             15
                             7     Surgery                                               17
                             8     Pathology                                             21
                             9     Chemotherapy and radiotherapy                         22
                             10    Follow up of patients treated
                                   for colorectal cancer                                 30
                             11    Palliative care and the management
                                   of symptoms in advanced disease                       31
                             12    Implementation and audit                              33
                             13    Information for discussion with patients and carers   35
                             14    Development of the guideline                          39
                             Abbreviations                                               42

                             References                                                  43




                                                                         March 2003
              http://chn-health.com
KEY TO EVIDENCE STATEMENTS AND GRADES OF RECOMMENDATIONS

LEVELS OF EVIDENCE

1++      High quality meta-analyses, systematic reviews of randomised controlled trials (RCTs),
         or RCTs with a very low risk of bias
1+       Well-conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low
         risk of bias
1-       Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of bias
2   ++
         High quality systematic reviews of case control or cohort studies
         High quality case control or cohort studies with a very low risk of confounding or bias
         and a high probability that the relationship is causal
2+       Well-conducted case control or cohort studies with a low risk of confounding or bias
         and a moderate probability that the relationship is causal
2-       Case control or cohort studies with a high risk of confounding or bias
         and a significant risk that the relationship is not causal
3        Non-analytic studies, e.g. case reports, case series
4        Expert opinion

GRADES OF RECOMMENDATION

Note: The grade of recommendation relates to the strength of the evidence on which the
recommendation is based. It does not reflect the clinical importance of the recommendation.

    A    At least one meta-analysis, systematic review of RCTs, or RCT rated as 1++
         and directly applicable to the target population; or
         A body of evidence consisting principally of studies rated as 1+, directly applicable to
         the target population, and demonstrating overall consistency of results

    B    A body of evidence including studies rated as 2++, directly applicable to the target
         population, and demonstrating overall consistency of results; or
         Extrapolated evidence from studies rated as 1++ or 1+

    C    A body of evidence including studies rated as 2+, directly applicable to the target
         population and demonstrating overall consistency of results; or
         Extrapolated evidence from studies rated as 2++

    D    Evidence level 3 or 4; or
         Extrapolated evidence from studies rated as 2+

GOOD PRACTICE POINTS

    þ    Recommended best practice based on the clinical experience of the guideline
         development group

© Scottish Intercollegiate Guidelines Network
ISBN 1 899893 53 9
First published 2003
SIGN consents to the photocopying of this guideline for the
purpose of implementation in NHSScotland
Scottish Intercollegiate Guidelines Network
Royal College of Physicians
9 Queen Street
Edinburgh EH2 1JQ

www.sign.ac.uk
                     http://chn-health.com                                                            1 INTRODUCTION




1     Introduction
1.1   BACKGROUND
      Scotland has one of the highest incidences of colorectal cancer in the world (41 per 100,000 in
      men, 29 per 100,000 in women),1 and, as with many Western countries, the disease represents
      the second most common cause of cancer death.2 Between 1989 and 1998 there was an increase
      in incidence in men (21.2%) and a slight increase in women (1.5% during the same period).3 The
      causes for this are unclear, although there is evidence that excess weight may increase risk, whereas
      a diet with high levels of vegetable intake may be protective, as is exercise. Long term smoking is
      emerging as a possible risk factor. Interestingly, despite the increased incidence, age-standardised
      mortality from colorectal cancer has decreased over the last 20 years,3 indicating an improvement
      in prognosis. Again, the reasons underlying this observation are not known, but improvements in
      disease management may have played a role.

1.2   THE NEED FOR A GUIDELINE
      The first SIGN colorectal cancer guideline was published in 1996, and was prompted by the poor
      survival from colorectal cancer in Scotland relative to the United States of America (USA) and
      parts of Europe.4,5 More recent comparative data indicate that survival in Scotland continues to
      rank below average in Europe, although at least part of this may be accounted for by variations in
      data quality.6 There is little doubt that delivery of certain aspects of colorectal cancer care varies
      between health boards throughout Scotland, and the evidence relating to the optimal management
      of this condition has changed substantially over the last five years.1 This, coupled with the remit
      of NHS Quality Improvement Scotland (QIS) which includes the former Clinical Standards Board
      for Scotland (CSBS) to review standards of colorectal cancer care across the country, has made it
      imperative to completely rewrite the guideline employing the latest SIGN methodology.

1.3   REMIT OF THE GUIDELINE
      As with the previous guideline, the main aims are as follows:
      n   to encourage measures to reduce the risk of developing colorectal cancer in the general
          population and in high risk groups
      n   to encourage early diagnosis in the general population and in high risk groups
      n   to improve the consistency of referral patterns
      n   to improve all aspects of the management of colorectal cancer patients in order to improve
          overall and disease-free survival and health-related quality of life.

1.4   TARGET USERS OF THE GUIDELINE
      It is recognised that the effective management of colorectal cancer requires a multidisciplinary
      approach. It follows that any unit treating this disease must form an appropriate core
      multidisciplinary team (MDT) consisting of surgeon(s), oncologist(s), pathologist(s), radiologist(s)
      and nurse(s). In addition this team should interact with a wider team including gastroenterologists,
      palliative care specialists and general practitioners (GPs). This guideline will be of interest to all
      of these professionals, as well as to patients, managers and policy makers.

1.5   STATEMENT OF INTENT
      This guideline is not intended to be construed or to serve as a standard of medical care. Standards
      of care are determined on the basis of all clinical data available for an individual case and are
      subject to change as scientific knowledge and technology advance and patterns of care evolve.
      These parameters of practice should be considered guidelines only. Adherence to them will not
      ensure a successful outcome in every case, nor should they be construed as including all proper
      methods of care or excluding other acceptable methods of care aimed at the same results.




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        The ultimate judgement regarding a particular clinical procedure or treatment plan must be made
        by the doctor, following discussion of the options with the patient, in light of the diagnostic and
        treatment choices available. However, it is advised that significant departures from the national
        guideline or any local guidelines derived from it should be fully documented in the patient’s case
        notes at the time the relevant decision is taken.

  1.6   REVIEW AND UPDATING
        This guideline was issued in 2003 and will be reviewed periodically as required to reflect new
        evidence. All updates to the guideline will be noted on the SIGN website: www.sign.ac.uk




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2       Prevention and screening
        Various lifestyle factors and drugs have been associated with reduced risk of colorectal cancer,
        and some with increased risk. In this section the evidence and recommendations on cancer prevention
        are subdivided into diet, physical activity, smoking, alcohol, hormone therapy and chemoprevention.
        There is also a section on screening for colorectal cancer.

2.1     DIET AND EXCESS WEIGHT
        Diet has long been regarded as the most important environmental influence on colorectal cancer,
        and this is reflected in the volume of studies testing the dietary hypothesis. However, there are
        two major problems in the interpretation of the observational studies, firstly, that diet is related to
        other aspects of lifestyle that may influence risk and, secondly, that people eat food rather than
        nutrients. In consequence, it is difficult to identify the specific components of diet that influence
        risk.

2.1.1   WEIGHT
        There have been almost 20 studies on excess weight and colon cancer covering more than 3,000
        cases, and there is consistent evidence of a positive association with obesity. In one meta-analysis
        of cohort and case control studies, there was a 15% increase in the risk of colon cancer for an           2++
        overweight person (body mass index, BMI >25.0 kg/m2) compared with a person of normal
        weight and a 33% increase in risk for an obese person (BMI >30 kg/m2) compared with a person
        of normal weight (BMI 18.5-25.0 kg/m2).7

         B     The population of Scotland should be advised to maintain a body mass index of
               18.5-25 kg/m2 throughout life.

2.1.2   FRUIT AND VEGETABLE CONSUMPTION
        With regard to fruit and vegetable consumption, there have been six cohort studies, including
        more than 2,600 cases,8 and 22 case control studies made up of over 6,000 cases.9 The evidence
        from the case control studies consistently supports an inverse association between vegetable intake
        and colon cancer, although the evidence from the cohort studies, particularly the most recent             2++
        ones, is less convincing. The role of dietary fibre has also been widely studied, but the cohort
        studies suggest no clear association between fibre intake and colorectal cancer, and the results of
        case control studies have been inconsistent.9,10 Furthermore, a small number of randomised
        controlled trials (RCTs) of wheat bran supplements provide little support for a protective effect
        against recurrence of colorectal adenomas.11

         C     Individuals in Scotland should be advised to eat five or more portions of fruits and vegetables
               a day, in line with the current guidance from the Health Education Board for Scotland.

2.1.3   MEAT CONSUMPTION
        Two meta-analyses of meat consumption were identified, one based on cohort studies only,12 the
        other based on both case control and cohort studies.13 The cohort studies include around 3,500
        newly incident cases, and the case control studies around 16,000 cases. The association between
        total meat consumption and colorectal cancer is inconsistent, and both meta-analyses show no
        statistically significant overall association. There is considerable heterogeneity between the results    2++
        of case control studies.13 In the cohort studies in which a positive association was found, the
        possibility that confounding factors might account for the results has not been excluded.12 Data
        on red meat and processed meat suggest positive associations with the risk for colorectal cancer.
        However, the volume of evidence on these is substantially less than for total meat consumption,
        and it is possible that publication bias has favoured positive results. For these reasons it is not
        possible to make a recommendation on the restriction of meat consumption.




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  2.1.4   BETA-CAROTENE
          Data on colorectal cancer are available from two randomised trials of beta-carotene with or
          without other agents in the prevention of cancer and 11 observational studies of colorectal cancer
          and serum or plasma concentration of beta-carotene.14 These do not support a role for beta-               2++
          carotene in the prevention of colorectal cancer.

  2.2     PHYSICAL ACTIVITY
          Approximately 50 case control or cohort studies of physical activity and colorectal cancer have
          been carried out, including more than 13,000 cases of colon cancer. These studies indicate a
          consistent inverse relationship, with a 50% reduction in risk among those with the highest level          2++
          of physical activity.15-18 The relationship appears to be stronger in men, and the effect seems to be
          restricted to colon cancer, with little effect of exercise on rectal cancer in men or women.

           B     The population of Scotland should be encouraged to take at least 30 minutes of physical
                 activity (such as brisk walking) on most days, citing decreased colorectal cancer risk as
                 one of the reasons.


  2.3     SMOKING
          Although earlier studies of smoking and colorectal cancer showed no association, in more recent
          studies long term smokers have been found to be at elevated risk, with relative risks typically in
          the range of 1.5 to 3.0.19 The temporal pattern of the studies is consistent with an induction
                                                                                                                    2++
          period of 30 to 40 years, and the emergence of an association for men before women is consistent
          with the pattern of smoking uptake occurring earlier in men in many countries. It has been
          estimated that one in five colorectal cancers in the USA might be attributed to tobacco use,19 and
          reducing the amount of smoking in the population may have effects on colorectal cancer as well
          as on other adverse outcomes of smoking.

           B     The population of Scotland should be encouraged not to smoke, citing decreased colorectal
                 cancer risk as one of the reasons.


  2.4     ALCOHOL
          The association between colorectal cancer and alcohol intake is not clear. Although the majority
          of studies suggest a positive association between alcohol consumption and colorectal cancer, a
          substantial proportion of studies show no association.9 In a recent meta-analysis there was significant
          heterogeneity in the relationship between colon cancer and alcohol intake between the cohort and
          case control studies included, and for the studies of rectal cancer there was significant heterogeneity
          by study quality and gender.20
          Although the consumption of alcohol in moderation is beneficial to cardiovascular health in men
          over 40 and postmenopausal women, specific advice about alcohol cannot be given in the context
          of colorectal cancer prevention.

  2.5     HORMONE THERAPY
          Protective effects of both hormone replacement therapy (HRT) and oral contraceptives (OC) have
          been postulated. The majority of evidence, especially that from more rigorously designed studies,
          shows an inverse relationship between postmenopausal oestrogen replacement therapy and
          colorectal cancer.21,22 In all four available meta-analyses, there was significant heterogeneity in the
          magnitude of the effect between studies.23-26 One randomised trial has shown a reduction in risk          1+
          for colorectal cancer and hip fractures, but this risk reduction was outweighed by increased risk for     2++
          coronary heart disease (CHD) events, strokes, pulmonary embolism and invasive breast cancer.22
          The relative risks appear to be lower for current than for past users. The protective effect reduces
          several years after stopping hormone use,24 and there appears to be no association with rectal
          cancer.26 Fewer data are available on OC use, although recent, rather than long term intake appears
          to be related to some risk reduction.27 Despite consistent findings, there is concern that unidentified



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                                           2 PREVENTION AND SCREENING




        confounding factors or the “healthy user effect” may have influenced the observed effect, and
        there is lack of information on the influence of hormone type, dose and duration of use.

         B     The use of hormone replacement therapy specifically to prevent colorectal cancer is not
               recommended.


2.6     CHEMOPREVENTION USING NSAIDS
        The weight of evidence (covering more than 18,000 cases) for a protective effect of aspirin use
        against colorectal cancer, and the consistency of the effect in studies differing in design, location,
        population and motivating hypothesis means that chance alone cannot explain the inverse relation
        between aspirin use and colorectal cancer.28 Detection bias, bias due to indications for use of          2++
        aspirin, other confounding factors, problems in the measurement of aspirin use and publication
        bias individually would not provide a reasonable explanation for the findings, although a possible
        cumulative effect of these issues cannot be completely excluded. The evidence relating to other
        types of non-steroidal anti-inflammatory drug (NSAID) is much less substantial.28
        Detailed consideration of the total benefits in the prevention of colorectal cancer and other diseases
        in relation to toxicity will be required before use of aspirin in the prevention of colorectal cancer
        can be recommended.

2.7     SCREENING
        Screening is the term used to describe the investigation of asymptomatic individuals in order to
        detect disease at an early stage when it is more amenable to treatment. In colorectal cancer
        screening may be applied to populations (limited only by age range) or to high risk groups. In this
        section, the high risk groups considered are those who have had adenomas or inflammatory bowel
        disease diagnosed. Patients who have had colorectal cancer are dealt with in section 10, and those
        with a family history are discussed in section 4.

2.7.1   POPULATION SCREENING
        Because of the high incidence of colorectal cancer, screening an appropriate age range within an
        entire population has been the subject of high-quality research in several Western countries. The
        most widely investigated screening modality has been faecal occult blood testing (FOBT), and a 1++
        meta-analysis of four randomised controlled trials and two non-randomised trials of around 443,000
        people aged 40 or over in five countries has been carried out.29 This concluded that FOBT screening
        resulted in a 16% reduction in colorectal cancer mortality, and when adjusted for attendance for
        screening, this improved to a 23% reduction.
        There is now evidence from a long-running randomised trial, based in Minnesota, that FOBT
        screening results in a reduction in the incidence of colorectal cancer, presumably owing to the 1+
        detection and removal of adenomas.30
        Other modalities, notably colorectal endoscopy have been put forward as screening tests, and
        once-only flexible sigmoidoscopy is the subject of a large UK randomised trial, but mortality data
        will not be available from this study until 2007.31
        A demonstration pilot of FOBT screening in 50-69 year-olds is underway in two populations in
        Scotland (Grampian, Tayside & Fife) and England (Coventry and Warwickshire), covering a total
        population of around two million.32 This is being externally assessed in order to ensure that the
        short term outcomes of the randomised trials can be reproduced in large, representative populations,
        and that the necessary quality in investigation and treatment can be delivered. A decision regarding
        a national colorectal screening programme will be informed by the results of this pilot.




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  2.7.2   SCREENING PATIENTS WITH INFLAMMATORY BOWEL DISEASE
          It is generally accepted that patients with long-standing ulcerative colitis are at higher risk of
          developing colorectal cancer than the general population. Although this risk is hard to quantify, a
          meta-analysis of 116 studies estimated the overall incidence of colorectal cancer in any patient
                                                                                                                   1++
          with ulcerative colitis to be 3.7%, with cumulative probabilities of 2% by 10 years, 8% by 20 2++
          years and 18% by 30 years. There was no measurable association between extent of disease and
          level of risk.33 In addition to ulcerative colitis, Crohn’s colitis is also recognised as a risk factor,
          and there is evidence that the cumulative risks of developing colorectal cancer in the two disease
          processes are similar.34
          Despite the lack of direct evidence that screening inflammatory bowel disease patients reduces
          mortality from colorectal cancer there is consensus that some form of colonoscopic surveillance is
          appropriate for individuals with long-standing disease. It is common practice to perform colonoscopy
          every one to two years beginning eight years after the onset of pancolitis and 15 years after the
                                                                                                                   4
          onset of left-sided colitis35 but, given the evidence cited above, a different regimen may be more
          appropriate. If colonoscopy is to be valuable, in addition to biopsy of suspicious lesions, it is
          important that mucosal biopsies are taken to look for dysplasia; 40% of patients with high grade
          dysplasia either have colorectal cancer or develop it within a short time interval.36

           D     n   Patients with left-sided colitis or pancolitis of 10 years duration should undergo three
                     yearly colonoscopy with mucosal biopsies and biopsy of any suspicious lesions.
                 n   The frequency of examination should increase to yearly when the disease has been
                     present for 20 years, or when indeterminate dysplasia has been diagnosed.

           D         Colectomy should be performed for high grade dysplasia, and considered for low
                     grade dysplasia.

  2.7.3   SCREENING PATIENTS AFTER REMOVAL OF ADENOMATOUS POLYPS
          The majority of colorectal cancers arise from adenomatous polyps and it follows that these lesions
                                                                                                                   1+
          should be removed.36 There is good evidence that this policy reduces the risk of developing
                                                                                                                   4
          colorectal cancer. 30, 35
          Once an individual has been found to have one or more adenomas, follow up colonoscopy to
          seek and remove further polyps is advised by most authorities. The National Polyp Study has
          shown that three yearly colonoscopy is as effective in detecting adenomas with advanced pathological     1+
          features as yearly examination.35 The risk of recurrent polyps appears to be greater when multiple       2+
          polyps are found at the first colonoscopy or if the index polyp has a villous or severely dysplastic
          component37 Patients with one or two tubular adenomas without severe dysplasia are just as well
          served by follow up colonoscopy at five years.38
           D     n   Patients who have undergone colonoscopic polypectomy for adenomas should be offered
                     follow up colonoscopy.
                 n   If one or two adenomas <1 cm are found at colonoscopy, a repeat colonoscopy should
                     be performed at five years. If this is normal, colonoscopic surveillance may cease.
                 n   If there are three or more adenomas, or at least one ³1 cm, or at least one showing
                     severe dysplasia, repeat colonoscopy should be performed at three years. If surveillance
                     colonoscopy is subsequently normal on two consecutive occasions, it may cease.

           þ     If there is uncertainty regarding completeness of adenoma removal owing to the presence
                 of multiple adenomas or technical difficulties with the examination it may be appropriate
                 to offer follow up colonoscopy at one year or sooner.

           þ     Colonoscopic follow up should continue until the age and fitness of the patient dictate
                 that it should cease. This decision should result from a consensus between the patient and
                 the doctor.




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2.7.4   PSYCHOLOGICAL CONSEQUENCES OF SCREENING
        The psychological consequences of screening have not been systematically assessed. One RCT in
        Norway, in which healthy people were screened, identified no short term adverse psychological
                                                                                                                1+
        effect.39 Another RCT in the UK looked at the effect of information about cancer screening on
        those about to be screened and found no adverse effects.40
        The long term effects of screening, such as reassurance in cases of false negative tests or increased
        distress in anxious individuals have not been studied.




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  3     The impact of colorectal cancer on patients and
        their families
        Colorectal cancer has a significant psychosocial impact on the individual and it is important to
        develop strategies to deal with this.41 In this section, the following issues are addressed: interventions
        to alleviate the impact of a diagnosis of colorectal cancer; information required by patients and
        their families to cope with and understand colorectal cancer; methods and sources of
        communication; involving the patient in the decision-making process and the role of specialist
        nurses within the multidisciplinary team.

  3.1   INTERVENTIONS TO ALLEVIATE THE IMPACT OF COLORECTAL CANCER
        Psychological distress is common in patients with all forms of cancer and usually remains
        undetected.42 Diagnosis is difficult because the symptoms of depression, anxiety, effects of treatment,
        and the cancer itself, overlap. Furthermore, differentiating depression from profound sadness and
        from demoralisation is not easy. Core features of depression include: persisting negative thoughts           3
        about self and the future, inability to take pleasure from day to day activities and a wish to self-
        harm. Biological features such as insomnia are commonly due to the cancer itself and its treatment.
        Liaison psychiatrists are in a good position to advise on diagnosis and the use of medication in
        patients with psychological effects of physical illness.
        There is some evidence that providing emotional and practical support may have a positive effect
        on patients’ well being, although the types of help offered are very varied.43 As there are many
        national and local support services (eg BACUP, Macmillan, clinical nurse specialists, liaison                3
        psychiatry, “drop-in” centres, day centres, complementary therapy services etc.) it is important
        that only those services which are relevant to the individual are offered.
        Relatives of patients with cancer can have just as great, if not greater concerns than the patients
                                                                                                                     3
        themselves, and psychological morbidity can be detected in up to 50% of relatives. 44-47

         D     Information about local support services should be made available to both the patient and
               their relatives.

         þ     Clear follow up arrangements to see specialists should be made as waiting and uncertainty
               add to distress. The reasons for these arrangements should be explained to the patient.

        Systematic reviews of observational studies show that after potentially curative surgery, patients
        continue to experience problems in all areas of quality of life.48-50 There is also evidence that, 2++
        although the prevalence of postoperative symptoms is greater after techniques which result in 2+
        permanent stoma formation, sphincter-saving operations do not necessarily result in a good quality 3
        of life.48-50 There is no strong evidence that adjuvant chemotherapy adds to patient distress, however,
        patients do find the wait to see an oncologist particularly difficult.51

         B     Clinicians must be aware of the potential for physical, psychological, social and sexual
               problems after all colorectal cancer surgery, including sphincter-saving operations.


  3.2   INFORMATION REQUIRED TO COPE WITH AND UNDERSTAND COLORECTAL
        CANCER
        Many cancer patients and their relatives feel poorly informed, and most patients prefer to have as
        much information about their illness as possible.47 Some patients do not want extensive information,
        and the reasons for this may be complex.52 In patients with colorectal cancer the greatest need for          3
        information appears to be at diagnosis; after discharge from surgery while waiting for an oncology
        appointment to discuss chemotherapy; and on completion of chemotherapy.51




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       þ     Health professionals should appreciate that information helps patients to understand how
             their disease may affect them and to anticipate problems and plan their lives.

       þ     Patients should be offered the amount of information that is appropriate to their wishes in
             a way which is sensitive, understandable and accurate.


3.3   METHODS AND SOURCES OF COMMUNICATION
      Complaints from cancer patients about poor communication with healthcare professionals and
      lack of continuity of care are common. There is evidence that training programmes for nurses can
      improve listening and communication skills.53 Although the included trials were small and
      heterogeneous, one systematic review has suggested that providing a record of the consultation 1
                                                                                                       +


      with a specialist can increase both the amount of information recalled and satisfaction with the
      information given.54 One randomised trial showed that patients preferred information based on
      their own medical records rather than general information about their type of cancer.55

       B     Listening and explaining skills can be improved by high quality courses, and all healthcare
             professionals in cancer care should undergo such training.

       B     Healthcare professionals in cancer care should consider giving either written summaries
             or audio-tapes of consultations to people who have expressed a preference for them.


3.4   INVOLVING THE PATIENT IN THE DECISION-MAKING PROCESS
      There is increasing evidence that cancer patients wish to be more involved in making decisions
      regarding their own care than clinicians may think.56 One systematic review of a large number of +
      controlled studies was only able to conclude that interventions aimed at facilitating decision 1++
                                                                                                            2
      making are under-researched and that there was a need for more and better randomised trials.57 In 3
      a single descriptive study it was found that colorectal cancer patients preferred a more passive role
      in decision making than breast cancer patients, and this may be age- and sex-related.58

       D     Healthcare professionals should respect patients’ wishes to be involved when making
             plans about their own management.

       D     Patients should be given clear information about the potential risks and benefits of treatment,
             in order that they can make choices.

       þ     Severe physical symptoms should be addressed before patients are asked to make complex
             treatment choices.


3.5   THE ROLE OF SPECIALIST NURSES WITHIN THE MULTIDISCIPLINARY TEAM
      Patients with cancer often have complex needs that cannot be addressed by a single specialty or
      discipline. This has led to the development of multidisciplinary teams within Managed Clinical
      Networks to ensure a consistent and equitable approach to planning and managing care. It is now
      recognised that the clinical nurse specialist (CNS) should be an integral part of this network.59,60 A
      key component of the CNS role is to coordinate care between settings in addition to providing
      support, advice and information for patients and their carers throughout their illness.

       þ     All patients newly diagnosed or with a suspected diagnosis of colorectal cancer should
             have access at diagnosis to a clinical nurse specialist (CNS) for support, advice and
             information.

      Patients with colorectal cancer who require stoma formation generally experience more problems
      than those who do not and the support and advice of a stoma nurse specialist is widely acknowledged
      to be of considerable value.

       þ     All patients who may require stoma formation (permanent or temporary) should be referred
             and assessed by a stoma nurse specialist before admission to hospital.



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  4        Genetics
           In this section consideration is given to asymptomatic individuals with a family history of colorectal
           cancer and the problems of both hereditary non-polyposis colorectal cancer (HNPCC) and familial
           adenomatous polyposis (FAP).

  4.1      FAMILY HISTORY OF COLORECTAL CANCER
           A family history of colorectal cancer is common.61 The Scottish Cancer Group’s Sub-Group on
           Cancer Genetics has defined three levels of risk; low, moderate and high.62 The criteria for each
           level are given in Table 1. The guidelines for management of individuals in the moderate risk 4
           category recommend the offer of a one-off colonoscopy around the age of 35 with a further
           colonoscopy at 55. Individuals at moderate risk undergoing colonoscopic screening should be
           included in the audit of the Scottish Executive cancer genetics guidelines.
           Table 1:The Scottish Cancer Group criteria for screening individuals at risk of colorectal cancer (CRC)


        Risk level        Criteria for screening                    Screening                      Age of screening

          High       n   at least three family           n   colonoscopy every 2 years      n   from 30 to 70 years (or 5
                         members affected by CRC         n   discuss gynaecological             years younger than the
                         or at least two with CRC            screening for endometrial          youngest affected relative)
                         and one with endometrial            and ovarian cancer             n   for stomach cancer from
                         cancer in at least two                                                 50 to 70 years or 5 years
                                                         n   offer 2-yearly upper
                         generations; one affected                                              younger than the youngest
                                                             gastrointestinal endoscopy
                         relative must be age £50                                               stomach cancer
                                                             for gastric cancer
                         years at diagnosis; one of
                         the relatives must be a first   n   consider screening for
                         degree relative of the other        other cancers which may
                         two.                                occur in specific families
                                                             and are part of the HNPCC
                     n   gene carriers (HNPCC
                                                             spectrum
                         genes)
                     n   untested primary relatives
                         of gene carriers


        Moderate     n   one first degree relative       n   single colonoscopy             n   at 30 - 35 years and again at
                         affected by colorectal          n   single repeat colonoscopy if       55 years
                         cancer when aged <45                first colonoscopy normal
                         years;
                         or
                     n   two affected first degree
                         relatives (one less than 55
                         years);
                         or
                     n   two (one CRC less than 55
                         years) or three affected
                         individuals with colorectal
                         or endometrial cancer who
                         are first degree relatives of
                         each other and one a first
                         degree relative of
                         consultand

          Low        n   anyone not fulfilling medium    n   reassure and encourage         not required
                         or high risk criteria               healthy lifestyle




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      Individuals with two or more first degree relatives with colorectal cancer, one of whom is aged
      under 55 or one relative with colorectal cancer under the age of 45, have a moderate increase in
      their risk of developing colon cancer. Their risk is greater than five times the risk to an individual 2++
      of the same age in the general population without a family history.61,63 No data on absolute risk of
      development of bowel cancer have been published, although a simple estimate can be made by
      multiplying age-specific risk by five.
      As genetically determined tumours are frequently located on the right side of the colon, colonoscopy
      is a more appropriate investigation than flexible sigmoidoscopy.64 There is general consensus that
      the risk of a 40 year old with a family history developing colorectal cancer is equivalent to the risk 2+
      of a 50 year old with no family history.35,61,63 Colonic adenoma rates at colonoscopy in first degree 4
      relatives of colorectal cancer patients are 2.1% for the age group 30-39 and 8.3% for the age group
      40-49 compared with 0% in age matched controls.65
      Reviews of published reports on the outcome of screening of at-risk relatives show the pick up rate ++
                                                                                                          2
      of carcinomas under the age of 50 is low with none of the studies reviewed identifying a cancer in +
                                                                                                          2
      a relative under 40 years.66,67

          C      A three generation family history should be taken from all individuals with
                 colorectal cancer.

          D      Individuals at moderate risk of developing colorectal cancer on the basis of their family
                 history should be offered a single colonoscopy at 30-35 years and again at 55 years.

          þ      Referral to Clinical Genetics for risk estimation should be considered prior to enrollment
                 of an asymptomatic individual in a colonoscopic screening programme.


4.2   INDIVIDUALS WITH A HIGH RISK FAMILY HISTORY OF COLORECTAL CANCER
      (INCLUDING HNPCC)
      HNPCC is an autosomal dominant condition caused by a mismatch repair gene mutation.
      Diagnosis requires:
      n       at least three relatives with a HNPCC-associated cancer (colorectal, endometrial, small bowel,
              ureter or renal pelvis) one of whom should be a first degree relative of the other two
      n       at least two consecutive generations should be affected
      n       at least one individual should be diagnosed before age 50.68
      DNA mismatch repair gene mutations also predispose patients to extracolonic tumours,
      predominantly endometrial but also ovarian, genitourinary, small bowel and biliary tract. Broadening 2+
      of the criteria for HNPCC to include extracolonic tumours increases the proportion of families 3
      with mismatch repair mutations identified,69,70 but with reduction in positive predictive value in
      some cases.71-73
      There are considerable clinical benefits in identifying families in whom a mismatch repair gene
      defect is present. Individuals carrying the mutation can be targeted for regular endoscopic screening
      whilst those demonstrated not to carry the mutation can be spared invasive investigations. The
      majority of tumours associated with mismatch repair gene mutations exhibit microsatellite instability
      (MSI) whilst only about 15% of unselected tumours have this property.74 The testing of all colorectal
      tumours for MSI as a prescreen for subsequent mutation analysis has been proposed.75 However,
      the technique is not routinely available and would require considerable resource to establish. A
      more cost-effective approach would be to test a clinically defined subset of tumours, and this is
      currently under assessment in Scotland.
      When a mismatch repair gene mutation has been identified, the risk of the carrier developing
      colorectal cancer by the age of 70 is over 70% for men and 40% for women. A significant
      proportion of these patients will have developed their cancer before the age of 35 years.76,77 2+
      Female mismatch repair mutation carriers have a risk of gynaecological malignancy equivalent to
      their risk of colorectal cancer.76,77 As presymptomatic screening for ovarian and endometrial cancer
      is of unproven benefit, prophylactic surgery should be discussed as an option for female mutation
      carriers who have completed their families.



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         þ     First degree relatives of individuals in whom a mismatch repair gene mutation has been
               identified should be offered presymptomatic testing through a local clinical genetic service.

         C     Referral of individuals with a high risk of developing colorectal cancer should be made to
               the local clinical genetic service for consideration of mismatch repair gene mutation
               analysis.

         C     Individuals carrying a mismatch repair gene mutation or fulfilling high risk criteria for
               HNPCC should be offered endoscopic screening starting in the twenties if possible and
               repeated every two to three years, taking into account the patient’s general condition and
               uptake.


  4.3   FAMILIAL ADENOMATOUS POLYPOSIS (FAP)
        FAP is an autosomal dominant condition caused by an APC gene mutation and characterised by
        the development of multiple adenomatous colorectal polyps and the subsequent development of
        one or more colorectal cancers.78 Where a diagnosis of FAP has been made on clinical criteria,
        contact should be made with the regional genetic service to discuss the possibility of searches
        being initiated for the APC mutation in members of the families at risk. When an individual has
        been identified as being at risk of FAP, regular endoscopic screening should be offered, and when
        adenomas have developed, surgical treatment is recommended.
        The main therapeutic options in FAP are proctocolectomy with ileostomy or ileoanal pouch
        reconstruction and colectomy with ileorectal anastomosis.76,79 The former procedures are associated
        with greater operative morbidity and less satisfactory functional results. The latter requires regular   2+
        sigmoidoscopic surveillance of the rectum postoperatively because of the risk of developing cancer       4
        in the retained rectum. It must also be remembered that FAP patients are at risk of developing
        duodenal adenomas and cancer.

         C     Patients with clinically diagnosed FAP should be referred to the local clinical genetic
               service for APC gene mutation analysis.

         C     Individuals at risk of FAP, determined either by a positive family history or on the basis of
               mutation analysis, should be offered colonoscopy every two to three years and yearly
               sigmoidoscopy.

         C     n   Patients with FAP should be offered proctocolectomy with or without ileoanal
                   reconstruction or total colectomy with ileorectal anastomosis once adenomas have
                   developed.
               n   Subsequent management should include lifelong surveillance of the residual rectum
                   where appropriate and regular upper gastrointestinal endoscopy to detect duodenal
                   adenomas or malignancy.




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                     http://chn-health.com CARE AND REFERRAL
                                         5 PRIMARY




5     Primary care and referral
      In the management of colorectal cancer a crucial role of primary care is to recognise the patient
      who is likely to have the disease, and to refer them promptly for investigation. Whether the
      investigations are organised by the general practitioner prior to hospital referral or by the hospital
      doctor will depend on local circumstances. This section is subdivided into sections on the significant
      symptoms, the importance of delay in diagnosis, and strategies to reduce delay.

5.1   IMPORTANT SYMPTOMS OF COLORECTAL CANCER.
      1.5% of all patients with colorectal cancer are under 45 years of age, and 85% are over 60.80
      Rectal bleeding is commonly experienced in the general population and, although it is an important
      symptom of colorectal cancer,81,82 over half of those experiencing it do not seek consultation.83
      The most important symptoms of colorectal cancer appear to be change of bowel habit, rectal
      bleeding of short duration and blood mixed in the stool.81,84 Iron deficiency anaemia, although
      not strictly a symptom, is also an important presenting feature, and should always be thoroughly         2+
      investigated with colorectal cancer in mind.85 Although faecal occult blood testing is an effective      4
      means of population screening it is too insensitive to be used in guiding investigation of
      symptomatic patients (see section 2.7.1).29
      Colorectal cancer risk assessment can be made using the patient’s age and the presence or absence
      of presenting symptoms and physical signs, shown in Table 2.81,86
      Table 2: Colorectal cancer risk assessment
       Symptom/sign combinations with a high predictive value for colorectal cancer
      Rectal bleeding with a change in bowel habit to looseness or increased frequency
      Rectal bleeding without anal symptoms (soreness, discomfort, itching, lumps or pain)
      Palpable abdominal mass
      Palpable rectal mass
      Intestinal obstruction
       Symptom/sign combinations with a low predictive value for colorectal cancer
      Rectal bleeding with anal symptoms
      Change in bowel habit to decreased frequency and harder stools
      Abdominal pain without signs of intestinal obstruction

       C     Patients over the age of 50 years with any of the following symptoms over a period of six
             weeks should be urgently and appropriately investigated:
             n  rectal bleeding with a change in bowel habit to looseness or increased frequency
             n  rectal bleeding without anal symptoms
             n  palpable abdominal or rectal mass
             n  intestinal obstruction.

       C     All patients with iron-deficiency anaemia (Hb<11g/dl in men or<10g/dl in
             postmenopausal women) without overt cause should be thoroughly investigated for
             colorectal cancer.


5.2   EFFECT OF DELAY IN DIAGNOSIS
      Two retrospective cohort studies have been unable to demonstrate any adverse effect of delay in
      diagnosis.87,88 For example, patients with anaemia and no symptoms have a better survival rate
      than those with symptoms despite significant delays in diagnosis in the former. Aggressive disease       2+
      is more likely to cause severe symptoms prompting rapid diagnosis, so that disease which takes a
      long time to diagnose appears to be associated with similar or even better survival.



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         þ     Reduction in referral delay has not been shown to confer any survival benefit in colorectal
               cancer, but this should not deter the general practitioner from striving to identify those
               patients who warrant urgent investigation.


  5.3   STRATEGIES TO REDUCE DELAY IN DIAGNOSIS OF COLORECTAL CANCER
        Delay in diagnosis occurs at three levels: patient-related, primary care and secondary care. At
        patient level, delays appear to be due to ignorance of the significance of symptoms and fear of           3
        cancer.83,89,90 Younger patients are more likely to notice symptoms than older patients, but older        4
        patients are less likely to delay in presenting to their GP.89
        In general practice, incomplete examination, particularly lack of a rectal examination is an
        important factor 87,91 and referral to a non-surgical specialty is associated with significant delay.88
                                                                                                                  2+
        When the patient reaches hospital, delay is caused by failure to initiate appropriate investigations,
                                                                                                                  4
        and failure to complete investigation, especially in iron deficiency anaemia. Both barium enema
        and colonoscopy have a false negative rate, and, especially in iron deficiency anaemia, and also in
        patients with with persistent significant symptoms, a single negative result should not be accepted.

         D     Patient groups at risk of colorectal cancer, especially those over 50 years of age, should be
               informed about significant symptoms and encouraged to seek medical attention early
               should they develop such symptoms.

         D     General practitioners should perform a thorough abdominal and rectal examination on all
               patients with symptoms suspicious of colorectal cancer.

         D     When a patient presents with suspicious symptoms or signs, they should be urgently
               investigated and referred to a surgical unit with a declared interest in colorectal cancer.




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                     http://chn-health.com                                                                         6 DIAGNOSIS




6     Diagnosis
      Three methods have been shown to be effective in the primary diagnosis of colorectal cancer:
      endoscopy, double contrast barium enema, and Computed Tomography (CT) pneumocolon. The
      success of each method depends on adequate bowel preparation.

       þ     Where colorectal cancer is suspected clinically, the whole of the large bowel should be
             examined.

      Currently, the evidence relating to comparisons between colonoscopy and double contrast barium
      enema comes from only one randomised trial92 and cohort studies containing elements of bias.93                1+
      The trial showed that there was no significant difference in accuracy between double contrast                 2-
      barium enema combined with flexible sigmoidoscopy and colonoscopy in the detection of cancers
      or polyps equal to or greater than 9 mm in size.
      There is currently no clear consensus as to which should be the investigation of choice for the
      diagnosis of colorectal cancer.94

       þ     The diagnosis of colorectal cancer on purely clinical grounds is unreliable. Since the prognosis
             depends to a large extent on the stage of the disease at the time of diagnosis, early investigation
             of symptoms and signs is appropriate.


6.1   ENDOSCOPY
      Relevant endoscopic techniques include rigid sigmoidoscopy, flexible sigmoidscopy and
      colonoscopy. Flexible sigmoidoscopy is more effective than rigid sigmoidoscopy for visualising                4
      the rectum and distal colon.95,96
      Colonoscopy is an extremely sensitive diagnostic test for colorectal cancer and has the major
      advantages of allowing both biopsy and polypectomy and does not involve exposure to ionising
      radiation.97 It also has some disadvantages: in a variable proportion of cases (5-30%) the caecum             3
      is not reached,98 intravenous (IV) sedation is nearly always required, the localisation of tumour             4
      can be inaccurate,99 and there is a small but significant risk of complications.100,101 The procedure-
      related mortality is approximately 1 in 5,000 for colonoscopy and 1 in 50,000 for sigmoidoscopy
      and for double contrast barium enema.

       D     Colonoscopy is recommended as a very sensitive method of diagnosing colorectal cancer,
             enabling biopsy and polypectomy.


6.2   DOUBLE CONTRAST BARIUM ENEMA
      Double contrast barium enema is a sensitive, safe, well tolerated method not requiring sedation,
      and has a high completion rate.102-104 In addition, it is widely available throughout Scotland.               2+
      Disadvantages include the radiation dose and reduced accuracy in the presence of sigmoid                      4
      diverticular disease.98 The radiation dose can be significantly reduced by modern digital technology.
      Accuracy is significantly increased when double contrast barium enema is combined with flexible
                                                                                                                    1+
      sigmoidoscopy.105

       B     Double contrast barium enema may be employed as a sensitive, safe alternative to
             colonoscopy.

       B     Where the sigmoid colon is not well visualised, eg in the presence of severe diverticular
             disease, double contrast barium enema should be combined with flexible sigmoidoscopy.

       þ     In all cases the rectum should be visualised by rigid or flexible sigmoidoscopy.




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  6.3   COMPUTED TOMOGRAPHY PNEUMOCOLON
        Computed Tomography (CT) pneumocolon is a sensitive method for the detection of colorectal
                                                                                                                2+
        cancer, but not for polyps less than 10 mm.106
        CT pneumocolon is well tolerated by patients and as it provides information outside the colon
        and rectum it can be used for staging malignant disease (local invasion, liver metastases, lymph
        node spread etc.).98 It is not possible to detect or exclude tumours in normally sized lymph nodes.
        The technique is particularly useful in frail, immobile and elderly patients. The radiation dose
        with modern equipment and best practice can be comparable with conventional barium enema                4
        radiation dose levels.107 In the UK, expertise with, and access to fast CT scanners are limited at
        present, but the increasing use of multi-slice CT and more sophisticated computer software is
        likely to increase the clinical application of this technique. Recent evidence in support of magnetic
        resonance colography is encouraging108 but lack of access and available expertise makes widespread
        use of this technique in Scotland impractical at present.

         D     Where the radiological expertise and equipment exist, a CT pneumocolon is recommended
               as a sensitive test for colorectal cancer.




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7     Surgery
      Surgery remains the definitive treatment for apparently localised colorectal cancer, offering the
      only chance of cure. In this section, recommendations for preparation for surgery are followed by
      technical considerations and recommendations for surgery for the emergency situation and for
      advanced disease. Specialisation and workload are also addressed.

7.1   PREOPERATIVE STAGING
      Given the very different therapeutic strategies required for operable localised disease and locally
      advanced or disseminated disease, preoperative staging is indicated in most instances. Preoperative
      liver and chest imaging to detect metastases is advisable unless the patient’s management would
                                                                                                              1+
      not be altered by the findings.109 For liver metastases, preoperative assessment with CT or magnetic
                                                                                                              2+
      resonance imaging is more sensitive than with transabdominal ultrasound, although the most              4
      accurate modality appears to be a combination of intraoperative ultrasound and palpation at the
      time of surgery.110 The accuracy of staging investigations for primary rectal cancer is improving,
      and the current body of evidence supports MRI (for more advanced tumours) and endorectal
      ultrasound (for early lesions) as the best modalities.111,112
      Another important aspect of preoperative staging is complete visualisation of the large bowel.
      Synchronous cancers occur in 5% of cases, and these may not be readily detectable at surgery.113
      When a cancer has been diagnosed, a complete colonoscopy or barium enema should be carried              2+
      out before surgery wherever possible. When this is impossible owing to obstruction or other
      emergency presentation, it should be performed within three months of resection.

       B     n   All patients undergoing elective surgery for colorectal cancer should have
                 preoperative imaging of the liver and chest.
             n   In patients requiring emergency surgery intraoperative liver ultrasound or
                 postoperative imaging is acceptable.

       þ     Intraoperative ultrasound is appropriate if a preoperative diagnosis of liver metastases would
             not alter the need for operative intervention. Preoperative imaging of primary rectal cancer
             may clarify operability and aid decisions regarding chemotherapy or radiotherapy delivered
             preoperatively (neoadjuvant chemo-irradiation).

       C     Complete colonic examination by colonoscopy, CT pneumocolon or barium enema should
             be carried out, ideally preoperatively, in patients with colorectal cancer.


7.2   PREOPERATIVE PREPARATION
      Patients undergoing surgery for colorectal cancer are at risk of both venous thromboembolism and
      wound infection. It is therefore recommended that prophylactic measures are taken as outlined in
      the appropriate SIGN guidelines.114,115 The use of antibiotic prophylaxis in colorectal surgery is      4
      further supported by a recent meta-analysis.116 Mechanical bowel preparation is also widely             1++
      employed, but current evidence, consisting of three underpowered randomised trials does not             1-
      support its routine use.117-119 All patients who will or might require a permanent or temporary
      stoma should be seen preoperatively by a stoma nurse specialist if possible (see section 3.5).

       A     Patients undergoing surgery for colorectal cancer should have:
             n  venous thomboembolism prophylaxis,
             n  antibiotic prophylaxis consisting of a single dose of antibiotics providing both
                aerobic and anaerobic cover given within 30 minutes of induction of anaesthesia.
      Although there is no evidence that bowel preparation confers benefit, the quality of evidence
      suggesting no effect is too weak to make a definitive statement that it is not necessary.




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           þ     The decision to use bowel preparation must be individualised according to the patient’s
                 need and the surgeon’s experience.


  7.3     PERIOPERATIVE BLOOD TRANSFUSION
          Concern has been raised over the potential for increased risk of cancer recurrence following
          perioperative blood transfusion.120 A meta-analysis of three randomised and two cohort studies
          where control groups received either leucodepleted or autologous blood transfusion found no
          significant difference in cancer recurrence. Due to the small number of patients taking part in the         1+
          trials, the meta-analysis was insufficiently powered to detect a difference of less than 20% in risk.
          The inability of these studies to exclude a small effect is of less significance now that leucodepletion
          of blood for transfusion is universal in the UK.121

           B     If a patient undergoing colorectal cancer surgery is deemed to require a blood transfusion,
                 this should not be withheld on account of a possible association with increased risk of
                 cancer recurrence.


  7.4     TECHNIQUES IN COLORECTAL CANCER SURGERY

  7.4.1   RECTAL CANCER
          There is now evidence from large cohort studies using historical controls that the use of total
          mesorectal excision (TME) reduces the risk of local recurrence after rectal cancer surgery, and
          improves survival.122-124 This appears to be due to good circumferential clearance of tumour. It is
                                                                                                                      2++
          unlikely that tumours of the upper rectum will benefit from total excision of the mesorectum, as
                                                                                                                      2+
          long as the principles of careful dissection in the plane immediately outside the mesorectum are            4
          applied.125 The low anastomosis necessitated by TME results in poorer functional results than a
          higher anastomosis, and should be avoided unless doing so would compromise adequate mesorectal
          exision.126 It is also important to preserve the autonomic nerves in the pelvis to minimise bladder
          and sexual dysfunction.127

           B     Mesorectal excision is recommended for most rectal cancers where the patient is fit for
                 radical surgery. The mesorectal excision should be total for tumours of the middle and
                 lower thirds of the rectum, and care should be taken to preserve the pelvic autonomic
                 nerves wherever this is possible without compromising tumour clearance.

  7.4.2   COLON CANCER
          In contrast to rectal cancer surgery, there is little evidence relating to the radicality of colon cancer
          surgery. Two underpowered randomised controlled trials were unable to demonstrate a beneficial
                                                                                                                      1-
          effect of “no touch” technique128 or formal left hemicolectomy129 respectively.There is no evidence
          that the radicality of excision has an effect on outcomes in patients with colon cancer.

           þ     Where a resectable organ, (eg kidney, ureter, duodenum, liver, stomach, bladder, uterus
                 or vagina) is involved by the primary tumour, careful consideration should be given to
                 removal (partial or total as appropriate) of that organ.

  7.4.3   ANASTOMOSES
          Anastomotic leakage is an important and potentially fatal complication of colorectal cancer surgery,
          and measures to minimise it should be taken. There is no high quality evidence to support any
                                                                                                                      1++
          specific technique, but a recent meta-analysis indicated that the only difference between hand-
          sewn and stapled anastomoses is a slightly increased risk of anastomotic stricture with stapling. 130
          Risk factors for anastomotic dehiscence are well known and include male sex, increasing age and
          obesity, but in anterior resection leakage is increased with a low (<5 cm from anorectal junction)          2++
          anastomosis.131




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      It has also been shown that a defunctioning stoma reduces the risk of a clinically evident leak in
      low colorectal anastomoses.132 Another disadvantage of the low anastomosis is poor function,           2+
                                                                                                             1+
      and there is good evidence from randomised trials to support the use of a colopouch in this
      situation.133-135

       C     With a low rectal anastomosis, consider giving a defunctioning stoma.

       C     With a low rectal anastomosis after TME, consider a colopouch.

       þ     Not all patients will benefit from a low rectal anastomsis, and if the patient is deemed to
             be at unacceptable risk of anastomotic breakdown or poor function, then a permanent
             colostomy (low Hartmann’s procedure) should be employed.


7.5   LOCAL EXCISION OF COLORECTAL CANCERS
      Certain rectal cancers are technically amenable to local excision, and there is evidence from a
      randomised trial that this is associated with less morbidity than radical surgery. 136 There is also   1+
      non-randomised evidence that local excision is associated with higher rates of local recurrence        4
      than radical surgery, presumably owing to residual tumour in lymph nodes.137
      Adjuvant radiotherapy and chemotherapy may reduce local recurrence rates, but a reliable and
      widely accepted regimen has not yet been developed.137 T1 tumours (those with the smallest local
      spread) are often deemed suitable for local excision, but it must be stressed that extensive
      involvement of the submucosa is associated with a 17% rate of lymph node involvement. Minimal          2+
      involvement of the submucosa (T1 sm1 tumours) appears to be associated with minimal risk of            4
      lymph node involvement.138 Colon (and some rectal) cancers may be excised by polypectomy at
      colonoscopy (polyp cancers), and cohort studies indicate that such lesions do not require further
      surgery unless there is histopathological evidence of tumour at the margin (incomplete excision),
      lymphovascular invasion or the invasive tumour is poorly differentiated.139,140
      Currently, it is not possible to identify a subgroup of rectal cancer patients in whom regional
      lymph node involvement can be comprehensively excluded thus allowing unreserved
      recommendation for local excision, although T1 sm1 tumours may be suitable.

       C     The relative risks of operative morbidity and recurrence must be carefully weighed and
             explained fully to the patient so that an informed decision can be made regarding local
             excision and rectal cancer.

       C     Further surgery for pedunculated polyp cancers is indicated if:
             n  there is histological evidence of tumour at, or within 1 mm of, the resection margin;
             n  there is lymphovascular invasion;
             n  the invasive tumour is poorly differentiated.

7.6   LAPAROSCOPIC SURGERY FOR COLORECTAL CANCER.
      Evidence from several randomised controlled trials, case control studies, and cohorts indicates
      that laparoscopic surgery for colorectal cancer is feasible, and can reduce postoperative pain,
      analgesia use, hospital stay and blood loss in the short term.141 Most of the randomised trials have
      the potential for bias, as blinding is impractical. Reliable outcomes are also lacking.

       þ     Laparoscopic surgery can be considered for colorectal cancer.


7.7   MANAGEMENT OF MALIGNANT COLONIC OBSTRUCTION
      When a mechanical large bowel obstruction is suspected, a water-soluble contrast enema can
                                                                                                             2+
      confirm this and avoid operative intervention for pseudo-obstruction.142

       C     Mechanical large bowel obstruction should be distinguished from pseudo-obstruction
             before surgery.




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        There is evidence that, in suitable patients, and with sufficient surgical expertise, removal of the
        tumour at the first operation is feasible.143 If primary resection is carried out, immediate anastomosis
                                                                                                                    1++
        is feasible, again given a suitable patient and appropriate surgical expertise, and there is randomised     2+
        evidence that segmental resection is preferable to subtotal colectomy in terms of functional
        outcome.144
        Colonic stenting is also possible, and can provide both palliation in patients with inoperable
                                                                                                                    3
        disease and relief of obstruction in those with operable disease prior to semi-elective resection.145,146

         C     Patients with malignant obstruction of the large bowel should be considered for immediate
               resection.

         A     If immediate reconstruction after resection is deemed feasible, segmental resection is
               preferred for left-sided lesions.

         D     Where facilities and expertise are available, colonic stenting should be considered.


  7.8   SURGERY FOR ADVANCED DISEASE
        There is evidence from cohorts with historical controls that survival can be improved by hepatic
        resection for technically suitable metastatic disease,147 and the same may be true of lung resection.148    3
                                                                                                                    4
        In situ ablation for liver metastases which are not suitable for resection is also feasible, but the
        benefit is less clear.149
        In the patient with locally advanced primary or recurrent disease, it must be remembered that
        surgical removal offers the only chance of cure, but that quality of life may be adversely affected
                                                                                                                    4
        by inappropriate attempts at resection.150 For disease that is clearly inoperable, interventions such
        as stenting or laser ablation may provide useful palliation.151

         D     Patients with liver and lung metastases should be considered for resection or, in the case
               of liver disease, in situ ablation.

         D     In patients with advanced local or recurrent disease, careful consideration should be given
               to surgical excision or palliative intraluminal procedures.


  7.9   SPECIALISATION AND WORK LOAD IN COLORECTAL CANCER SURGERY
        There is evidence from cohorts and historical controls that morbidity and survival are affected by
        surgeon and hospital workload but the evidence is insufficient to recommend a specific yearly
                                                                                                                    2++
        volume.152 Evidence from North America, where specific colorectal accreditation is available,
        indicates better outcomes from specialists,153 and evidence from Europe convincingly demonstrates
        better outcomes after specialist training in rectal cancer surgery.124

         B     Surgery for colorectal cancer should only be carried out by appropriately trained surgeons
               whose work is audited. Low rectal cancer surgery should only be performed by those
               trained to carry out TME.




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                     http://chn-health.com                                                                 8 PATHOLOGY




8     Pathology
      Pathological examination of the resection specimen is of the utmost importance in determining
      prognosis and the need for adjuvant therapy. In this section, the important histopathological
      features, the need for proforma reporting and the role of pathologists in the multidisciplinary team
      are discussed.
      There is good evidence that staging identifies those patients who might benefit from adjuvant
      chemotherapy, and circumferential resection margin (CRM) reporting helps to select patients with
      rectal cancer who might benefit from postoperative radiotherapy (see section 9). For this reason,
      the pathologist is a key member of the local core multidisciplinary colorectal cancer team.

8.1   IMPORTANT PATHOLOGICAL PARAMETERS IN COLORECTAL CANCER
      Resection specimens for colorectal cancer need to be carefully prepared and dissected to obtain
      accurate assessment of the important prognostic parameters. Cohort studies have shown that
      tumour stage (Dukes’ or tumour, node, metastasis (TNM) system - see Annex 1) is an important
      prognostic parameter. The presence of clear vascular invasion outwith the bowel wall (assessed on
      routine haematoxylin and eosin stained preparations) is a further adverse parameter, correlating         2++
                                                                                                               2+
      particularly with the development of hepatic metastases.154,155 Ulceration of the peritoneum, defined
      by the presence of tumour cells directly on the surface, is another important microscopic indicator
      of a poor outcome.154,156 Rectal cancer presents problems of its own in that much of the rectum
      lies embedded in the soft tissues of the pelvis. It is now clearly recognised that local recurrence of
      rectal cancer can be accurately predicted by pathological assessment of circumferential margin
      involvement in these tumours.156

       B     Pathological reporting of colorectal cancer resection specimens should include
             information on:
             n   tumour differentiation
             n   staging (Dukes’ and TNM systems)
             n   margins (peritoneal and CRM)
             n   extramural vascular invasion.

       þ     Specimens should ideally be received fresh in the laboratory and opened from either end
             up to, but not through, the tumour. The peritoneal and/or circumferential margins are
             marked with ink and the bowel pinned and fixed for at least 48 hours. The region of the
             tumour is examined by slicing in serial thin (5 mm) transverse sections to allow for optimum
             assessment of depth of invasion and margins. As a routine four blocks of tumour are taken
             for microscopy. The fat is carefully dissected to retrieve all lymph nodes.156

       þ     For rectal cancers comments should be made on the quality of the surgical mesorectal
             dissection and on whether or not the anterior quadrant is involved for tumours lying below
             the peritoneal reflection.


8.2   REPORTING IN COLORECTAL CANCER
      Recent studies have shown that template proformas significantly increase the rate of inclusion of        1+
      data items in reports of colorectal cancer resection specimens.157,158                                   2+

       B     All reporting of colorectal cancer specimens should be done according to or supplemented
             by the Royal College of Pathologists’ minimum data set.




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  9     Chemotherapy and radiotherapy
        Chemotherapy and radiotherapy are important therapeutic modalities in colorectal cancer. This
        section is subdivided into adjuvant chemotherapy, adjuvant radiotherapy, chemotherapy for
        metastatic disease and radiotherapy for locally advanced disease.

         þ     Chemotherapy and radiotherapy should be prescribed, dispensed, administered and
               supervised in a safe and effective manner in accordance with the Joint Collegiate Council
               for Oncology guidelines159 and Scottish Executive advice.160

        Both radiotherapy and chemotherapy can improve survival rates after potentially curative surgery,
        and chemotherapy prolongs overall survival in cohorts of patients with advanced disease. However,
        neither radiotherapy nor chemotherapy can guarantee cure, it is not possible to identify which
        individuals will benefit personally and there is a “cost” in terms of disruption of lifestyle and
        treatment related toxicity.

         þ     It is essential that the pros and cons of intervention be discussed carefully with the patient
               so that each individual can make an informed choice that is consistent with their wishes
               and personal circumstances.


  9.1   ADJUVANT CHEMOTHERAPY
        There is evidence showing absolute survival benefit (of 4%-13% at five years) from adjuvant
        chemotherapy for patients with Dukes’ C colon cancer.161-163 Somewhat weaker evidence suggests             1++
        that there is also survival benefit from adjuvant chemotherapy for rectal cancer.164 It is, however,       1+
        difficult to distinguish the benefits of radiotherapy from those of chemotherapy in patients with
        rectal cancer.

         A     Patients with Dukes’ C tumours of the colon or rectum should be considered for adjuvant
               chemotherapy.

        Chemotherapy may not be appropriate for all patients due to comorbidity or personal preference.
        The proportion of older (>70 years) patients entered into trials of adjuvant therapy is small, and
        not representative of the population suffering from colorectal cancer in Scotland (see Table 3).
        Table 3: Comparison of age distribution of patients randomised into the QUASAR study165 with
        the population data for people suffering from colorectal cancer in Scotland (ISD data).166
                  Age (years)                   QUASAR (n=9,790)                     Scotland (n=14,774)
                  <50                                   15%                                  5%
                  50 to 59                              26%                                  12%
                  60 to 69                              39%                                  26%
                  >70                                   19%                                  57%

         þ     In older patients or in patients with significant coexisting illness (eg cardiovascular problems)
               the risks of toxicity may increase and decisions about adjuvant chemotherapy should be
               based on careful discussion between the patient and oncologist.

        The evidence for patients with Dukes’ B tumours shows no overall benefit from adjuvant                     1+
        chemotherapy. 163,167

         A     Patients with Dukes’ B tumours of the colon or rectum should not be treated routinely
               with adjuvant chemotherapy.




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9.1.1   PORTAL VEIN INFUSION AND INTRAPERITONEAL ADJUVANT CHEMOTHERAPY
        There is conflicting evidence on the survival benefit from portal venous infusion of fluorouracil
        (5-FU). Some studies suggest a modest effect with a 4.7% absolute increase in five year survival          1++
        (Number Needed to Treat, NNT=20).168-170 Preliminary results of the AXIS trial indicate no                1+
        difference in absolute survival rate.171 Further data are required to clarify this question. Greater
        benefits can be achieved with systemic administration of chemotherapy.

         B     Portal vein chemotherapy should not be used as the sole regimen in postoperative adjuvant
               treatment.

        There is a single RCT which suggests a benefit from combining intra-peritoneal fluorouracil and
        folinic acid (FUFA) with systemic chemotherapy in colorectal cancer but the control arm comprised
        a different systemic regimen (fluorouracil/levamisole) and this trial therefore does not demonstrate      1+
        a clear advantage for intraperitoneal therapy.172

9.1.2   ADJUVANT IMMUNOTHERAPY
        Evidence on the use of monoclonal antibody 17 1A is conflicting: one RCT173 showed improved
        survival in Dukes’ C cancer of the colon compared to no treatment, but a second, reported in              1+
        abstract only, showed no benefit from adding 17 1A to FUFA chemotherapy.174
        Two randomised trials have failed to show benefit from adding interferon alfa to conventional
        chemotherapy.175,176 There is also evidence that adding levamisole to FUFA provides no additional         1++
        benefit.177

         þ     Adjuvant immunotherapy with the monoclonal antibody 17 1A should not be used except
               in a randomised controlled trial.

         A     The addition of levamisole or interferon alfa to FUFA chemotherapy as adjuvant treatment
               is ineffective in colorectal cancer and should not be considered.

        Active specific immunotherapy (ASI) has been evaluated in a single randomised trial, but this was
        of insufficient quality to allow a conclusion to be drawn and further studies with this mode of           1-
        treatment are needed.178

9.1.3   WHAT IS THE MOST EFFECTIVE CHEMOTHERAPY REGIMEN FOR ADJUVANT TREATMENT
        OF COLORECTAL CANCER?
        FUFA given by intravenous injection for five days every four weeks for six cycles is the regimen for
        which the most evidence is available and it is clearly effective in prolonging survival in patients
        with Dukes’ C tumours.161, 162 One study has shown no benefit from higher (175 mg) as opposed             1+
        to lower (25 mg) doses of L-folinic acid.179 Low dose FUFA has not been shown to be superior to
        12 months of fluorouracil in combination with levamisole, but levamisole is not licensed in
        Scotland.

         A     The recommended adjuvant regimen in patients with Dukes’ C tumours is bolus fluorouracil
               and low-dose folinic acid (FUFA), administered over five days every four weeks. The
               duration of treatment should be six months.

        In a retrospective analysis of data from the QUASAR (QUick And Simple And Reliable) trial, it
        has been shown that weekly bolus FUFA is as active and less toxic than five day, four weekly              2++
        FUFA, but the level of evidence supporting its use, is lower than that for the four weekly schedule.180

         C     The schedule of FUFA given once weekly for 30 weeks used in the QUASAR (QUick And
               Simple And Reliable) trial may be an acceptable option for certain patients.

        Preliminary results from the SAFFA study show that, compared to six months of bolus FUFA, three
        months of protracted venous infusion (PVI) flourouracil is superior, in terms of disease-free survival,
        but there was no difference in survival between the two arms of this study.181 Quality of life
        whilst on treatment is better with PVI flourouracil and there are fewer life-threatening adverse
        effects.




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          Randomised trials of adjuvant treatment using other regimens, such as de Gramont FUFA,
          capecitabine and tegafur/uracil (UFT) were identified. De Gramont FUFA and capecitabine have
          been shown to be more effective and less toxic, than bolus FUFA in patients with advanced
          disease.182,202 Increased response rates have been reported in patients with metastatic disease when
          combination chemotherapy is administered (see section 9.3.3). Data from RCTs in the adjuvant
          setting, including these regimens, will be available in the near future.

  9.2     ADJUVANT RADIOTHERAPY
          Local failure may be distressing for patients and is both difficult and expensive to treat effectively.
          Improving local control, even if without improvement in survival, is a worthwhile therapeutic
          goal. There is no easy or obvious explanation for the fact that improvement in local control
          apparently fails to translate into improved survival.
          There is unequivocal evidence from 27 randomised trials and two meta-analyses that adjuvant
          radiotherapy improves local control in patients undergoing potentially curative resections for             1++
                                                                                                                     1+
          rectal cancer.183,184 The pooled estimate for the absolute reduction in risk of loss of local control
          favouring radiotherapy and surgery, as opposed to surgery alone, is 9% (NNT=11).
          The evidence for increased survival is less convincing. Meta-analyses show no overall benefit.
          Only one trial, the Swedish Rectal Trial, showed convincing benefit with survival as an endpoint:
          an absolute risk reduction in survival of 10% in favour of preoperative radiotherapy (NNT=10).185          1+
          Follow up of the long term survivors from the Swedish Rectal Trial shows that bowel function is
          significantly worse in irradiated patients; the survival benefits are at the cost of increased late
          toxicity.186 See Box 1 for a discussion of the difficulties involved in generalising from research
          evidence.
          There is strong evidence of an increase in non-cancer deaths during the first year after treatment in
          patients irradiated preoperatively187 which may, in part, offset any potential survival benefit of
          improved local control. Further evidence indicates that this excess mortality is related to radiotherapy   1++
          technique, in particular outmoded regimens which treated large volumes with parallel opposed               1+
          fields.188,189 Trials using three or four field plans to more conservative volumes fail to show any
          increase in non-cancer deaths.190

           A     Preoperative radiotherapy, planned with three or four fields, should be considered in
                 patients with operable rectal cancer.

           þ     Where there is doubt about the value of preoperative radiotherapy, patients should be
                 considered for inclusion into a randomised trial (eg CR07).

  9.2.1   PREOPERATIVE VERSUS POSTOPERATIVE TREATMENT
          Only one randomised trial has directly compared preoperative radiotherapy with postoperative
          radiotherapy.191 The dose of postoperative radiotherapy used in this study was relatively high, 60
          to 64 Gy in 2 Gy fractions, split course. The results favour preoperative radiotherapy with a              1-
          significant excess of late morbidity in long term survivors who had been irradiated postoperatively.
          The absolute rate difference was 21% (Number Needed to Harm, NNH=5). However, this study
          has a high risk of bias with wide confidence intervals and cannot support a recommendation.




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        Indirect evidence from systematic reviews also suggests that radiotherapy may be more effective if
        given preoperatively.192 When trials of preoperative radiotherapy are compared with trials of
        postoperative radiotherapy, the magnitude of benefit, in terms of local control, is similar. The         1+
        preoperative trials used lower doses of radiotherapy, £40 Gy at 2 Gy equivalent fractions based on
        a/b=10 Gy, whereas the postoperative trials used doses ³40 Gy. Similar effects on tumours were
        produced using lower biological doses with preoperative, as opposed to postoperative, treatment.

         þ      Postoperative radiotherapy should be considered in patients with rectal cancer who did
                not receive preoperative radiotherapy and who are at high risk of local recurrence (see
                section 8).

         C      When postoperative radiotherapy is indicated, a schedule of 45Gy in 25 fractions over
                five weeks is recommended. Patients should not be treated with parallel opposed fields; a
                planned technique with three or four fields should be used.

9.2.2   CHEMOTHERAPY SYNCHRONOUS WITH RADIOTHERAPY
        There are no results from studies comparing short course (five fractions) radiotherapy with and
        without chemotherapy. The following discussion applies to long course (>20 fractions)
        radiotherapy.
        Only three trials have randomised patients with rectal cancer to radiotherapy as opposed to
        chemotherapy synchronous with radiotherapy (CRT). All were of low quality and reporting is
        incomplete. The more useful evidence comes from several prospective cohort studies.193,194 The           2+
        addition of chemotherapy to radiotherapy improves complete response rate and the resectability           4
        rate in more advanced tumours. The design of the studies does not allow an assessment of survival.
        The regimens using intermittently infused FUFA (Bosset) or continuous flourouracil (Lokich) have
        been widely and safely used.

         C      Chemotherapy should be given synchronously with the radiotherapy using one of the
                following three regimens:
                n   intermittently infused FUFA (Bosset);
                n   continuous flourouracil (Lokich) or
                n   bolus FUFA.


        Box 1
        Generalisability of trial results
        It is not easy to assess the relevance of the published trials to clinical practice. The local failure
        rate in the surgery alone arms is about 25%. This reflects previous surgical practice and would no
        longer be considered acceptable. The Dutch Colorectal Cancer Group trial does show that, even
        with low local failure rates associated with modern surgical techniques (see section 7.4 on mesorectal
        excision), short course preoperative radiotherapy may still be of benefit: an absolute reduction in
        rate of local failure of 5.8% (3.8 to 7.9), NNT=17 (13 to 26).195 This has to be set against the
        increased late bowel morbidity in preoperatively irradiated patients.
        Further difficulties in generalising from the Dutch study arise from the fact that it is the only
        randomised trial in which pathological assessment has been based on the Quirke system.196 There
        are no other trials on the rate of circumferential margin involvement in patients irradiated
        preoperatively, nor are there any that assess the role of postoperative radiotherapy in patients with
        positive resection margins. The MRC2 study197 and the Northwest study198 both investigated the
        role of preoperative radiotherapy in locally advanced tumours (eg tethered but operable tumours)
        and demonstrated improvement in local control, but not survival. Finally, the age ranges of patients
        recruited to clinical trials often do not reflect those of the general population as is clearly
        demonstrated in Table 3 in the field of adjuvant chemotherapy.




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  9.3     CHEMOTHERAPY FOR METASTATIC DISEASE
          There is evidence from two systematic reviews that chemotherapy for metastatic colorectal cancer
          can improve survival, and should be considered in all cases.199,200 This form of therapy is given        1++
          with palliative intent, and a major aim should be to alleviate symptoms or delay their onset.

           A     All patients with metastatic colorectal cancer should be considered for chemotherapy.

          Some patients experience the toxicity of treatment without benefit and patients should be informed
          of the potential benefits and morbidity of treatment and fully involved in decision-making. Ideally,
          a consultant oncologist should carry out the assessment of a patient and discuss management with
          them in a socially supportive environment and offer the opportunity for relatives or friends and a
          clinical nurse specialist to be present. Patients should receive written as well as verbal information
          about treatment and should be informed about other sources of information such as other health
          care professionals, Cancer BACUP (www.cancerbacup.org.uk) and other internet sites. Patients
          often require time to discuss issues with others and a second appointment may be required before
          patients decide between treatment options.

           þ     The benefits and morbidity of chemotherapy should be discussed with a consultant
                 oncologist in the presence of relatives/friends if the patient chooses. Access to a clinical
                 nurse specialist should be offered to the patient. Patients should also receive written
                 information.

  9.3.1   DEFERRED VS IMMEDIATE CHEMOTHERAPY IN ASYMPTOMATIC PATIENTS
          Two systematic reviews demonstrate that chemotherapy prolongs survival, but insufficient, high
          quality data are available relating to the timing of chemotherapy.199,200 There are no useful data on
          quality of life or relief of symptoms. The patients included in the 13 randomised trials attempting
          to address this question are unrepresentative. In the Cochrane overview only 16/858 (<2%) of the
          patients for whom individual patient data were available were over 75 years old. Scottish Cancer
          Registry data show that 57% of patients with colorectal cancer are over 70 years old, 24% are over
          80 years.
          There remains no clear indication for immediate, as opposed to deferred, chemotherapy in
          asymptomatic patients with metastatic colorectal cancer. The advantages and disadvantages of
          immediate treatment should be carefully discussed with each patient and, if an appropriate
          randomised trial is available, entry into the trial should be considered.

  9.3.2   FIRST LINE CHEMOTHERAPY REGIMEN
          The regimen of bolus FUFA (Mayo) has been compared with other regimens in several randomised
          controlled trials and protracted infusions of fluorouracil was compared with bolus fluorouracil
          alone.182,201-203 Tegafur/uracil (UFT) in combination with folinic acid has also been compared with
          one Mayo regimen and has shown similar efficacy and reduced toxicity (published in abstract
          only).204,205 Bolus fluorouracil regimens have been shown in a meta-analysis to be inferior to           1++
          fluorouracil infusion regimens in terms of response rate.206 The Mayo regimen itself is the least
          effective and the most toxic of the regimens that have been widely tested in randomised trials. The
          de Gramont regimen (intermittently infused FUFA), the Lokich regimen (continuously infused
          fluorouracil), and oral capecitabine are more effective than regimens using bolus 5-FU in terms of
          response rate, and are also less toxic.182,207,208
          Other orally administered agents are undergoing clinical trials and the results of these studies are
          likely to influence future recommendations.
          Raltitrexed is as effective as the Mayo FUFA regimen, but evidence concerning its toxicity is
          conflicting.209-211 A randomised adjuvant trial of raltitrexed compared to fluorouracil and folinic
          acid (PETACC-1) was stopped prematurely when drug-related deaths in the raltitrexed arm were             1++
          double those of the control arm and a greater proportion of patients failed to complete the intended     3
                                                                                                                   4
          treatment.212 Some of these problems may be related to the effects of impaired renal function
          upon toxicity associated with raltitrexed.213




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        In patients with metastatic disease, raltitrexed was also associated with an increased incidence of
        treatment related deaths (6%) when compared to the de Gramont and Lokich regimens, although
        overall survival was similar in each of the three groups. Nevertheless, ralixitred may be useful in
        the management of patients with severe coronary artery disease as it does not, in contrast to the
        other regimens, induce coronary vasospasm.214
        The results of the MRC CR06 trial show that, in a randomised comparison of raltitrexed, the de
        Gramont (intermittently infused FUFA) regimen, and the Lokich (continuously infused fluorouracil)
        regimen, the regimens were of similar effectiveness in terms of survival and response rates. 215                                   1+
        Raltitrexed was more toxic than the other regimens and the quality of life of patients treated with
        raltitrexed was inferior to that of patients treated with the other two regimens.

         A       Bolus 5-FU regimens are not recommended as routine first line chemotherapy for advanced
                 disease.

         A       Outside a clinical trial, the choice of an appropriate regimen includes continuous infusional
                 flourouracil (Lokich), FUFA infusion (de Gramont) or capecitabine.

         D       Raltitrexed is not recommended as a first line therapy but may be considered as an alternative
                 in those patients intolerant of 5-FU regimens or in whom 5-FU is contraindicated due to
                 cardiotoxicity.*

        Each of these regimens is very different in terms of administration, scheduling, hospital admission
        and potential toxicity, and the choice of treatment will be influenced by a number of factors. The
        most important factors are patient preference and availability of expertise.

9.3.3   COMBINATION CHEMOTHERAPY
        Evidence from two randomised trials shows that adding irinotecan to FUFA increases the response
        rate and also produces a modest improvement in survival.217,218 Two randomised trials comparing
        FUFA alone with FUFA plus oxaliplatin fail to show survival benefit but there is improvement in
        response rate.219,220 Interpretation of survival data from these studies is confused by crossover                                  1+
        issues: patients failing FUFA were able to crossover to the combination regimen. There is good
        evidence to support initial combination chemotherapy for patients with metastatic colorectal
        cancer, but any benefit from the use of these regimens has to be set against the increase in toxicity
        when compared with FUFA alone.
        In a randomised study assessing the value of adding mitomycin to protracted infusion flourouracil,
        it was shown that the response rate increased and time to progression was prolonged but there was                                  1++
        no difference in overall survival and haematological toxicity was increased by the addition of
        mitomycin.221

         þ       Until the balance between benefits and harms can be better defined, there is no
                 justification for the routine use of combination therapy as first line treatment for all patients
                 with metastatic colorectal cancer, but the decision should be made on an individual basis.

        Evidence from a large cohort study of combination chemotherapy with oxaliplatin and fluorouracil
        and folinic acid on the treatment of liver metastases showed that chemotherapy allowed surgical
        resection in 13.5% of patients treated and subsequent survival was similar to a comparable series                                  2+
        of operable patients treated by surgical resection. This evidence supports the use of neoadjuvant
        chemotherapy to allow surgical resection of liver metastases.222

         C       Initial combination chemotherapy, including oxaliplatin, should be considered in patients
                 fit for hepatic resection but who have inoperable hepatic metastases that might become
                 resectable on treatment.

         þ       The optimal route and schedule of administration of palliative chemotherapy remains
                 uncertain and all patients should be considered for entry into prospective randomised
                 clinical trials.
        * Although as efficacious as alternative regimens, raltitrexed is associated with significantly greater toxicity and its benefit
        to patients who are intolerant to 5FU or with coronary heart disease should be carefully weighted against the potential harms.
        This recommendation differs from the HTBS comment 216 on the NICE appraisal (March 2002) which recommends that the use
        of raltitrexed is restricted to clinical studies.



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  9.3.4   HEPATIC ARTERY INFUSION (HAI) FOR LIVER METASTASES.
          Two meta-analyses223,224 and two randomised trials225,226 have found that response rates are higher
                                                                                                                 1++
          with HAI but improvements in survival are meagre. Any advantages achieved through the use of
                                                                                                                 1+
          hepatic artery infusion are offset by the technical difficulties associated with the technique.

           þ     HAI use should be confined to specialist centres or clinical trials.

  9.3.5   SECOND LINE CHEMOTHERAPY
          Two randomised trials show that patients who have failed to respond to, or who have progressed
          after treatment with 5FU/FA may respond to treatment with irinotecan.227,228 These responses may
                                                                                                                 1+
          translate into improved survival although the benefits are modest - an increase of 10 weeks in
          median survival - and by 24 months the survival curves converge again.

           A     Carefully selected patients with good performance status, normal liver function tests and
                 no evidence of gastrointestinal obstruction with metastatic colorectal cancer, who have
                 progressive disease despite treatment with 5FU/FA, should be considered for second line
                 treatment with irinotecan.

  9.3.6   THERAPIES BASED ON MANIPULATION OF THE IMMUNE SYSTEM
          Two randomised trials show no benefit from adding interferon alfa to conventional
          chemotherapy.175,176 A further trial, using the anti-idiotypic monoclonal antibody 105 AD7 showed      1+
          no benefit in survival in comparison with placebo.229

           A     Immune modulation should not be used routinely in the management of advanced
                 colorectal cancer.

  9.3.7   CHRONOMODULATED THERAPY
          Chronomodulation is a method of delivering chemotherapy in which programmable pumps are
          used to vary the rate of drug delivery over a 24 hour period. The hypothesis is that scheduling
          therapy in this way will improve selective toxicity by exploiting differences in circadian rhythms
          between tumours and normal tissues. Only one randomised trial has addressed directly the issue
          of benefit from chronomodulated therapy in patients with colorectal cancer.230 The study utilised
          a non-standard control arm which was relatively toxic resulting in no convincing evidence that
          chronomodulated chemotherapy offers any significant survival advantage over conventionally
          scheduled treatment for patients with metastatic colorectal cancer.

  9.4     RADIOTHERAPY FOR ADVANCED DISEASE
          The potential roles for radiotherapy in advanced rectal cancer are:
          n  to improve the operability of unresectable disease;
          n  in the curative treatment of inoperable disease;
          n  in the palliative management of symptoms in patients with persistent or locally recurrent
             disease.

  9.4.1   IMPROVING THE OPERABILITY OF UNRESECTABLE DISEASE
          Evidence indicates that adding synchronous chemotherapy to local radiotherapy increases the
                                                                                                                 1+
          response rate of rectal cancer.231-233 Regimens using intermittently infused 5FU/FA234 or continuous   2+
          5FU235,236 have been widely and safely used.

           C     Radiotherapy to convert inoperable rectal cancer into operable disease should be combined
                 with chemotherapy. Suitable regimens include intermittent infusional 5FU/FA (Bosset),
                 continuously infused 5FU (Lokich) or bolus 5FU/FA.




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9.4.2   CURATIVE TREATMENT OF TOTALLY INOPERABLE DISEASE
        If surgery is not feasible, either because of the local extent of disease or owing to the patient’s
        general medical condition, then the use of higher doses of radiotherapy, in conjunction with
        chemotherapy, should be considered. In these circumstances, the chances of cure are slender and
        disruption and toxicity from treatment are certain. It is essential that the harms as well as the
        potential benefits from an aggressive approach should be carefully discussed with the patient.
        Ultimately, the decision whether or not to opt for radical therapy should rest with the patient.
        The presence of hepatic metastases is not in itself a contraindication to the radical treatment of
        the primary tumour. If the local tumour has been controlled then resection or in situ ablation of
        the liver metastases should be considered.

         þ     For patients with totally inoperable rectal cancer, and who are fit for an aggressive approach
               to treatment, chemo-radiotherapy should be offered as for potentially resectable disease.

9.4.3   PALLIATION OF LOCAL SYMPTOMS
        There is no high quality evidence on the effectiveness of radiotherapy in relieving symptoms
        caused by residual or recurrent rectal cancer. Evidence suggests that 44 Gy in 12 fractions over 10
        to 12 weeks may be effective and will produce minimal toxicity, either acute or late.237 A regimen      3
        of 30 Gy in 10 to 15 fractions is widely used, but there is no good evidence to support this
        practice.
        The choice of regimen will depend upon a number of factors including the patient’s preference
        and general condition; the distance from the treating centre and the nature and severity of symptoms.

         D     Palliative radiotherapy should be considered for patients who have distressing pelvic
               symptoms from rectal cancer.




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  10    Follow up of patients treated for colorectal
        cancer
        Patients who have undergone apparently curative resection for colorectal cancer are followed up
        for four reasons:
        1. to detect metastatic disease in the hope that early detection and treatment will result in
           improved survival;
        2. to survey the remaining colon and rectum to detect intraluminal recurrence and/or other cancer
           or adenomatous polyps;
        3. for the psychological support of the patient;
        4. for audit purposes.
        In this guideline, only the first two reasons are addressed.
        Individual randomised trials show no advantage of follow up238-242 as measured by survival. Meta-
        analyses indicate that follow up can offer survival benefit by means of earlier detection of metastatic   1++
        disease. In particular, interval CT scanning and serial carcinoembryonic antigen (CEA) levels             1+
        appear to be useful in this respect.243-245
        There is no evidence that FOBT is of any value in follow up of patients after curative resective
        surgery.
        There is some conflicting evidence that those who have had curative resection of rectal cancer
        may benefit from endoscopic surveillance.242,246 As the incidence of colorectal cancer is increased
        after the first occurrence, and adenomatous polyps occur with increased frequency,35 most clinicians
        would recommend colonoscopic follow up in patients after colorectal cancer resection as for
        those with adenomatous polyps (see section 2.7.3).

         A     Patients who have undergone curative resection for colorectal cancer should undergo
               formal follow up in order to facilitate the early detection of metastatic disease.

         þ     Interval CT scanning and CEA estimation may be of value in the follow up of patients who
               have undergone curative resection for colorectal cancer but further studies are required to
               define an optimum approach.

         þ     Colonoscopic follow up after curative resection for colorectal cancer should be carried out
               as for adenomatous polyps.

         þ     Where the clinician suspects intraluminal recurrence, colonoscopy is indicated.

         þ     Clinicians should be aware of the need to have symptoms and signs of metastatic recurrence
               promptly investigated.




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                        11 PALLIATIVE CARE AND THE MANAGEMENT OF SYMPTOMS




11       Palliative care and the management of symptoms
         in advanced disease
         As in advanced cancer of any site it is important to help the patients to understand where they are
         in their illness with regard to stage of advancement and what may or may not be realistically
         achieved.

11.1     REFERRAL TO PALLIATIVE CARE
         There are many reports suggesting unmet needs, both physical and emotional, in patients with
         advanced colorectal cancer leading to the view that patients may benefit from access to palliative
         care services before the “terminal” phase.247

          þ     Patients with advanced colorectal cancer whose physical or emotional symptoms are difficult
                to control should be referred to a specialist in palliative care without delay.


11.2     SYMPTOM MANAGEMENT
         Patients with advanced disease frequently have multiple symptoms. Pain, fatigue and emotional
         distress are those most commonly reported, and the number and severity of symptoms increases as
         the cancer advances.248

11.2.1   PAIN
         Pain is still common in severely ill patients with cancer and its severity underestimated.249 In a
         recent national audit, 58% of cancer patients in the acute hospital setting recorded their pain as    3
         either moderate or severe.250
         Abdominal pain is common, and may be caused by the tumour itself or bowel obstruction. It may
         also be due to liver metastases or coeliac plexus involvement.
         Involvement of the coeliac plexus, lumbosacral root, spinal cord or cauda equina can cause pain
         in a nerve root distribution which is difficult to describe and may be burning, numbing, tingling,
         shooting, or like toothache. Treatment of the pain requires a multidisciplinary approach, and
         although the pain may respond to opioids, additional drugs such as gabapentin, amitriptyline or
         ketamine may be used. Perineal pain and tenesmus may respond to opioids and to agents such as
         gabapentin.
         For a more detailed discussion of pain assessment and management see the SIGN guideline on
         control of pain in patients with cancer.251

11.2.2   MALIGNANT BOWEL OBSTRUCTION
         Patients who develop small or large bowel obstruction, and in whom surgery is inappropriate, can
         be managed in most cases without intravenous fluids or a nasogastric tube. Pain (visceral and
         colic), nausea and vomiting, can often be controlled for weeks using analgesics, anti-emetics and
         antisecretory drugs parenterally - most often given by syringe driver. Patients may then be able to   1+
         eat and drink. Parenteral hydration is sometimes indicated to control nausea, whereas regular         4
         mouth care is the treatment of choice for dry mouth.252 A Cochrane review concluded that there
         was weak evidence that corticosteroids (dexamethasone 6-16 mg IV) may help the resolution of
         inoperable obstruction in some patients253 with few side effects.

          D     Medical measures such as analgesics, antiemetics and antisecretory drugs should be used
                alone or in combination to relieve the symptoms of bowel obstruction.




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  11.2.3   FATIGUE
           Fatigue has been identified as a common problem for patients.254 In the absence of any correctable
           cause corticosteroids may be of some benefit.255

  11.2.4   NUTRITION AND WEIGHT LOSS
           Patients and families understandably focus on what patients are able to eat. Although there is no
           evidence that nutritional supplements, parenteral or enteral feeding are of benefit in preventing
                                                                                                                      4
           cancer cachexia when the disease is advanced, evidence is emerging that it may be of value at an
           earlier stage.256 Referral to a specialist state registered dietitian or advice from a nutrition support
           team should be sought where appropriate.

            þ     As anorexia and weight loss are so distressing for the patient and their family, the issue of
                  nutrition must be addressed.




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                                           12 IMPLEMENTATION AND AUDIT




12       Implementation and audit
12.1     LOCAL IMPLEMENTATION
         Implementation of national clinical guidelines is the responsibility of each NHS Trust and is an
         essential part of clinical governance. It is acknowledged that every Trust cannot implement every
         guideline immediately on publication, but mechanisms should be in place to ensure that the care
         provided is reviewed against the guideline recommendations and the reasons for any differences
         assessed and, where appropriate, addressed. These discussions should involve both clinical staff
         and management. Local arrangements may then be made to implement the national guideline in
         individual hospitals, units and practices, and to monitor compliance. This may be done by a
         variety of means including patient-specific reminders, continuing education and training, and
         clinical audit.

12.2     KEY POINTS FOR AUDIT AND RECOMMENDATIONS FOR RESEARCH

12.2.1   AUDIT
         In order to review the previous SIGN dataset for colorectal cancer in the light of this revised
         guideline, a multidisciplinary working group was convened consisting of representatives of SIGN,
         the Clinical Standards Board for Scotland (CSBS) and the Scottish Cancer Intelligence Unit (SCIU).
         The group met several times throughout the period of development of the guideline and established
         a common dataset which allows the audit not only of SIGN guideline recommendations but also
         facilitates the collection of data relevant to clinical standards, core cancer registration data items
         and key information for calculation of waiting times.
         The dataset is available for download from the following websites:
         SIGN - http://www.sign.ac.uk
         SCIU - http://www.show.scot.nhs.uk/isd/cancer/research/audit.htm
         CSBS - http://www.clinicalstandards.org
         Further details of the timing of implementation of this data set and associated data definitions are
         available from the SCIU website.

12.2.2   RESEARCH RECOMMENDATIONS
         The guideline development group have highlighted a number of areas which could not be addressed
         by the systematic review of evidence and have flagged these up as urgent areas for future research
         activity.
         Screening and risk factors
         Elucidation of dietary and lifestyle risk factors of colorectal cancer
         Development of strategies to change diet and lifestyle in patients at high risk of developing cancer
         Improving the sensitivity and specificity of existing screening tests
         Improving uptake for screening
         Establishing ideal intervals for colonoscopic surveillance in patients with inflammatory bowel
         disease
         Establishing ideal intervals for colonoscopic surveillance in patients with adenomatous polyps
         Research into the psychological consequences of screening both general populations and high risk
         groups




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        Primary care and diagnosis
        Research into ideal referral strategies between primary and secondary care
        Research into the use of magnetic resonance imaging to diagnose and stage colorectal cancer.
        Research into the role of CT pneumocolon
        Surgery
        Research into standardising techniques for rectal cancer surgery
        Establishing the role of local excision of colorectal cancer
        Establishing the role of stenting in the management of malignant colonic obstruction
        Clarifying the role of in situ ablation for liver metastases
        Chemotherapy and Radiotherapy
        Patients in older age groups should be included in future trials given that they are the band of
        population most commonly affected by colorectal cancer, that they may have a different toxicity
        profile, or response to therapy and that they may have a higher surgical risk profile.
        There is a need for a randomised trial of adjuvant chemotherapy in patients with Dukes’ B tumours
        who are considered, on the basis of histopathological features, to be at high risk of recurrence.
        Such patients would include those with perforated tumours or with evidence of peritoneal
        involvement.
        There is no RCT evidence concerning regimens, such as de Gramont FUFA or orally active agents,
        which have been shown in patients with advanced disease to be more effective and less toxic,
        than bolus FUFA. Given these uncertainties, entry into appropriate randomised trials, comparing
        different adjuvant regimens, is recommended for patients with Dukes’ C cancer of the colon and
        rectum.
        Further trials are needed to define whether portal vein infusion or intraperitoneal chemotherapy
        provides any additional benefit to that achieved using systemic chemotherapy.
        Development and implementation of new anti-cancer agents with increased effectiveness and
        reduced toxicity for advanced disease.
        Active specific immunotherapy (ASI) has been evaluated in a single randomised trial, but this was
        of insufficient quality to allow a conclusion to be drawn and further studies with this mode of
        treatment are needed.
        Clinical trials should be supported which investigate whether shorter and/or more convenient
        and/or less toxic chemotherapy regimens (e.g. PVI 5-FU as in SAFFA) are better than bolus FUFA.
        In addition, trials are required investigating combination regimens, which have been shown to be
        associated with higher response rates in patients with advanced disease.
        Communication and teamwork
        It is not easy to explain the concept of adjuvant chemotherapy to patients. It is particularly
        difficult to deal with the balance between the risks and benefits at the individual, as opposed to
        the population, level. More high quality research is required on how best to communicate prognostic
        information and how to ensure that the decisions made by individual patients are truly informed.
        Research into the role of specialist nursing in colorectal cancer
        Follow up
        Further information is required on the clinical and cost-effectiveness of the various follow up
        methodologies.
        Having one or more of these risk factors does not guarantee that a person will develop colorectal
        cancer, however it increases the chances. People may want to talk with a doctor about these risk
        factors. The doctor may be able to suggest ways to reduce the chance of developing colorectal
        cancer and can plan an appropriate schedule for check-ups.




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                               13 INFORMATION FOR DISCUSSION




13     Information for discussion with patients and
       carers
       The following sample information sheet can be used in discussion with patients to highlight
       issues of particular importance. It is intended as a guide only and should not be used to plan
       treatment or to replace the important consultations that should be held between patient and
       clinicians.

13.1   NOTES FOR DISCUSSION WITH PATIENTS AND CARERS
       What is colorectal cancer?
       The colon and rectum are parts of the body’s digestive system, which remove nutrients from food
       and stores waste until it passes out of the body. Together, the colon and rectum form a long,
       muscular tube called the large intestine (also called the large bowel). The colon is the first six feet
       of the large intestine, and the rectum is the last eight to ten inches.
       Cancer that begins in the colon is called colon cancer, and cancer that begins in the rectum is
       called rectal cancer. Cancers affecting either of these organs may also be called colorectal cancer.
       Who is at risk of colorectal cancer?
       The exact causes of colorectal cancer are not known. Studies show that the following risk factors
       increase a person’s chances of developing colorectal cancer:
       n   Age: Colorectal cancer is more likely to occur as people get older. This disease is more common
           in people over the age of 50. However, colorectal cancer can occur at younger ages, even, in
           rare cases, in the teens.
       n   Lifestyle factors: Colorectal cancer seems to be associated with low levels of physical activity,
           excess weight, and low intake of vegetables. There is accumulating evidence that long term
           smoking increases risk.
       n   Polyps: Polyps are benign growths on the inner wall of the colon and rectum. They are fairly
           common in people over age 50. Some types of polyps increase a person’s risk of developing
           colorectal cancer.
       n   A rare, inherited condition called familial polyposis, causes hundreds of polyps to form in the
           colon and rectum. Unless this condition is treated, familial polyposis is almost certain to lead
           to colorectal cancer.
       n   Personal medical history: Research shows that women with a history of cancer of the ovary,
           uterus, or breast have a somewhat increased chance of developing colorectal cancer. Also, a
           person who has already had colorectal cancer may develop this disease a second time.
       n   Family medical history: First degree relatives (parents, siblings, children) of a person who has
           had colorectal cancer are somewhat more likely to develop this type of cancer themselves,
           especially if the relative had the cancer at a young age. If many family members have had
           colorectal cancer, the chances increase even more.
       n   Ulcerative colitis: Ulcerative colitis is a condition in which the lining of the colon becomes
           inflamed. Having this condition increases a person’s chance of developing colorectal cancer.




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        Recognising symptoms
        Common signs and symptoms of colorectal cancer include:
        n a change in bowel habits
        n diarrhoea, constipation, or feeling that the bowel does not empty completely
        n blood (either bright red or very dark) in the stool
        n stools that are narrower than usual
        n general abdominal discomfort (frequent gas pains, bloating, fullness, and/or cramps)
        n weight loss with no known reason
        n constant tiredness
        n vomiting.
        These symptoms may be caused by colorectal cancer or by other conditions. It is important to
        check with a doctor.
        Diagnosing colorectal cancer
        To help find the cause of symptoms, the doctor evaluates a person’s medical history. The doctor
        also performs a physical examination and may order one or more diagnostic tests:
        n   x-rays of the large intestine can reveal polyps or other changes
        n   a sigmoidoscopy lets the doctor see inside the rectum and the lower colon and remove polyps
            or other abnormal tissue for examination under a microscope
        n   a colonoscopy lets the doctor see inside the rectum and the entire colon and remove polyps or
            other abnormal tissue for examination under a microscope
        n   a biopsy is the removal of a tissue sample for examination under a microscope by a pathologist
            to make a diagnosis.
        Treatment for colorectal cancer
        Treatment depends mainly on the size, location, and extent of the tumour, and on the patient’s
        general health. Patients are often treated by a team of specialists, which may include a
        gastroenterologist, surgeon, medical oncologist, and radiation oncologist. Several different types
        of treatment are used to treat colorectal cancer. Sometimes different treatments are combined.
        n   Surgery to remove the tumour is the most common treatment for colorectal cancer. Generally,
            the surgeon removes the tumour along with part of the healthy colon or rectum and nearby
            lymph nodes. In most cases, the doctor is able to reconnect the healthy portions of the colon
            or rectum. When the surgeon cannot reconnect the healthy portions, a temporary or permanent
            colostomy is necessary. Colostomy, a surgical opening (stoma) through the wall of the abdomen
            into the colon, provides a new path for waste material to leave the body. After a colostomy,
            the patient wears a special bag to collect body waste. Some patients need a temporary colostomy
            to allow the lower colon or rectum to heal after surgery. About 15 percent of colorectal cancer
            patients require a permanent colostomy.
        n   Chemotherapy is the use of anticancer drugs to kill cancer cells. Chemotherapy may be given
            to destroy any cancerous cells that may remain in the body after surgery, to control tumour
            growth, or to relieve symptoms of the disease. Chemotherapy is a systemic therapy, meaning
            that the drugs enter the bloodstream and travel through the body. Most anticancer drugs are
            given by injection directly into a vein (IV) or by means of a catheter, a thin tube that is placed
            into a large vein and remains there as long as it is needed. Some anticancer drugs are given in
            the form of a pill.
        n   Radiation therapy, also called radiotherapy, involves the use of high energy x-rays to kill
            cancer cells. Radiation therapy is a local therapy, meaning that it affects the cancer cells only
            in the treated area. Most often it is used in patients whose cancer is in the rectum. Doctors
            may use radiation therapy before surgery (to shrink a tumour so that it is easier to remove) or
            after surgery (to destroy any cancer cells that remain in the treated area). Radiation therapy is
            also used to relieve symptoms. The radiation may come from a machine (external radiation) or
            from an implant (a small container of radioactive material) placed directly into or near the
            tumour (internal radiation). Some patients have both kinds of radiation therapy.




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                              13 INFORMATION FOR DISCUSSION




       The importance of follow up care
       Follow up care after treatment for colorectal cancer is important. Regular check-ups ensure that
       changes in health are noticed. If the cancer returns or a new cancer develops, it can be treated as
       soon as possible. Check-ups may include a physical exam, a blood test, a colonoscopy, chest x-
       rays, and laboratory tests. Between scheduled check-ups, a person who has had colorectal cancer
       should report any health problems to the doctor as soon as they appear.

13.2   SOURCES OF FURTHER INFORMATION FOR PATIENTS AND CARERS
       British Colostomy Association
       15 Station Road, Reading, Berkshire RG1 1LG.
       Tel: 0118 939 1537 Helpline: 0800 328 4257
       www.bcass.org.uk
       The British Colostomy Association is the national registered charity which represents the
       interests of people with a colostomy and which provides support, reassurance and practical
       information to anyone who has had, or is about to have, a colostomy.
       CancerBACUP Scotland
       Suite 2, 3rd Floor, Cranston House, 104-114 Argyll Street, Glasgow, G2 8BH.
       Tel: 0808 800 1234 (Freephone) or 0141 223 7676
       www.cancerbacup.org.uk
       CancerBACUP offers a free cancer information service staffed by qualified and experienced
       cancer nurses. There are a growing number of CancerBACUP local centres in hospitals up and
       down the country, also staffed by specialist cancer nurses.
       Cancer Research UK
       P.O. Box 123, Lincoln’s Inn Fields, London WC2A 3PX.
       Tel: 020 7242 0200
       www.cancerresearchuk.org
       Cancer Research UK is a new charity which was formed in 2002 as a result of the merger
       between The Cancer Research Campaign and Imperial Cancer Research Fund. Cancer Research
       UK is the largest volunteer-funded cancer research organisation in the world.
       Colon Cancer Concern
       9 Rickett Street, London, SW6 1RU.
       Tel: 020 7381 9711, Infoline: 08708 50 50 50
       www.coloncancer.org.uk
       The Ileostomy and Internal Pouch Support Group
       Peverill House,1-5 Mill Road, Ballyclare, Co. Antrim, BT39 9DR.
       Freephone: 0800 018 4724
       www.ileostomypouch.demon.co.uk
       Lynn’s Bowel Cancer Campaign
       5 St. Georges Road, St. Margarets, Twickenham, TW11QS.
       Tel: 020 8891 5937, Fax: 030 8744 2266
       www.bowelcancer.tv, Email: lynn@bowelcancer.tv
       Charity set up by TV presenter Lynn Faulds Wood to raise funds and increase awareness of
       bowel cancer.
       Macmillan Cancer Relief Scotland
       9 Castle Terrace, Edinburgh, EH1 2DP.
       Tel: 0131 229 3276
       www.macmillan.org.uk
       Macmillan Cancer Relief is a UK charity supporting people with cancer and their families with
       specialist information, treatment and care.




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         Marie Curie Cancer Care Scotland
         29 Albany Street Edinburgh, EH1 3QN.
         Tel: 0131 456 3700
         www.mariecurie.org.uk
         Marie Curie Cancer Care is dedicated to the cure of people affected by cancer and the
         enhancement of their quality of life through its caring services, research and education.

  13.3   SOURCES OF FURTHER INFORMATION FOR HEALTH PROFESSIONALS
         CancerIndex
         www.cancerindex.org
         This non-profit guide contains over 100 pages and more than 4,000 links to cancer related
         information.




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                                        14 DEVELOPMENT OF THE GUIDELINE




14     Development of the guideline
14.1   INTRODUCTION
       SIGN is a collaborative network of clinicians, other health care professionals, and patient
       organisations, funded by the Scottish Executive Health Department. SIGN guidelines are developed
       by multidisciplinary groups of practising clinicians using a standard methodology based on a
       systematic review of the evidence. Further details about SIGN and the guideline development
       methodology are contained in “SIGN 50: A guideline developer’s handbook”, available at
       www.sign.ac.uk

14.2   THE GUIDELINE DEVELOPMENT GROUP

       Professor Robert Steele       Professor of Surgical Oncology, Ninewells Hospital, Dundee
       (Chairman)
       Mr John Anderson              Consultant Colorectal Surgeon, Glasgow Royal Infirmary
       Dr David Brewster             Director of Cancer Registration in Scotland,
                                     Information & Statistics Division
       Professor Frank Carey         Consultant Pathologist, Ninewells Hospital, Dundee
       Mr Andrew Denholm             Patient Representative, Inverness
       Dr Simon Dover                Consultant Physician and Gastroenterologist,
                                     Gartnavel Hospital, Glasgow
       Dr John Drummond              General Practitioner, Ayrshire
       Dr Ewan Forrest               Consultant Gastroenterologist, Victoria Infirmary, Glasgow
       Dr David Goudie               Geneticist, Ninewells Hospital, Dundee
       Dr Tim Habeshaw               Consultant in Clinical Oncology,
                                     Beatson Oncology Centre, Glasgow
       Dr Duncan Jodrell             Reader in Oncology, Western General Hospital, Edinburgh
       Ms Gillian Knowles            Clinical Nurse Specialist, Western General Hospital, Edinburgh
       Ms Amy Leslie                 Surgical Research Fellow, Ninewells Hospital, Dundee
       Dr Pamela Levack              MacMillan Consultant in Palliative Medicine,
                                     Ninewells Hospital & Roxburghe House, Dundee.
       Professor Julian Little       Professor of Epidemiology, Department of Medicine
                                     and Therapeutics, University of Aberdeen
       Ms Jill Macintyre             Principal Pharmacist in Oncology,
                                     Western General Hospital, Edinburgh
       Dr James MacKenzie            General Practitioner, Glasgow
       Mrs Grace MacLeod             Cancer BACUP, Glasgow
       Professor Alastair Munro      Consultant Oncologist, Ninewells Hospital, Dundee
       Dr Moray Nairn                Programme Manager, SIGN
       Dr Mary Porteous              Consultant Clinical Geneticist,
                                     Western General Hospital, Edinburgh
       Dr Vicky Save                 Lecturer in Pathology, Ninewells Hospital, Dundee
       Mr Duncan Service             Information Officer, SIGN
       Mrs Sandra Teo                Patient representative, Biggar
       Ms Joanne Topalian            Programme Manager, SIGN
       Dr Ramsay Vallance            Consultant Radiologist, Gartnavel General Hospital, Glasgow
       The membership of the guideline development group was confirmed following consultation with
       the member organisations of SIGN. Declarations of interests were made by all members of the
       guideline development group. Further details are available from the SIGN Executive.




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  14.3     SYSTEMATIC LITERATURE REVIEW
           The evidence base for this guideline was synthesised in accordance with SIGN methodology. A
           systematic review of the literature was carried out using an explicit search strategy devised by the
           SIGN Information Officer in collaboration with members of the guideline development group.
           The search for systematic reviews and meta-analyses covered the Cochrane Library, MEDLINE,
           EMBASE, CINAHL and HEALTHSTAR databases, and the internet, from January 1990 to January
           2001. The search for randomised controlled trials, cohort studies, case control studies, and cross-
           sectional surveys covered the Cochrane Library, MEDLINE, PUBMED, EMBASE, CANCERLIT and
           CINAHL databases, and the internet, from January 1993 to January 2001. The evidence base was
           updated during the course of development of the guideline, and the search was supplemented by
           reviewing references identified from papers from the searches and from personal databases of the
           guideline development group members. The MEDLINE version of the search strategies used can be
           viewed on the SIGN website.

  14.4     CONSULTATION AND PEER REVIEW

  14.4.1   NATIONAL OPEN MEETING
           A national open meeting is the main consultative phase of SIGN guideline development, at which
           the guideline development group present their draft recommendations for the first time. The
           national open meeting for this guideline was held on 9 October 2001 and was attended by around
           250 representatives of all the key specialties relevant to the guideline. The draft guideline was also
           available on the SIGN web site for a limited period at this stage to allow those unable to attend
           the meeting to contribute to the development of the guideline.

  14.4.2   SPECIALIST REVIEW
           The guideline was also reviewed in draft form by a panel of independent expert referees, who were
           asked to comment primarily on the comprehensiveness and accuracy of interpretation of the
           evidence base supporting the recommendations in the guideline. SIGN is very grateful to all of
           these experts for their contribution to this guideline.
           Professor Clive Bartram         Consultant Gastrointestinal Radiologist, Harrow
           Mr Ian Finlay                   Consultant in General Surgery, Glasgow Royal Infirmary
           Professor Neva Haites           Professor of Medical Genetics, Aberdeen
           Ms Cathy Hutchison              Consultant Nurse: Cancer, Glasgow
           Professor Zygmunt Krukowski     Consultant in General Surgery, Aberdeen
           Dr Catriona McLean              Senior Registrar: Radiotherapy, Edinburgh
           Dr Allan Merry                  General Practitioner, Ardrossan
           Mr Patrick O’Kelly              Consultant Colorectal Surgeon, Aberdeen Royal Infirmary
           Dr Fat Wui Poon                 Consultant Gastrointestinal Radiologist, Glasgow
           Dr Leslie Samuel                Consultant in Clinical Oncology, Aberdeen

  14.4.3   SIGN EDITORIAL GROUP
           As a final quality control check, the guideline is reviewed by an Editorial Group comprising the
           relevant specialty representatives on SIGN Council to ensure that the peer reviewers’ comments
           have been addressed adequately and that any risk of bias in the guideline development process as
           a whole has been minimised. The Editorial Group for this guideline was as follows:
           Dr Doreen Campbell              Clinical Resource and Audit Group
           Professor Peter Donnelly        Academy of Medicine
           Mr Douglas Harper               Royal College of Surgeons, Edinburgh
           Professor Gordon Lowe           Chairman of SIGN
           Dr Grahame Howard               Royal College of Radiologists, Faculty of Oncology
           Ms Hilary Hood                  Allied Health Professional
           Dr Safia Qureshi                Programme Director, SIGN
           Dr Joanna Wardlaw               Royal College of Radiologists, Faculty of Radiology
           Dr Peter Wimpenny               School of Nursing and Midwifery
           Each member of the guideline development group then approved the final guideline for publication.


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Annex 1
TNM (TUMOUR, NODE, METASTASIS) STAGING

 T     Primary Tumour

 TX    Primary tumour cannot be assessed
 T0    No evidence of primary tumour
 Tis   Carcinoma in situ1
 T1    Tumour invades submucosa.
 T2    Tumour invades muscularis propria.
 T3    Tumour invades through the muscularis propria into the subserosa, or into the non-
       peritonealised pericolic or perirectal tissues.
 T4    Tumour directly invades other organs or structures, and/or perforates visceral
       peritoneum.2,3
 N     Regional Lymph Nodes

 NX Regional lymph nodes cannot be assessed (eg previously removed)
 N0 No regional lymph node metastasis.
 N1 Metastasis in 1 to 3 regional lymph nodes.
 N2 Metastasis in 4 or more regional lymph nodes.
 M     Distant Metastates

 MX Distant metastasis cannot be assessed
 M0 No distant metastasis.
 M1 Distant metastasis present.

DUKES’ STAGING

A      Limited to the submucosa
B1     Tumor invades into but not through the muscularis propria, no lymph node involvement
B2     Tumor invades through the muscularis propria, no lymph node involvement
B3     Tumor directly invades other organs or structures (added)
C1     Regional lymph nodes involved
C2     Metastases present in nodes at mesenteric artery ligature (apical nodes)
D      Distant spread




 1
   Tis includes cancer cells confined within the glandular basement membrane (intraepithelial) or lamina propria
 (intramucosal) with no extension through muscularis mucosae into the submucosa
 2
  Direct invasion in T4 includes invasion of other segments of the colorectum by way of the serosa, eg invasion
 of the sigmoid colon by a carcinoma of the caecum.
 3
   Tumour that is adherent to other organs or structures, macroscopically, is classified T4. However, if no tumour
 is present in the adhesion, microscopically, the classification should be pT3.




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  Abbreviations
        5-FU        Fluorouracil
        ASI         Active specific immunotherapy
        BMI         Body Mass Index
        CEA         Carcinoembryonic antigen
        CHD         Coronary heart disease
        CI          Confidence interval
        CNS         Clinical nurse specialist
        CRC         Colorectal cancer
        CRM         Circumferential resection margin
        CRT         Chemotherapy synchronous with radiotherapy
        CSBS        Clinical Standards Board for Scotland
        CT          Computed tomography
        FAP         Familial adenomatous polyposis
        FOBT        Faecal occult blood testing
        FUFA        Fluorouracil and folinic acid
        GP          General Practitioner
        HNPCC       Hereditary non-polyposis colorectal cancer
        HRT         Hormone replacement therapy
        IV          Intravenous
        MDT         Multidisciplinary team
        MSI         Microsatellite instability
        NNH         Number Needed to Harm
        NNT         Number Needed to Treat
        NSAID       Non-steroidal anti-inflammatory drug
        OC          Oral contraceptive
        QUASAR      QUick And Simple And Reliable trial
        RCT         Randomised controlled trial
        SCIU        Scottish Cancer Intelligence Unit
        SIGN        Scottish Intercollegiate Guidelines Network
        TME         Total mesorectal excision
        TNM         Tumour, node, metastasis staging system
        UFT         Tegafur/uracil
        WHO         World Health Organisation




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  182   Hoff PM, Ansari R, Batist G, Cox J, Kocha W, Kuperminc M, et al. Comparison                comparison of continuous infusion fluorouracil with a conventional bolus
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  184   Munro AJ, Bentley AHM. Adjuvant radiotherapy in operable rectal cancer: a                  J Clin Oncol 1997;15:808-15.
        systematic review. Semin Colon Rectal Surg 2002;13:31-42.                            208   Zalcberg J. Overview of the tolerability of ‘Tomudex’ (raltitrexed): collective
  185   Improved survival with preoperative radiotherapy in resectable rectal cancer.              clinical experience in advanced colorectal cancer. Anticancer Drugs
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  186   Dahlberg M, Glimelius B, Graf W, Pahlman L. Preoperative irradiation affects         209   Cunningham D. Mature results from three large controlled studies with
        functional results after surgery for rectal cancer: results from a randomized              raltitrexed (‘Tomudex’). Br J Cancer 1998;77:15-21.
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  188   Cedermark B, Johansson H, Rutqvist LE, Wilking N. The Stockholm I trial of                 cancer [abstract]. ASCO Abstracts 1999;18:Abstract 2220.
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                                                                                                                                                                                  47
                                                                             http://chn-health.com
                                                  CHEMOTHERAPY AND RADIOTHERAPY                                                                                          FOLLOW UP OF PATIENTS TREATED FOR COLORECTAL CANCER

þ Chemotherapy and radiotherapy should be prescribed, dispensed, administered and supervised in a safe and effective manner in accordance with                           A   Patients who have undergone curative resection for colorectal
    the Joint Collegiate Council for Oncology guidelines and Scottish Executive advice.                                                                                      cancer should undergo formal follow up in order to facilitate the
                                                                                                                                                                             early detection of metastatic disease.
þ It is essential that the pros and cons of intervention be discussed carefully with the patient so that each individual can make an informed choice that
    is consistent with their wishes and personal circumstances.                                                                                                          PALLIATIVE CARE & SYMPTOMS OF ADVANCED DISEASE
                                                                                                                                                                         þ § Patients with advanced colorectal cancer whose physical or
 ADJUVANT CHEMOTHERAPY                                                          FIRST LINE CHEMOTHERAPY REGIMEN                                                                 emotional symptoms are difficult to control should be referred to
                                                                                                                                                                                a specialist in palliative care without delay.
A    Patients with Dukes’ C tumours of the colon or rectum should be            A     Bolus 5-FU regimens are not recommended as routine first line
     considered for adjuvant chemotherapy.                                            chemotherapy for advanced disease.                                                     § As anorexia and weight loss are so distressing for the patient and
                                                                                                                                                                               their family, the issue of nutrition must be addressed.
A    Patients with Dukes’ B tumours of the colon or rectum should not           A     Outside a clinical trial, the choice of an appropriate regimen
     routinely be treated with adjuvant chemotherapy.                                 includes continuous infusional flourouracil (Lokich), FUFA infusion                D   Medical measures such as analgesics, anti emetics and anti-
                                                                                                                                                                             secretory drugs should be used alone or in combination to relieve
                                                                                      (de Gramont) or capecitabine.
                                                                                                                                                                             the symptoms of bowel obstruction.
A    The recommended adjuvant regimen in patients with Dukes’ C
     tumours is bolus fluorouracil and low-dose folinic acid (FUFA),            D     Raltitrexed is not recommended as a first line therapy but may be
                                                                                                                                                                         SOURCES OF FURTHER INFORMATION
     administered over five days every four weeks. The duration of                    considered as an alternative in those patients intolerant of 5-FU
     treatment should be six months.                                                  regimens or in whom 5-FU is contraindicated due to
                                                                                      cardiotoxicity.*                                                                   Beating Bowel Cancer
A    The addition of levamisole or interferon alfa to FUFA
                                                                                                                                                                         39 Crown Road, St, Margarets, Twickenham, Middlesex. TW1 3EJ.
     chemotherapy as adjuvant treatment is ineffective in colorectal
                                                                                COMBINATION CHEMOTHERAPY                                                                 Tel: 020 8892 5256
     cancer and should not be considered.
                                                                                                                                                                         www.bowelcancer.org
                                                                                þ     Until the balance between benefits and harms can be better defined,
                                                                                      there is no justification for the routine use of combination therapy as            British Colostomy Association
                                                                                      first-line treatment for all patients with metastatic colorectal cancer.           15 Station Road, Reading, Berkshire RG1 1LG.
 ADJUVANT RADIOTHERAPY                                                                                                                                                   Tel: 0118 939 1537 Helpline: 0800 328 4257
                                                                                      The decision should be made on an individual basis.
A    Preoperative radiotherapy, planned with three or four fields,                                                                                                       www.bcass.org.uk
     should be considered in patients with operable rectal cancer.              C     Initial combination chemotherapy, including oxaliplatin, should be
                                                                                                                                                                         CancerBACUP Scotland
                                                                                      considered in patients with inoperable hepatic metastases that
                                                                                                                                                                         Suite 2, 3rd Floor, Cranston House, 104-114 Argyll Street, Glasgow, G2 8BH.
þ    Postoperative radiotherapy, should be considered in patients with                might become resectable on treatment.
                                                                                                                                                                         Tel: 0808 800 1234 (Freephone) or 0141 223 7676
     rectal cancer who did not receive preoperative radiotherapy and                                                                                                     www.cancerbacup.org.uk
     who are at high risk of local recurrence.
                                                                                SECOND LINE CHEMOTHERAPY
                                                                                                                                                                         Cancer Research UK
C    When postoperative radiotherapy is indicated, a schedule of 45Gy           A     Carefully selected patients with good performance status, normal                   P.O. Box 123, Lincoln’s Inn Fields, London WC2A 3PX.
     in 25 fractions over five weeks is recommended. Patients should                  liver function tests and no evidence of gastrointestinal obstruction               Tel: 020 7242 0200
     not be treated with parallel opposed fields; a planned technique                 with metastatic colorectal cancer, who have progressive disease                    www.cancerresearchuk.org
     with three or four fields should be used.                                        despite treatment with 5FU/FA, should be considered for second                     Colon Cancer Concern
                                                                                      line treatment with irinotecan.                                                    9 Ricket Streett, London, SW6 1RU.
                                                                                                                                                                         Tel: 020 7381 9711, Infoline: 08708 50 50 50
 CHEMOTHERAPY SYNCHRONOUS WITH RADIOTHERAPY (CRT)                               RADIOTHERAPY FOR ADVANCED DISEASE                                                        www.coloncancer.org.uk
                                                                                                                                                                         The Ileostomy and Internal Pouch Support Group
C    Chemotherapy should be given synchronously with the                        C     Radiotherapy to convert inoperable rectal cancer into operable
                                                                                      disease should be combined with chemotherapy. Suitable regimens                    Peverill House,1-5 Mill Road, Ballyclare, Co. Antrim, BT39 9DR.
     radiotherapy using one of the following three regimens:
                                                                                      include intermittent infusional 5FU/FA (Bosset), continuously                      Freephone: 0800 018 4724
     § intermittently infused FUFA (Bosset);                                                                                                                             www.ileostomypouch.demon.co.uk
                                                                                      infused 5FU (Lokich) or bolus 5FU/FA.
     § continuous flourouracil (Lokich) or
                                                                                                                                                                         Macmillan Cancer Relief Scotland
     § bolus FUFA.                                                              D     Palliative radiotherapy should be considered for patients who have
                                                                                                                                                                         9 Castle Terrace, Edinburgh, EH1 2DP.
                                                                                      distressing pelvic symptoms from rectal cancer.
                                                                                                                                                                         Tel: 0131 229 3276
                                                                                                                                                                         www.macmillan.org.uk
                                                                                    * Although as efficacious as alternative regimens, raltitrexed is associated
 CHEMOTHERAPY FOR METASTATIC DISEASE                                                with significantly greater toxicity and its benefit to patients who are intolerant   Marie Curie Cancer Care Scotland
                                                                                    to 5FU or with coronary heart disease should be carefully weighted against           29 Albany Street Edinburgh, EH1 3QN.
A    All patients with metastatic colorectal cancer should be                       the potential harms. This recommendation differs from the HTBS comment
                                                                                                                                                                         Tel: 0131 456 3700
     considered for chemotherapy.                                                   on the NICE appraisal (March 2002) which recommends that the use of
                                                                                                                                                                         www.mariecurie.org.uk
                                                                                    raltitrexed is restricted to clinical studies.
                                                                            http://chn-health.com
    67
                                                                    MANAGEMENT OF COLORECTAL CANCER                                                                                   Quick Reference Guide

PREVENTION                                                                   PRIMARY CARE AND REFERRAL                                                                               SURGERY
    Lifestyle factors are associated with reduced risk of colon cancer      C   Patients over the age of 50 years with any of the following            PREOPERATIVE STAGING AND PREVENTATION
    and the population of Scotland should be encouraged:                        symptoms over a period of six weeks should be urgently and
                                                                                appropriately investigated:                                            B   § All patients undergoing elective surgery for colorectal cancer
B   § to take at least 30 minutes of physical activity (such as                                                                                              should have preoperative imaging of the liver and chest.
      brisk walking) on most days                                               § rectal bleeding with a change in bowel habit to looseness or
                                                                                  increased frequency                                                      § In patients requiring emergency surgery intraoperative liver
B   § to maintain a Body Mass Index of 18.5-25 kg/m2                                                                                                         ultrasound or postoperative imaging is acceptable.
    § to eat five or more portions of fruits and vegetables a day               § rectal bleeding without anal symptoms
C
B   § not to smoke.                                                             § palpable abdominal or rectal mass                                    C   Complete colonic examination by colonoscopy, CT pneumocolon
                                                                                                                                                           or barium enema should be carried out, ideally preoperatively, in
                                                                                § intestinal obstruction.
                                                                                                                                                           patients with colorectal cancer.
B   The use of hormone replacement therapy specifically to prevent
    colorectal cancer is not recommended.                                   C   All patients with iron-deficiency anaemia (Hb<11g/dl in men or         A   Patients undergoing surgery for colorectal cancer should have:
                                                                                <10g/dl in postmenopausal women) without overt cause should be
                                                                                                                                                           § venous thomboembolism prophylaxis,
                                                                                thoroughly investigated for colorectal cancer.
                                                                                                                                                           § antibiotic prophylaxis consisting of a single dose of antibiotics
                                                                            D   § Patient groups at risk of colorectal cancer, especially those over         providing both aerobic and anaerobic cover given within 30
SCREENING
                                                                                  50 years of age, should be informed about significant symptoms             minutes of induction of anaesthesia.
D   § Patients with left-sided colitis or pancolitis of 10 years duration         and encouraged to seek medical attention early should they
      should undergo three yearly colonoscopy with mucosal biopsies               develop such symptoms.                                               SURGICAL TECHNIQUES
      and biopsy of any suspicious lesions.                                     § GPs should perform a thorough abdominal and rectal                   B   Mesorectal excision is recommended for most rectal cancers
    § Patients who have undergone colonoscopic polypectomy for                    examination on all patients with symptoms suspicious of                  where the patient is fit for radical surgery. The excision should be
      adenomas should be offered follow up colonoscopy.                           colorectal cancer.                                                       total for tumours of the middle and lower thirds of the rectum,
                                                                                § Patients presenting with suspicious symptoms or signs should be          preserving the pelvic autonomic nerves wherever possible.
                                                                                  urgently investigated and referred to a surgical unit with a
                                                                                  declared interest in colorectal cancer.                              þ Where a resectable organ, is involved by the primary tumour careful
                                                                                                                                                           consideration should be given to removal (partial or total as
IMPACT ON PATIENTS AND THEIR FAMILIES                                                                                                                      appropriate) of that organ.
                                                                             DIAGNOSIS
D   Information about local support services should be made available                                                                                  C   With a low rectal anastomosis:
    to both the patient and their relatives.                                D   Colonoscopy is recommended as a very sensitive method of                   § consider giving a defunctioning stoma
                                                                                diagnosing colorectal cancer, enabling biopsy and polypectomy.
                                                                                                                                                           § after TME, consider a colopouch.
þ   Clear follow up arrangements to see specialists should be made and
    explained as waiting and uncertainty add to distress.                   B   Double contrast barium enema may be employed as a sensitive,           C   Further surgery for pedunculated polyp cancers is indicated if:
                                                                                safe alternative to colonoscopy. It should be combined with
                                                                                                                                                           § there is histological evidence of tumour at, or within 1 mm of,
B   Clinicians must be aware of the potential for physical,                     flexible sigmoidoscopy when the sigmoid colon is not well
                                                                                                                                                             the resection margin;
    psychological, social and sexual problems after all colorectal              visualised.
    cancer surgery, including sphincter-saving operations.                                                                                                 § there is lymphovascular invasion;
                                                                            D   Where the radiological expertise and equipment exist, a CT
                                                                                                                                                           § the invasive tumour is poorly differentiated.
                                                                                pneumocolon is recommended as a sensitive test for colorectal
D   Patients should be given clear information about the potential risks
                                                                                cancer.
    and benefits of treatment, in order that they can make choices.                                                                                    C   Patients with malignant obstruction of the large bowel should be
                                                                                                                                                           considered for immediate resection.
þ   § Severe physical symptoms should be addressed before patients           GENETICS                                                                  A   If immediate reconstruction after resection is feasible, segmental
      are asked to make complex treatment choices.                                                                                                         resection is preferred for left-sided lesions.
    § All patients should have access at diagnosis to a clinical nurse      C   A three generation family history should be taken from all
      specialist for support, advice and information.                           individuals with colorectal cancer.                                    D   Where facilities and expertise are available, colonic stenting
                                                                                                                                                           should be considered.
                                                                            D   Individuals at moderate risk of developing colorectal cancer on the
þ   All patients who may require stoma formation (permanent or
                                                                                basis of their family history should be offered a single colonoscopy
    temporary) should be referred and assessed by a stoma nurse                                                                                        SPECILISATION AND WORK LOAD
                                                                                at 30-35 years and again at 55 years.
    specialist before admission to hospital.
                                                                                                                                                       B   Surgery for colorectal cancer should only be carried out by
                                                                            C   Referral of individuals with a high risk of developing colorectal          appropriately trained surgeons whose work is audited. Low rectal
                                                                                cancer should be made to the local clinical genetic service for            cancer surgery should only be performed by those trained to carry
                                                                                consideration of mismatch repair gene mutation analysis.                   out TME.

								
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