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http://chn-health.com 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. 1 http://chn-health.com MANAGEMENT OF COLORECTAL CANCER 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 patients 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 2 http://chn-health.com 2 PREVENTION AND SCREENING 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. 3 http://chn-health.com MANAGEMENT OF COLORECTAL CANCER 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 4 http://chn-health.com 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. 5 http://chn-health.com MANAGEMENT OF COLORECTAL CANCER 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, Crohns 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. 6 http://chn-health.com 2 PREVENTION AND SCREENING 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. 7 http://chn-health.com MANAGEMENT OF COLORECTAL CANCER 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 8 http://chn-health.com 3 THE IMPACT OF COLORECTAL CANCER ON PATIENTS AND THEIR FAMILIES 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. 9 http://chn-health.com MANAGEMENT OF COLORECTAL CANCER 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 Groups 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 10 http://chn-health.com 4 GENETICS 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. 11 http://chn-health.com MANAGEMENT OF COLORECTAL CANCER 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 patients 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. 12 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 patients 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. 13 http://chn-health.com MANAGEMENT OF COLORECTAL CANCER 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. 14 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. 15 http://chn-health.com MANAGEMENT OF COLORECTAL CANCER 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. 16 http://chn-health.com 7 SURGERY 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 patients 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. 17 http://chn-health.com MANAGEMENT OF COLORECTAL CANCER þ The decision to use bowel preparation must be individualised according to the patients need and the surgeons 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 18 http://chn-health.com 7 SURGERY 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 Hartmanns 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. 19 http://chn-health.com MANAGEMENT OF COLORECTAL CANCER 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. 20 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. 21 http://chn-health.com MANAGEMENT OF COLORECTAL CANCER 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. 22 http://chn-health.com AND RADIOTHERAPY 9 CHEMOTHERAPY 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. 23 http://chn-health.com MANAGEMENT OF COLORECTAL CANCER 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. 24 http://chn-health.com AND RADIOTHERAPY 9 CHEMOTHERAPY 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. 25 http://chn-health.com MANAGEMENT OF COLORECTAL CANCER 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 26 http://chn-health.com AND RADIOTHERAPY 9 CHEMOTHERAPY 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. 27 http://chn-health.com MANAGEMENT OF COLORECTAL CANCER 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. 28 http://chn-health.com AND RADIOTHERAPY 9 CHEMOTHERAPY 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 patients 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 patients 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. 29 http://chn-health.com MANAGEMENT OF COLORECTAL CANCER 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. 30 http://chn-health.com IN ADVANCED DISEASE 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. 31 http://chn-health.com MANAGEMENT OF COLORECTAL CANCER 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. 32 http://chn-health.com 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 33 http://chn-health.com MANAGEMENT OF COLORECTAL CANCER 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. 34 http://chn-health.com WITH PATIENTS AND CARERS 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 bodys 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 persons 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 persons 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 persons chance of developing colorectal cancer. 35 http://chn-health.com MANAGEMENT OF COLORECTAL CANCER 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 persons 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 patients 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. 36 http://chn-health.com WITH PATIENTS AND CARERS 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, Lincolns 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 Lynns Bowel Cancer Campaign 5 St. Georges Road, St. Margarets, Twickenham, TW11QS. Tel: 020 8891 5937, Fax: 030 8744 2266 www.bowelcancer.tv, Email: email@example.com 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. 37 http://chn-health.com MANAGEMENT OF COLORECTAL CANCER 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. 38 http://chn-health.com 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 developers 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. 39 http://chn-health.com MANAGEMENT OF COLORECTAL CANCER 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 OKelly 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. 40 http://chn-health.com ANNEX 1 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. 41 http://chn-health.com MANAGEMENT OF COLORECTAL CANCER 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 42 http://chn-health.com REFERENCES References 29 Towler B, Irwig L, Glasziou P, Kewenter J, Weller D, Silagy C. 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Am J Clin Oncol 2001;24:107-12. 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, Lincolns 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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