Preface by F.H. Menko, MD, PhD, consultant clinical geneticist (chairman) and Prof. N. Hoogerbrugge, MD, PhD, internist (vice-chairperson)
There is no doubt that new insights in clinical and molecular genetics are of great importance to the prevention of disease and death as a result of hereditary and familial colorectal cancer. Syndromes, which could only be defined in the past on the basis of their clinical picture and the pattern with which they occurred in the family, can now be regrouped on the basis of genetic studies of tumours and blood tests for pathogenic mutations. Application of these techniques enables better advice to be provided for treatment and follow-up of patients with colorectal cancer and for preventative measures in family members. For example, all patients under the age of 50 years found to have colorectal cancer are eligible for genetic diagnostics.
The guideline Hereditary Colorectal Cancer is intended to incorporate the new genetic techniques in health care in a careful and easy manner, and to make optimal use of techniques for early detection and treatment.
In doing so, an important issue is the multidisciplinary character of patient care. In the area of oncology, the surgeon, internist, gastroenterologist and radiotherapist have already been working together for a long time to decide on optimal management for cancer patients. However, genetics is also playing an increasing role in decision making for the cancer patient. Pathological examination of tumours not only leads to a histological diagnosis, but also, on the basis of genetic markers, to knowledge regarding the manner in which tumours have originated and their biological behaviour. Clinical geneticists are increasingly becoming involved in the diagnostics of patients with cancer and risk counseling for relatives The general practitioner is also receiving many questions about this topic. This has made the terrain of multidisciplinary care more complex.
The brief outline above was the basis for development of the evidence-based guideline before you. Evidence-based means that the evidence available in literature for a particular policy was weighed and that substantiated advice was subsequently formulated by the working group. It is the overview of literature information, followed by the considerations made within the working group, which need to provide the reader with clarity regarding the basis of the advice provided.
We hope that the guideline can be put to good use in practice. To facilitate further consultation, a list of addresses and telephone numbers of centres, organisations and associations (see appendix 8)) with specific expertise in the area of hereditary tumours is included.
We would appreciate any comments and suggestions.
Introduction With respect to incidence, colorectal carcinoma (CRC) is the third most common carcinoma in men (after lung and prostate carcinoma), with over 5,100 patients per year, and the second most common in women (after mammary carcinoma), with over 4,700 patients per year. Diagnostics, treatment and follow-up of colorectal carcinoma take place in general, university as well as in specialised hospitals.
The risk of CRC for the general population in the Netherlands can be found in table below. Cumulative risk of colorectal carcinoma by age and gender
Approximately 5% of all cases of CRC are genetically determined. While hereditary tumours form a relatively small section of all cases of CRC, this guideline nonetheless refers to a large groups of patients for several reasons. Firstly, there is a high frequency of CRC, so that 5% represents a large number of patients and family members. However, more important is the fact that the question of hereditary predisposition arises in approximately 15 - 20% of all cases of CRC, due to the young age at which the diagnosis is made (< 50 years old) and/or a positive family history for colorectal cancer. In 'familial colorectal carcinoma' there is also an increased chance of healthy relatives developing the disorder. Finally, a large group of patients is being monitored as a result of adenomatous colorectal polyps; colorectal carcinoma generally develops from the preliminary stage of an adenomatous polyp. Both adenomatous polyps and colorectal carcinoma occur in families.
All in all, many general practitioners, gastroenterologists and clinical geneticists receive questions about hereditary and familial colorectal carcinoma.
Oncogenetics and multidisciplinary care
There were around 16,000 requests for genetic counselling in the Netherlands in 2003. Almost 40% of these were in the category hereditary tumours. The majority of questions were about breast cancer and colorectal carcinoma 252. Oncogenetics covers a large part of clinical-genetic care. This care consists of diagnostics (family studies, DNA diagnostics) and patient information regarding the risk of tumours.
Patients with an hereditary predisposition to tumours require multidisciplinary care. The expertise of the clinical genetic centre is needed for family research, DNA diagnostics and risk counseling . The expertise of treating specialisms is required for the treatment and prevention (surveillance, prophylactic surgery).
Syndromes CRC is the collective term for a group of disorders, which are heterogeneous in relation to causative factors, biological behaviour, prognosis and sensitivity to various treatment modalities. 'Hereditary colorectal cancer' is also the collective term for a number of subgroups. This guideline looks at three main syndromes: Lynch syndrome (hereditary non-polyposis CRC), familial (non-polyposis) CRC and hereditary CRC with adenomatous polyposis (FAP/AFAP and MAP: as a result of APC and MUTYH mutations, respectively).
A number of other subgroups are not covered: rare hereditary disorders with an increased risk of CRC, accompanied by hamartomatous polyposis (Peutz-Jeghers syndrome, juvenile polyposis), hyperplastic polyposis and mixed polyposis. Diagnostic criteria for these syndromes can be found in the terminology list (see appendix 5). Hereditary syndromes with only a slight increase in risk of colorectal carcinoma, in which colorectal carcinoma is therefore only rarely the result of the disorder (such as with Li-Fraumeni syndrome due to TP53 mutations) are not covered in this guideline.
Terminology Terminology undergoes changes with increasing insight into syndromes. While this growing insight is of course very welcome, the changing terminology also makes the situation more complex. For example, the terminology for hereditary non-polyposis CRC has evolved from ‘cancer family syndrome' via ‘HNPCC (hereditary non-polyposis colorectal carcinoma)' and recenly to ‘Lynch syndrome' (after Henry T. Lynch, who described the syndrome) on the basis of germline mutations in DNA mismatch repair genes. It has recently become apparant that familial adenomatous polyposis (FAP) is not always an autosomal dominant syndrome caused by mutations in the APC gene; some of the patients have an autosomal recessive syndrome, caused by mutations in the MUTYH gene. As a result, the term MAP (MUTYH-associated polyposis) was introduced alongside FAP.
This guideline must do justice to this complex reality, but the working group also found it important that a distinction was only made where there were practical consequences associated with a division into different subgroups. The terminology in this guideline is therefore aimed at ease of use in practice.
Objective This guideline is a document with recommendations to support daily practice. The guideline is based on results of scientific research and opinions formed from these results, focused on determining good medical practice.
This guideline provides recommendations regarding diagnostics, treatment, follow-up, surveillance and prophylactic surgery in hereditary and familial colorectal cancer. The guideline also draws attention to psychosocial care and patient education. In addition, recommendations regarding the organisation of care are formulated in which attention is given to areas such as task division and the role of specialised centres. The guideline can be used to provide information to patients. The guideline also provides points of reference for, amongst other things, local protocols to advance implementation.
Colorectal carcinoma as example Hereditary colorectal cancer differs in some respects to other hereditary tumour syndromes. For example, there are excellent methods for prevention of illness in the case of a high risk of CRC. Moreover, the most common hereditary form, hereditary non-polyposis CRC (Lynch syndrome) can be recognised from genetic characteristics of the tumour. This provides the pathologist with an indication of hereditary illness when determining CRC using additional testing. In the near future, a scale of genetic characteristics will become known for CRC and other tumours, which are important for the biological behaviour of the tumour, the sensitivity for chemotherapy and radiotherapy and that are indicative of an hereditary cause. These developments make good alignment between participating specialisms of great importance. Therefore, providing details on this topic for hereditary CRC can also be of benefit for the development of guidelines for other hereditary tumours.
Target group The guideline is intended for all disciplines involved in care for patients with (a predisposition to) hereditary CRC, such as clinical geneticists, genetic counselors, pathologists, general practitioners, gastroenterologists, surgeons, internists, gynaecologists, paediatricians, nurses, psychologists, social workers and epidemiologists.
Clinical questions The clinical questions forming the basis of the various chapters of this guideline are enclosed as a separate appendix (see appendix 4). The guideline aims to provide an answer to the most pressing bottlenecks from the field and not to provide a complete overview of all aspects important to the diagnosis and treatment, as in a textbook.
Working group composition A multidisciplinary working group was set up to develop the guideline, consisting of 14 disciplines (see appendix 1). The patient organisation HNPCC Association (HNPCC Vereniging) and Polyposis Contact Group (Polyposis Contactgroep) participated in the working group.
The geographical distribution of the working group members was taken into account in composing the working group, focusing on a proportional representation of the different scientific associations, 'schools' and academic backgrounds. The working group members acted independently and received a mandate from their respective associations (see appendix 2).
Methods of the working group The working group worked on a concept guideline text for two years (12 meetings). The group started with an inventory of bottlenecks. A large number of specialists from different disciplines involved in hereditary intestinal cancers were asked about bottlenecks in relation to the content of the care, care organisation and care process. In addition, a couple of group gatherings were organised to learn from patients and family members (that were directly involved), which problems they were confronted with in practice. The inventory of bottlenecks was used to formulate clinical questions.
Given the amount of work involved, a number of subgroups were formed with representatives from relevant disciplines. Relevant literature was collected via systematic searches and 'reference checking'. The working group members have evaluated the literature on content and quality. The working group members subsequently formulated the texts, in which the evaluated literature was incorporated. These texts were discussed during meetings and, after comments were processed, agreed on.
Together, the eventual texts formed the concept guideline that was offered to all scientific associations in May 2007. People were also given the opportunity to comment on the guideline via the websites of the VIKC and the Dutch Institute for Health care Improvement CBO (Kwaliteitsinstituut voor de Gezondheidszorg CBO). The comments have been incorporated in the definitive version of the guideline.
Scientific argumentation The recommendations in this guideline are, as much as possible, based on evidence from published scientific research. The keywords used for the patient population are in (see appendix 3). Relevant articles were found by performing systematic searches in the Cochrane Library, Medline, Embase, Cinahl en PsychInfo. The time period used in the searches was 1993 to 2005 for most chapters; in some cases the search went back further in time. In addition, some recent articles were also included.
Articles were also selected from reference lists of articles that had already been found. Other guidelines on hereditary intestinal cancer were also consulted.
The articles were selected on the basis of the following criteria: predominantly English, German or Dutch publications, published as ‘full paper' (abstracts in exceptional cases) and study type.
Articles of moderate or poor quality were excluded. After this selection, the remaining articles served as basis for the conclusions in the guideline (as indicated in the relevant sections). The selected articles were subsequently graded according to the degree of evidence.
A description and evaluation of the different articles can be found in the different texts under the heading 'summary of the literature'. The literature has been summarised in a conclusion, showing the level of the relevant evidence.
Formulating the recommendations To formulate a recommendation for the field, aspects other than scientific evidence are often important, such as: patient preferences, availability of special techniques or expertise, organisational aspects, social consequences or costs. These aspects are discussed after the 'Conclusion'; the conclusion is placed within the context of daily practice and an assessment is made of the benefits and disadvantages of the different policy options. The ultimate recommendation formulated is the result of the available evidence in combination with these considerations.
The objective behind following this procedure and formulation of the guideline in this 'format' is to increase the transparency of the guideline. It allows efficient discussion to take place during working group meetings and furthermore increases clarity for the user of the guideline.
Implementation and evaluation Implementation of the guideline and the actual feasibility of the recommendations have been taken into consideration as much as possible in the different development phases of the guideline concept.
The guideline is available on http://www.oncoline.nl/index.php?language=nl. The summary card of the guideline will be distributed to all relevant professional groups and hospitals. A summary of the guideline will be offered for publishing in the Dutch Journal of Medicine (Nederlands Tijdschrift voor Geneeskunde). Attention will be given to the guideline in various specific professional magazines. The guideline will also appear in print.
In order to evaluate the effect of implementation of the recommendations in the guideline, indicators will be developed. An indicator is a measurable characteristic of health care with a signal function for (an aspect of) the quality of care. Indicators make it possible for health care providers to measure if the required care is being provided and to identify areas for improvement.
Health care providers responsible for patients and families with hereditary and familial intestinal cancer are seriously advised to implement this guideline in daily care. Protocols can be used at the local level. The indicators supplied can work in a supportive manner in evaluation and improvement of the total care of the patient.
Legal implications Guidelines are not legal requirements, but rather scientifically founded and widely accepted views and recommendations to which health care providers would have to adhere to provide quality care. Given guidelines are based on the 'average patient', care providers can deviate from the recommendations in the guideline in individual cases as required. Deviating from guidelines, if the situation of the patient requires it, is sometimes even necessary. However, when deviating from this guideline, it must be substantiated, documented and, where necessary, done in consultation with the patient.
Authorisation The guideline is authorised by the following associations (see appendix 11).
Revision In 2012 at the latest, the organisation commissioning the guideline/responsible organisation will determine if this guideline is still current. If required, a new working group will be established to revise the guideline. The validity of the guideline may cease at an earlier point in time if new developments arise that are cause for the revision process to commence.
Relationship to other guidelines STOET/ VKGN guideline
The Foundation for the Detection of Hereditary Tumours (Stichting Opsporing Erfelijke Tumoren, StOET) and the Working Group of Clinical Oncogenetics (Werkgroep Klinische Oncogenetica, WKO) of the VKGN have published a guideline booklet in 2001 on hereditary tumours, in which the tasks of the StOET and the Cancer family clinic were demarcated. A revised version in the form of a booklet was published in 2005. The latter guideline can be found at http://www.stoet.nl/ and via http://www.oncoline.nl/. The EBRO guideline Hereditary Intestinal Cancer, outlined here, replaces the StOET/VKGN guidelines of 2005 in relation to hereditary and familial intestinal cancer.
EBRO Guidelines colon and rectum carcinoma At the initiative of the National Working Group on Gastrointestinal Cancers (Landelijke Werkgroep Gastro-intestinale tumoren) of the VIKC, the diagnostics and treatment of patients with colon carcinoma and rectum carcinoma respectively, were included in 2007 in the EBRO guidelines. These guidelines concern sporadic colon carcinoma and rectal carcinoma.
EBRO Guideline Follow-up after polypectomy The EBRO Guideline Follow-up after polypectomy was published by the Netherlands Society of Gastroenterohepatology (Nederlands Genootschap van Maag-Darm-Leverartsen) in October 2000. The text can be found at http://www.cbo.nl/ and has been published in the Dutch Journal of Medicine (Nederlands Tijdschrift voor Geneeskunde 232.