Which kind of systemic therapy can be used in metastatic breast cancer?


Patients with a metastatic ER+ and/or PgR+ breast cancer are eligible for hormonal therapy. The choice of hormonal therapy is determined by the menopausal status of the patient and the toxicity profile of the therapy (see the below schedule).


In the case of rapid progression, and especially with visceral metastases, treatment with chemotherapy is preferable.


Chemotherapy is the treatment of choice if:

  • the hormone receptors are negative
  • hormonal therapy no longer appears to be effective
  • there is rapid disease progression
  • extensive and rapidly growing visceral metastases have developed (lung, liver, lymphangitis)
  • there is serious cytopaenia as a result of mass bone marrow metastasis


Anthracycline-containing schedules are the preferred primary treatment.


Liposomal doxorubicin may be considered with anthracycline pre-treatment.


After progression during first-line chemotherapy, there is no recommendation for an optimal choice of sequence for the subsequent lines of chemotherapy. The choice between a combination of cytostatic drugs, or sequential administration should be made on the basis of the remission rate, toxicity and quality of life.


Dose escalation should not be applied outside a research context.


In patients with a HER-2-positive metastatic breast cancer who have already received anthracycline-containing therapy, the combination trastuzumab with vinorelbine or a taxane (both paclitaxel and docetaxel) is preferable as first-line therapy.


In patients with a HER-2-positive metastatic breast cancer who develop trastuzumab resistance, continuing the HER-2 blockade in follow-up treatments is preferable to a follow-up treatment without HER-2 blockade.


In patients with a metastatic breast cancer with both hormone receptor and HER-2-overexpression, the combination of HER-2 blockade with hormonal therapy is preferable to hormonal treatment only.


When paclitaxel is chosen as first-line treatment, it is worthwhile to add bevacizumab to this therapy.



Level 1

For premenopausal patients with a metastatic, hormone receptor-positive breast cancer, the combination tamoxifen with LHRH in the first-line provides a longer disease-free survival than treatment with only one of the two.


A1        Klijn 2001


Level 1

For postmenopausal patients with a metastatic, hormone receptor-positive breast cancer, aromatase inhibitors (steroidal and non-steroidal) in the first-line provide a higher remission percentage and a   longer disease-free survival than tamoxifen.


A2        Bonneterre 2000, Mauri 2006, Mouridsen 2001, Nabholtz 2000, Paridaens 2004  


Level 3

The response rate with standard chemotherapy schedules as first-line treatment is approximately 40-60% with a median response duration of 8-12 months.


The response chance is greater and the response duration and time to progression is longer with use of   anthracycline-containing schedules compared to CMF chemotherapy, for example   [Bontenbal, 1998].


B          Bontenbal 1998


Level 1

Taxoids are less effective than an adequately dosed anthracycline.


The addition of a taxoid to an anthracycline-containing therapy does extend the progression-free interval, but not survival.


A1        Ghersi 2005, Piccart-Gebhart 2007


Level 3

Capecitabine has been found to be an effective agent after pre-treatment with anthracyclines and taxanes.


C          Ershler 2006


Level 1

The combination of two cytostatic drugs provides a higher response rate and longer progression-free interval than sequential treatment, but also more side-effects. Addition of a third drug leads to more   toxicity, but not a survival advantage.


A1        Carrick 2005, Jones 2006


Level 1

In patients with a metastatic breast cancer with HER-2-overexpression, the combination trastuzumab with an anthracycline or a taxane (both paclitaxel and docetaxel) as first-line therapy has been found to be more effective than monotherapy.


A2        Chan 2007, Marty 2005, Slamon 2001


Level 1

Addition of trastuzumab to taxanes or vinorelbine-containing chemotherapy in the first-line increases the remission rate and extends the progression-free interval and survival in patients with HER-2-positive tumours.


A2        Chan 2007, Marty 2005, Slamon 2001


Level 1

When trastuzumab resistance develops, continuing the HER-2 blockade in combination with subsequent treatment is more effective than subsequent treatment without HER-2 blockade.


A2        von Minckwitz 2009, Blackwell 2010


Level 1

Addition of HER-2 blockade to hormonal therapy improves the response, the progression-free survival and clinical benefit in patients with a hormone-receptor and HER-2-positive tumour.


A2        Kaufman 2009, Johnston 2009


Level 3

Addition of bevacizumab to weekly paclitaxel in the first-line is more effective than treatment with paclitaxel only. Bevacizumab extends the progression-free survival, with an increase in side effects;   there is no increase in survival.


B          Miller 2007

Literature summary

Hormonal therapy

Patients with a metastatic ER+ and/or PgR+ breast cancer are eligible for hormonal therapy. The clinical benefit (number of patients with response + stable disease) of first-line hormonal therapy varies from approximately 50% with ER+/PgR- tumours to approximately 70% with ER+/PgR+ tumours [Clark, 1988]. The median duration of the clinical benefit is 12-18 months, but can be extremely variable [Clark, 1988]. The response to hormonal therapy is sometimes slow, an observation period of 3 months or longer may be required to observe regression [Muss, 1994]. Patients with rapid disease progression or extensive visceral metastases are therefore usually primarily treated with chemotherapy. The choice of hormonal therapy depends on the menopausal status of the patient, the toxicity profile of the medication and the interval after adjuvant hormonal therapy [Falkson, 1991; Dickson, 2000]. The response rate is approximately the same for all hormonal treatments. A patient is eligible for second-line hormonal treatment if there is a response or stabilisation to first-line endocrine therapy. However, the response rate decreases by approximately 50% with each subsequent line [Klijn, 2001]. Hormonal therapy may also be considered as consolidation therapy after chemotherapy. The recommended sequence in hormonal manipulation of metastatic breast cancer is summarised in the schedule below . Phase III studies show that for  first-line therapy for postmenopausal patients, the aromatase inhibitors anastrozole, letrozole and exemestane are of increased value compared to tamoxifen [Bonneterre, 2000; Mouridsen, 2001; Nabholtz, 2000; Paridaens, 2004]. This increased  value consists of a higher response rate, a longer time to progression and a longer survival period and less thrombo-embolic complications. This increased  value is a reason to recommend aromatase inhibitors as first-line therapy in postmenopausal patients [Lonning, 2000; Mauri, 2006]. After failure of a non-steroidal aromatase inhibitor, a response may sometimes occur with the steroidal aromatase inhibitor exemestane [Paridaens, 2004]. In a randomised study, the anti-oestrogen fulvestrant (in a dose of 250  mg i.m./4 weeks) was found to be almost as effective as tamoxifen in the first line and as anastrozole in the second line [Gibson, 2007; Howell, 2004]. This agent also shows activity in the third or fourth line [Osborne 2002]. Since then, a higher dose (500 mg) and loading schedule has been found to enable a significantly longer time to progression to be achieved compared to the earlier standard dose of 250 mg [Di Leo, 2010]. The role of  progestatic agents compared to fulvestrant is not yet clear.


Hormonal therapy schedule

Hormonal line





Induction of postmenopausal status

(if LHRH, preferably combined with tamoxifen)

A: Non-steroidal aromatase inhibitors

B: Steroidal aromatase inhibitors**


Same as postmenopausal patients



If a postmenopausal status is achieved, combination/ treatment with aromatase inhibitors is possible

A: Steroidal aromatase inhibitors**

B: Non-steroidal aromatase inhibitors


Fulvestrant (500 mg per 4 weeks)

*      There is insufficient data on the optimal sequence of hormonal intervention in the third line. In exceptional situations, administration of pharmacological doses of oestrogens or androgens in the last instance may be considered

**     There are no studies that have demonstrated the superiority of steroidal versus non-steroidal aromatase inhibitors


Chemotherapy is the treatment of choice if:

  • the hormone receptors are negative
  • hormonal therapy no longer appears to be effective
  • there is rapid disease progression
  • extensive and rapidly growing visceral metastases have developed (lung, liver, lymphangitis)
  • there is serious pancytopaenia as a result of mass bone marrow metastasis


The response rate of  chemotherapy is comparable  with hormonal therapy, but is often associated with a more rapid effect. If breast cancer recurs more than 6-12 months after completing adjuvant chemotherapy, the same combination may be considered with a reasonable response rate, depending on the schedule used (caution with cumulative doses of anthracyclines: doxorubicin 450 mg/m2 and epirubicin 900 mg/m2), partly dependant on the age and comorbidity. In case of a recurrence within this period, it is advisable to apply another schedule. For patients with a tumour with HER-2-overexpression: see paragraph 9.2.3: Focused therapy.


Anthracyclines and taxanes, combinations and sequence

The response rate with the standard chemotherapy schedules as first-line treatment is approximately 40-60% with a median response duration of 8-12 months [Bontenbal, 1998]. First-line chemotherapy may consist of an anthracycline-containing schedule (FAC, FEC, AC, EC etc.) or taxanes (paclitaxel/docetaxel). The response chance is greater and the response duration and time to progression is longer in most studies with use of anthracycline-containing schedules compared to CMF chemotherapy, for example [Bontenbal, 1998].However, only a few studies have found that anthracycline-containing chemotherapy provides a survival advantage compared to CMF [Fossati, 1998].

There are nine studies that have compared an anthracycline + taxane-containing combination with a standard anthracycline-containing schedule, FEC or FAC, AC or EC [Biganzoli, 2002; Bontenbal, 2005; Jassem, 2001; Langley, 2005; Luck, 2000; Mackey, 2002; Nabholtz, 2003; Sledge, 2003; Tubiana-Hulin, 2003]. The anthracycline/paclitaxel combinations (five studies) are at least as effective as the standard anthracycline-containing schedules, with a trend to higher response percentages in the anthracycline/paclitaxel arm of the studies. One study shows a significant improvement in the time to progression and survival for the anthracycline/paclitaxel combination [Biganzoli, 2002; Jassem, 2001; Langley, 2005; Luck, 2000; Sledge, 2003]. Out of 4 studies that have compared an anthracycline/docetaxel schedule with standard, anthracycline-containing chemotherapy, it appears the combination anthracycline/docetaxel in all studies leads to significantly higher response percentages and in three studies also to a longer disease-free survival. Survival is longer in two studies with the anthracycline/docetaxel combination [Bontenbal, 2005; Mackey, 2002; Nabholtz, 2003; Tubiana-Hulin, 2003]. The combination anthracycline/docetaxel is therefore effective, but the difference in neutropenic fever with standard courses (20-30% vs 2-10%) means such a schedule cannot be applied without support with growth factors.

Sequential treatment with an anthracycline and a taxane has only been compared to a combination of both agents in a few randomised studies [Conte, 2004]. There was no difference in survival despite higher response percentages and a longer disease-free survival with combination therapy in one study. The meta-analyses concerning the efficacy of the anthracycline/taxane combinations versus standard chemotherapy schedules show that the combinations do lead to a longer progression-free survival, but there is no increase in total survival [Ghersi, 2005; Seidman, 2004; Piccart-Gebhart, 2007]. Studies with liposomal doxorubicin in the first-line have also been published since [GEBU, 2010].

Capecitabine has been found to be an effective agent after pre-treatment with anthracyclines and taxanes [Ershler, 2006]. A combination with docetaxel leads to a longer PFS and OS than with capecitabine alone [O’Shaughnessy, 2002]. This combination is currently being compared to the sequential application of both agents (NCT00415285). Docetaxel in combination with capecitabine was more effective than docetaxel with epirubicin, with a PFS of 12 vs 7 months, median survival 37 vs 27 months [Bachelot, 2009]. However, a combination of capecitabine with gemcitabine was found to be as effective but less toxic than capecitabine with docetaxel [Chan, 2009].


In summary:

  • Anthracyclines and taxanes are the most effective agents for metastatic breast cancer
  • Previous adjuvant therapy (time interval, cumulative dose anthracyclines), the requirement for a higher response rate and longer response duration versus more toxicity (combination versus sequential treatment) must be taken into account when choosing the first- and second-line chemotherapy.
  • Multiple studies have shown that a weekly chedule of paclitaxel is more effective than three-weekly administration Jones, 2005; Piccart-Gebhart, 2007; Sparano, 2007; Tabernero, 2004], while a three-weekly schedule of docetaxel is in fact more effective than a weekly regimen [Jones, 2005; Sparano, 2007].


Subsequent lines of chemotherapy

The choice of treatment schedule, sequence of treatment, combination or sequential

Patients with progression after an earlier response, who have been treated previously with an anthracycline/taxane, are eligible for renewed treatment, depending on the condition of the patient (performance status), treatment wishes, age and comorbidity. There is little to no comparative research between contemporary alternatives such as capecitabine [O’Shaughnessy, 2002; Seidman, 2002; Ershler, 2006], vinorelbine [Kerbrat, 2007; Ejlertsen, 2004], gemcitabine [Chan, 2005; Martin, 2007], (pegylated) liposomal doxorubicin (PLD) [Keller, 2004; O’Brien, 2004; Sparano, 2007; GEBU, 2010] or mitoxantrone [Namer, 2001]. There is therefore no recommended optimal choice or sequence. The response percentages and duration of the response to these agents after pre-treatment are usually limited [Seidman, 2002]. Capecitabine is usually chosen in the third-line (after anthracycline and taxane). When remission or a stable situation has been achieved, treatment can be continued after the first 6 courses, as long as it does not seriously affect the quality of life in a negative manner. However, usually no more than 6-9 courses are administered. The survival advantage of a combination is furthermore rarely compared with sequential application of the same agents, which usually results in less side-effects with a better quality of life [Carrick, 2005; Jones, 2006; Miles, 2002; Ershler, 2006]. Pleural fluid or ascites may cause delayed excretion of methotrexate through accumulation of the agent in this third space with an increase in mucositis and myelotoxicity.


Focused therapy

HER-2 blockade

10-15% of breast cancers display overexpression of HER-2 [Baselga 2000]. These patients are eligible for treatment with trastuzumab. In phase II studies, treatment with trastuzumab monotherapy resulted in an objective response in 10-20% of the intensively pre-treated patients, with a response duration of approximately 9 months [Cobleigh 1999, Estrevez 2003]. In the study by Vogel (2002), trastuzumab monotherapy was administered as first-line treatment. The response rate in this study was approximately 35% with a median response duration of more than 12 months. On the basis of phase II studies, trastuzumab has furthermore been found to increase the efficacy of various cytostatic drugs [Burstein 2001, Marty 2005, Slamon 2001]. Combinations of trastuzumab with paclitaxel, doxorubicin and docetaxel showed a longer (progression-free) survival in randomised phase II/III studies [Slamon 2001, Chan 2007, Geyer 2006]. Patients with HER-2-overexpression are eligible for treatment with trastuzumab, preferably in combination with chemotherapy. Patients who have already received anthracycline-containing adjuvant chemotherapy, are eligible for a combination of a taxane or vinorelbine with trastuzumab. Combination with anthracyclines should be avoided due to the increased chance of cardiotoxicity. A combination with liposomal doxorubicin does appear possible, however [Sparano 2007].


The combination of trastuzumab with other cytostatic agents such as vinorelbine also appears to be more effective than treatment with these agents alone [Bartsch, 2007; Chan, 2007]. Treatment with trastuzumab monotherapy is not recommended, but the treatment after completing cytostatics courses may be continued. If resistance to trastuzumab has occurred, continuing trastuzumab in subsequent treatment lines is more effective; this was found in two randomised phase III studies [von Minckwitz, 2009; Blackwell, 2010]. The combination of capecitabine with trastuzumab improved the response rate and time to progression, compared to capecitabine alone (respectively 48% vs 27%; p=0.011; 8.2 vs 5.6 months, p=0.034) [von Minckwitz, 2009]. The combination trastuzumab with lapatinib improved the clinical benefit and progression-free survival compared to lapatinib alone (respectively 24.7% vs 12.4%; p=0.01; HR 0.73; p=0.008) [Blackwell, 2010]. Multiple retrospective analyses support this finding [Fountzilas, 2003; Tripathy, 2004; Gelmon, 2004]. Disease progression during treatment with trastuzumab is often in the form of metastases in the central nervous system, but a favourable effect of screening with a brain MRI or prophylactic cranial irradiation has not been demonstrated. Lapatinib may have a preventative effect here [Geyer, 2006].


The combination of trastuzumab with hormonal therapy was researched in the TanDEM study [Kaufman, 2009]. In this study, 207 postmenopausal women with both hormone receptor-positive and HER-2-positive metastatic breast cancer were randomised between anastrozole with or without trastuzumab. The response rate, progression-free survival and clinical benefit improved with the combination (respectively 20.3% vs 6.8%, p=0.018; 4.8 vs 2.4 months, p=0.0016 and 42.7 vs 27.9%, p=0.026). The combination letrozole with lapatinib showed comparable improvements [Johnston, 2009]. As a result, the addition of HER-2 blockage in patients with an indication for hormonal therapy is of added value and may be considered in patients with a tumour displaying aggressive clinical behaviour while chemotherapy treatment was not the first choice.


The cardiotoxicity of trastuzumab is usually reversible with conservative measures. Re-introduction of trastuzumab in patients after a break due to (a)symptomatic cardiotoxicity was feasible in 62%-88% of patients, without renewed worsening of the LVEF [Guarneri, 2006; Ewer, 2005]. If this was the case however, then continuation of trastuzumab was still possible in 50% of patients because the LVEF stabilised at a lower level [Ewer, 2005]. This data supports the long-term use of trastuzumab in which the favourable effects weigh up against the controllable (cardio)toxicity.


A HER-2 blockade using lapatinib may be applied in patients that have become resistant to trastuzumab. In combination with capecitabine, this extends the time to progression by several months [Blackwell, 2010; Geyer, 2006]. Symptomatic brain metastases were less common in the lapatinib treatment arm of this study. 



Bevacizumab is a monoclonal antibody that binds the circulating vascular endothelial growth factor (VEGF). As a result, binding of VEGF to the VEGFR-1 (Flt-1) and VEGFR-2 (KDR) receptors present on the surface of the endothelial cells is inhibited. The reduced activity of VEGF inhibits the new formation of blood vessels in tumours, which slows the tumour growth.


Three phase III studies have researched the value of adding bevacizumab to first-line chemotherapy in patients with metastatic breast cancer. In the E2100 study by Miller (2007), bevacizumab was added to a weekly schedule with paclitaxel as first-line treatment. The median progression-free survival of patients treated with bevacizumab and paclitaxel was 11.8 vs 5.9 months respectively for paclitaxel only (HR 0.60; p<0.0001). With a median follow-up duration of 22.6 months, the median survival was 26.7 vs 25.2 months (HR 0.88; 95%CI 0.66-1.03; p=0.137). After one year, 82.3% of patients were still alive versus 73.8% (p=0.007).

In the AVADO study, bevacizumab was added to a three-weekly schedule of docetaxel in the first-line. In the RIBBON 1 study, the combination bevacizumab with capecitabine, anthracycline-containing chemotherapy or a taxane (other than paclitaxel) was compared to chemotherapy only. A significant improvement in response rate and an increase from 1 to 2.9 months in progression-free survival was found in both studies, but there was no extension in general survival [Miles, 2010; Robert, 2011]. Bevacizumab in combination with weekly paclitaxel as first-line chemotherapy therefore has added value, and is registered by the EMA for this indication.


Bevacizumab in combination with capecitabine has originally been studied as a second- or third-line therapy in patients with metastatic breast cancer [Miller, 2005]. The combination was compared to capecitabine only. While combination therapy is more effective than capecitabine only (response rate 20 vs 9%), this did not result in a significant extension of the progression-free (4.9 vs 4.2 months) or general survival (15.1 vs 14.5 months). Addition of bevacizumab to second-line chemotherapy consisting of a taxane, gemcitabine, capecitabine or vinolrelbine in the RIBBON-2 study lead to few extra side effects and resulted in an extension of the progression-free survival of 5.1 to 7.2 months [O’Shaugnessy, 2008]. The value of bevacizumab in the second or later line is still unclear.

Authorization date and validity

Last review : 13-02-2012

Last authorization : 13-02-2012

The national Breast Cancer guideline 2012 is a living guideline, in other words there is no standard term of revision. NABON continually watches at new developments and clinical problems in the areas of screening, diagnostics, treatment and aftercare, and whether this requires an update.

Initiative and authorization

Initiative : Nationaal Borstkanker Overleg Nederland

Authorized by:
  • Nederlandse Internisten Vereniging
  • Nederlandse Vereniging voor Heelkunde
  • Nederlandse Vereniging voor Psychiatrie
  • Nederlandse Vereniging voor Radiologie
  • Nederlandse Vereniging voor Radiotherapie en Oncologie

General details

Approximately 14,000 women (and 100 men) are diagnosed with invasive breast cancer each year in the Netherlands, and about 1,900 have an in situ carcinoma. A woman's risk of having breast cancer over the course of her life is 12-13%. This means that breast cancer is the most common form of cancer in women in the Netherlands. Early detection, particularly via national breast cancer screening, combined with adjuvant therapy followed by locoregional treatment, improves the prognosis in women with breast cancer

The guideline on Breast Cancer Screening and Diagnostics, published in 2000, was updated in 2007. In 2002, the first multidisciplinary National Breast Cancer Guideline was published, it was revised in 2004, 2005 and 2006. In 2008 both guidelines were combined to Breast Cancer Guideline, which 2012 revision is now effected.

Scope and target group

This guideline is written for all the members of the professional groups that have contributed to its development.


This guideline is a document with recommendations and instructions to support daily practice. The guideline is based on the results of scientific research and expert opinion, with the aim of establishing good medical practice. It specifies the best general care for women with (suspected) breast cancer and for those who are eligible for screening. The guideline aims to serve as a guide for the daily practice of breast cancer screening, diagnostics, treatment and aftercare. This guideline is also used in the creation of informational materials for patients, in cooperation with the KWF (Dutch Cancer Society).

Samenstelling werkgroep

A core group consisting of a radiologist, surgeon, pathologist, medical oncologist and radiation therapist began preparing for the revision of the breast cancer practice guidelines in 2009. A multidisciplinary guideline development group was formed in early 2010 to implement the revision. This group consisted of mandated representatives from all of the relevant specialisations concerned with breast cancer, plus two delegates from the BVN (Dutch Breast Cancer Society) (see list of guideline development group members). The benefits of such a multidisciplinary approach are obvious: not only does it best reflect the care, but it offers the greatest possible expertise for the guideline. In composing the development group, geographic distribution of the members, balanced representation of the various organisations and agencies concerned, and a fair distribution in academic background were taken into account as much as possible.


The guideline development group received procedural and administrative support from IKNL (Comprehensive Cancer Centre for the Netherlands) and support on methodology from Bureau ME-TA. Partial funding was obtained from SKMS (Quality Funds Foundation of Dutch Medical Specialists). This subsidy would not have been possible without the extensive assistance provided by the NVvR (Radiological Society of the Netherlands).

Declaration of interest

Partial funding for the guideline revision was obtained from the Society of Dutch Medical Specialists in the framework of the SKMS. IKNL sponsored some of the cost. On two occasions, as well as at the beginning and end of the process, all of the members of the guideline development group were asked to fill out a statement of potential conflicts of interest, in which they stated their relationship with the pharmaceutical industry. A list of these statements of interest can be found in the appendices.

Patient involvement

In developing this guideline, four clinical questions were formulated. These questions emerge from an inventory of clinical problems collected in the field from professionals, patients and patient representatives.


Also, A multidisciplinary guideline development group was formed in early 2010 to create and implement the revision. This group consisted of mandated representatives from all of the relevant specialisations concerned with breast cancer, plus two delegates from the BVN (Dutch Breast Cancer Society).


Method of development

Evidence based


Feasibility has been taken into account in developing the guideline. This included attention to factors that could promote or hinder putting the advice into practice. Examples include the implementation of an analysis of problems, the multidisciplinary composition of the guideline development group, and making active use of support from the guideline development group members. Presenting the draft guideline to the field and communicating what, if anything, is being done with the responses, also promotes implementation. In this manner, a guideline has been developed that answers current questions in the field.

The guideline is distributed widely and is available in digital form on the Dutch Guideline Database. The guideline may also be brought to the attention of a wider audience in other periodicals or continuing education sessions, for example. To promote use of the guideline, we recommend that the regional tumour working groups and group practices, as well as scientific and professional organisations, repeatedly bring the guideline to the attention of their members. Any problems that may arise in using the guidelines can then be discussed and, when appropriate, submitted to the national guideline development group, as it is a "living" guideline. If desirable, parts of the guideline can be made more explicit by formulating regional additions or translation to the local situation in departmental and/or hospital protocols.

In principle, indicators are determined during development of the guideline that can be used to monitor implementation of the recommendations. Via a documentation project, these indicators can then be used to determine the extent of compliance with the guideline. The information from the documentation project becomes input for the revision of the guideline.

Methods and proces

This module has been evidence-based revised in 2008 and consensus based updated in 2012.


A revision of an existing guideline consists of revised and updated text. Revised text is new text based on an evidence-based review of the medical literature; updated text is the old guideline text which has been edited by the experts without performing a review of medical literature. Each section of the guideline states what type of revision has taken place. Each chapter of the guideline is structured according to a set format, given below. The purpose of this is to make the guideline transparent, so that each user can see on what literature and considerations the recommendations are based on.


Description of the literature

To the greatest extent possible, the answers to the fundamental questions (and therefore the recommendations in this guideline) were based on published scientific research. The articles selected were evaluated by an expert in methodology for their research quality, and graded in proportion to evidence using the following classification system:


Classification of research results based on level of evidence


Research   on the effects of diagnostics on clinical outcomes in a prospectively   monitored, well-defined patient group, with a predefined policy based on the   test outcomes to be investigated, or decision analysis research into the   effects of diagnostics on clinical outcomes based on results of a study of   A2-level and sufficient consideration is given to the interdependency of   diagnostic tests.


Research   relative to a reference test, where criteria for the test to be investigated   and for a reference test are predefined, with a good description of the test   and the clinical population to be investigated; this must involve a large   enough series of consecutive patients; predefined upper limits must be used,   and the results of the test and the "gold standard" must be   assessed independently. Interdependence is normally a feature of situations   involving multiple diagnostic tests, and their analysis must be adjusted   accordingly, for example using logistic regression.


Comparison   with a reference test, description of the test and population researched, but   without the other features mentioned in level A.


Non-comparative   trials


Opinions   of experts, such as guideline development group members



Based on the medical literature, one or more relevant conclusions are made for each section. The most important literature is listed according to the level of evidential strength, allowing conclusions to be drawn based on the level of
evidence. All the medical literature included in the conclusion is described in the bibliography.


Classification of conclusions based on literature analysis


Based   on 1 systematic review (A1) or at least 2 independent A2 reviews.


Based   on at least 2 independent B reviews


Based   on 1 level A2 of B research, or any level C research


Opinions   of experts, such as guideline development group members


Other considerations

Based on the conclusion(s), recommendations are made. However, there are other considerations that contribute to formulation of the recommendation besides literature evidence, such as safety, the patients' preferences, professional expertise, cost-effectiveness, organisational aspects and social consequences. The other considerations are mentioned separately. In this manner, it is clear how the guideline development group arrived at a particular recommendation.



The final wording of the recommendation is the result of the scientific conclusion, taking into account the other considerations. The purpose of following this procedure and drawing up the guidelines  in this format is to increase transparency.



An alphabetical list of literature references can be found at the end of the guideline.


All draft texts have been discussed by the guideline development group.

Search strategy

Searches are available upon request. Please contact the Richtlijnendatabase.