Question

For patients who have undergone breast-conserving therapy (BCT), what are the differences in local control, cosmetics and survival between hypofractionated radiation therapy regimens and the current (long-term) radiation therapy regimens?

Recommendation

BCT should only be offered to the patient if a good cosmetic result and an equally good locoregional tumour control can be expected.

 

If BCT is offered, fractionated radiotherapy of the entire breast with or without a boost should form an integral part of treatment.

 

Reoperation is indicated if there is more than a focal tumour positive resection surface (of the invasive and/or DCIS component). This is the most important risk factor for the occurrence of a local recurrence.

 

MRI compatible clips should be placed in a standardised manner in the tumour bed for the purpose of obtaining accuracy in radiotherapy.

 

The advantage provided by the boost should be offset against the age, comorbidity, and the chance of a reduction in cosmetic effect.

 

If the chance of a recurrence < 1% per year in patients older than 50 years and without additional risk factors, the boost may be omitted after an R0 resection.

 

Hypofractionation of the postoperative irradiation of the breast may be applied in women with a pT1-3aN0-1M0 breast cancer and tumour-free resection margins.

 

Partial breast irradiation should, given the still relatively short follow-up, preferably be applied within a study context.

Conclusions

 

Level 1

BCT is a safe therapy, because the chance of survival is comparable to that of mastectomy. Omitting radiotherapy with BCT has an unfavourable influence on locoregional control and survival.

 

A1        Sarrazin 1984, Veronesi 1990, Fisher 1989, Fisher 2002, Straus 1992, van Dongen 2000, EBCTCG 2000, EBCTCG 2005, Vinh-Hung 2003, Vinh-Hung 2004, Hughes 2004, Fyles 2004, Poggi   2003, Kronan 2004

 

Level 1

A boost aside from radiotherapy of the entire breast improves local control in all patients.

 

The absolute advantage of a boost after complete resection reduces with increasing age.

 

A1        Bartelink 2001, Bartelink 2007

 

Level 1

Young age (£ 40 years) is an independent (negative) risk factor for the occurrence of a local recurrence   after BCT.

 

A1        Bartelink 2001, Bartelink 2007, Voogd 2001, Arriagada 2005

C         Elkhuizen 1998, de la Rochefordiere 1993, van der Leest 2007 van der Sangen 2010

 


 

Level 3

The presence of more than focal tumour metastasis in the resection surface is the most important risk factor for the occurrence of a locoregional recurrence after BCT. The same applies to the DCIS component.

 

C          Borger 1994, Park 2000

 

Level 2

A BRCA 1/2 gene mutation is not a contraindication for BCT. The   risk of a locoregional recurrence is lightly elevated, but this does not influence survival.

 

B          Pierce 2010, Kirova 2010

 

Level 3

A good cosmetic result after BCT can be achieved in at least 70% of patients; the result is better when a boost is not given and better in the case of a small excision volume.

 

A2        Vrieling 1999

C          De la Rochefordiere 1992

 

Level 2

Partial breast irradiation leads to good results in select patient groups with a low a priori risk of local   recurrence.

 

A2        Polgar 2007

B          Vaidya 2010

C          Vicini 2006

 

Level 1

Hypofractionation with postoperative irradiation of a pT1-3aN0-1M0 breast cancer with tumour-free resection margins leads to a comparable five-year survival, local control and cosmetic result compared to conventional irradiation schedules.

 

A1        James 2008

A2        Bentzen 2008 (A), Bentzen 2008 (B), Hopwood 2010, Whelan 2010

 

Literature summary

BCT is defined as: a liberal locoregional excision of the tumour that is combined with an intervention for axillary node staging, followed by radiotherapy of the breast.

 

The aim of BCT is to obtain survival similar to that after mastectomy, with an optimal cosmetic result of the treated breast and as small as possible chance of a locoregional recurrence. Choosing between BCT and a mastectomy should be a multidisciplinary process, in which the findings and considerations of the surgeon, radiologist, pathologist and radiotherapist are determinant. If on medical grounds there is a preference for one of the two treatments, the advice and considerations should be discussed with the patient; if the patient has a preference for one of the treatments, this should weigh heavily.

 

For the purpose of accurate radiotherapy, MRI compatible clips should be placed in the tumour bed in a standardised manner according to the UK protocol [Coles, 2009], i.e.: clips in 5 directions:

  1. in the medial edge of the tumour bed, between the chest wall and skin
  2. in the lateral edge of the tumour bed, between the chest wall and skin
  3. in the cranial edge of the tumour bed, between the chest wall and skin
  4. in the caudal edge of the tumour bed, between the chest wall and skin
  5. at the deepest point of the tumour bed

 

An absolute contraindication for BCT is persistent extensive tumour positive surgical margins (including DCIS) after adequate attempts at locoregional excision. The most important aspects for the choice between locoregional treatment possibilities of the operable breast cancer are: the chance of a locoregional recurrence and, specific for BCT, the expected cosmetic result. Six large prospective randomised studies in which the treatment results of mastectomy were compared with BCT all showed that the chance of survival does not depend on the therapy chosen [EBCTCG, 2005; Sarrazin, 1984; Veronesi, 1990; Fisher, 1989; Straus, 1992; van Dongen, 2000; Blichert-Toft, 1992; EBCTCG, 2000]. While one study did find a difference in the chance of locoregional recurrence after a long follow-up period in favour of mastectomy, especially with larger tumours, this did not result in a difference in survival [van Dongen, 2000; Poggi, 2003; Kroman, 2004]. It is generally stated that a chance of a locoregional recurrence of at the most 1% per year (cumulative) is acceptable for BCT [Rutgers, 2001]. This is well possible in the Netherlands: the five-year locoregional recurrence percentage after BCT in the entire population is <3% [van der Heiden, 2010].

 

Most recurrences after BCT are due to growth of the residual tumour [Bartelink, 2001; Kurtz, 1989; Voogd, 1999]. Renewed tumour growth in the treated breast in these cases is assumed to derive from microscopic tumour foci that have remained behind in the breast after surgery. In two-thirds of mastectomy samples, tumour foci of an invasive and non-invasive nature were found around the tumour. Of these tumour foci, 43% were more than 2 cm outside the tumour. There was also no difference between primary tumours smaller or larger than 2 cm in relation to the number of tumour foci and distance in relation to the tumour [Holland, 1985]. In other words, independent of the tumour size, there is a chance that tumour remains in the breast after surgery. Radiotherapy should destroy these tumour cells. However, if the number of tumour cells is too extensive, patients may be confronted with a greater chance of a local recurrence.

 

The most important factor that predicts the chance of a locoregional recurrence is a tumour-positive surgical margin [Park, 2000]. Different series show follow-up recurrence percentages of 2% to 8% with tumour-free surgical margins and 9% to 27% with tumour-positive surgical margins, after 5 to 10 years follow-up. The highest percentages are found in the series with the longest follow-up and if the tumour reaches extensively (more than focal) into the resection surface [Park, 2000]. More than focal tumour-positive resection surfaces or the lack of margin tests (for example, if a carcinoma is unexpectedly found in a diagnostic biopsy) are indications for a re-excision; a residual tumour is then found in more than half of cases [Schnitt, 1987; Gwin, 1993; Kearny, 1995; Schmidt-Ullrich, 1993].

The chance is especially great in tumours surrounded by an extensive DCIS component (67%) and with multinodular or diffuse invasive lobular carcinomas (50%) [Schnitt, 1987]. It is unclear if a re-excision is worthwhile if the tumour extends focally to and into a resection surface; however, the locoregional recurrence risk is elevated in this case so that adjustment of the radiotherapy dose appears to be a good alternative [Park, 2000; Clarke, 1992; Romestaing, 1997].

 

Extensive lymphangio-invasive growth may also present a higher risk of residual tumour and as a result may lead to an increased locoregional recurrence percentage. This is found in various studies [Veronesi, 1995; Borger, 1994; Voogd, 2001]. However, the amount of lymphangio-invasion is difficult to classify and does not give a measure of the risk of residual tumour load. Lymphangio-invasion is also an important risk factor for locoregional recurrence after a mastectomy, so that the choice between BCT and mastectomy should not be made on the basis of this factor.

 

An important independent risk factor for locoregional recurrence after BCT is age. The chance of a locoregional recurrence after BCT is inversely proportional with age. While a young age (£ 40 years) is a factor for recurrence after BCT, no difference has been found in retrospective series in survival if BCT is selected instead of mastectomy; young age is associated with a poor survival prognosis, which does not appear to be influenced by locoregional therapy [Nixon, 1994; Vrieling, 2001; Elkhuizen, 1998; de la Rochefordiere, 1993; van der Sangen, 2010]. The conclusion is that young age is not a contraindication for breast-conserving treatment [Zhou 2004].

 

Radiotherapy and BCT

Omitting radiotherapy results in a strong increase in the incidence of locoregional recurrences. Radiotherapy is therefore considered an inherent component of BCT. No subgroups have been defined in which radiotherapy can be omitted [EBCTCG, 2005; Fisher, 2002].

 

In the Netherlands, a boost is generally administered on the tumour bed after radiotherapy of the entire breast. Results of the EORTC study 10882/22881 (boost - no boost) indicate that the chance of developing a local recurrence after radiotherapy of the breast followed by administration of a boost/no boost is 6.2% and 10.2% respectively after a median follow-up duration of more than 10 years [Bartelink, 2001; Bartelink, 2007]. Survival in both groups was not significantly different.The boost gives a significant equal relative decrease in the local recurrence percentage in all age groups, but the absolute advantage is greater with decreasing patient age. In patients under 40 years of age, the boost decreased the ten-year local recurrence percentage from 23.9% to 13.5%. In older patients, the boost also provided a significantly better control; however, the absolute difference was approximately 4% after 10 years: from 12.5% to 8.7%in patients of 41-50 years, from 7.8% to 4.9% in patients of 51-60 years and from 7.3% to 3.8% in patients over 60 years.This involved a follow-up of 10 years, so this may still change over time. It should be noted here that an additional boost has a negative influence on the cosmetic result. There is still no data available for the cosmetic aspect after ten years. The advantage provided by the boost should be offset against the age, comorbidity, and the chance of a reduction in cosmetic effect.

 

Radiotherapy leads to a smaller chance of a local recurrence for each subgroup of BCT patients; this leads to the greatest reduction with young women, the advantage with older women (R0; met tamoxifen) is limited to a few percent after 5 years [Vinh-Hung, 2004; Vinh-Hung, 2003; Fisher, 2002; Hughes, 2004].

There is a significant relationship between reduction in five-year locoregional recurrence percentages and survival advantage after 15 years [EBCTCG, 2005]. It appears from this meta-analysis that, in the hypothetical absence of other causes of death, the occurrence of four locoregional recurrences results in the occurrence of 1 breast cancer death after 15 years.

Hypofractionation

Evidence-based to June 2011:

What are the differences in locoregional control, cosmetic result and survival between hypofractionation irradiation schedules and the current (long-term) irradiation schedules in patients who have undergone breast-conserving treatment?

 

In a systematic review of good quality, two randomised trials were identified and meta-analysed [Lehman, 2008]. Hypofractionation (more than 2 Gy per fraction) was compared to conventional irradiation (1.8 to 2 Gy per fraction) in a population of 2,644 patients with T1-2N0M0, and tumour-free margins in the resection sample. Hypofractionation did not influence the five-year survival (RR: 0.97; 95%CI 0.78-1.19), cosmetic (RR: 1.01; 95%CI 0.88-1.17) or local control (difference in local recurrence-free survival: 0.4%, 95%CI -1.5-2.4%). Toxicity for the skin (after five years, RR: 0.99; 95%CI 0.44-2.22) and toxicity for the subcutaneous tissue (RR: 1.0; 95%CI 0.78-1.28) were comparable. The ten-year results of one of the included trials again showed no difference between hypofractionation or conventional fractionation [Whelan, 2010].

 

The START Trial A compared three different irradiation schedules: 41.6 Gy in 13 fractions (3.3 Gy per fraction, 5 weeks), 39 Gy in 13 fractions (3.0 Gy per fraction, 5 weeks) vs. 50 Gy in 25 fractions (2 Gy per fraction, 5 weeks) [Bentzen, 2008]. There were 2,236 women with pT1-3aN0-1M0 enrolled in the study, including 15% mastectomy patients; 61% of patients received a boost, 78% received tamoxifen and 34% adjuvant chemotherapy. The outcomes after 5 years did not differ concerning (local) recurrence, survival or side effects. The START Trial B compared two irradiation schedules 40 Gy in 15 fractions (3 weeks) vs. 50 Gy in 25 fractions (5 weeks) (n=2,215) [Bentzen, 2008]. The outcomes after 5 years did not differ concerning (local) recurrence or side effects. A surprising finding was the better survival in the 40 Gy group (HR death 0.76; 95%CI 0.59-0.98). The authors could not find a reason for this result and expected it was a coincidence. For both trials, the cosmetic results and quality of life data in subgroups were analysed and reported separately after 5 years (n=2.208) [Hopwood, 2010]. Scores for body image, and the arm or shoulder symptoms did not differ for the different irradiation regimes. Breast symptoms were examined in eight different items. For the item ‘negative skin change’, women in the 39 Gy and the 40 Gy groups scored better than women in the 50 Gy groups (HR 0.63; 95%CI 0.47-0.84, and 0.76; 95%CI 0.60-0.97 respectively). No differences were demonstrated between the groups for the other seven items.

 

The equivalence of hypofractionation and standard fractionation appears to apply to patients with pT1-3aN0-1M0 tumours, although there are subcategories with relatively few patients within these classifications. One trial compared local recurrences within particular subgroups [Whelan, 2010]. Hypofractionation was equivalent to standard fractionation for women under 50 years or over 50 years, for tumours greater or smaller than 2 cmcm, for oestrogen-receptor positive and negative tumours, and for patients who had or had not received systemic therapy. In the subgroup with high-grade tumours, there were more local recurrences in the hypofractionation group (16.6% vs. 4.7%; HR: 3.08; 95%CI 1.22-7.76). In answer to this finding, the 8-year results of the START Trial A and B were analysed post hoc for high grade tumours, in which no difference was found in local recurrence (HR: 0.83; 95%CI 0.56-1.23) [Haviland, 2010].

 

Gene mutation carriers

There is no absolute contraindication for breast-conserving treatment  with a demonstrated BRCA1 or 2 gene mutation (see section 1.3.1). These women have a greater chance of a second primary breast cancer (especially contralateral) and possibly a somewhat greater chance of an ipsilateral recurrence, but this does not influence survival [Pierce, 2010; Kirova, 2010].

 

Radiotherapy in women > 50 years of age

Given the chance of locoregional recurrence after BCT is dependent on age, various studies have looked at the necessity of radiotherapy after a breast-conserving treatment in older women. A randomised trial [Fyles, 2004] examined the locoregional recurrence percentages after radiotherapy plus tamoxifen versus tamoxifen only in 769 women over 50 years of age undergoing BCT due to a tumour smaller than 5 cm. In doing so, it appeared that the addition of radiotherapy to tamoxifen reduced the locoregional recurrence percentage from 7.7% to 0.6% after 5 years. With radiotherapy, the 5-year disease-free survival increased from 84% to 91%. An RTOG study randomised in the same manner [Hughes, 2004], this time with women older than 70 years with pT1N0 ER+ breast cancer. This resulted in a five-year locoregional recurrence percentage of 1% with radiotherapy and tamoxifen and 4% with tamoxifen only.

Locoregional recurrence percentages in the SEER database were also examined for women > 70 years with tumours ≤ 2 cm ER+/unknown, pN0 who did or did not undergo radiotherapy within the framework of BCT [Smith, 2006]. Radiotherapy reduced the locoregional recurrence percentage after 8 years from 8% to 2.3%. This shows that with older women, radiotherapy also plays an important role in locoregional control after BCT, however possible comorbidity in older women should be taken into account with each individual choice.

 

Partial breast irradiation

Seventy to eighty percent of local recurrences are localised in the original tumour area. This has lead to development of partial breast irradiation in which only the tumour area is irradiated and not the entire breast. Guidelines have been formulated by the ESTRO (www.estro.org) and ASTRO (www.astro.org) to outline to whom partial breast irradiation may apply; these are low-risk patients for local recurrence, such as older patients, tumour ≤ 2 cm, N0, radical surgical margins, ER+, no extensive DCIS around the invasive ductal carcinoma. Published data so far show promising results. In one-institute series, follow-up data has already been published, including that of Vicini with brachytherapy with 3.8% recurrences after 10 years and in the ELIOT series (2006) with intra-operative radiotherapy with 2.1 % recurrences.

Only a few randomised trials have been published so far. Polgar (2007) compared brachytherapy with complete breast irradiation. In this study, five-year recurrence percentages of 4.7% vs. 3.4% were seen. Results of the TARGIT trial were recently published in which complete breast irradiation was compared to intra-operative partial breast irradiation. Recurrence percentages of 0.9% and 1.2% respectively were found in this study with a median follow-up of only a bit over 2 years [Vayda, 2010]. However, extremely low risk patients were included in this study (median age of 63 years, 90% ER+, < 2 cm), some of whom were furthermore also treated hormonally (more than 60% of patients) and chemotherapy (10% of patients). In addition, there was only extremely superficial irradiation of the tumour bed in this study, in contrast with many other forms of partial breast irradiation. There are currently still many ongoing randomised trials with various techniques of partial breast irradiation, including studies with postoperative external radiotherapy. The role of partial breast irradiation will become clearer in coming years.

Considerations

Hypofractionation reduces the treatment with radiotherapy and is therefore an improvement, in terms of hospital logistics as well as the physical burden on the patient.

Given the still relatively short follow-up of most randomised studies, partial breast irradiation is only recommended within a research context for now.

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).

Member of workgroup

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

Implementation

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

A1

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.

A2

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.

B

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

C

Non-comparative   trials

D

Opinions   of experts, such as guideline development group members

 

Conclusions

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

1

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

2

Based   on at least 2 independent B reviews

3

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

4

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.

 

Recommendations

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.

 

References

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.