Question

How to diagnose and treat pregnancy associated breast cancer?

Recommendation

Diagnosis and treatment of pregnancy associated breast cancer is most certainly multidisciplinary; aside from the  breast care team, a perinatologist and neonatologist must also be involved.

 

Radiological diagnostic procedures are possible, taking the ALARA principle into account

  • Mammography and ultrasound for locoregional diagnosis
  • Conventional staging (chest X-ray, liver ultrasound and skeletal scintigraphy) only in the case of locally advanced disease or suspected metastasis (complaints)
  • As a standard, MRI (with intravenous gadolinium) and FDG-PET-CT are not recommended

 

Cytology and histology are possible. The pathologist must be informed about the pregnant or lactating status.

 

Treatment of breast cancer during pregnancy is possible, the pregnancy does not appear to influence the prognosis and does not need to be terminated for the sake of treatment.

 

Treatment is dependent on the stage of the disease and pregnancy. Prior to treatment, recommendations must be discussed within a multidisciplinary team, also involving a perinatologist and a neonatologist.

 

Surgery

  • mastectomy or BCT
  • SN procedure, if indicated, without patent blue, is possible in all stages of pregnancy

 

Radiotherapy

If radiotherapy is applied, the following steps are necessary:

  • Calculation and measurement of foetal dose using a phantom and calculation of foetal risks
  • Apply shielding measures for the pregnant uterus

 

Chemotherapy

  • Chemotherapy with FAC/FEC or AC during the second and third trimester of pregnancy is possible if postponement cannot be justified in relation to the mother
  • Little is known about taxanes administered during pregnancy
  • Methotrexate must be avoided during pregnancy
  • Chemotherapy must not be commenced or continued after 35 weeks of pregnancy, due to risk of:  

        a) neutropaenia during or shortly after birth (mother and newborn)

        b) limited detoxification by the newborn

 

Supporting therapy

Methylprednisolone or hydrocortisone are preferable when using corticosteroids.

 

Hormonal therapy

  • Tamoxifen is contraindicated
  • LHRH analogues are contraindicated

 

Trastuzumab

  • Trastuzumab is contraindicated

Conclusions

Level 3

The poorer prognosis of pregnancy associated breast cancer is not based on an unfavourable influence by the pregnancy, but on an unfavourable stage as a result of late detection of the disease and unfavourable tumour characteristics in this young subpopulation.

 

C          Gwyn 2001, Keleher 2001, Moore 2000, Amant 2010

 

Level 1

The following radiological and nuclear medicine diagnostic methods are possible during pregnancy without a notable risk of damage to the foetus: mammography, chest X-ray, an ultrasound of the breast, axilla and   liver, skeletal scintigraphy, SN procedure*.

 

The foetal dose of FDG-PET-CT consists of an FDG-PET and a CT component, rendering the fetal dose considerably higher (20-45 mSv) than conventional staging.

 

A1        ICRP 2001

B          McCollough 2007, Zanotti-Fregonara 2009

C          Kal 2005, Streford 2003 Russell 1997

* The use of patent blue is advised against during the SN procedure.

 

Level 3

The feasibility of MRI with gadolinium contrast in pregnant or lactating women is (still) unclear.

 

The imaging may be performed if indicated, without the application of special measures.

 

C          Webb 2005

 

Level 1

Good estimates of the irradiation risk for the foetus can be made. The nature and size of these risks are dependent on the stage of pregnancy.

 

The threshold dose for deterministic effects is 100 mSv. 

There is no threshold dose for stochastic effects.

 

A1        ICRP 2003

C          Kal 2005

 

Level 3

The uterus dose as a result of a planned therapeutic radiotherapy can be accurately calculated and measured using a phantom. It may also be reduced by a factor of 3 or 4 using shielding measures.

 

C          van der Giessen 1996, van der Giessen 2001

 

Level 3

Methotrexate during pregnancy may lead to damage of the foetus or an abortion.

 

C          Doll 1989, Amant 2010

 

Level 3

Treatment with FAC/FEC or AC chemotherapy may, if indicated, be used during the second and third trimester of the pregnancy, but not after the 35th week of pregnancy due to neonatal neutropenia and the risk of maternal and neonatal infection.

 

C          Berry 1999, Giacalone 1999, Ring 2005, Amant 2010

 

Level 3

Administration of taxanes and vinorelbine during the second and third trimester of pregnancy does not appear to lead to congenital abnormalities, but experience with these is limited.

 

C          Mir 2007, Amant 2010

 

Level 3

Congenital abnormalities have been described with the use of tamoxifen and with LHRH analogues during pregnancy.

 

C          Barthelmes 2004, Goldhirsch 2004, Isaacs 2001

 

Level 3

Trastuzumab during pregnancy may interfere with renal development of the foetus.

 

C          Mir 2007, Amant 2010

Literature summary

Pregnancy associated breast cancer (PABC) refers to breast cancer that occurs during pregnancy or in the first year after pregnancy. The incidence of PABC is estimated at 0.2-3.8% of all breast cancers [Wallack, 1983] and it occurs in 1 in 3,000-10,000 pregnancies [Pavlides, 2005; Ring, 2005; Sauders, 1993; Wallack, 1983]. PABC confronts patients and treating physicians with a diagnostic, therapeutic and ethical dilemma. Determining the diagnosis is complicated by the changes in the breasts that develop as a result of the pregnancy and through limitations in the diagnostic possibilities, so that a delay in diagnosis is fairly common. Traditionally, breast cancer during the period of pregnancy or lactation is associated with a poor prognosis [Gemignani, 2000; Gwyn, 2001; Haagensen, 1943; Keleher, 2001; Moore, 2000]. In a recent review on the basis of an international consensus meeting, it was found that the frequency of BRCA1/2 mutations is almost twice as high (9 instead of 5%) amongst PABC patients. In addition, hormone-receptor negative and HER-2-positive tumours are more common in this population [Amant, 2010]. In studies that correct for these factors and disease stage, no difference was found in the prognosis of breast cancer between pregnant and non-pregnant women, especially in patients with a low-stage breast cancer [Gemignani, 2000; Gwyn, 2001; Keleher, 2001; Moore, 2000]. The poorer prognosis is therefore not based on an unfavourable influence by the pregnancy, but on an unfavourable stage as a result of late detection of the disease. The recommendation to terminate the pregnancy is therefore not justified in order to improve the prognosis of the breast cancer [Anderson, 1996; Clark, 1989; Gemignani, 2000; Petrek, 2004].

 

Diagnostic investigations

A pregnancy associated breast cancer is difficult to diagnose. The breasts change as a result of the pregnancy (or lactation). Glandular tissue proliferates, and feels different (both for the patient and physicians). A lump in the breast in women of an age during which pregnancy usually occurs is generally benign, certainly during or shortly after pregnancy. From a differential diagnostic perspective, galactoceles, abscess, cyst, hyperplasia or fibroadenoma must be considered. Proliferation of the glandular tissue has an unfavourable influence on the evaluation of imaging research. Ultrasound is the method of choice in case of a palpable abnormality, followed by mammography if required. See also paragraph 2.2.

 

Radiological imaging

Radiological research is possible during pregnancy. The foetal radiation exposure (for most of the prevailing forms of imaging lies far under the threshold dose (100 milliSievert (mSv)). Especially if the uterus is not located within the bundle (or within 10 cm of the bundle), the doses received by the foetus is so low that there is no notable risk. In addition, the intention is always to keep theradiation dose as low as possible (As Low As Reasonably Achievable, the ALARA principle). The interpretation of mammographies during pregnancy  is complicated by the increased density of the breast tissue. The most important indication is the evaluation of microcalcifications. A patient can be offered a lead apron, particularly for peace of mind, because the foetal dose during mammography is negligible. The interpretation of an ultrasound of the breasts and axilla is not influenced as much by the pregnancy as is mammography.

 

Nuclear medicine imaging

The prevailing nuclear medicine diagnostic methods for breast cancer, the SN procedure, skeletal scintigraphy and FDG-PET make use of isotopes that do not pass the placenta [McCollough, 2007; Zanotti-Fregonara, 2009]. The main foetal radiation exposure involved in these imaging methods are that the isotopes are excreted renally, and may remain for some time in the urinary bladder. The recommendation for a pregnant woman who has an indication for a nuclear medicine investigation is therefore to drink a lot of water and urinate frequently in the first day after the investigation has been performed [ICRP, 2001; Russell, 1997]. The table shows the estimated maximum foetal radiation dose for a number of prevailing diagnostic procedures for women with breast cancer [EC, 1998; Fenig, 2001; ICRP, 2001; Kal, 2005; Nicklas, 2000; Russell, 1997; Streford, 2003; Valentin, 2003].

 

Foetal radiation exposure for a number of prevailing diagnostic procedures in the first trimester of pregnancy.The threshold dose for non-stochastic damage to the foetus is 100 mSv.

Diagnostisch procedure

Foetal exposure in milliSievert (mSv)

 

 

Mammography in 2 direction

< 0.001

Chest   X-ray

< 0.01

X-ray of the lumbar spine

1.7

Pelvic   X-ray

2.0

Abdominal   X-ray

1.4

CT Abdomen

10-30

 

 

SN   procedure

< 0.007

Skeletal   scintigraphy**

< 4.5

FDG-PET**

10-15

**    Radiation exposure decreases with duration of the pregnancy

 

MRI scan with intravenous gadolinium

Opinions are divided about MRI with gadolinium contrast during pregnancy. The European Society of Radiology has found the procedure is probably safe. However, this method is discouraged in the United States of America. No teratogenous effects on the foetus have been described for gadolinium-containing contrast medium. It passes the placenta, but after 48 hours it could no longer be detected in animal studies [Muller, 2011]. Different authors state that MRI with gadolinium is safe during lactation, because the amount of gadolinium absorbed by the child is negligibly small [Kok, 2004; Webb, 2005; de Wilde, 2005]. Like mammography, an MRI of the breasts is more difficult to interprete, because there is a strong increase in colouration due to high hormone levels and increased blood flow [Talele, 2003].

 

As described earlier in paragraph 2.3, staging investigations for metastases are not indicated for stage I and II breast cancer. For locally advanced breast cancer, conventional staging can be conducted without risk. The foetal dose of FDG-PET-CT consists of an FDG-PET and a CT component, together considerably higher (20-45 mSv) than that of conventional staging.

 

Fine needle aspiration and histological needle biopsy

Cytological analysis and a histological biopsy are reliable analyses during pregnancyHowever, both false-negative results (sampling errors), due to the large and congested breasts, and false-positive results, due to increased proliferation of glandular tissue, are possible. The pathologist must therefore be informed of the fact the patient is pregnant [Mitre, 1997]. There is virtually no data available on the influence of pregnancy on the determination of hormone receptors. Immunohistochemical assays detect both bound and unbound receptors and should be reliable during pregnancy.

 

Treatment

Similar to diagnostics, the treatment of PABC must be based on multidisciplinary consultation. Discussion within the multidisciplinary team prior to treatment is essential in order to ensure optimal coordination of the different treatment modalities, the sequence of these and any obstetric steps.A treatment sequence should be chosen that couples a maximum chance of cure for the patient with a minimum risk of foetal damage. This is highly dependent upon the stage of the pregnancy at which the diagnosis is made. No randomised studies have been performed on the treatment of breast cancer during pregnancy. The recommendations hereunder are therefore largely based on retrospective studies and case histories.

 

Surgery during pregnancy

If the changing physiology of the woman during pregnancy is taken into account, anaesthesia and surgery may be safely performed [Ni Mhuireachtaigh, 2006; Moran, 2007]. Possible disadvantageous effects of surgery on the foetus are more often the result of hypoxia, hypotension and hypoglycaemia than teratogenous effects of anaesthetics. These conditions and therefore also the associated undesirable foetal consequences can usually be prevented. A left lateral tilt position prevents compression of the vena cava, this applies especially if the uterus is larger (after 24 weeks). Postoperative pain may lead to an increase in maternal oxytocin release, and therefore preterm contractions. This can often be prevented using adequate analgesia [de Buck, 2008].

A mastectomy or BCT may be performed in the local treatment of breast cancer during pregnancy [Navrozoglou, 2008]. The SN procedure is a safe alternative for an ALND in women with a cT1-2N0 tumour. In 2004, Gentilio (2004) found that administered 99mTC sulfur colloid especially concentrates in the location of the injection and the lymph nodes. Keleher (2004) has calculated that the foetal dose, if the mother is injected with 92.5 MBq 99mTC sulfur colloid, is 4.3mSv. This falls well within safety margins. Allergic reactions have been reported for patent blue (blue patent V). This agent is better avoided during pregnancy [Khera, 2008, Gentilini 2004].

 

Radiotherapy during pregnancy

In contrast to what is often said, even therapeutic radiotherapy during pregnancy is not a priori impossible. It must be realised that the foetus is more sensitive to any damage and that any damage is more severe the earlier the stage in pregnancy. On the other hand, the uterus is small during early pregnancy and lies further from the radiation fields, so that it is often easier to limit the total foetal dose [Kal, 2005].

The risks may be subdivided in deterministic and stochastic effects. Examples of deterministic effects are an increased chance of deformities of organs (at 2-8 weeks of pregnancy), or mental retardation (of 8-15 weeks and to a lesser extent at 16-26 weeks of pregnancy). These effects are dose-dependent and have a threshold dose. In its regular reports, the International Committee for Radiological Protection (ICRP) expresses these risks in chance per millisievert (1 Sievert (Sv) corresponds to 1 Gray (Gy), see the below table) [ICRP, 2001; Valentin, 2003]. In the ICRP-90 report, a threshold dose of 100 mSv (in one administered dose) is reported for these side effects [Valentin, 2003]. Stochastic effects, in particular the induction of tumours, may (in principle) occur on damage of one cell nucleus and do not have a threshold dose. In the third trimester, (a part of the) foetus is closer to the radiation fields and the chance of tumour induction is therefore relatively high. Some people therefore advise against radiotherapy in the third trimester [Amant, 2010].

 

The dose to the uterus during radiotherapy is dependent on the size of the radiotherapy fields used and the distance of the uterus to the fields [van der Giessen, 1996; van der Giessen, 2001; Kase, 1983; Stovall, 1995]. This dose is usually low and may differ somewhat per radiotherapy machine. It may also be reduced by a factor 3 or 4 using shielding measures. If radiotherapy is being considered for a pregnant patient, the uterus dose must be calculated and measured using a phantom, with and without shielding [van der Giessen, 2001]. A decision can then be made in consultation with the patient whether or not to postpone radiotherapy. For example, during radiotherapy of the breast or chest wall with a reference dose of 50 Gy in 5 weeks, the calculated maximum dose at the location of the foetus may be 0.03 Sv at 8 weeks pregnant to 0.2 Sv at 24 weeks pregnant. By applying the appropriate shielding, the (physical) dose at the location of the foetus may be reduced by a factor of 3 or 4 to 0.05-0.07 Sv = 50-70 mSv. In this example, the threshold dose of 100 mSv mentioned in the ICRP-90 report is not exceeded. The chance of tumour induction would be a maximum of 1.5 * 10-4 * 70 = 0.0105 or 1%.

 

Risks of irradiation exposure by the foetus

Pregnancy term

Risk

Risk estimation

Threshhold dose

Pre-implantation

0-8 days

early abortion

10-3 mSv-1

unknown

Organogenesis

2-8 weeks

organ abnormalities

4*10-4   mSv-1

100 mSv

Brain development*

8-15 weeks

mental retardation

4*10-4 mSv-1

100mSv

Development of brain support tissue

16-25 weeks

mental retardation

10-4 mSv-1

100 mSv

Maturation

25-40 weeks

growth retardation**

(< 10-4   mSv-1)

100 mSv

Tumour induction

Entire pregnancy

juvenile cancer

1.5*10-4   mSv-1

none

*   Retardation can also be quantified as a loss of approximately 30 IQ points per Sievert

**   Uncertainty about the role of radiation; growth retardation is a general result of stress

 

The abovementioned deterministic risks must be weighed up against the spontaneous chance of congenital abnormalities, which is approximately 4%. The increased chance of tumour induction must be related to the general chance of malignancy in children (0-15 years) in the Netherlands of 0.2%.

In good consultation with the multidisciplinary team and patient, risks for the foetus must be weighed up against the risks of (further) delaying radiotherapy, such as a reduction in the chance of locoregional control [Huang, 2003].

 

Adjuvant systemic therapy during pregnancy

There are no prospective randomised studies on the effects of (adjuvant) systemic therapy on the foetus. All information has been obtained from retrospective studies and case histories.

 

Chemotherapy

Administration of chemotherapy during organogenesis is associated with an increased chance of a spontaneous abortion and congenital abnormalities of the foetus [Doll, 1989; Ebert, 1997]. In the study by Ebert (1997), most of the 15 women who had a spontaneous abortion were treated with methotrexate. A few larger studies described foetal effects of chemotherapy during the second and third trimester of pregnancy in patients with breast cancer [Berry, 1999; Giacalone, 1999; Ring, 2005]. In the French retrospective study in which 18/20 patients were treated with different types of chemotherapy, no foetal malformations were observed [Giacalone, 1999]. In the (non-randomised) prospective study from the MDACC, Berry (1999) treated 24 pregnant patients with a median four courses of FAC chemotherapy over a period of 8 years. He did not find an increase in congenital abnormalities or complications during pregnancy in this group of patients. The median pregnancy duration at birth was 38 weeks. The birth weight, the Apgar score and health of the children directly after birth were normal. Ring (2005) described the experiences of five London hospitals in which 16 pregnant patients were treated with anthracycline-containing chemotherapy and 11 patients with CMF (cyclophosphamide, methotrexate, fluorouracil). One child was born with a hemangioma on the abdomen (possibly unrelated). None of the children had a birth weight under the 10th percentile for the pregnancy duration. Two children had breathing difficulties, and five were admitted to the high neonatal care unit. An international panel has recently reviewed existing literature on chemotherapeutic agents used for breast cancer during pregnancy. The most commonly used schedules were FAC/FEC and AC. The authors arrive at the conclusion that these chemotherapy schedules are relatively safe during pregnancy, as long as they are not administered any earlier than an amenorrhoea duration of 14 weeks [Amant, 2010].

However, there is still uncertainty about possible negative effects on development of the central nervous system, intra-uterine growth retardation, the chance of premature birth, cardiac damage to the foetus, and possible genetic abnormalities in the descents of these children [Epstein 2007, Gwyn 2005]. In 2001, Aviles published data on the health and development of 84 children exposed in utero to combination chemotherapy, administered for a haematological malignancy in the mother. After a median follow-up of 18.7 years, there were no abnormalities in physical, neurological and psychological development in the 84 first generation children, nor in the 12 second generation children. Hahn (2006) held a telephone survey amongst carers of 40 children in the age bracket 0-13 years, and found no problems in this group related to chemotherapy in utero. Van Calsteren (2006) could not determine a developmental defect in a small group of 10 children from 0 to 6 years (although there was a trend in a somewhat thinner ventricular wall in children exposed to chemotherapy in utero). The development of children born healthy after exposure in utero to chemotherapy for breast cancer therefore appears to be normal in most cases, but the follow-up of this group is still too short for a definitive conclusion.

 

Mir (2007) published a review about the use of other agents. No congenital abnormalities were found in nine documented case histories on paclitaxel. This also applied to six women who received docetaxel and five treated with vinorelbine. These agents were administered during the second or third trimester. The median follow-up of the children varied between 16 and 23 months. Three children, whose mother received chemotherapy in the last three weeks before birth, had anaemia or neutropenia. Amant (2010) concluded that, while information is still limited on the safety of taxanes, these agents can probably be administered with limited risk during the pregnancy.

 

Supporting therapy

In some cases, supporting medication is indicated during chemotherapeutic treatment. If required, metoclopramide, alizapride, 5-HT antagonists, NK1-antagonists, corticosteroids, GCS-F and erythropoietin may be administered during pregnancy [Gralla, 1999; Amant, 2010]. Extra attention must be given to the type of corticosteroid; methylprednisolone and hydrocortisone are better metabolised in the placenta than dexa/betamethasone, so that a smaller amount reaches the foetal circulation [Blanford, 1977]. Long-term follow-up of children who received multiple antenatal doses of betamethasone for lung maturation, shows an increase in attention problems and spasticity [Crowther, 2007]. Methylprednisolone or hydrocortisone is therefore preferable in the use of corticosteroids as anti-emetic or to prevent an allergic reaction.

 

Chemotherapy in relation to the birth

Chemotherapy should not be administered later than at 35 weeks of pregnancy. Neutropenia during birth and long-term exposure of a newborn to chemotherapy, administered shortly before birth, increases the chance of complications for mother and child [Amant, 2010]. It is preferable to aim for a full-term baby (≥ 37 weeks).

 

Hormonal therapy

Studies with animals have shown that tamoxifen use during pregnancy may lead to congenital abnormalities in the foetus [Chamness, 1979; Diwan, 1997]. Six cases have been described with tamoxifen-use during pregnancy [Barthelmes, 2004; Isaacs, 2001; Koizumi, 1986; Ökzüzoglu, 2002; Tewari, 1997]. One child was born with abnormalities of the genitals and a second child, who was also exposed to other potentially toxic substances, had a craniofacial defect. No abnormalities were found with the four other children. Additional but less detailed information has been obtained by the manufacturer of tamoxifen [Cullins, 1994]. From 50 pregnancies that developed during tamoxifen-use, 19 healthy children were born, 10 had a congenital abnormality, 8 pregnancies ended in an abortion and no details are available for the remaining 13. Abortions and congenital abnormalities have been described after exposure of the foetus to LHRH analogues [Goldhirsch, 2004; Jimenez-Gordo, 2000]. On the basis of this (although limited) information, hormonal treatment (tamoxifen or LHRH analogues) should be advised against during pregnancy.

 

Trastuzumab

Fourteen cases have been described in literature of full-term newborns, exposed to trastuzumab in utero. Oligo- and/or anhydramnion was observed in 8/14 cases. Four neonatal deaths were described, secondary to respiratory and renal failure. This may be explained by the fact that HER-2 expression is extremely strong on foetal renal epithelium, and is strongly influenced by trastuzumab [Press, 1990]. Another hypothesis is that trastuzumab causes inhibition of vascular endothelial growth factor (VEGF), which regulates the production and re-absorption of amniotic fluid[Pant, 2008]. The administration of trastuzumab is not recommended in pregnancy [van der Sangen, 2008].

Considerations

The discovery of breast cancer during pregnancy is for patients, their partners and their doctors a complicated and emotionally stressfull event that leads to many questions and may confront treating physicians and patients with ethical dilemmas.

The pregnancy does not have an unfavourable influence on the course of the disease. Full treatment for breast cancer during pregnancy is possible without a notable burden on the foetus, even if the breast cancer is detected early in pregnancy. Terminating the pregnancy is not needed in order to ensure the mother can be adequately treated for her breast cancer. This should be clearly communicated to the patient.

Imaging diagnostics should not be avoided for the sake of the pregnancy, but mammography and MRI are less reliable. It is essential that all diagnostics and treatment recommendations are discussed first in the context of multidisciplinary consultation, in which a perinatologist is also involved

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.