Question

Which arsenal in palliative treatment of metastatic breast cancer is available?

Recommendation

With (pain) complaints on the basis of metastasis, palliative short-term radiotherapy should always be considered. This applies to metastasis in the brain, lymph nodes, skin/subcutis and skeleton, for example. Local radiotherapy may be considered with complaints of the primary tumour in the breast.

 

In principle, short-term palliative radiotherapy may be repeated if complaints return.

 

Administering a single dose of 8 Gy is preferable to combat pain complaints caused by skeletal metastases. If there is extensive osteolysis or a threatening fracture, a fractionated schedule to 20-30 Gy is preferable. A stabilising osteosynthesis should always be considered for long bones.

 

If there is limited intracerebral metastasis (1-3 metastases, diameter < 4 cm), stereotactical irradiation should be considered instead of irradiation of the entire brain.

 

Emergency radiotherapy (within 24 hours after diagnosis) is indicated for epidural myelum/caudal compression demonstrated by MRI to prevent progression of neurological complaints and these complaints becoming irreversible. Radiotherapy may lead to a recovery in function.

 

In patients with vertebral metastases and a good prognosis, the combination with neurosurgical/orthopaedic intervention must be considered. If the patient is not eligible for surgery, a higher total dose should be considered (30 Gy), to prevent complaints from recurring.

Conclusions

 

Level 1

Radiotherapy is effective for palliation of pain complaints caused by skeletal metastases.

 

A2        Chow 2007, van der Linden 2006, van der Linden 2004, Sze 2004

 

Level 1

A single dose of 8 Gy and 6x4 Gy results in the same and substantial reduction in pain in the majority of patients.

 

A2        van der Linden 2006, Sze 2004

 

Level 1

Neurological deficits indicating epidural myelum/caudal compression are an emergency indication for dexamethasone and radiotherapy.

 

Primary neurosurgical/orthopaedic intervention is preferable for patients with a good prognosis and condition, limited vertebral metastasis and other disease activity, and an age < 65 years.

 

In many cases, radiotherapy may prevent further neurological deficit as a result of epidural myelum/caudal compression and lead to a recovery in function.

 

A2        Patchell 2005, Chi 2009, Maranzano 2009

B          Rades 2002, Rades 2006, Rades 2010

 


Level 1

Radiotherapy may prevent further neurological deficit as a result of brain metastasis, lead to a recovery in function and a limited increase in survival.

 

A2        Koch 2011, Chang 2009

B          Bezjak 2002, Verhagen 2006, Sperduto 2010

Literature summary

Palliative surgery and radiotherapy

Radiotherapy plays an important role in the treatment of complaints caused by breast cancer metastases. Both single and more fractionated irradiations may be effective here to reduce or prevent complaints. Palliative radiotherapy of the primary tumour in the breast may be considered with (threatening) ulceration. In some cases palliative surgery is indicated.

 

The most important indications for palliative radiotherapy and/or surgery are:

 

Painful skeletal metastases or (threatening) pathological fractures

Radiotherapy is an effective treatment modality for painful bone metastases; the majority of patients experience a significant reduction in pain and in 33-50% the pain even disappears completely [Chow, 2007; van der Linden, 2004]. In most cases, also in patients with an expected better prognosis [van der Linden, 2006], a single irradiation (8 Gy) is sufficient, which may be repeated over time (if required) [Sze, 2004]. In the case of extensive osteolytic laesions in long bones with chance of a pathological fracture [van der Linden, 2003] or vertebral metastases with risk of damage to the myelum without neurological complaints, a higher dose in a fractionated schedule is generally chosen. Aside from pain reduction, the aim of treatment is also induction of remineralisation to strengthen the bone [Koswig, 1999]. Given the morbidity of a spontaneous fracture, a prophylactic surgical stabilising intervention must first be considered in the event of threatening pathological fractures in long bones. If a fracture has already occurred, a surgical stabilisation must first be performed, in combination with postoperative radiotherapy to prevent luxation of the osteosynthesis material by local tumour progression [Townsend, 1995]. A vertebroplasty may also be considered for vertebral collapse through osteolytic metastases in order to strengthen the vertebra [Mendel, 2009]. Emergency radiotherapy is indicated for progressive cranial nerve deficit due to osseous skull base metastasis to prevent irreversible deficit.

 

Epidural myelum or caudal compression with spinal metastases

Haste is of the essence in patients with neurological complaints due to myelum or caudal compression, given the increased chance of irreversible neurological deficit when waiting longer. Recovery in function may be substantially more favourable in some cases after emergency neurosurgical intervention followed by radiotherapy, than after radiotherapy only [Patchell, 2005]. However, in that case there needs to be vertebral metastases on a few levels at the most, a good condition, a reasonable life expectancy, limited disease activity elsewhere and the patient should be under 65 years of age [Chi, 2009]. As a result, the majority of patients are not eligible for surgery. Preferably, radiotherapy should be administered as fast as possible because the treatment result is strongly dependent on the neurological residual function and the speed with which the neurological complaints developed [Rades 2002]. If the patient is still ambulant, but has progressive deficit, emergency radiotherapy (within 24 hours) may lead to recovery or stabilisation of the neurological deficit. There is no haste with stable neurological complaints that have existed for a longer period of time. If paraplegia has already occurred, a large percentage of these patients will remain bedridden [Rades, 2006]. It is important with neurological complaints to start as soon as possible with high-dose oral/iv dexamethasone in order to counteract compression of the oedema component. Short-term radiotherapy (1-2x8 Gy, or 5x4 Gy) is the treatment of choice for patients with a moderate prognosis (<1 year) [Maranzano, 2009]. A higher dose, e.g. 30 Gy in 10 fractions, should be considered if there is a better prognosis and limited disease activity [Rades, 2010].

For futher considerations, see the national Guideline Spinal epidural metastases at http://oncoline.nl/spinale-epidurale-metastasen.

 

Brain metastases

Brain metastases often cause serious neurological symptoms that strongly reduce quality of life. After diagnosis, the patient is started on dexamethasone to reduce tumour-induced oedema and therefore intracranial pressure. The aim of irradiation is reduction or stabilisation of metastases and neurological deficits, reduction in dexamethasone-dependency and a limited survival advantage [Bezjak, 2002, Tsao, 2005]. A feasible method to estimate the prognosis and the resulting value of palliative radiotherapy is the GPA classification [Sperduto, 2011].

A small percentage of patients have a solitary brain metastasis. More intensive local treatment may lead to a significant improvement in survival. A metastasectomy may be considered here. Stereotactical irradiation is a good alternative to surgery in patients with 1 to 3 metastases, a diameter of < 4 cm, who have little other disease activity [Akyurek, 2007; Rades, 2007; Kocher, 2011]. If a recurrence develops at a later stage, additional stereotactical or total brain irradiation may be administered [Chang, 2009].

For futher considerations, see the national Guideline Brain metastases at http://www.oncoline.nl/hersenmetastasen.

 

Meningitis carcinomatosa

Where there are neurological deficits due to tumour depositions in the meninges, treatment may consist of radiotherapy at locations causing clinically threatening symptoms. This generally concerns the entire brain up to and including the base of the skull, sometimes also the entire myelum and/or cauda equina. Given the blood-brain barrier usually does not function when a patient has meningitis carcinomatosa, systemic therapy may also be effective. This is partly dependent on the condition of the patient and any disease activity elsewhere partly determines the modality chosen.

For futher considerations, see the national Guideline Leptomeningeal metastases at http://www.oncoline.nl/leptomeningeale-metastasen.

 

Progressive, ulcerating and/or bleeding breast cancer or lymph node metastases

Radiotherapy has a favourable influence on locally progressive, ulcerating and/or bleeding primary tumours or on metastases in the skin, subcutis or lymph nodes. A single dose of 6 Gy or 20 Gy in 5 fractions may have a good analgesic and/or haemostatic effect. With larger and/or ulcerating laesions, a higher dose fractionated irradiation schedule is chosen, depending on the condition of the patient. A combination of hyperthermia and local radiotherapy may be considered in patients who have already received irradiation to a high dose [Zagar, 2010].

 

Tumour infiltration of the brachial plexus

Tumour infiltration of the brachial plexus is usually the result of periclavicular lymph node metastasis. Early diagnosis is important to prevent serious, chronic pain complaints and neurological deficit with loss of arm/shoulder function. High-dose radiotherapy provides some of patients with good palliation of pain and prevents (further) neurological deficit.

 

Orbital and intraocular metastases

Both orbital and choroidal metastases form an indication for radiotherapy. This treatment has a favourable influence on ptosis and eye movements and leads to a reduction in pain complaints, maintaining or even recovery in vision for most patients [Wiegel, 2002]. There may be an indication for emergency intervention, depending on the severity and progression of complaints.

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.