Clinical practice recommendations and practice points

The recommendations are based on the statements of evidence for the management of central nervous system (CNS) metastases in women with metastatic breast cancer. Practice points and supporting information are also provided to help guide clinical decisions for the management of CNS metastases in women with metastatic breast cancer. Practice points are based on expert opinion when the evidence to make a recommendation is insufficient or where the evidence is outside the scope of the systematic review.

All recommendations have been graded using the National Health and Medical Research Council (NHMRC) evidence grading system.⁸ The FORM framework consists of five components (evidence base, consistency, clinical impact, generalisability and applicability) which are used by guideline developers to structure their decisions on how to convey the strength of a recommendation through wording and grading via a considered judgment form. The NHMRC grades (A-D) assigned to the recommendation given are intended to indicate the strength of the body of evidence underpinning the recommendation (refer to Table 1). Appendix 1 provides further detail of the NHMRC FORM grading methodology and the process undertaken in the grading of all recommendations contained in this guideline. See also Appendix 2 for Evidence Statements for Grading the Recommendations.

Table 1: Definition of NHMRC grades of recommendations^8,9

Grade of recommendation	Description
A	Body of evidence can be trusted to guide practice
B	Body of evidence can be trusted to guide practice in most situations
C	Body of evidence provides some support for recommendation(s) but care should be taken in its application
D	Body of evidence is weak and recommendation must be applied with caution

Recommendations and practice points should be considered in the context of clinical judgement for each patient.

Considerations should include the absolute benefits and harms of treatments, other treatments used, patient’s preferences and quality of life issues. These factors should be discussed with the woman and her family and carer(s), tailored to their preferences for information and decision-making involvement.

The recommendations for the management of central nervous system (CNS) metastases in women with metastatic breast cancer should be considered within a multidisciplinary team setting.

Multidisciplinary care is the best practice approach to providing evidence-based cancer care. Multidisciplinary care (MDC) is an integrated team-based approach to cancer care where medical and allied health care professionals consider all relevant treatment options and collaboratively develop an individual treatment and care plan for each patient.¹⁰ A multidisciplinary team approach to care should be considered for all patients with advanced breast cancer. The multidisciplinary team for advanced disease should reflect clinical and psychosocial aspects of care.¹¹

RECOMMENDATIONS – SURGERY		Grade	References
1	In patients with a single metastasis or limited number of brain metastases, the multidisciplinary team should consider initial surgery or radiosurgery(RS)^# (see rec #3) for selected patients. Patients with good performance status with a single (or small number of metastases) accessible lesion(s), inactive/well-controlled extra-cranial disease and limited co-morbidities, and patients with raised intracranial pressure or other uncontrolled symptoms.	B	Hart 2011¹² Andrews 2004¹³ Aoyama 2006¹⁴ Akyurek 2007¹⁵
2	In patients who have had local therapy (surgery or RS) for all metastases and have no measurable CNS disease, give consideration to observation alone with an appropriate salvage technique (surgery, RS or WBRT) used on brain progression. Further treatment should be based on individual patterns of relapse.	B	EORTC 22952-26001 (Kocher 2011 and Soffieti 2013)^16,17
PRACTICE POINTS – SURGERY			References
a	Following surgical resection or radiosurgery to brain metastases, monitor the patient with imaging every three months to identify lesions early to maximise management options.		EORTC 22952-26001 (Kocher 2011 and Soffieti 2013)^16,17
b	For selected patients* with multiple brain metastases, surgical resection of a symptomatic lesion(s) may be considered. * Patients with good performance status with an accessible lesion(s), inactive/well-controlled extra-cranial disease and limited co-morbidities, and patients with raised intracranial pressure or other uncontrolled symptoms, and/or HER2-positive.
c	Ensure pathological review of surgically resected specimens to confirm histology and hormone and HER2 receptor status, which may differ from the primary tumour.
d	Anticonvulsant medication is indicated only if a patient has had a seizure.		Mikkelson et al (2010)¹⁸ Quality Standards Subcommittee of the American Academy of Neurology (2000)¹⁹
e	The minimum effective dose of steroids (dexamethasone) should be used when indicated for the relief of neurological symptoms. Consider avoiding a night-time dose of steroids to minimise the toxicity profile.		Vecht 1994²⁰
f	Driving is not recommended for patients with newly diagnosed CNS metastases. Return to driving may be considered based on seizure control, neurological deficit, tumour control and response to therapy. Refer to the local licensing authority for up-to-date information about driving and returning to driving, and any testing that may be required http://www.austroads.com.au/drivers-vehicles/assessing-fitness-to-drive Consider referral to social work services for local transport assistance options.		Austroads 2012²¹ Beran 2013²²
g	Following surgery, radiotherapy or chemotherapy, consider assessment by allied health and/or rehabilitation services to optimise function and quality of life.
h	The multidisciplinary team should consider use of the Breast-GPA as a tool to assess prognosis and to aid treatment decisions. The Breast-GPA is a prognostic index for breast cancer patients with brain metastases. The GPA was developed following the Radiation Therapy Oncology Group’s (RTOG) Recursive Partitioning Analysis as an updated index for patients with brain metastases.		Sperduto 2012²³,²⁴

Abbreviations: GPA – Graded Prognostic Assessment

^#Note: the term radiosurgery in these guidelines applies to the use of a single dose (or limited number of doses) of ablative radiotherapy to brain metastases using highly precise immobilisation, dosimetric planning, delivery and verification system and can include (but is not limited to) stereotactic radiosurgery, gamma knife radiosurgery, Cyber knife radiosurgery or radiosurgery delivered using Tomotherapy or IMRT/VMAT.

RECOMMENDATIONS – RADIOTHERAPY		Grade	References
3	On diagnosis of brain metastases, the multidisciplinary team should consider local therapies (radiosurgery or surgery, refer to rec #1) in selected patients. Patients with good performance status (KPS score above 70), small number and small size of metastases suitable for localised therapies, adequate haematological reserve and well-controlled primary disease.	B	Hart 2011¹² Andrews 2004¹³ Aoyama 2006¹⁴ Akyurek 2007¹⁵
4	Consider WBRT for patients^* who are not eligible for surgery or radiosurgery. * Patients with multiple metastases, uncontrolled extra-cranial disease, limited prognosis, or not expected to benefit from radiosurgery or surgery.	C	Harwood 1977²⁵ Kurtz 1981²⁶ Andrews 2004²⁰
2	In patients who have had local therapy (surgery or RS) for all metastases and have no measurable CNS disease, give consideration to observation alone with an appropriate salvage technique (surgery, RS or WBRT) used on brain progression. Further treatment should be based on individual patterns of relapse.	B	EORTC 22952-26001 (Kocher 2011 and Soffieti 2013)^16,17
PRACTICE POINTS – RADIOTHERAPY			References
i	If adjuvant WBRT is delayed following local therapy of limited brain metastases, monitor the patient with imaging every three months.		EORTC 22952-26001 (Kocher 2011 and Soffieti 2013)^16,17
j	Patients with poor performance status who are considered unlikely to benefit from local therapies or WBRT should be referred to specialist palliative care services, based on a determination of their prognosis and complexity of needs.		NICE guidelines²⁷
e	The minimum effective dose of steroids (dexamethasone) should be used when indicated for the relief of neurological symptoms. Consider avoiding a night-time dose of steroids to minimise the toxicity profile.		Vecht 1994²⁰
f	Driving is not recommended for patients with newly diagnosed CNS metastases. Return to driving may be considered based on seizure control, neurological deficit, tumour control and response to therapy. Refer to the local licensing authority for up-to-date information about driving and returning to driving, and any testing that may be required http://www.austroads.com.au/drivers-vehicles/assessing-fitness-to-drive Consider referral to social work services for local transport assistance options.		Austroads 2012²¹ Beran 2013²²
g	Following surgery, radiotherapy or chemotherapy, consider assessment by allied health and/or rehabilitation services to optimise function and quality of life.
h	The multidisciplinary team should consider use of the Breast-GPA as a tool to assess prognosis and to aid treatment decisions. The Breast-GPA is a prognostic index for breast cancer patients with brain metastases. The GPA was developed following the Radiation Therapy Oncology Group’s (RTOG) Recursive Partitioning Analysis as an updated index for patients with brain metastases.		Sperduto 2012²³, ²⁴

Abbreviations: CNS – central nervous system; GPA – Graded Prognostic Assessment; MRI – magnetic resonance imaging; RS –radiosurgery*; WBRT – whole brain radiotherapy; KPS – Karnofsky Performance Status.

*Note: the term radiosurgery (RS) in these guidelines applies to the use of a single dose (or limited number of doses) of ablative radiotherapy to brain metastases using highly precise immobilisation, dosimetric planning, delivery and verification system and can include (but is not limited to) stereotactic radiosurgery, gamma knife radiosurgery, Cyber knife radiosurgery or radiosurgery delivered using Tomotherapy or IMRT/VMAT.

RECOMMENDATIONS – SYSTEMIC THERAPIES		Grade	References
5	Avoid routine use of chemotherapy with WBRT in patients with newly diagnosed brain metastases.	C	Mehta 2010²⁸
6	To achieve optimal control of extra-cranial disease, HER2- targeted therapies (such as trastuzumab) should be started or continued in HER2-positive patients after the diagnosis of brain metastases.	C	Pestalozzi 2013²⁹ Bartsch 2007³⁰ Church 2008³¹ Dawood 2008³² Park 2009³³ Le Scodan 2011³⁴ HERA 2013²⁹
7	HER2-positive patients with progressive or residual disease following local therapy and trastuzumab may be offered lapatinib in combination with capecitabine.	C	Lin 2009³⁵
PRACTICE POINTS – SYSTEMIC THERAPIES			References
k	Consider lapatinib and capecitabine for initial treatment for HER2-positive patients who develop brain metastases without mass effect. Close observation of response is appropriate, and radiotherapy or surgery may be offered on progression.		Bachelot 2013³⁶
l	For patients with progressive brain metastases who are fit for further chemotherapy, platinum-based agents or high dose methotrexate may be considered.
m	Only start anticonvulsant medication if a patient has had a seizure.		Mikkelson et al (2010)¹⁸ Quality Standards Subcommittee of the American Academy of Neurology (2000)¹⁹
e	The minimum effective dose of steroids (dexamethasone) should be used when indicated for the relief of neurological symptoms. Consider avoiding a night-time dose of steroids to minimise the toxicity profile.		Vecht 1994²⁰
f	Driving is not recommended for patients with newly diagnosed CNS metastases. Return to driving may be considered based on seizure control, neurological deficit, tumour control and response to therapy. Refer to the local licensing authority for up-to-date information about driving and returning to driving, and any testing that may be required (include link) Consider referral to social work services for local transport assistance options.		Austroads 2012²¹ Beran 2013²²
g	Following surgery, radiotherapy or chemotherapy, consider assessment by allied health and/or rehabilitation services to optimise function and quality of life.
h	The multidisciplinary team should consider use of the Breast-GPA as a tool to assess prognosis and to aid treatment decisions. The Breast-GPA is a prognostic index for breast cancer patients with brain metastases. The GPA was developed following the Radiation Therapy Oncology Group’s (RTOG) Recursive Partitioning Analysis as an updated index for patients with brain metastases.		Sperduto 2012²³, ²⁴

Abbreviations: GPA – Graded Prognostic Assessment; HER2 – human epidermal growth factor receptor 2; WBRT – whole brain radiotherapy

RECOMMENDATIONS – SPINAL CORD COMPRESSION		Grade	References
8	In patients* with symptomatic spinal cord compression caused by metastatic disease, circumferential surgical decompression should be performed (within 24 hours), with or without fusion, followed by radiotherapy. *Patients who are acceptable surgical candidates and have expected survival of at least three months.	B	Patchell 2005⁴⁰
9	Start external beam radiotherapy as soon as possible for patients considered unsuitable for surgery.	B	Loblaw 2005⁴¹
PRACTICE POINTS – SPINAL CORD COMPRESSION			References
n	Dexamethasone should be started on suspicion of spinal cord compression and while awaiting assessment. Monitor closely for side effects and taper after radiotherapy.		Vecht 1989³⁷ Sorensen 1994³⁸ Heimdal 1992³⁹
o	Spinal cord compression is a medical emergency and urgent multidisciplinary management is advisable.		Loblaw 2005⁴¹
p	Consider use of whole spine MRI to investigate suspected spinal cord compression.		Loblaw 2005⁴¹
g	Following surgery or radiotherapy consider assessment by allied health and/or rehabilitation services to optimise function and quality of life.
q	Patients considered unsuitable for disease-specific treatment, or with progression of neurological deficit after treatment, require input from specialist palliative care services based on a determination of their long-term survival and complexity of needs. Consider seeking advice from a spinal injuries unit for appropriate care needs of patients with spinal cord compression.		NICE guidelines²⁷

Abbreviations: MRI – magnetic resonance imaging

Clinical practice recommendations and practice points