Appendix 2: evidence statements for grading the recommendations

SURGERY

Recommendation 1 – Surgery

In patients* with a single metastasis or limited number of brain metastases, the multidisciplinary team should consider initial surgery or radiosurgery^# (see rec #2) 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.

Hart 2011¹²; Andrews 2004¹³; Aoyama 2006¹⁴; Akyurek 2007¹⁵

Component	Grading
1. Evidence base Three randomised controlled trials included in a systematic review	B	One or two Level II studies with low risk of bias or a SR/multiple Level III studies with low risk of bias
2. Consistency	B	Most studies consistent and inconsistency can be explained
3. Clinical impact	C	Moderate
4. Generalisability Not all trial populations had breast cancer, but findings may be applied	C	Evidence not directly generalisable to the target population but could be sensibly applied
5. Applicability	B	Evidence applicable to Australian healthcare context with few caveats
Overall grade of recommendation	B
Other factors None identified
UNRESOLVED ISSUES None identified
IMPLEMENTATION OF RECOMMENDATION
Will this recommendation result in changes in usual care?		YES Minor changes to usual care; increased number of surgeries in some locations, little change in other areas
Are there any resource implications associated with implementing this recommendation?		YES Resource requirements may increase regarding surgical infrastructure and clinical staff
Will the implementation of this recommendation require changes in the way care is currently organised?		YES Increased communication between clinical disciplines and/or multidisciplinary teams may be required to support implementation
Are the guideline development group aware of any barriers to the implementation of this recommendation?		YES Increased demand for theatre time may exceed availability in some locations

Recommendation 2 – Surgery

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.

EORTC 22952-26001 (Kocher 2011 and Soffieti 2013)^16,17

Component	Grading
1. Evidence base Two randomised controlled trials	B	One or two Level II studies with low risk of bias or a SR/multiple Level III studies with low risk of bias
2. Consistency	B	Most studies consistent and inconsistency can be explained
3. Clinical impact	B	Substantial
4. Generalisability Limited number of breast cancer patients, however the Working Group considered it appropriate to apply to this population	B	Evidence directly generalizable to the target population with some caveats
5. Applicability	A	Evidence directly applicable to Australian healthcare context
Overall grade of recommendation	B
Other factors None identified
UNRESOLVED ISSUES None identified
IMPLEMENTATION OF RECOMMENDATION
Will this recommendation result in changes in usual care?		YES This recommendation supports delaying WBRT
Are there any resource implications associated with implementing this recommendation?		NO No significant resource implications associated with implementing this recommendation
Will the implementation of this recommendation require changes in the way care is currently organised?		NO This recommendation will not result in changes in the way care is currently organised
Are the guideline development group aware of any barriers to the implementation of this recommendation?		NO No barriers identified to the implementation of this recommendation

RADIOTHERAPY

Recommendation 3 – Radiotherapy

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.

Hart 2011¹²; Andrews 2004¹³; Aoyama 2006¹⁴; Akyurek 2007¹⁵

Component	Grading
1. Evidence base Two randomised controlled trials	B	One or two Level II studies with low risk of bias or a SR/multiple Level III studies with low risk of bias
2. Consistency	B	Most studies consistent and inconsistency can be explained
3. Clinical impact WBRT no longer standard of care for application to all patients	B	Substantial
4. Generalisability Limited number of breast cancer patients, however the Working Group considered it appropriate to apply to this population	B	Evidence directly generalizable to the target population with some caveats
5. Applicability	A	Evidence directly applicable to Australian healthcare context
Overall grade of recommendation	B
Other factors None identified
UNRESOLVED ISSUES None identified
IMPLEMENTATION OF RECOMMENDATION
Will this recommendation result in changes in usual care?	YES WBRT the previous standard of care
Are there any resource implications associated with implementing this recommendation?	YES Potentially, as more radiosurgery resources may be required
Will the implementation of this recommendation require changes in the way care is currently organised?	NO This recommendation will not result in changes in the way care is currently organised
Are the guideline development group aware of any barriers to the implementation of this recommendation?	YES There may be resource allocation issues

Recommendation 4 – Radiotherapy

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.

Harwood 1977²⁵; Kurtz 1981²⁶; Andrews 2004²⁰

Component	Grading
1. Evidence base	D	Level IV studies, or Level I to III studies with high risk of bias
2. Consistency	A	All studies consistent
3. Clinical impact	C	Moderate
4. Generalisability	B	Evidence directly generalizable to the target population with some caveats
5. Applicability	A	Evidence directly applicable to Australian healthcare context
Overall grade of recommendation	C
Other factors None identified
UNRESOLVED ISSUES None identified
IMPLEMENTATION OF RECOMMENDATION
Will this recommendation result in changes in usual care?		YES No perceived change in standard clinical practice as WBRT was the previous standard of care
Are there any resource implications associated with implementing this recommendation?		NO No significant resource implications associated with implementing this recommendation
Will the implementation of this recommendation require changes in the way care is currently organised?		NO This recommendation will not result in changes in the way care is currently organised
Are the guideline development group aware of any barriers to the implementation of this recommendation?		NO No barriers identified to the implementation of this recommendation

Recommendation 2 – Radiotherapy

EORTC 22952-26001 (Kocher 2011 and Soffieti 2013)^16,17

Component	Grading
6. Evidence base Two randomised controlled trials	B	One or two Level II studies with low risk of bias or a SR/multiple Level III studies with low risk of bias
7. Consistency	B	Most studies consistent and inconsistency can be explained
8. Clinical impact	B	Substantial
9. Generalisability Limited number of breast cancer patients, however the Working Group considered it appropriate to apply to this population	B	Evidence directly generalizable to the target population with some caveats
10. Applicability	A	Evidence directly applicable to Australian healthcare context
Overall grade of recommendation	B
Other factors None identified
UNRESOLVED ISSUES None identified
IMPLEMENTATION OF RECOMMENDATION
Will this recommendation result in changes in usual care?		YES This recommendation supports delaying WBRT
Are there any resource implications associated with implementing this recommendation?		NO No significant resource implications associated with implementing this recommendation
Will the implementation of this recommendation require changes in the way care is currently organised?		NO This recommendation will not result in changes in the way care is currently organised
Are the guideline development group aware of any barriers to the implementation of this recommendation?		NO No barriers identified to the implementation of this recommendation

SYSTEMIC THERAPIES

Recommendation 5 – Systemic therapies

Avoid routine use of chemotherapy with WBRT in patients with newly diagnosed brain metastases.

Mehta 2010²⁸

Component	Grading
1. Evidence base Five studies included in systematic review by Mehta – four randomised, including two phase II studies. Small numbers of breast cancer patients included in trials	C	Level III studies with low risk of bias, or Level I or II studies with moderate risk of bias
2. Consistency Similar results shown across studies	B	Most studies consistent and inconsistency can be explained
3. Clinical impact No evidence of benefit shown in included studies	C	Moderate
4. Generalisability Most included patients from lung cancer trials, however can be applied to breast cancer patients	C	Evidence not directly generalisable to the target population but could be sensibly applied
5. Applicability It is feasible to apply this recommendation	B	Evidence applicable to Australian healthcare context with few caveats
Overall grade of recommendation	C
Other factors If patient is receiving chemotherapy for control of extra-cranial disease, it is not clear from the available evidence whether that should be stopped or not
UNRESOLVED ISSUES None identified
IMPLEMENTATION OF RECOMMENDATION
Will this recommendation result in changes in usual care?		NO No perceived change in standard clinical practice and care
Are there any resource implications associated with implementing this recommendation?		YES Positive effect – cost savings through less medications, potential for less treatment-related morbidity
Will the implementation of this recommendation require changes in the way care is currently organised?		NO This recommendation will not result in changes in the way care is currently organised
Are the guideline development group aware of any barriers to the implementation of this recommendation?		NO No barriers identified to the implementation of this recommendation

Recommendation 6 – Systemic therapies

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.

Pestalozzi 2013²⁹; Bartsch 2007³⁰; Church 2008³¹; Dawood 2008³²; Park 2009³³; Le Scodan 2011³⁴; HERA 2013²⁹

Component	Grading
1. Evidence base Retrospective trials	C	Level III studies with low risk of bias, or Level I or II studies with moderate risk of bias
2. Consistency	B	Most studies consistent and inconsistency can be explained
3. Clinical impact Trastuzumab does not cross blood-brain barrier but patients tend to do better with well-controlled systemic disease, minimal harm observed	B	Substantial
4. Generalisability	B	Evidence directly generalizable to target population with some caveats
5. Applicability Feasible to apply within PBS	B	Evidence applicable to Australian healthcare context with some caveats
Overall grade of recommendation	C
Other factors None identified
UNRESOLVED ISSUES None identified
IMPLEMENTATION OF RECOMMENDATION
Will this recommendation result in changes in usual care?		NO No perceived change in standard clinical practice and care
Are there any resource implications associated with implementing this recommendation?		YES Expense associated with ongoing treatment, requires intravenous treatment, monitoring of cardiac function may be required, used for any metastatic disease
Will the implementation of this recommendation require changes in the way care is currently organised?		NO This recommendation will not result in changes in the way care is currently organised
Are the guideline development group aware of any barriers to the implementation of this recommendation?		NO No barriers identified to the implementation of this recommendation

Recommendation 7 – Systemic therapies

HER2-positive patients with progressive or residual disease following local therapy and trastuzumab may be offered lapatinib in combination with capecitabine.

Lin 2009³⁵

Component	Grading
1. Evidence base One phase II randomised study	D	Level IV studies, or Level I to III studies with high risk of bias
2. Consistency	N/A	One study only
3. Clinical impact Patients limited in other choices following progression after local therapy, better control over longer period of time, reluctance to change to lapatinib among oncologists	C	Moderate
4. Generalisability Feasible within PBS guidelines	D	Evidence not directly generalizable to target population and hard to judge whether it is sensible to apply
5. Applicability Feasible to apply	C	Evidence probably applicable to Australian healthcare context with some caveats
Overall grade of recommendation	C
Other factors None identified
UNRESOLVED ISSUES None identified
IMPLEMENTATION OF RECOMMENDATION
Will this recommendation result in changes in usual care?		YES Limited number of clinicians currently offering this as standard treatment, reluctance to change to lapatinib
Are there any resource implications associated with implementing this recommendation?		YES Oncologist time unfunded as no item number available for non-IV delivery
Will the implementation of this recommendation require changes in the way care is currently organised?		YES Non-IV delivery indicates there will be no chemo nurse providing regular support, increasing the supportive care burden on treating oncologist
Are the guideline development group aware of any barriers to the implementation of this recommendation?		YES PBS item number not available

SPINAL CORD COMPRESSION

Recommendation 8 – Spinal cord compression

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.

Patchell 2005⁴⁰

Component	Grading
1. Evidence base One RCT	B	One or two Level II studies with a low risk of bias or SR/several Level III studies with a low risk of bias
2. Consistency	N/A	One study only
3. Clinical impact	B	Substantial impact
4. Generalisability	C	Evidence not directly generalisable to the target population but could be sensibly applied
5. Applicability	B	Evidence applicable to Australian healthcare context with few caveats
Overall grade of recommendation	B
Other factors None identified
UNRESOLVED ISSUES None identified
IMPLEMENTATION OF RECOMMENDATION
Will this recommendation result in changes in usual care?		YES Standard treatment for spinal cord compression is corticosteroids and radiotherapy
Are there any resource implications associated with implementing this recommendation?		YES Not all health services have access to neurosurgery and MRI
Will the implementation of this recommendation require changes in the way care is currently organised?		NO
Are the guideline development group aware of any barriers to the implementation of this recommendation?		YES Demand for after-hours MRI and surgical services may be increased and this may stretch existing infrastructure and staff

Recommendation 9 – Spinal cord compression

Start external beam radiotherapy as soon as possible for patients considered unsuitable for surgery.

Loblaw 2005⁴¹

Component	Grading
1. Evidence base One systematic review	B	One or two Level II studies with a low risk of bias or SR/several Level III studies with a low risk of bias
2. Consistency	N/A	One study only
3. Clinical impact	B	Moderate
4. Generalisability	B	Evidence directly generalisable to the target population with some caveats
5. Applicability	B	Evidence applicable to Australian healthcare context with some caveats
Overall grade of recommendation	B
Other factors None identified
UNRESOLVED ISSUES None identified
IMPLEMENTATION OF RECOMMENDATION
Will this recommendation result in changes in usual care?		NO Standard treatment for spinal cord compression is corticosteroids and radiotherapy
Are there any resource implications associated with implementing this recommendation?		YES A shortage of radiotherapy machines and specialists is currently limiting timely access to urgent radiotherapy treatment
Will the implementation of this recommendation require changes in the way care is currently organised?		NO
Are the guideline development group aware of any barriers to the implementation of this recommendation?		YES Access to radiotherapy machines and specialists.

Appendix 2: evidence statements for grading the recommendations