The statements of evidence are based on evidence identified in the Cancer Australia systematic review7 as well as primary studies included in the identified Cochrane reviews. Further details are available in the Cancer Australia systematic review and the Evidence from trial or study results section. The systematic review focused on evidence for the management of CNS metastases in women with metastatic breast cancer, however some studies were included that had patient populations with various primary tumours.
| No. | STATEMENTS OF EVIDENCE – SURGERY | Reference | Level of evidence8 |
|---|---|---|---|
|
|
Overall survival |
|
|
|
1 |
Pooled data from three RCTs including patients with multiple cancer primaries, showed no significant difference in overall survival among patients having surgery and WBRT compared to patients having WBRT alone. |
Hart 201112 |
I |
|
2 |
Mortality at 30 days was not significantly different in patients who had surgery and WBRT compared to patients who had WBRT alone in three RCTs (I2=0%). |
Mintz 199642 |
II |
|
|
Functionally independent survival / neurological death |
|
|
|
3 |
In one RCT, compared to WBRT alone, surgery and WBRT was found to increase the duration of Functionally Independent Survival and may reduce the risk of death due to neurological cause. |
Patchell 199043 |
II |
|
|
Adverse effects |
|
|
|
4 |
The risk of adverse effects was not significantly different among patients who had surgical resection and WBRT compared to patients who had WBRT alone. |
Vecht 199344 Mintz 199642 |
II |
Abbreviations: RCT – randomised controlled trial; WBRT – whole brain radiotherapy
| No. | STATEMENTS OF EVIDENCE – RADIOTHERAPY | Reference | Level of evidence |
|---|---|---|---|
|
Radiosurgery* |
|||
|
|
Overall survival |
|
|
|
1 |
Among patients with 1-4 brain metastases from various primary tumours, no significant survival benefit was demonstrated for WBRT plus stereotactic radiosurgery boost versus WBRT alone. |
Tsao 201245 |
I |
|
2 |
Among patients with a single, un-resectable brain metastasis, improved survival was observed for WBRT plus SRS (6.5 months) compared to WBRT alone (4.9 months). |
Andrews 200413 |
II |
|
|
Recurrence |
|
|
|
3 |
WBRT plus radiosurgery boost may improve local disease control in selected patients, compared to WBRT alone. |
Andrews 200413 Kondziolka 199946 |
II |
|
4 |
One year local control rates were 79% for patients receiving SRS as initial treatment, and 77% for patients receiving salvage SRS after WBRT treatment. Rates of distant brain metastases-free survival were not statistically different between patients receiving SRS alone as initial treatment (64%) compared to SRS as salvage treatment after initial WBRT (57%) at one year. |
Akyurek 200715
|
IV |
|
WBRT |
|
|
|
|
|
Overall survival |
|
|
|
5 |
Among patients who have had prior radiosurgery or surgery, similar rates of survival are found following WBRT or observation. |
Kocher 2011(EORTC 22952-2600)16 |
II |
|
6 |
Among patients with 1-4 brain metastases, no significant difference between radiosurgery alone and radiosurgery plus WBRT was observed. |
Tsao 201245 |
I |
|
7 |
Among patients treated with WBRT, improved survival rates were associated with KPS >70, age less than 65 years, controlled primary disease, and no extra-cranial metastases. Shorter median survival rates were associated with KPS <70. |
Gaspar199747
|
IV |
|
8 |
Analysis of breast cancer patients treated with different WBRT regimens as the primary therapy for brain metastases identified that improved survival was significantly associated with KPS score >70, lower RPA class, lower number of brain metastases (1-3) and no extra-cranial metastases on multivariate analyses. |
Rades 201148 Rades 200749 |
IV |
|
|
Recurrence |
|
|
|
9 |
Compared to observation alone, WBRT reduced the probability of intra-cranial progression at initial sites and new sites in the brain following surgery or radiosurgery. WBRT also reduced the need for salvage treatment. |
Kocher (EORTC 22952-26001)16 |
II |
|
10 |
Radiosurgery plus WBRT conferred a significant benefit in local control (p=<0.0001) and distant brain control (p=<0.00001) compared to radiosurgery alone in three RCTs. Retrospective analysis of breast cancer patients with brain metastases observed no significant difference between SRS alone and SRS plus WBRT. |
Tsao 201245 Aoyama 200614 Chang 200950 Kocher 201116 |
II |
|
11 |
WBRT plus SRS was significantly associated with improved brain tumour control (p=0.002) and less frequent need for salvage treatment compared to SRS alone. |
Aoyama 200614 |
II |
|
12 |
Among patients with a single brain metastasis, compared with surgical resection alone, WBRT following surgery confers significant reduction in recurrence in the brain (18% vs. 70%, p=<0.001). Recurrence was less frequent at the original site and at distant sites within the brain (p=0.001). The time to any recurrence was significantly longer among the group who had post-operative WBRT. |
Patchell 199851 |
II |
|
13 |
Retrospective analysis comparing SRS as initial treatment to SRS as salvage treatment following WBRT observed similar rates of distant brain metastases-free survival (64% and 57% at one year). Of the 34 patients treated with initial SRS alone, ten (29%) later received WBRT. The one-year freedom from WBRT was 62%. |
Akyurek 200715 |
IV |
|
|
Quality of life |
|
|
|
14 |
Palliative WBRT is associated with significant improvements in intracranial pressure (p=<0.01), headache (p=<0.001) and sensory dysfunction (p=<0.01). Improvements (though not significant) were also observed for motor function and convulsions. |
Yaneva 200652 |
III |
|
15 |
One prospective trial observed a significant improvement in global health-related quality of life scores at 9 months among patients who had observation only following local therapy (surgery or SRS) compared to patients who had adjuvant WBRT (p=0.0148). Included patients had 1-3 brain metastases from various primary tumours. Improved mean scores were reported for physical, role and cognitive functioning using the EORTC-C30 scale. No differences were found at any other time points. |
Soffietti (EORTC 22952-26001)17 |
II |
|
Altered fractionation WBRT |
|||
|
|
Overall survival |
|
|
|
16 |
No survival benefit was shown in altered fractionation WBRT compared to the control dose (30 Gy in 10 daily fractions), although one RCT (with 19% of included patients have brain metastases from breast cancer) found a significant difference favouring the control dose, compared to 12 Gy in two fractions. |
Tsao 201245 Rades 200749 Rades and Lohrynska 200753 Rades 201148 Priestman 199654 |
I |
|
|
Neurological function |
|
|
|
17 |
Significant improvement in neurological function is associated with the standard WBRT regimen (30 Gy in 10 fractions) compared to a lower dose (p=0.03). There was no significant difference in neurological function for those treated with a higher dose compared to the standard dose. |
Tsao 201245 Borgelt 198055 Borgelt 198156 Kurtz 198126 |
I |
|
|
Recurrence |
|
|
|
18 |
Similar rates of progression of intra-cerebral disease were observed among patients receiving a WBRT regimen of 5 fractions of 4 Gy (12%) and patients receiving higher doses (9%). |
Rades & Lohrynska 200753 |
IV |
|
|
Adverse events |
|
|
|
19 |
Similar rates of adverse events (including grade three toxicity) were observed in patients receiving a standard WBRT regimen of 30 Gy in 10 fractions compared to higher doses (45 Gy in 15 fractions and 40 Gy in 20 fractions) or shorter schedules (20 Gy in 5 fractions). |
Rades 200749; Rades & Lohrynska 200753 |
IV |
|
WBRT plus radiosensitisers |
|||
|
20 |
The addition of radiosensitisers to WBRT compared to WBRT alone did not confer any benefit in rates of survival or brain tumour response. |
Tsao 201245 |
I |
|
Subgroups |
|||
|
21 |
Following WBRT, HER2-positive status is significantly associated with improved survival compared to HER2-negative status, hormone receptor-positive or triple receptor-negative disease. |
Wolstenholme 200857 Dawood 201058 |
IV |
Abbreviations: EORTC – European Organisation for Research and Treatment of Cancer; HER2 – human epidermal growth factor receptor 2; KPS – Karnofsky Performance Status; SRS – stereotactic radiosurgery; WBRT – whole brain radiotherapy
| No. | STATEMENTS OF EVIDENCE – SYSTEMIC THERAPIES | Reference | Level of evidence |
|---|---|---|---|
|
Chemotherapy |
|||
|
|
Overall survival |
|
|
|
1 |
Among patients with newly diagnosed brain metastases from various primary tumours, the addition of chemotherapy to WBRT added no benefit for overall survival or neurologic progression compared to WBRT alone. |
Mehta 201028 |
I |
|
2 |
Two studies investigating the use of methotrexate alone or in combination with other chemotherapies in patients with brain metastases from breast cancer observed median overall survival of 6.5 months and 6.9 months. |
Bazan 201159 Jacot 201060 |
IV |
|
|
Progression free survival / time to progression |
|
|
|
3 |
In a systematic review, six studies investigated temozolomide alone or in combination with other chemotherapies in patients with recurrent/progressive metastatic brain disease from various primary tumours. A median time to recurrence or progression after re-treatment of 2–4 months was observed. Some patients had an objective radiographic response and/or improvement in functional status after chemotherapy treatment. |
Ammirati 201061
|
II |
|
|
Adverse events |
|
|
|
4 |
Commonly reported adverse events of various chemotherapies include thrombocytopenia, nausea, vomiting, headache, fatigue, leukopenia, anaemia and neutropenia. |
Bazan 201159 Christodoulou 200562 Freedman 201163 Melisko 200964 Murphy 200965 Rivera 200666 Siena 201067 |
III |
|
Trastuzumab |
|||
|
|
Overall survival |
|
|
|
5 |
For women with HER2-positive breast cancer, increased survival was reported among those treated with trastuzumab or who continued trastuzumab after diagnosis of CNS metastases.
|
Bartsch 200730 Church 200831 Dawood 200832 Park 200933 Le Scodan 201134 |
IV |
|
6 |
In hormone receptor-negative, HER2-positive patients, the median survival after a brain metastases diagnosis was significantly longer in patients given trastuzumab after brain metastases compared with no trastuzumab treatment after brain metastases diagnosis. |
Park 200933 |
IV |
|
7 |
Survival was significantly longer among HER2-positive patients receiving trastuzumab compared with HER2-negative patients (p=0.027). |
Church 200831 |
IV |
|
|
Incidence of CNS metastases as first relapse site |
|
|
|
8 |
Compared to no treatment, one year of trastuzumab for patients with HER2-positive early breast cancer significantly reduces the cumulative incidence of non-CNS relapses as the first recurrent event (p=<0.0001), however the frequency of CNS relapse did not differ. |
HERA trial29 |
IV |
|
|
Time to progression |
|
|
|
9 |
Among HER2-positive breast cancer patients, trastuzumab was significantly associated with longer time to progression than no trastuzumab treatment. |
Park 200933 |
IV |
|
Lapatinib and capecitabine: previously untreated CNS metastases^ |
|||
|
|
Overall survival |
|
|
|
10 |
Among HER2-positive patients treated with lapatinib and capecitabine, a median overall survival of 17 months was observed, with 90.9% overall survival at six months. |
Bachelot 201336 (LANDSCAPE) |
III |
|
|
Response rate |
|
|
|
11 |
Of HER2-positive patients taking lapatinib and capecitabine, 65.9% had an objective CNS response (n=29, all partial responses). |
Bachelot 201336 (LANDSCAPE) |
III |
|
12 |
The rates of objective CNS responses following lapatinib and capecitabine were similar among patients previously treated with trastuzumab compared to no previous trastuzumab treatment. |
Bachelot 201336 (LANDSCAPE) |
III |
|
|
Volumetric reduction |
|
|
|
13 |
A CNS volumetric reduction of 80% or greater was observed in nine HER2-positive patients (20%) taking lapatinib and capecitabine. 84% of patients (n=37) had a reduction in tumour volume from baseline measurements. |
Bachelot 201336 (LANDSCAPE) |
III |
|
|
Time to progression |
|
|
|
14 |
Median time to progression for HER2-positive patients treated with lapatinib and capecitabine was 5.5 months. The median time to radiotherapy was 8.3 months. The reported sites of first progression were:
|
Bachelot 201336 (LANDSCAPE) |
III |
|
|
Adverse events |
|
|
|
15 |
Of HER2-positive patients treated with lapatinib and capecitabine, approximately half experienced at least one grade 3 or grade 4 adverse event, most commonly diarrhoea and hand-foot syndrome. |
Bachelot 201336 (LANDSCAPE) |
III |
|
Lapatinib and capecitabine: previously treated CNS metastases^ |
|||
|
|
Overall survival |
|
|
|
16 |
Treatment with lapatinib and capecitabine is significantly associated with improved median survival after brain progression compared to trastuzumab-based therapy alone (27.9 months vs. 16.7 months, p=0.01). At a median of 26 months follow-up, overall survival was not reached for the 6 patients who received lapatinib and capecitabine as the first systemic therapy after diagnosis of brain metastases. |
Metro 201168
|
IV |
|
|
Response rate |
|
|
|
17 |
Among HER2-positive patients previously treated with WBRT and chemotherapy plus trastuzumab, lapatinib in combination with capecitabine was shown to have higher response rates than lapatinib alone. No objective responses were observed in patients who received lapatinib with topotecan. |
Lin 200935 Lin 201169 |
III |
|
|
Adverse events |
|
|
|
18 |
Among HER2-positive breast cancer patients receiving lapatinib the most commonly reported adverse events as diarrhoea, fatigue, rash, headache and vomiting. |
Lin 200870 Lin 200935 |
III |
|
19 |
Among HER2-positive breast cancer patients receiving lapatinib in combination with capecitabine, the most commonly reported adverse events were diarrhoea, palmar-plantar erythrodysesthesia, nausea and fatigue. |
Lin 200935 Lin 201169 |
III |
|
20 |
A prospective study comparing lapatinib and capecitabine to lapatinib and topotecan closed accrual of patients to the lapatinib and topotecan arm due to tolerability issues in combination with a lack of early efficacy. |
Lin 201169 |
III |
Abbreviations: CNS – central nervous system; CDDP - cis-diamminedichloroplatinum (Cisplatin); HER2 – human epidermal growth factor receptor 2; KPS – Karnofsky Performance Status; SRS – stereotactic radiosurgery; WBRT – whole brain radiotherapy
| No. | STATEMENTS OF EVIDENCE – SPINAL CORD COMPRESSION | Reference | Level of evidence |
|---|---|---|---|
|
|
Symptoms of spinal cord compression |
|
|
|
1 |
Frequently observed symptoms of spinal cord compression include back pain, motor weakness, sensory changes and bladder dysfunction. |
Loblaw 200541 |
II |
|
|
Investigation of suspected spinal cord compression |
|
|
|
2 |
Three case series and a retrospective review on the accuracy of MRI, reported sensitivity from 0.44 to 0.93 and specificity from 0.90 to 0.98. |
Husband 200171 Hagenau 198772 Carmody 198973 Li 198874 |
IV |
|
|
Use of corticosteroids |
|
|
|
3 |
In an RCT comparing a 100mg to 10mg initial dose of dexamethasone, there were no significant differences in pain, ambulation or bladder function. All patients were treated with radiotherapy and maintenance dexamethasone of 16mg/d orally after the initial treatment. |
Vecht 198937 |
II |
|
4 |
In one RCT comparing high-dose dexamethasone with no dexamethasone as adjunct to radiotherapy a successful treatment result, defined as gait function after treatment, was achieved in 81% of patients treated with dexamethasone compared with 63% of patients not receiving dexamethasone. In a subgroup analysis of breast cancer patients a successful treatment result was achieved in 94% of dexamethasone patients compared with 69% of patients without dexamethasone, although difference was not significant. |
Sorensen 199438 |
II |
|
5 |
Life table analysis demonstrated a higher percentage of patients receiving dexamethasone surviving with gait function during 1 year compared with those not receiving dexamethasone (p=0.046). |
Sorensen 199438 |
II |
|
|
Surgery for spinal cord compression |
|
|
|
6 |
One RCT comparing surgery followed by radiotherapy (n=50) to radiotherapy alone (n=51) found significantly more patients in the surgical arm were able to walk after treatment compared to those receiving radiotherapy (84% vs. 57%, odds ratio 6.2, p=0.001). Patients treated with surgery maintained the ability to walk significantly longer than those treated with radiotherapy alone (median 122 days vs. 13 days, p=0.003). |
Patchell 200540 |
II |
|
7 |
Thirty-day mortality rates were 6% in the surgical arm compared to 14% in the radiotherapy arm (p=0.32). The median hospital stay was 10 days for patients in both treatment arms (p=0.86). |
Patchell 200540 |
II |
|
8 |
The RCT found surgical treatment was significantly associated with the maintenance of continence, muscle strength, functional ability and increased survival times. |
Patchell 200540 |
II |
|
|
Radiotherapy |
|
|
|
9 |
Various doses of radiotherapy to treat spinal cord compression were investigated in eight studies. No regimens demonstrated higher rates of ambulation compared with another. |
Maranzano 199575; Maranzano 199676 Helweg-Larsen 199677 Maranzano 199878 Greenberg 198079 Kovner 199980 Ampil 199581 Rades 200282 |
III-2 - IV |
* 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.
^ Based on a trial population not treated with WBRT or SRS
^ Based on trial populations who may have been treated with WBRT or SRS