Evidence from trial or study resultsEvidence from trial or study results Anonymous (not verified)
A Cancer Australia systematic review7 on the management of CNS metastases in women with metastatic breast cancer was undertaken, with available evidence published between January 2001 and April 2012.
A systematic literature search was conducted in Medline, Embase and Pubmed to identify relevant studies which addressed the inclusion criteria. A search of conference websites was also conducted, including the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium. The search undertaken for the systematic review identified a conference abstract on the LANDSCAPE study; a full paper for this study was published in February 201336 and was included in the systematic review and is referred to in these guidelines.
The systematic review focused on evidence for the management of CNS metastases in women with metastatic breast cancer not CNS metastases from various primary tumours. However, some studies included in the systematic review had patient populations with mixed primary tumours and where available, the results specific to the breast cancer populations of these studies were reported. The systematic review included evidence reported for metastases in the brain and in the spinal cord (including metastatic spinal cord compression), and for both parenchymal and meningeal (leptomeningeal) metastases.
A total of 1315 citations were identified. Following application of the exclusion criteria, a total of 108 citations and one abstract were identified as eligible for the current review.
Fifty-seven citations addressed the primary research questions:
- What is the effectiveness of surgery in the management of CNS metastases from breast cancer?
- What is the effectiveness of radiotherapy in the management of CNS metastases from breast cancer?
- What is the effectiveness of systemic therapies in the management of CNS metastases from breast cancer?
- What is the effectiveness of combinations of the above treatments in the management of CNS metastases from breast cancer?
- Are there specific requirements for the management of the sub-group of patients diagnosed with asymptomatic CNS metastases?
In addition, 51 citations addressed other issues:
- The incidence/prevalence of CNS metastases in breast cancer patients, specifically those with HER2-positive and triple negative breast cancer.
- The course, nature and extent of neurocognitive and psychological impairments in CNS metastases in metastatic breast cancer, and how these impairments are assessed.
- The impacts of these impairments on everyday functioning and quality of life of women with CNS metastases from breast cancer including restrictions on driving, seizures.
- The identification of effective strategies for providing supportive and palliative care to women with CNS metastases from breast cancer.
- Multidisciplinary care including involvement of allied health such as physiotherapy and rehabilitation, psychology, care coordinators, social work, speech pathology.
- Measurements of Quality of Life (QoL).
- Meningeal metastases in women with metastatic breast cancer.
- Use of other medications including steroids and anticonvulsants.
There were few large prospective trials identified that investigated the use of surgery, radiotherapy, systemic therapies or multimodal treatment for the management of CNS metastases in women with metastatic breast cancer, specifically from breast cancer. Most of the relevant trial data were limited to small breast cancer patient cohorts or retrospective studies.
The systematic review identified seven systematic reviews, including two Cochrane reviews. These systematic reviews included evidence for management for CNS metastases in populations of mixed primary cancers. While they were not specific to the management of CNS metastases from breast cancer, the Cochrane reviews and included primary studies have been used as primary references in the recommendations and statements of evidence of this clinical practice guideline due to the limited high quality evidence identified for the management of CNS metastases from breast cancer. Details of the Cochrane reviews and the included primary studies are outlined in Evidence from trial or study results.
Refer to the Cancer Australia systematic review7 for detailed evidence from studies on the management of CNS metastases in patients with metastatic breast cancer.
Evidence from trial or study results: surgeryEvidence from trial or study results: surgery Anonymous (not verified)
A Cochrane review by Hart et al 201112 assessed if resection of single brain metastasis followed by WBRT holds any clinical advantage over WBRT alone. Three RCTs were identified that included a total of 195 patients. Of note, the three RCTs by Mintz et al 1996,42 Patchell et al 199043 and Vetch et al 1993,44 included in the Cochrane review were published before 2001. All studies included populations with mixed primary tumours, including one study (Patchell 1990) with less than ten breast cancer patients. No results were reported by Hart et al for breast cancer patients separately.
Two retrospective studies on surgery among breast cancer patients were identified.
The surgical trials identified in the Hart et al Cochrane review were limited to patients with good performance status, with a single or limited number (1-3) of accessible lesions, inactive or well-controlled primary disease and limited co-morbidities, and patients with raised intracranial pressure or other uncontrolled symptoms. Generally, patients were considered unsuitable for surgery when there were multiple lesions, when the lesion was surgically inaccessible, or patients with active primary disease or significant comorbidities.12
The Hart et al Cochrane review found no significant difference in survival (HR 0.72, 95% CI 0.34 to 1.55, random effects, p = 0.40) although there was heterogeneity between trials
(I2 = 83%).12 There was some indication that surgery and WBRT might reduce the risk of deaths due to neurological cause. The Hart et al Cochrane review reported that those treated with surgery and WBRT were less likely to die from neurological causes although this did not reach statistical significance (RR 0.68, 95% CI 0.43 to 1.09, p=0.11; three trials).12 Mortality at 30 days was similar in both arms of each trial.
Although no statistically significant difference between surgery plus WBRT and WBRT alone was observed, the Patchell 199043 and Vecht 199344 trials were in favour of surgery while the Mintz 199642 trial was in favour of WBRT alone. The Patchell 1990 trial included a majority of patients with non-small cell lung cancer, which is highly radio-resistant and would not be expected to respond well to WBRT. There may have been selection bias in this trial also, as patients were selected for surgery by a single neurosurgeon. The Mintz 1996 trial included patients with a poorer KPS, and a larger proportion of patients had extra-cranial metastases.42
Functionally independent survival
One trial in the Hart et al Cochrane review (Patchell 1990) reported results on functional independent survival.43 The trial found that patients treated by surgery and WBRT maintained their functional independence for longer than those treated by WBRT alone (HR 0.42, 95% CI 0.22 to 0.82, p=0.01).43
The results of each trial identified in the Hart et al Cochrane review found that neither surgery in combination with WBRT or WBRT alone was more likely to cause adverse effects (RR 1.27, 95% CI 0.77 to 2.09, p=0.35).12 It is noted that the reporting of the trials did not allow for clustering of adverse effects within patients. Commonly reported adverse events for patients in the surgical arms of the trials included respiratory problems, haematoma and infections.
Evidence from trial or study results: radiotherapyEvidence from trial or study results: radiotherapy Anonymous (not verified)
A Cochrane review by Tsao et al (2012) assessed the effectiveness of whole brain radiotherapy (WBRT) either alone or in combination with other therapies in adult participants with newly diagnosed multiple brain metastases.45 The review updated a previous 2006 Cochrane review. Nine new RCTs involving 1420 participants were added to the updated review. The updated review included a total of 39 trials involving 10,835 participants with mixed primary tumours. Results are presented under stereotactic radiosurgery (SRS), WBRT, altered fractionations and radiosensitizers.45
The Tsao et al 2012 Cochrane review compared WBRT plus radiosurgery versus WBRT.45 Three trials (Andrews 2004,13 Chougule 2000, Kondziolka 199946) examining the use of WBRT with or without radiosurgery boost for up to four brain metastases (469 participants in total) were included. Two trials were fully published (Andrews 2004,13 Kondziolka 199946) and included populations of mixed primary tumours. In addition, five retrospective analyses reporting results of radiosurgery in patients with central nervous (CNS) metastases were identified; three are discussed here.14,15,83
Pooled results of two randomised controlled trials comparing WBRT plus radiosurgery and WBRT alone (Andrews 200419 and Kondziolka 199946 showed no difference in six-month survival (p=0.24).45 The Andrews trial reported improved survival (p=0.0393) for a subset of patients with a single, surgically un-resectable brain metastasis treated with WBRT and radiosurgery (6.5 months) compared to WBRT alone (4.9 months).
Kased et al 2009 retrospectively reviewed 176 patients who underwent gamma knife stereotactic radiosurgery (SRS) for brain metastases from breast cancer.83 Among the 95 patients with newly diagnosed brain metastases, median survival time was 16 months. Among the 81 patients treated for recurrent brain metastases, median survival time was 11.7 months. In patients treated with SRS alone initially, survival was 17.1 months compared to 15.9 months for patients treated with SRS and upfront WBRT (p=0.20). Factors associated with longer survival included age less than 50 years, primary tumour control, ER positivity, and HER2-positive disease.83
Akyurek 2007 retrospectively reviewed 49 breast cancer patients who underwent SRS for brain metastases; 34 patients as primary treatment, and 15 as salvage treatment following prior WBRT.15 The median overall survival for patients receiving SRS as primary treatment was 25 months and 14 months for patients receiving SRS as salvage treatment.
The Tsao et al 2012 Cochrane review pooled data for local brain control at one year from two studies (Andrews 2004 and Kondziolka 1999).13,46 A statistically significant improvement in local brain control favouring WBRT and radiosurgery boost compared to WBRT alone was observed (RR 1.20, p=0.003).
The Kondziolka 1999 trial also reported median time to local brain failure of 6 months for patients receiving WBRT alone in comparison to 36 months after WBRT and radiosurgery.46 The Andrews trial found no statistically significant difference (p=0.1278) regarding overall time to intracranial tumour progression.13
A retrospective analysis of breast cancer patients (Akyurek 2007) reported on local brain tumour control.15 One year local control rates were 79% for patients receiving SRS as initial treatment, and 77% for patients receiving salvage SRS after WBRT treatment. Two-year local control rates were 49% for the group receiving SRS alone and 46% for the SRS salvage treatment group. The difference was not statistically significant (p=0.99).15 Akyurek 2007 also reported distant brain metastases-free survival; at one year, the survival rate was 69% in the 49 patients receiving either initial SRS alone or salvage SRS.15 The one-year distant brain metastases-free survival rate was 64% among the group receiving initial SRS compared to 57% for the group receiving SRS salvage treatment. The difference was not statistically significant (p=0.62).
Kased et al 2009 reported on 176 patients who underwent SRS for brain metastases from brain cancer.83 No significant difference was observed in freedom from progression between SRS alone and SRS with WBRT in the newly diagnosed patients. The median freedom from new brain metastases was 14.8 months for patients treated with SRS alone, compared to 11.3 months for patients in the SRS and WBRT arm (p=0.83).83
Andrews 2004 reported that KPS was improved at six months in 13% of patients treated with WBRT and radiosurgery, compared to 4% of patients treated with WBRT alone (p=0.0331).13 Mental status as measured using a mini-mental status examination did not show a significant difference.
Tsao 2009 and the updated review in 2012 reported adverse effects identified in the Andrews 2004 trial.84 In this trial, early and late toxic effects did not differ greatly for patients receiving WBRT alone compared to WBRT plus radiosurgery. More patients in the WBRT plus radiosurgery arm experienced acute grade three and four toxicity (4 of 160 patients), compared to those receiving WBRT alone (0 of 166 patients). More patients in the WBRT plus radiosurgery arm experienced late grade three and four toxicity (6 of 160 patients) compared to those receiving WBRT alone (3 of 166 patients).13
WHOLE BRAIN RADIOTHERAPY (WBRT)
The Cochrane review by Tsao et al (2012) identified three RCTs comparing radiosurgery alone to radiosurgery plus WBRT.45 The trials (Aoyama 2006,14 Chang 2009,50 Kocher 201116) included patients with up to three or four brain metastases from mixed primary tumours.
The systematic review by Kalkanis et al 201085 identified one RCT (Patchell et al 1998)51 and three retrospective cohort studies that addressed the question of surgery alone versus surgery plus WBRT for the initial management of a single brain metastasis. The RCT by Patchell et al (1998) randomised patients to postoperative WBRT (50.4 Gy over 5 ½ weeks (n=49) or no further treatment (observation, n=46). The study included patients with various primary tumours including nine (9%) breast cancer patients.51
Gaspar 1997 was not identified in the systematic review as it was published prior to the search period of 2001 to 2012, but was included for additional background information on WBRT.47 A prospective study was identified (Yaneva) that assessed the effect of palliative radiotherapy on quality of life in 65 patients with brain metastases from various primary tumours (33 breast cancer, 50.8%).52
Pooled data from two trials identified in the Tsao et al Cochrane review, found no difference in overall survival (Aoyama 2006 and Chang 2009), (HR 0.98, 95% CI 0.71 to 1.35, P = 0.88).45
Aoyama et al 2006 undertook a randomised controlled trial comparing WBRT plus SRS with SRS alone for the treatment of 132 patients with one to four brain metastases from various primary tumours (7% breast cancer patients).14 Median survival time in the WBRT plus SRS group was 7.5 months compared to 8.0 months for the SRS alone group (p=0.42). Death was attributed to neurologic causes in 13 patients in the WBRT plus SRS group, and in 12 patients in the SRS alone group (p=0.64).14
Patients with one to three brain metastases from various solid tumours (12% breast cancer patients) treated with SRS or surgery were randomised to WBRT or observation in the European Organisation for Research and Treatment of Cancer (EORTC) 22952-26001 study.16
Tsao 2012 reported that for the Kocher 2011 trial, overall survival for the radiosurgery alone arm versus WBRT and radiosurgery boost could not be isolated.45 Kocher et al 2011 reported that overall survival did not differ between the two arms, with a median survival of 10.9 months for patients who had observation only (surgery alone or radiosurgery alone), compared to 10.7 months for patients treated with WBRT (surgery and WBRT or radiosurgery and WBRT) (p=0.89). Malignant disease was the dominant cause of death in both arms.16 The Patchell et al 1998 study included patients who had undergone complete surgical resection for a single brain metastasis, comparing patients randomly assigned to post-operative WBRT or no further treatment.51 Overall survival rates did not differ significantly. Among the 49 patients who received WBRT, median length of survival was 48 weeks, compared to 43 weeks for the 46 patients who did not have further treatment (p=0.39). Patients who had WBRT were more likely to die of systemic disease rather than neurologic progression (p=<0.001).51
Rades et al 2007 retrospectively investigated whether SRS alone improved outcomes compared with WBRT for patients with one to three brain metastases.86 Only patients in recursive partitioning analysis (RPA) classes 1 and 2 were included in the study. Median survival was 7 months for patients receiving WBRT compared to 13 months for patients receiving SRS.
Gaspar 1997 reviewed prognostic factors of patients with brain metastases in three RTOG trials conducted between 1979 and 1993, testing dose fractionation and radiation sensitisers.47 The majority of included patients had a lung primary tumour (61%) with patients with a breast cancer primary comprising 12% of the population. Improved survival was associated with age less than 65 years, a Karnofsky Performance Status (KPS) of at least 70, and controlled primary tumour with the brain the only site of metastases. Shorter survival was observed among patients with a KPS of less than 70.
Pooled data in three trials (Aoyama 2006; Chang 2009; Kocher 2011) identified in the Tsao 2012 Cochrane review found the addition of WBRT to radiosurgery significantly improves locally treated brain metastases control (HR 2.61, 95% CI 1.68 to 4.06, P < 0.0001) and distant brain control (HR 2.15, 95% CI 1.55 to 2.99, P < 0.00001).45
In Aoyama et al 2006 comparison of WBRT plus SRS with SRS alone, multivariate analysis shows that WBRT plus SRS was associated with a reduced risk of recurrence (p=<0.001).14 Twenty-three patients in the WBRT plus SRS group experienced either distant or local brain tumour recurrence, compared to 40 in the SRS alone group. The 12 month brain tumour recurrence rate was 46.8% in the WBRT plus SRS group and 76.4% in the SRS alone group (p=<0.001). Twenty-one patients in the WBRT plus SRS group had new brain metastases at distant sites compared with 34 in the SRS alone group. The 12-month actuarial rate of developing new brain metastases was 41.5% in the WBRT plus SRS group and 63.7% in the SRS-alone group (P=0.003). Salvage treatment for progression of brain metastases was required significantly more frequently in patients receiving SRS alone compared to the group receiving SRS plus WBRT (29 patients vs. 10 patients respectively, p=<0.001).14 Salvage WBRT was used for 11 of the patients who had SRS alone, but not used for any patient in the WBRT plus SRS group. Salvage SRS was used for 19 patients in the SRS alone group, and for 9 patients in the WBRT plus SRS.
Recurrence outcomes from the EORTC 22952-26001 study comparing WBRT to observation were reported in Kocher et al 2011.16 Median progression-free survival was slightly longer in patients receiving WBRT (4.6 months) compared to patients in the observation arm (3.4 months) (p=0.20). Extra-cranial progression was reported at similar rates; in 64% of patients in the observation arm and 66% of patients in the WBRT arm. Progression at intracranial sites occurred significantly more frequently in patients in the observation arm compared to patients in the WBRT arm (p=<0.001). After surgery and SRS, WBRT reduced the probability of relapse at initial sites and at new sites. Salvage therapies for intracranial relapse were used more frequently in patients following observation (51%) compared to patients treated with WBRT (16%).16 Thirty-one per cent of patients in the observation arm required salvage WBRT, compared to 3% in the WBRT arm.
In the Patchell et al 1998 study, patients who had WBRT after surgical resection to a single brain metastasis had significantly lower rates of tumour recurrence anywhere in the brain, compared to patients who had no further treatment after surgery (18% vs. 70%, p=<0.001).51 The time to any brain recurrence was also significantly longer (p=<0.001). Multivariate analysis showed only post-operative radiotherapy lessened the risk of brain recurrence (p=<0.001).
Aoyama et al 2006 reported systemic functional preservation rates at 12 months were 33.9% in the WBRT plus SRS group, and 26.9% in the SRS alone group (p=0.53).14
Chang et al 2009 reported on patients with one to three brain metastases from various primary tumours, assigned to SRS plus WBRT or SRS alone. The trial was halted early based on the probability of decline in neurological function among patients in the SRS plus WBRT group compared to the SRS alone group.50
Quality of life
Patients with one to three brain metastases from various solid tumours treated with SRS or surgery were randomised to WBRT or observation in the EORTC 22952-26001 study.17 Soffietti et al 2013 reported on quality of life findings, using the Health-related Quality of Life (HRQOL) scale. A statistically significant and clinically meaningful difference in global HRQOL mean scores was detected at 9 months follow-up, in favour of patients who had observation alone (p=0.0148). No differences were found at any other time points. Patients in the observation only group had better mean scores in physical, role and cognitive functioning.17
Yaneva et al 2006 evaluated the influence of WBRT on quality of life and neurologic symptoms.52 Patients with various primary tumours were included, including 50.8% breast cancer patients. All patients had a KPS above 70. After radiotherapy, all patients showed improvement in their clinical status and functioning including physical, role, emotional, cognitive and social functioning. Fatigue, pain, nausea, insomnia and appetite loss also improved significantly after WBRT.52
Aoyama et al 2006 reported that symptomatic acute neurological toxicity was observed in four of the 65 patients in the WBRT plus SRS arm, and in eight of the 67 patients in the SRS alone arm (p=0.36). Symptomatic late neurologic radiation toxic effects were observed in seven patients in the WBRT plus SRS group, and in three patients in the SRS alone group (p=0.20). Toxic effects were experienced for a median of 15.6 months in the WBRT plus SRS group and 6.2 months in the SRS alone group.14
The EORTC 22952-26001 study reported sixteen serious adverse events; 13 among patients in the WBRT arm compared to three in patients who underwent observation. Acute toxicity of WBRT was reported as mild.16
ALTERED FRACTIONATION WBRT
The Cochrane review by Tsao et al (2012) addressed altered WBRT schedules.45 A total of nine published reports involved participants randomised to altered WBRT dose-fractionation schedules compared to standard 30 Gy in 10 daily fractions (Borgelt 1980,56 Borgelt 1981,56 Chatani 1985,87 Chatani 1994,88 Haie-Meder 1993, Harwood 1977,25 Kurtz 1981,26 Murray 1997,89 Priestman 199654). One study (Haie-Meder 1993) was excluded because the trial design did not include a standard WBRT dose-fractionation arm (30 Gy in 10 fractions or 20 Gy in five fractions). Eight studies therefore met the inclusion criteria for the review (3645 participants with mixed primary tumours).
Overall survival and recurrence
The Tsao et al 2012 Cochrane review identified six trials reporting on overall survival. Three trials (Chatani 199488; Harwood 197725; Priestman 199654) compared a standard dose of 30 Gy in 10 fractions to a lower dose fractionation (20 Gy in 5 fractions, 10 Gy in a single fraction or 12 Gy in 2 fractions). Meta-analysis found a significant difference favouring the control dose of 30 Gy in 10 fractions (p=0.01). Of note, Chatani 1994 and Harwood 1977 reported no statistically significant difference, however Priestman 1996 did.
Four trials (Chatani 198587; Chatani 199488; Kurtz 198126; Murray 199789) compared a standard dose of 30 Gy in 10 fractions to a higher dose (50 Gy in 20 fractions, 54 Gy in 34 fractions). No statistically significant difference was observed in overall survival (p=0.65).45
Three retrospective studies were identified in the Cancer Australia systematic review7 that compared various radiotherapy regimens in patients with CNS metastases; two comparing shorter course WBRT with longer course and the third investigated the potential benefit of dose escalation beyond the standard 30 Gy treatment.
Rades et al (2007) investigated the potential benefit of dose escalation beyond the standard 30 Gy treatment in patients with ≥2 brain metastases from breast (26% of patients), lung and other primaries.49 Two hundred and fifty seven patients who received 30 Gy in 10 fractions (10 fractions of 3 Gy each, with an overall treatment time of 2 weeks) were compared with 159 patients who received higher doses such as 45 Gy in 15 fractions (57 patients) and 40 Gy in 20 fractions (102 patients).49 Rades et al found dose escalation beyond 30 Gy in 10 fractions did not improve survival (p=0.86) or local control (p=0.61).49 Univariate and multivariate analyses of recurrence of brain metastases showed a significant association between breast cancer as the primary tumour and improved local control (p=<0.001 and p=0.012, respectively).
Rades and Lohrynska et al (2007) retrospectively compared survival and local control for short-course WBRT compared with longer programs in breast cancer patients.53 Sixty-nine patients received short course WBRT with 20 Gy in 5 fractions. Long course WBRT with either 30 Gy in 10 fractions or 40 Gy in 20 fractions was given to 138 patients.53 The WBRT schedule was not found to be associated with survival (p=0.254) or local control (p=0.397).
In another retrospective study by Rades et al (2011) shorter course and longer course WBRT were compared for elderly patients (≥ 65 years) treated between 2001 and 2010 for brain metastases.48 The analysis compared 162 patients (23 breast cancer patients, 14%) who received 20 Gy in 5 fractions and 293 patients (53 breast cancer patients, 18%) who received 30 Gy in 10 fractions.48 On univariate analysis, the WBRT regimen of 20 Gy in 5 fractions was significantly associated with improved overall survival (vs. 30 Gy in 10 fractions, p=0.020), however this was not maintained on multivariate analysis (p=0.13). The WBRT regimen was not significantly associated with improved local control (p=0.32). Breast cancer as the primary tumour (vs. lung cancer or other tumours) almost reached statistical significance for improved local control (p=0.054).48
The Tsao 2012 systematic review identified three studies (Borgelt 198055; Borgelt 198156; Kurtz 198126) reporting on neurological function for patients with a baseline neurological function of grade two or three.45 Among these patients there was a statistically significant difference in neurological function improvement favouring those treated with the control dose (30Gy in 10 fractions) compared to a lower dose (OR 1.74, p=0.03). There was no statistically significant difference in rates of neurological function improvement for those treated with higher doses compared to the control dose (OR 1.14, p=0.23).45
The Rades et al 200749 and Rades and Lohrynska et al 200753 retrospective reviews reported no significant differences in grade three toxicity among patients receiving a control dose of 30 Gy in 10 fractions compared to patients on other WBRT regimens.
Rades et al 2007 reported similar rates of grade 3 acute toxicity among patients receiving 30 Gy (5.8%) and higher doses (5%, p=0.92).49 Neurocognitive dysfunction was noted in six patients treated with 30 Gy in 10 fractions (2.3%) compared to eight patients (5%) treated with higher doses (p=0.24).
Rades and Lohrynska et al 2007 reported that 9% of patients treated with 20 Gy in 5 fractions experienced grade three acute toxicity, compared with 4% of patients receiving 30 Gy in 10 fractions.53 The rates of > grade three late toxicity were less than 5% in each treatment group.
WBRT PLUS RADIOSENSITIZERS
The Cochrane review by Tsao et al (2012)45 identified six published trials (DeAngelis 1989,90 Eyre 1984,91 Komarnicky 1991,92 Mehta 2003,93 Phillips 1995,94 Suh 200695) examining the use of radiosensitizers in addition to WBRT (2016 participants with mixed primary tumours). The radiosensitizers used were lonidamide (DeAngelis 198990), metronidazole (Eyre 198491), misonidazole (Komarnicky 199192), bromodeoxyuridine (BrdU) (Phillips 199594), motexafin gadolinium (Mehta 200393) and efaproxiral (Suh 200695).
The Cochrane review reported that the addition of radiosensitizers in the identified RCTs did not confer additional benefit to WBRT in either the overall survival times (HR 1.08, 95% CI 0.98 to 1.18, P = 0.11) or brain tumour response rates (HR 0.87, 95% CI 0.60 to 1.26, P = 0.46).45
HER2 STATUS AND RADIOTHERAPY
A retrospective study, Wolstenholme et al (2008) assessed whether HER2 status had an effect on outcomes after WBRT.57 A total of 181 patients with known HER2 status were included in the study (88 HER2-positive and 93 HER2-negative).
Dawood et al 2010 retrospectively reviewed the effect of receptor status in 223 women with breast cancer and brain metastases.58 Sixty-seven patients had hormone receptor-positive/HER2-negative disease, 101 had HER2-positive disease, and 54 had triple-negative disease.
Significantly longer survival for HER2-positive compared to HER2-negative patients was reported in these two retrospective studies following WBRT.57,58 Dawood et al 2010 found that the risk of death among women with triple-negative disease was not significantly different from women with hormone receptor-positive/HER2-negative disease (p=0.54).58
Matsunaga et al 2010 reviewed prognostic factors for women undergoing Gamma Knife surgery for brain metastases from breast cancer between 1992 and 2008.96 Of the 101 included patients, 28 had HER2-positive disease, 37 had luminal A or B disease*, 36 had triple-negative disease. Median overall survival for women with HER2-positive disease (25 months) was significantly longer than survival with luminal (12 months) or triple-negative disease (5 months) on univariate and multivariate analyses (p=0.001). The difference in overall survival between patients with luminal disease and triple-negative disease was not statistically significant (p=0.569). There was no statistically significant differences between the three breast cancer subtypes for the incidence of new brain metastases following initial Gamma Knife surgery.96
± 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.
* Luminal A – hormone receptor-positive/HER2-negative disease; Luminal B – hormone receptor-positive/HER2-positive disease
Evidence from trial or study results: systemic therapiesEvidence from trial or study results: systemic therapies Anonymous (not verified)
The systematic review by Mehta et al (2010) addressed the role of chemotherapy in the management of newly diagnosed brain metastases.28 The use of chemotherapy for brain metastases was investigated in four questions, however, only the comparison of chemotherapy plus WBRT vs. WBRT alone was relevant as the other questions included studies of only lung cancer patients.
Five studies met the inclusion criteria for the question chemotherapy plus WBRT vs. WBRT alone: two phase III RCT’s, two phase II RCT’s and one retrospective cohort study.28 In each RCT, patients were randomised to receive WBRT or WBRT plus carboplatin, chloroethylnitrosoureas or temozolomide.
The systematic review by Ammirati et al (2010) addressed the treatment of patients who develop recurrent/progressive brain metastases after initial therapy.61 The review identified ten studies evaluating the role of chemotherapy in patients with recurrent/progressive metastatic brain disease. Of these, five are prospective single arm phase II studies, and five are case series. The chemotherapy agents assessed include cisplatin, temozolomide, vinorelbine, or fotemustine.
Six prospective studies were identified investigating different chemotherapies including temozolomide, sagopilone and patupilone.62-67 All were phase I or phase II single arm studies, including small patient populations. These chemotherapies are not considered appropriate for use in breast cancer or funded through the Pharmaceutical Benefits Scheme; off-label use is not recommended. Four studies were in populations with CNS metastases from breast cancer only63-66 and two studies were in populations with CNS metastases from various primary cancers including breast cancer.62,67 Four studies investigated the use of temozolomide either alone or in combination with other chemotherapies; one study investigated sagopilone, and one study investigated patupilone.62-67
The systematic review by Mehta 2010 did not pool the results of the five identified studies. In the four RCTs, there was no significant survival difference between the control or intervention arms.28
The systematic review by Ammirati et al (2010) reported that median survival ranged from 3.5 months to 6.6 months in patients with recurrent or progressive brain metastases from various primary tumours.61
Among the prospective studies investigating temozolomide, sagopilone or patupilone, median survival ranged from 5.3 months to 6.9 months.62-67
Progression free survival
The ten studies identified in the systematic review by Ammirati et al (2010) indicated that some patients with recurrent or progressive brain metastases will have an objective radiographic response and/or improvement in functional status following treatment with chemotherapy.61 Median time to recurrence after retreatment with various chemotherapy regimens ranged from 2 to 4 months. Of the three studies investigating chemotherapy regimens (temozolomide with cisplatin or vinorelbine), two studies reported a median time to recurrence ranging from 1.9 to 2.9 months.61 Christodoulou 2005 investigated temozolomide and cisplatin; of the 32 patients assessed, complete response was observed for one patient, partial response was observed in nine patients, and five patients had stable disease.62 The two studies investigating temozolomide and vinorelbine (Iwamoto 200897 and Omuro 200698) observed complete responses for one patient each. Patients experienced progressive disease at a rate of 76% (Iwamoto 200897) and 56% (Omuro 200698).61
HER2-DIRECTED THERAPIES: Trastuzumab
Five studies reported on overall survival, see Table 2 below for results.30-34 Patients with HER2-positive disease who received trastuzumab treatment, experienced longer median survival times compared to HER2-positive patients who did not receive trastuzumab and compared to HER2-negative patients.
Table 2: Overall median survival outcomes by HER2 status and trastuzumab treatment
|HER2-positive receiving trastuzumab
|HER2-positive not receiving trastuzumab
Chemotherapy, no T: 9 months
T before BM:
T after BM:
Le Scodan 201134
Abbreviations: BM – brain metastases; HER2 - human epidermal growth factor receptor 2, NR – not reported, T – trastuzumab
Two studies (Park 2009; and Park, Park et al 2009) reported on overall survival for HER2-positive patients only,33,99 (see Table 3 below for results). Both studies found significantly improved survival associated with trastuzumab treatment.
Table 3: Overall median survival outcomes among HER2-positive patients
|HER2-positive patients receiving trastuzumab after brain metastases
|HER2-positive patients receiving trastuzumab before brain metastases
|HER2-positive patients never receiving trastuzumab
Park, Park et al 200999
Abbreviations: HER2 - human epidermal growth factor receptor 2.
Time to diagnosis of brain metastases
Three studies reported on the association between trastuzumab treatment and time to diagnosis of brain metastases.30,33,99 Each study found that brain metastases were delayed in HER2-positive patients on trastuzumab compared to HER2-positive patients not taking trastuzumab or HER2-negative patients.
Park 2009 reported patients receiving trastuzumab had a median time to diagnosis of brain metastases of 19 months, compared to 8 months for patients who did not receive trastuzumab, or had trastuzumab treatment after brain metastases were diagnosed (p=<0.001).33 Similar results were identified in the Park, Park et al 2009 study: 15 months for patients with prior trastuzumab treatment compared to 10 months among patients never receiving trastuzumab (p=0.035).99
The Dawood 2008 analysis found the median time to diagnosis of brain metastases among the whole cohort was 11.3 months.32 Among HER2-negative patients, time to diagnosis was 8.9 months; 2.1 months for HER2-positive patients who did not receive trastuzumab, and 13.1 months for HER2-positive patients who did receive trastuzumab for first line treatment of first site of metastases.
Time to progression
Park 2009 investigated median time to progression of intracranial tumours, finding that progression was prolonged in patients treated with trastuzumab after diagnosis of brain metastases (7.8 months) compared to patients who never received trastuzumab (3.9 months) or who had trastuzumab after diagnosis of brain metastases (2.9 months) (p=0.006).33
Incidence of CNS metastases as first relapse site
The HERA trial (Pestalozzi et al 2013) investigated use of trastuzumab compared to observation in patients with HER2-positive early breast cancer.29 The incidence of CNS relapse as the first disease-free survival event did not differ between patients (p=0.55), however one year of trastuzumab was significantly associated with reduced incidence of non-CNS relapse (p=<0.0001).
HER2-DIRECTED THERAPIES: Lapatinib in previously untreated CNS metastases
The Cancer Australia systematic review7 identified one study (LANDSCAPE), a single arm phase II study36, which investigated the use of lapatinib in combination with capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer. Exclusion criteria included single brain metastases amenable to surgical resection, previous WBRT or SRS, current radiation therapy or current systemic treatment for breast cancer.
Overall survival at six months was 90.9%. Median overall survival was 17 months.36
Response to treatment
An objective CNS response (all partial responses) was observed in 29 (65.9%) patients. A CNS volumetric reduction of 80% or greater was observed in nine patients (20%), and overall, 37 patients (84%) had some reduction in tumour volume. Forty-two of 44 patients were available for assessment of best CNS response according to Response Evaluation Criteria In Solid Tumors (RECIST); two patients (5%) had a complete response, 22 patients (52%) had a partial response; thus 24 patients (57%) had an objective CNS response.36
Among the 30 patients who had prior trastuzumab treatment, 20 (67%) experienced an objective CNS response. Of the 14 patients who had not had prior trastuzumab, nine (64%) had an objective CNS response.36
Among 41 patients with available data, the site of first progression was CNS alone for 32 patients (78%); extra-CNS alone in two patients (5%) and, for five patients (12%) progression was observed in both the CNS and extra-cranially. Median time to progression was 5.5 months, and median time to radiotherapy was 8.3 months.36
Twenty-two of 45 patients experienced at least one grade 3 or grade 4 adverse event, and 14 (31%) experienced at least one serious adverse event.36 The most commonly reported adverse events were diarrhoea and hand-foot syndrome. Sixteen patients required a reduction to their dose of lapatinib; 11 of which were during the first two cycles of treatment. Twenty-six patients required a dose reduction for capecitabine, most frequently in the second, third or fourth cycles.
Treatment discontinuation due to adverse events occurred in four patients (9%).36
HER2-DIRECTED THERAPIES: Lapatinib in previously treated CNS metastases
Eight studies were identified in the Cancer Australia systematic review7 that examined the use of lapatinib for the treatment of CNS metastases in HER2-positive metastatic breast cancer patients previously treated.
Lin et al conducted two prospective phase II trials of lapatinib in patients with brain metastases from HER2 positive breast cancer, previously treated with trastuzumab and radiotherapy.35,70 In Lin 2009 a subset of patients who progressed on lapatinib went on to receive lapatinib and capecitabine.35 A subsequent randomised phase II trial comparing lapatinib in combination with capecitabine or topotecan was undertaken.69 While these are small studies, they are some of the few high level evidence studies.
Two studies investigating the use of lapatinib reported on overall survival.35,68 Metro 2011 found that patients treated with lapatinib and capecitabine (n=30) had a median overall survival of 27.9 months, significantly longer than patients treated only with trastuzumab-based therapies (n=23, 16.7 months; p=0.01).68 Among the patients (n=6) who received lapatinib and capecitabine as the first systemic option after development of brain metastases, median overall survival was not reached. Among the 24 patients who received lapatinib and capecitabine after at least one trastuzumab-based therapy following development of brain metastases, overall survival was 27.1 months.68
Lin 2009 reported on outcomes for 242 patients treated with lapatinib, following prior trastuzumab treatment and local therapies. Median overall survival was 6.4 months.35
Five studies investigating lapatinib use reported on response rates.35,68-70,101 Lin 2008 assessed 39 patients receiving lapatinib after prior treatment with trastuzumab and other systemic and local therapies.70 One patient achieved a partial CNS response, and four patients achieved partial responses in non-CNS sites. Three patients achieved at least 30% volumetric reductions in CNS lesions, and an additional seven patients achieved reductions of 10% to 30%. A trend towards a longer time to progression was found for patients with at least 30% volumetric reduction compared to other patients.70
Lin 2009 investigated the use of lapatinib among 242 patients, with 50 patients opting to enter a subsequent phase of treatment with lapatinib and capecitabine.35 Among the 242 patients treated with lapatinib, an objective CNS response rate of 6% was observed. No complete responses were seen; 15 partial responses occurred. Assessment of volumetric changes to CNS lesions were available for 200 patients. Nineteen patients (8%) experienced a volumetric reduction of >50%, and a total of 50 patients (21%) experienced a >20% reduction to their CNS lesions. A lower risk of disease progression compared to the rest of the study population was observed among patients who had at least a >20% volumetric reduction to their CNS lesions. Of the fifty patients who opted to enter the lapatinib and capecitabine extension phase, ten (20%) experienced an objective CNS response; all were classified as partial responses.35
Lin 2011 compared lapatinib and capecitabine with lapatinib and topotecan.69 Of the 13 patients treated with lapatinib and capecitabine, five patients experienced a partial response. No objective responses were observed among the nine patients treated with lapatinib and topotecan.
Time to progression
Sutherland 2010 investigated lapatinib and capecitabine and reported on time to progression.101 Median time to progression for the 34 patients with CNS metastases was 22 weeks. Among those previously treated with capecitabine, median time to progression was 17 weeks, compared to 30 weeks for patients who are capecitabine-naïve (p=0.06).
Progression free survival
Two studies reported on progression free survival.35,68 On review of 237 patients treated with lapatinib in Lin 2009, the median progression free survival was 2.4 months.35 Among the 50 patients opting to have a lapatinib and capecitabine extension phase of treatment, the median progression free survival was 3.65 months.
Metro 2011 assessed 30 patients for progression free survival from the start of lapatinib and capecitabine.68 The median progression free survival was 5.1 months, with a median brain-progression free survival of 5.6 months.
Three studies reported on adverse events associated with lapatinib.35,69,70 The most commonly reported adverse events include diarrhoea, rash, nausea and vomiting. The most commonly reported adverse events associated with lapatinib and capecitabine were palmar-plantar erythrodysesthesia, diarrhoea and nausea.
Among patients treated with lapatinib and topotecan, commonly reported adverse events include diarrhoea, nausea, fatigue and thrombocytopenia. The Lin 2011 study closed accrual of patients to the lapatinib and topotecan arm due to tolerability issues, in combination with a lack of early efficacy.69
TRIPLE NEGATIVE PATIENTS
One retrospective analysis of patients with metastatic triple-negative breast cancer was identified.104 Lin and Claus et al 2008 retrospectively reviewed 116 patients with triple-negative breast cancer. Sixteen patients (14%) were diagnosed with CNS metastases at the initial metastatic diagnosis, 53 (46%) had a CNS metastasis at some point.104
Among the 53 patients with CNS metastases, the median survival from time of diagnosis of any metastasis was 11.6 months, and 4.9 months from time of diagnosis of first CNS metastasis. 104
Of the 53 assessed patients, 3 were judged to have stable or responsive systemic disease. 104
Evidence from trial or study results: multimodal treatmentEvidence from trial or study results: multimodal treatment Anonymous (not verified)
Five studies reported on various combinations of treatments in patients with central nervous system (CNS) metastases from breast cancer.105-109
Two non-comparative phase II trials investigated the combination of radiotherapy and chemotherapy.105,106 Objective response rates were 58% and 76%, and complete response rates were observed in 7.4% and 12% of patients with breast cancer primary tumours in the Addeo 2008 and Cassier 2008 trials respectively. In the two studies, median overall survival was 8.8 months and 6.5 months, and 1 year survival was 18.5% and 28% in the Addeo 2008 and Cassier 2008 trials respectively. Median progression free survival was 6 months and 5.2 months in the Addeo 2008 and Cassier 2008 trials respectively.
One retrospective study reported significantly longer survival for surgery and radiotherapy compared to radiotherapy alone (p=0.001) as well as longer survival in patients who receive systemic chemotherapy after radiotherapy (p=0.015).108 Treatment modality, KPS and administration of systemic chemotherapy were significant prognostic factors for overall survival on multivariate analysis.
One retrospective study that included 15% patients with breast cancer as the primary tumour reported that surgery and SRS was associated with longer survival compared with SRS alone (p=0.020) and that the survival of SRS alone patients was statistically superior to the survival of patients who received WBRT alone (p=<0.001).107
A third retrospective study that included 17% patients with breast cancer primary tumour found significant improvement in local control (p=0.002) with the addition of a boost to WBRT and surgery.109
Evidence from trial or study results: asymptomatic patientsEvidence from trial or study results: asymptomatic patients Anonymous (not verified)
One prospective study (Niwinska 2010) assessed outcomes in HER2-positive breast cancer patients with occult brain metastases compared with patients with symptomatic brain metastases.110 Occult brain metastases were detected in 36% of the screening group. The median time between recurrence (distant and/or locoregional) and the diagnosis of occult brain metastases was 9 months.110 Twenty-six patients were given WBRT, with 24 patients available for assessment of radiological response. At three months follow-up, MRI found that 29% of patients were in complete remission, 63% were in partial remission, and there was no change in the brain for 8%. At the time of analysis, complete remission was maintained for two of the five survivors.110
Evidence from trial or study results: spinal cord compressionEvidence from trial or study results: spinal cord compression Anonymous (not verified)
This section is based on the 2001 Clinical practice guidelines for the management of advanced breast cancer1 and updated to include results from a randomised trial on decompressive surgery40 and a systematic review by Loblaw et al.41 Results from a retrospective analysis of breast cancer patients by Tancioni et al included in the systematic review are also noted below.111
Symptoms of spinal cord compression
Patients who are known to have bony metastatic disease and their carers should be warned about the possibility of, and educated regarding the early symptoms of spinal cord compression. Patients should be encouraged to notify their doctor of such symptoms as soon as possible. Primary medical carers should also be aware of the risks of spinal cord compression and paraplegia and the importance of prompt action. Symptoms suspicious of spinal cord compression should be investigated in the absence of signs.1
The systematic review by Loblaw et al (2005) identified twelve studies investigating the clinical symptoms of metastatic spinal cord compression from various primary tumours.41 Frequently observed symptoms include back pain, motor weakness, sensory changes and bladder dysfunction.
A retrospective review was included in the Loblaw 2005 systematic review(Talcott et al 1999) which identified six predictive factors for spinal cord compression, including the inability to walk, increased deep tendon reflexes, compression fractures on radiographs of the spine, bone metastases present, bone metastases diagnosed more than one year prior, and age less than 60 years.112
A prospective cohort study (Husband 1998) found that approximately 70% of patients with spinal cord compression experienced loss of neurologic function between the onset of symptoms and the start of treatment.113 The majority of delays were attributed to lack of symptom recognition by the patient and diagnostic delay at the general practitioner or hospital level.
Investigation of suspected spinal cord compression
If spinal cord compression is suspected, whether on symptomatic or clinical grounds, the investigation of choice is MRI scan.114 This is non-invasive and the precise level or levels of cord compression can be ascertained. If this is not available, then CT scan should be used.115 The Loblaw 2005 systematic review identified four studies investigating the accuracy of MRI, reporting sensitivity ranging from 0.44-0.93 and specificity ranging from 0.90-0.98.
Use of corticosteroids
One small RCT identified in the Loblaw 2005 systematic review (Vecht et al 1989) compared high (100mg) to moderate (10mg) initial dose of dexamethasone in patients with complex myelographic obstruction.37 All patients were treated with radiotherapy and maintenance dexamethasone of 16mg/d orally after the initial treatment. At one week, no significant differences were reported between the high and moderate dose groups in pain, ambulation or bladder function.
A second RCT by Sorensen et al (1994) included in the Loblaw 2005 systematic review compared high-dose dexamethasone therapy as an adjunct to radiotherapy (n=27) with no dexamethasone (n=30).38 Immediately after myelography or MRI, patients randomised to dexamethasone treatment received an intravenous bolus of 96mg. The patients were then maintained on a dose of 96mg dexamethasone for 3 days (given orally when possible in four divided doses), and the treatment was then tapered in 10 days. Successful treatment, defined as preservation of gait in ambulatory patients or restoration of gait within 3 months in non-ambulatory patients, was obtained in 81% of the patients treated with dexamethasone compared to 63% of the patients without dexamethasone treatment. 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.38
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).38 Six months after treatment, 59% of the patients in the dexamethasone group were still ambulatory compared to 33% in the no dexamethasone group (p=0.05). Median survival was 6 months in the two treatment groups. Significant side-effects were reported in three (11%) of the patients receiving glucocorticoids, two of whom discontinued the treatment.38
A case-control study (Heimdel et al 1992) compared high and moderate doses of maintenance corticosteroids in patients treated with radiotherapy for spinal cord compression.39 A statistically significant increase in the number of serious side effects was observed among patients receiving the high dose (4 of 28 patients, 14%), compared with no reports of serious side effects in the moderate dose group (p=0.0284). Serious adverse effects included ulcers with haemorrhage, rectal bleeding and gastrointestinal perforations. The total incidence of side effects was also significantly higher in the high dose group compared with the normal dose group; 8/28 vs. 3/38 respectively, p=0.0429.
Patients presenting with suspected spinal cord compression should be reviewed as early as possible by a spinal surgeon or neurosurgeon with an interest and expertise in spinal problems in consultation with a multidisciplinary team as appropriate.1
A randomised trial assigned patients with spinal cord compression caused by metastatic cancer to either surgery followed by radiotherapy (n=50, breast cancer patients=7) or radiotherapy alone (n=51, breast cancer patients=6).40 Radiotherapy for both groups was given as 30 Gy in 10 fractions. Patients with a displaced spinal cord by an epidural mass, restricted to a single area were eligible for inclusion. Patients were excluded if they had multiple compressive lesions, certain radiosensitive tumours (such as lymphoma) or pre-existing or concomitant neurological problems. Patients were required to have a good general medical status to be acceptable surgical candidates, with an expected survival of at least three months.40 The primary endpoint of the trial was the ability to walk. Secondary endpoints were urinary continence, muscle strength and functional status, the need for corticosteroids and opioid analgesics, and survival time.
Because of demonstrated superiority of surgical treatment, the trial was stopped early by the data safety and monitoring committee.
Significantly more patients in the surgery group (84%) than in the radiotherapy group (57%) were able to walk after treatment (odds ratio 6.2, p=0.001).40 Patients treated with surgery also retained the ability to walk significantly longer than did those with radiotherapy alone (median 122 days vs. 13 days, p=0.003).
Among the subgroup of patients who could walk at study entry, 94% (32 of 34 patients) in the surgery group continued to walk after treatment, compared with 74% (26 of 35 patients) in the radiation group (p=0.024). Patients receiving surgery maintained the ability to walk significantly longer than patients receiving radiotherapy (median 153 days compared to median 54 days, odds ratio 1.82, p=0.024). Among the 16 patients in each group unable to walk at study entry, ten patients (62%) in the surgery group regained the ability to walk, compared with three patients (19%) receiving radiotherapy (p=0.012).
Surgical treatment was significantly associated with maintenance of continence, muscle strength, functional ability and increased survival times. The need for corticosteroids and opioid analgesics was significantly reduced among patients in the surgical group.40
Thirty-day mortality rates were 6% in the surgical arm compared to 14% in the radiation arm (p=0.32). The median hospital stay was 10 days for patients in the surgical and radiotherapy arms (p=0.86).
The authors concluded that decompressive surgery plus postoperative radiotherapy is superior to treatment with radiotherapy alone for patients with spinal cord compression caused by metastatic cancer.40 The surgical approach should be dictated by the position of the tumour within the vertebra. When surgery is not considered appropriate, radiotherapy should be started immediately.
A retrospective analysis of breast cancer patients with metastatic epidural spinal cord compression identified 23 patients who underwent either minimal resection (n=5), curettage leaving microscopic residual tumour (n=18) or total resection (n=3) followed by radiotherapy within 30 days. Median survival of 36 months was reported. The median duration of clinical remission was 26 months. Complete or partial clinical remission of pain was obtained in all cases, and all 17 patients presenting with neurologic deficit experienced compete recovery.111
Three prospective studies, two case-control studies, one case series and three retrospective reviews were identified in the Loblaw 2005 systematic review comparing various doses of radiotherapy to treat metastatic spinal cord compression.41 Doses included:
- 30 Gy in 10 fractions
- 37.5 Gy in 15 fractions
- 40 Gy in 20 fractions
- 28 Gy in 7 fractions
- 15 Gy in 3 fractions / 15 Gy in 5 fractions
- 8 Gy twice
No regimens demonstrated higher rates of ambulation compared with another.
As noted in the Surgery section above, a randomised controlled trial (Patchell 2005) comparing surgery followed by radiotherapy with radiotherapy alone was stopped early due to proven superiority of the surgical treatment. Ten patients in the radiation group (20%) experienced substantial decline in motor strength during radiotherapy and crossed over to receive surgery. None of these patients could walk at the time of surgery; three (30%) regained the ability to walk.