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Awake Craniotomy for Resection of Brain Metastases: A Systematic Review
Original Article
Awake Craniotomy for Resection of Brain Metastases: A Systematic Review Tzy Harn Chua1, Angela An Qi See2,3, Beng Ti Ang2-4, Nicolas Kon Kam King2-4
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BACKGROUND: Surgery for brain metastases aims to reduce mass effect and achieve local control through maximizing resection. There is increasing recognition that awake craniotomy (AC) is especially relevant for resection of brain metastases in eloquent areas. This study seeks to examine the neurologic outcomes of using AC for brain metastases resection.
neurologic function after the procedure showed excellent recovery. AC should be considered as a technique to optimize outcomes in brain metastases in eloquent areas.
METHODS: A systematic search for studies examining the role of AC in patients with brain metastases was conducted via PubMed without limitations on the year of publication, language, or study design, using the following search terms: (cerebral OR brain) and (metastases OR tumor) and (awake OR intraoperative OR eloquent OR supramarginal). Studies were included if patients underwent AC for resection of brain metastases and data on preand postoperative neurologic function were available.
INTRODUCTION
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RESULTS: Seven studies published between 2001 and 2017 with 104 patients who underwent 107 ACs were identified. Gross total resection was achieved in 61% of patients, supramarginal resection was achieved in 32%, and subtotal resection was achieved in 7%. Immediately after operation, 73% of patients experienced no change or improvement in neurologic outcomes, whereas 27% experienced worsening. In the long term, 96% of those with postoperative worsening of function experienced improvements in neurologic function.
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CONCLUSIONS: Most patients experienced improvements in neurologic function immediately after AC, and most patients that experienced short-term worsening of
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Key words Awake craniotomy - Brain metastases - Neurologic outcomes - Recurrence - Surgical resection -
Abbreviations and Acronyms AC: Awake craniotomy DTI: Diffusion tensor imaging fMRI: Functional magnetic resonance imaging MRI: Magnetic resonance imaging SRS: Stereotactic radiosurgery WBRT: Whole brain radiation therapy
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ntracranial tumors are most commonly caused by brain metastases, with an estimated incidence of 8.3e14.3 per 100,000 persons.1,2 The incidence rate of hospitalization doubled from 7 to 14 patients per 100,000 persons based on data collected between 1987 and 2006.3 With the availability of more effective chemoradiotherapy and improvements in imaging modalities enabling earlier detection of metastases, the more recent incidence rates of brain metastases have been reported to be 9%e17% based on several studies, but exact incidence rates in more recent years have not been reported.4 It is well established that surgical resection of brain metastases improves both the local recurrence rate and length of survival.5 More recently, maximal resection of brain metastasis in noneloquent areas through microscopic means has also been shown to reduce the local recurrence rate.6 However, in some cases, microscopic maximal resection of tumors in eloquent areas of the brain may not be attempted under general anesthesia because of the increased concern over causing adverse neurologic outcomes. The role of awake craniotomy (AC) in resection of primary tumors has been increasingly supported by several studies,7-9 especially in terms of optimizing tumor resection and subsequent neurologic function. There is also increasing recognition in the literature that most brain metastases exhibit some evidence of infiltration similar to gliomas and are not purely well-demarcated lesions.10-13 This is
From the 1School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia; 2Department of Neurosurgery, Singapore General Hospital, Singapore; 3Department of Neurosurgery, National Neuroscience Institute, Singapore; and 4 Duke-NUS Medical School, Singapore, Singapore To whom correspondence should be addressed: Nicolas Kon Kam King, Ph.D. [E-mail: [email protected]] Citation: World Neurosurg. (2018). https://doi.org/10.1016/j.wneu.2018.08.243 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2018 Elsevier Inc. All rights reserved.
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especially relevant when trying to achieve gross total resection in eloquent areas. Despite this, there are few studies that have investigated the use of awake techniques in brain metastases surgery. The present study aims to study the utility of AC for metastases in eloquent areas. METHODS Literature Search Strategy A literature search was performed via PubMed on December 16, 2017, using a combination of the following terms as either key words or Medical Subject Headings: (cerebral OR brain) and (metastases OR tumor) and (awake OR intraoperative OR eloquent OR supramarginal). No limitations on the year of publication, language, or study design were imposed. Duplication and unrelated literature were excluded after careful scanning of titles and abstracts. After initial screening, full-text articles of the remaining literature were retrieved and assessed for eligibility criteria by 2 reviewers. Any disagreement on study eligibility was resolved through discussion with a third reviewer to reach a consensus when needed. In addition, the references of review articles and retrieved full-text articles were checked to identify other potentially eligible studies which did not turn up in the database search. Study Selection and Exclusion Criteria For a study to be included, it would have to fulfill the following criteria: 1) be published in a peer-reviewed journal, 2) have a target population of adult patients older than 18 years old of age with cerebral metastasis or metastases, 3) include patients who underwent AC for resection of tumor, and 4) have data on pre- and postoperative neurologic function. Studies on both primary and metastatic brain tumors without a separate data analysis for patients with brain metastases, review articles, and animal studies were excluded. Data Extraction A 4-phase approach including identification, screening, eligibility, and inclusion based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement14 was performed. The data extracted included mean age (years), proportion of men (%), site of primary tumor (lung, melanoma, gastrointestinal tract, renal, breast, sarcoma, adrenal, urogenital, and unknown), symptoms at presentation (weakness/paresis, seizure, speech deficits, sensory deficits, headache, gait/coordination disturbances, memory deficits, and none), use of preoperative functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI), intraoperative cortical mapping, proportion of gross total resection and subtotal/partial resection, and location of tumor (precentral, central, postcentral, temporal, parietal, parietal, frontoparietal, and periventricular). Data on preoperative radiotherapy, postoperative radiotherapy, local and distant recurrence, and survival were extracted as well. These data have been extracted for the purpose of providing sufficient baseline characteristics of individual studies that may have an impact on the primary outcome of this study. Neurologic Outcomes Neurologic outcomes were determined clinically, using scales including the Karnofsky Performance Status scale and modified Rankin Scale. Pre- and postoperative neurologic symptoms and
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function were compared. Short-term neurologic outcomes that were determined immediately after the procedure, and long-term neurologic outcomes at 3- to 6-month follow-up after the procedure were compared as well. Tumor Recurrence Local recurrence was defined as a tumor appearing at the site of resection, and distant recurrence was defined as recurrence in a location outside the site of resection. Recurrence was determined based on evidence from follow-up magnetic resonance imaging (MRI). No specific criteria were used to determine tumor recurrence. Quality Assessment The quality of evidence was assessed using a modified version of the Downs and Black checklist15 by 2 reviewers. The checklist consists of 27 questions grouped into 5 sections: reporting (10 questions); external validity (3 questions); internal validity, bias (7 questions); internal validity, confounding/selection bias (6 questions); and power (1 question). A score of 1 was given for a positive response, and a score of 0 was given for a negative or indeterminate response. Based on Gorber et al.’s method,16 a median split of the quality scores generated from the Downs and Black checklist was used to classify studies as higher or lower quality. Any disagreement was resolved through discussion with a third reviewer to reach a consensus when needed. RESULTS Study Selection, Characteristics, and Quality A total of 356 studies were identified through the PubMed search. Duplicated studies and studies that did not meet the eligibility criteria based on title and abstract were excluded. Subsequently, 28 potentially relevant full-text articles were obtained for a detailed evaluation. Then, 34 more full-text articles were identified from the reference lists of the 28 full-text articles. Finally, 7 studies with a total of 104 patients and 107 procedures met the inclusion criteria and were included (Figure 1). Of the patients, 34% were men, with a mean age of 56.0 6.8 years. In Tan and Black,17 3 patients (3%) had a reoperation, but the reason for repeat surgery was not specified. Among the 7 studies,13,17-22 1 study with 8 patients (7.7%)20 was prospective, and the rest13,17-19,21,22 with a total of 96 patients (92. 3%) were retrospective in nature. These studies presented data from patients over a period of 20 years, from July 1995 to July 2015. Two studies13,17 solely presented data on patients that underwent AC for resection of brain metastases, whereas the other studies were retrospective case series of ACs or brain metastases, and hence individual patient data were extracted from these studies. Duration of follow-up was not reported in 3 studies, and the remaining studies had a mean follow-up duration of 14.7 months (range, 4e20 months). Study characteristics are summarized in Table 1. The methodologic quality of each included study was assessed with the modified Downs and Black checklist.15 The median quality score of the studies in our sample was 13 (range, 11e14) of a maximum score of 28. Two studies17,21 had the highest methodologic quality with a score of 14, whereas 4 studies13,18,20,22 had a score of 13; Shinoura et al.19 had the lowest methodologic quality with a score of 11.
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ORIGINAL ARTICLE TZY HARN CHUA ET AL.
SYSTEMATIC REVIEW OF AWAKE CRANIOTOMY FOR BRAIN METASTASES
Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart for study selection.
Study Population and Clinical Presentation Baseline characteristics are summarized in Table 2. The most common brain metastases involving eloquent areas in the overall series originated from the lungs (47%), followed by melanoma
(17%) and the breast (11%). At presentation, 42 patients (40%) had weakness or paresis of upper or lower limbs, 26 (25%) had seizures, and 15 (14%) had speech deficits, whereas 7% were asymptomatic. Preoperative fMRI and DTI were done in patients
Table 1. Study Characteristics Study
Country
Study Period
Type
Number of Patients with Brain Metastases (%)
Follow-Up (Months)
United States
1995e2000
Retrospective
21 (100)
12
United States
1999e2004
Retrospective
15 (88)
16.2
Shinoura et al., 2011
Japan
2004e2008
Retrospective
14 (67)
NR
Spena et al., 201320
Italy
2008e2010
Prospective
8 (47)
4e20
17
Tan and Black, 2001
18
Weil and Losner, 2005
19
Kamp et al., 201513
Germany
2009e2013
Retrospective
34 (100)
15.8 1.5
Joswig et al., 201621
Switzerland
2014e2015
Retrospective
3 (14)
NR
Spain
2003e2013
Retrospective
9 (27)
NR
22
Sanmillan et al., 2017 NR, not reported.
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for 3 studies.19,20,22 Patients were selected for AC based on the proximity of the tumor to eloquent cortex on preoperative MRI scans. About 68% of brain metastases (50/73) were found in the precentral region. There were 38 patients (52%) with precentral tumors from 3 studies which investigated only patients with tumors in the motor
areas18,19,22 and 12 patients from other studies, making a total of 50 patients with tumors in the precentral region. Other tumor locations included the central region (11%), postcentral region (11%), parietal area (4%), frontoparietal area (3%), temporal area (1%), and periventricular area (1%).
Table 2. Patient Characteristics Tan and Black, 200117
Weil and Losner, 200518
Shinoura et al., 201119
Spena et al., 201320
Kamp et al., 201513
Joswig et al., 201621
64 8.9
57 10.3
58 9.8
51 9.0
60 (33e83)*
43 4.2
NR
56
67
40
36
NR
29
0
NR
34
10 (48)
3 (23)
NR
NR
19 (56)
2 (66)
NR
34 (47)
Melanoma
5 (24)
2 (15)
NR
NR
5 (15)
0 (0)
NR
12 (17)
Gastrointestinal tract
2 (10)
0 (0)
NR
NR
4 (12)
0 (0)
NR
6 (8)
Renal
1 (5)
1 (8)
NR
NR
0 (0)
0 (0)
NR
2 (3)
Breast
1 (5)
4 (31)
NR
NR
5 (15)
1 (33)
NR
11 (11)
Sarcoma
1 (5)
0 (0)
NR
NR
0 (0)
0 (0)
NR
1 (1)
Adrenal
0 (0)
1 (8)
NR
NR
0 (0)
0 (0)
NR
1 (1)
Characteristic Mean age SD (years) Male (%)
Sanmillan et al., 201722
Overall
Primary tumor Lung
Urogenital
0 (0)
0 (0)
NR
NR
1 (3)
0 (0)
NR
1 (1)
Unknown
1 (5)
4 (31)
NR
NR
0 (0)
0 (0)
NR
5 (7)
Symptoms at presentation Weakness/paresis
16 (76)
14 (93)
NR
1 (13)
5 (15)
3 (100)
3 (33)
40 (38)
Seizure
9 (43)
4 (27)
NR
0 (0)
7 (21)
1 (33)
5 (56)
25 (24)
Speech deficits
6 (29)
0 (0)
NR
2 (25)
7 (21)
0 (0)
0 (0)
14 (13)
Sensory deficits
3 (14)
0 (0)
NR
2 (25)
0 (0)
0 (0)
0 (0)
5 (5)
Headache
3 (14)
0 (0)
NR
1 (13)
0 (0)
1 (33)
1 (11)
6 (6)
Gait/coordination disturbances
0 (0)
0 (0)
NR
0 (0)
4 (12)
0 (0)
0 (0)
4 (4)
Memory deficits
0 (0)
0 (0)
NR
0 (0)
3 (9)
0 (0)
0 (0)
3 (3)
None
6 (18)
7 (7)
0 (0)
0 (0)
NR
2 (25)
0 (0)
0 (0)
Preoperative fMRI
NR
NR
Yes
Yes
NR
NR
Yes
Preoperative DTI
NR
NR
Yes
Yes
NR
NR
Yes
Precentral
8 (33)
15 (100)
14 (100)
4 (50)
NR
0 (0)
9 (100)
Central
8 (33)
0 (0)
0 (0)
0 (0)
NR
0 (0)
0 (0)
Location of tumor 50 (68) 8 (11)
Postcentral
5 (21)
0 (0)
0 (0)
3 (38)
NR
0 (0)
0 (0)
8 (11)
Temporal (nondominant)
1 (4)
0 (0)
0 (0)
0 (0)
NR
0 (0)
0 (0)
1 (1)
Parietal
1 (4)
0 (0)
0 (0)
0 (0)
NR
2 (66)
0 (0)
3 (4)
Frontoparietal
0 (0)
0 (0)
0 (0)
1 (12)
NR
1 (33)
0 (0)
2 (3)
Periventricular
1 (4)
0 (0)
0 (0)
0 (0)
NR
0 (0)
0 (0)
1 (1)
Values are number of cases (%) or as otherwise indicated. NR, not reported; fMRI, functional magnetic resonance imaging; DTI, diffusion tensor imaging. *Figure in parentheses represent the range. Standard deviation was not reported in the original article.
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SYSTEMATIC REVIEW OF AWAKE CRANIOTOMY FOR BRAIN METASTASES
Surgical Technique All patients underwent sedation with intravenous sedative agents and received local anesthetic prior to craniotomy. Stereotactic neuronavigation was used to identify the tumor in 5 studies.17-20,22 Intraoperative MRI was used in 13% of patients in Tan and Black.17 Two studies13,21 did not state the use of neuronavigation. Surgeries in most of the studies13,18-20,22 were carried out as awake surgery in an asleep-awake-asleep protocol, except for 2 studies which used either a sedated-awake-sedated protocol17 or a sedated-awake-asleep protocol.21 Cortical stimulation was performed in all patients except 5 patients (17%) in Tan and Black17 and 1 patient (7%) in Shinoura et al.19 In Tan and Black,17 identification of sensory and motor cortices was achieved through the anesthesiologist’s observation of any movements and the patient’s self-reporting of sensory or motor symptoms. Speech and language areas were identified by observing for speech arrest and stimulation-evoked speech errors. Weil and Lonser18 did not mention how intraoperative deficits were identified. In Shinoura et al.,19 patients were continuously observed for any abnormal movements by the neurosurgeons. In Spena et al.,20 the patient was asked to perform several language tasks, including reading and object naming, and to report any numbness. Patients were observed for changes in speech, motor, and sensory function in Kamp et al.13 In Joswig et al.,21 a speech and language pathology assistant assessed the performance of sensory, motor, and language testing. Patients in Sanmillan et al.22 were observed for speech arrest and language function via a counting task and picture-naming task, respectively, followed by a finger-to-thumb task, bimanual hand coordination task, and verb generation task to assess the function of the supplementary motor area. The extent of resection was confirmed by contrast-enhanced MRI in 6 studies.13,17,18,20-22 The use of postoperative MRI was not stated in Shinoura et al.19 Postoperative MRI was performed within 24 hours of surgery in Weil and Lonser,18 immediately after operation in Spena et al.,20 and within 72 hours of surgery in Kamp et al.13 Tan and Black,17 Joswig et al.,21 and Sanmillan et al.22 did not specify when postoperative MRI was performed. Ultrasound was also used to confirm gross total resection in Weil and Lonser.18 Gross total resection was attempted in all tumors. Resection was terminated if the patient became symptomatic during resection or when functional areas identified on cortical mapping contained the tumor. Out of 107 procedures, gross total resection was achieved in 65 patients (61%), whereas supramarginal resection was achieved in 34 patients (32%) in Kamp et al.,13 which refers to gross resection of the metastasis and a further removal or approximately 5 mm of the surrounding tissue.13 In the 8 patients with subtotal resection, resection in 2 patients was stopped based on postoperative MRI,17 whereas resection in 6 patients19 was halted when the motor function did not recover over the 5 minutes after the procedure was paused based on the presentation of symptoms. Neurologic Outcomes Neurologic outcomes are summarized in Table 3. All studies reported short-term neurologic outcomes that were determined immediately after the operation. All but 1 study19 reported long-
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term neurologic outcomes that were determined at 3e6 months after the operation. Intraoperative seizures were reported in 2 patients (10%) in Tan and Black,17 whereas 10 out of 14 patients (71%) in Shinoura et al.19 experienced intraoperative deterioration of motor function. Among the 10 patients that experienced intraoperative deterioration of motor function in Shinoura et al.,19 motor function recovered within 5 minutes after the procedure was paused. Immediately after the operation, 76 out of 104 patients (73%) experienced no change, improvements or complete resolution in their neurologic symptoms. At 3e6 months after the operation, 23 out of 24 patients (96%) who had temporary immediate postoperative worsening of neurologic symptoms improved. A permanent neurologic deficit (acquired during the surgery) was sustained in 1 patient (1%).17 Adjuvant Treatment Out of 70 patients, 59 (84%) received postoperative radiotherapy in the form of whole brain radiation therapy (WBRT), whereas 1 patient received stereotactic radiosurgery (SRS). Five patients in Weil and Lonser18 received radiotherapy prior to treatment with surgical resection of the brain metastases. Tumor Recurrence and Survival Tumor recurrence data were only available in 3 studies.13,17,18 Among the 3 studies with a total of 70 patients, there was an overall recurrence rate of 35% (n ¼ 24), a local recurrence rate of 9% (n ¼ 6), a distant recurrence rate of 19% (n ¼ 13), and a combined local and distant recurrence rate of 7% (n ¼ 5). Data on survival could only be obtained from 2 studies. Tan and Black17 reported a median survival of 16.2 months, whereas Weil and Lonser18 reported a median survival of 12 months. Mean follow-up duration among the 3 studies was 14.7 2.3 months. DISCUSSION Our systematic review has several key findings that are of importance in the resection of brain metastases. Neurologic function improved or was not changed in 73% of all patients after the operation, while 27% of the patients experiencing a worsening of neurologic function. Out of 24 patients who experienced worsening immediately after operation, 96% improved and only 1 patient sustained a permanent neurologic deficit from the surgery. AC has also maximized the extent of surgical resection, with 93% achieving gross total or supramarginal resection and only 7% achieving subtotal resection, which is a key factor in influencing the local recurrence rate.6 Local recurrence rates (9%) are also similar to historical local recurrence rates (8%) in brain tumor resections under general anesthesia.5 Our findings suggest that AC could be a safe procedure that can be undertaken when resecting brain metastases in eloquent areas, with rates of transient and permanent neurologic deficits comparable with other studies23-29 that explored the role of AC in a heterogeneous group including both primary and metastatic tumors. Transient neurologic deficits are common immediately after the procedure, but few patients remain symptomatic permanently. This highlights the key role of awake technique with intraoperative
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SYSTEMATIC REVIEW OF AWAKE CRANIOTOMY FOR BRAIN METASTASES
Table 3. Immediate and 3- to 6-Month Postoperative Neurologic Outcomes Neurologic Outcomes Improved or resolved immediately postoperative
Tan and Weil and Shinoura Spena Kamp Joswig Sanmillan Black, 200117 Losner, 200518 et al., 201119 et al., 201320 et al., 201513 et al., 201621 et al., 201722 Overall 7 (33)
14 (93)
3 (21)
2 (24)
No change immediately postoperative
3 (14)
0 (0)
7 (50)
3 (38)
*
0 (0)
0 (0)
Persistent or worsened immediately postoperative
11 (53)
1 (7)
4 (29)
3 (38)
5 (15)
2 (66)
2 (22)
28 (27)
10 (91)
1 (100)
NR
3 (100)
5 (100)
2 (100)
2 (100)
23 (96)
1 (9)
0 (0)
NR
0 (0)
0 (0)
0 (0)
0 (0)
1 (4)
Improved or resolved at 3e6 months postoperative Permanent deficit
*
1 (33)
7 (78)
76 (73)*
Values are number of cases (%). NR, not reported. *One study reported 29 patients as improved or no change immediately post-op, but there was insufficient information to separate them into the individual categories.
mapping.30 Performing intraoperative mapping under awake conditions is necessary for tumors located in eloquent areas that require the patient to execute tasks such as speech function. For other areas such as the motor areas, intraoperative cortical stimulation under general anesthesia is an alternative.31 With that said, performing intraoperative mapping under awake conditions is still relevant because there is increasing recognition that an execution of a motor function represents muscle contraction, along with a combination of sensory feedback and higher cortical functions,32 which can only be appreciated under awake conditions. Furthermore, intraoperative brain mapping and monitoring require dedicated and specialized equipment and workforce, which may not be available in all centers worldwide. Hence, AC remains a safe and good option at a lower price point. A meta-analysis33 looking at the role of intraoperative brain mapping in the management of gliomas has also concluded that intraoperative brain mapping, usually done with the patient awake,34 resulted in lower rates of postoperative permanent neurologic deficits when compared with patients that did not undergo intraoperative brain mapping (3.4% vs. 8.3%, respectively). They also noted a higher proportion of patients that underwent intraoperative brain mapping developed early severe deficits compared with those that did not undergo intraoperative brain mapping (36.0% vs. 11.3%, respectively). Our current series compares favorably with this meta-analysis33 in terms of permanent neurologic deficits (1.0% in this study vs. 3.4%) and early postoperative deficits (27.0% in this study vs. 36.0%), which is suggestive that AC may even be safer in brain metastases. Preoperative fMRI and DTI are often performed to allow surgical planning in resecting lesions in eloquent areas. Although both imaging modalities have been found to provide useful preoperative information in terms of the proximity between the tumor and functional areas,35 fMRI only correlated with 92.3% of sensorimotor cortex mapping,35 and DTI is limited by brain shift during surgery.36 We have identified 3 studies that reported the use of both fMRI and DTI prior to performing AC.19,20,22 Both Spena et al.20 and
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Sanmillan et al.22 recognized and acknowledged the limitations of both imaging modalities that were previously mentioned. Although Shinoura et al.19 recognized the limitations of these 2 modalities, they found that fMRI was the most reliable modality for localizing the primary motor area in patients with tumors in this area and localization of the primary motor area on the contralateral side can still provide useful information about the affected side. Immediate postoperative neurologic deficits after AC are largely because of cerebral edema, damage to deep white matter tracts, and ischemia as a result of vascular injury.37 A diagnosis of brain metastases is also significantly associated with a higher risk of intraoperative brain swelling,38 which may account for intraoperative seizures or worsening of neurologic deficits. In a study of 309 patients that underwent AC for both primary and metastatic tumors near eloquent areas, intraoperative neurologic deficits were found to be significantly associated with a higher rate of worsened neurologic outcome at 1 month,26 which is consistent with our findings of the single patient that sustained a permanent neurologic deficit that was acquired during the procedure. Historically, the overall recurrence rate in brain metastases resected under general anesthesia with postoperative radiotherapy has been reported to be 20%, with a local recurrence rate of 8%, a local and distant recurrence rate of 12%, and a distant recurrence rate of 8%, with a median follow-up of 10 months.5 In a review of studies looking at the outcomes of patients that underwent asleep craniotomy for brain metastases, the authors reported local recurrence rates of 10%e59% at 1e2 years.39 We found a comparable local recurrence rate of 9% with AC for the resection of brain metastases. Alternative options in the management of brain metastases located in eloquent regions include SRS and WBRT. However, recurrence rates have been reported to be 46.8% in patients that underwent both SRS and WBRT, whereas that for SRS alone ranged from 47%e76.4%.40,41 In addition, SRS and WBRT have higher toxicity to patients compared with SRS alone and are associated with a higher rate of radiation necrosis.42 We found a lower overall recurrence rate of 35% for AC for the resection of brain metastases than reported for SRS and WBRT.
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ORIGINAL ARTICLE TZY HARN CHUA ET AL.
SYSTEMATIC REVIEW OF AWAKE CRANIOTOMY FOR BRAIN METASTASES
Therefore, surgical resection with AC may confer an advantage in reducing recurrence rates without compromising neurologic function in the long term in brain metastases. It must however be acknowledged that AC has risks and complications. In particular, the risk of intraoperative seizure has been reported to be higher in patients that underwent AC for resection of intra-axial brain tumors,43 and the risk of intraoperative seizure has been associated with tumors located in certain brain regions, including the supplementary motor area.44 The occurrence of intraoperative seizure is important because it is associated with procedure failure, reduced rate of gross total resection, and higher incidence of short-term postoperative motor and speech deterioration.43,45 Additionally, the length of stay may differ depending on the age of the patients, and elderly patients may have a longer length of stay,46 which may be related to these patients’ tolerability of the procedure. The decision to perform AC in this group of patients needs to be considered prudently. Limitations of our systematic review include the retrospective nature of most studies and the marked heterogeneity among the studies. Our study has also highlighted the low number of studies currently available and the absence of studies directly comparing awake surgery with asleep surgery in the resection of brain metastases in eloquent areas. The primary outcome in our systematic review was pre- and postoperative neurologic function, and as such, the inclusion criterion of studies reporting pre- and postoperative neurologic function may have excluded studies reporting findings on our secondary outcomes, including the extent of resection, recurrence rates, and survival. However, this is the first
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systematic review investigating the role of AC in the resection of brain metastases in eloquent regions, and support of maximizing resection through AC is emerging over the last few years. AC may be insufficiently studied in resecting metastases, and this systematic review provides preliminary evidence for AC as possibly a safe and useful option in resecting metastases in eloquent areas. Although no specific inferences can be made, this systematic review seems to suggest that awake surgery may lead to better surgical outcomes in patients undergoing resection of brain metastases. CONCLUSIONS To our knowledge, this is the first systematic review examining the role of AC in brain metastases. We found that immediately after operation, 73% of the patients improved or had no change whereas 27% experienced transient worsening of neurologic function. However, follow-up in the long term revealed that 96% of the patients who had experienced worsening function in the short term, experienced an improvement in neurologic function. In addition, the recurrence rates in these patients were found to be comparable or lower than those reported in patients who received the current standard of care. There is likely to be a role for AC in maximizing resection. In metastatic tumors located in eloquent areas, AC should be considered as a technique to optimize outcomes. Use of AC has additional value over standard craniotomy. Further studies are required to assess the impact of AC for surgical resection of brain metastases.
8. Sanai N, Mirzadeh Z, Berger MS. Functional outcome after language mapping for glioma resection. N Engl J Med. 2008;358:18-27. 9. Benedictis AD, Moritz-Gasser S, Duffau H. Awake mapping optimizes the extent of resection for low-grade gliomas in eloquent areas. Neurosurgery. 2010;66:1074-1084. 10. Neves S, Mazal PR, Wanschitz J, Rudnay AC, Drlicek M, Czech T, et al. Pseudogliomatous growth pattern of anaplastic small cell carcinomas metastatic to the brain. Clin Neuropathol. 2001;20: 38-42.
4. Nayak L, Lee EQ, Wen PY. Epidemiology of brain metastases. Curr Oncol Rep. 2012;14:48-54.
11. Baumert BG, Rutten I, Dehing-Oberije C, Twijnstra A, Dirx MJ, Debougnoux-Huppertz RM, et al. A pathology-based substrate for target definition in radiosurgery of brain metastases. Int J Radiat Oncol Biol Phys. 2006;66:187-194.
5. Patchell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama Y, Kryscio RJ, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med. 1990;322:494-500.
12. Berghoff AS, Rajky O, Winkler F, Bartsch R, Furtner J, Hainfellner JA, et al. Invasion patterns in brain metastases of solid cancers. Neuro Oncol. 2013;15:1664-1672.
6. Yoo H, Kim YZ, Nam BH, Shin SH, Yang HS, Lee JS, et al. Reduced local recurrence of a single brain metastasis through microscopic total resection. J Neurosurg. 2009;110:730-736.
13. Kamp MA, Rapp M, Slotty PJ, Turowski B, Sadat H, Smuga M, et al. Incidence of local inbrain progression after supramarginal resection of cerebral metastases. Acta Neurochir. 2015;157: 905-911.
7. Meyer FB, Bates LM, Goerss SJ, Friedman JA, Windschitl WL, Duffy JR, et al. Awake craniotomy for aggressive resection of primary gliomas located in eloquent brain. Mayo Clin Proc. 2001;76: 677-687.
14. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol. 2009;62: 1006-1012.
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15. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health. 1998;52:377-384. 16. Gorber SC, Schofield-Hurwitz S, Hardt J, Levasseur G, Tremblay M. The accuracy of selfreported smoking: a systematic review of the relationship between self-reported and cotinineassessed smoking status. Nicotine Tob Res. 2009; 11:12-24. 17. Tan TC, Black PM. Awake craniotomy for excision of brain metastases involving eloquent cortex. Tech Neurosurg. 2001;7:85-90. 18. Weil RJ, Lonser RR. Selective excision of metastatic brain tumors originating in the motor cortex with preservation of function. J Clin Oncol. 2005;23: 1209-1217. 19. Shinoura N, Yamada R, Tabei Y, Saito K, Suzuki Y, Yagi K. Advantages and disadvantages of awake surgery for brain tumours in the primary motor cortex: institutional experience and review of literature. Br J Neurosurg. 2011;25:218-224. 20. Spena G, Garbossa D, Panciani PP, Griva F, Fontanella MM. Purely subcortical tumors in eloquent cortex: awake surgery and cortical and subcortical electrical stimulation (CSES) ensure safe and effective surgery. Clin Neurol Neurosurg. 2013;115:1595-1601. 21. Joswig H, Bratelj D, Brunner T, Jacomet A, Hildebrandt G, Surbeck W. Awake craniotomy:
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first-year experiences and patient perception. World Neurosurg. 2016;90:588-596. 22. Sanmillan JL, Fernández-Coello A, FernándezConejero I, Plans G, Gabarrós A. Functional approach using intraoperative brain mapping and neurophysiological monitoring for the surgical treatment of brain metastases in the central region. J Neurosurg. 2017;126:698-707. 23. Taylor MD, Bernstein M. Awake craniotomy with brain mapping as the routine surgical approach to treating patients with supratentorial intraaxial tumors: a prospective trial of 200 cases. J Neurosurg. 1999;90:35-41. 24. Low D, Ng I, Ng WH. Awake craniotomy under local anaesthesia and monitored conscious sedation for resection of brain tumours in eloquent cortex e outcomes in 20 patients. Ann Acad Med Singapore. 2007;36:326-331.
SYSTEMATIC REVIEW OF AWAKE CRANIOTOMY FOR BRAIN METASTASES
31. Bello L, Fava E, Casaceli G, Bertani G, Carrabba G, Papagno C, et al. Intraoperative mapping for tumor resection. Neuroimaging Clin N Am. 2009;19: 597-614. 32. Duffau H. Awake surgery for nonlanguage mapping. Neurosurgery. 2010;66:523-529. 33. De Witt Hamer PC, Robles SG, Zwinderman AH, Duffau H, Berger MS. Impact of intraoperative stimulation brain mapping on glioma surgery outcome: a meta-analysis. J Clin Oncol. 2012;30: 2559-2565. 34. Szelényi A, Bello L, Duffau H, Fava E, Feigl GC, Galanda M, et al. Intraoperative electrical stimulation in awake craniotomy: methodological aspects of current practice. Neurosurg Focus. 2010;28: E7.
25. Serletis D, Bernstein M. Prospective study of awake craniotomy used routinely and nonselectively for supratentorial tumors. J Neurosurg. 2007;107:1-6.
35. Spena G, Nava A, Cassini F, Pepoli A, Bruno M, D’Agata F, et al. Preoperative and intraoperative brain mapping for the resection of eloquent-area tumors. A prospective analysis of methodology, correlation, and usefulness based on clinical outcomes. Acta Neurochir. 2010;152:1835-1846.
26. Kim SS, McCutcheon IE, Suki D, Weinberg JS, Sawaya R, Lang FF, et al. Awake craniotomy for brain tumors near eloquent cortex: correlation of intraoperative cortical mapping with neurological outcomes in 309 consecutive patients. Neurosurgery. 2009;64:836-846.
36. Kumar A, Chandra PS, Sharma BS, Garg A, Rath GK, Bithal PK, et al. The role of neuronavigation-guided functional MRI and diffusion tensor tractography along with cortical stimulation in patients with eloquent cortex lesions. Br J Neurosurg. 2014;28:226-233.
27. Sacko O, Lauwers-Cances V, Brauge D, Sesay M, Brenner A, Roux FE. Awake craniotomy vs surgery under general anesthesia for resection of supratentorial lesions. Neurosurgery. 2011;68:1192-1199.
37. Brown T, Shah AH, Bregy A, Shah NH, Thambuswamy M, Barbarite E, et al. Awake craniotomy for brain tumor resection: the rule rather than the exception? J Neurosurg Anesthesiol. 2013;25:240-247.
28. Chacko AG, Thomas SG, Babu KS, Daniel RT, Chacko G, Prabhu K, et al. Awake craniotomy and electrophysiological mapping for eloquent area tumours. Clin Neurol Neurosurg. 2013;115:329-334. 29. Groshev A, Padalia D, Patel S, Garcia-Getting R, Sahebjam S, Forsyth PA, et al. Clinical outcomes from maximum-safe resection of primary and metastatic brain tumors using awake craniotomy. Clin Neurol Neurosurg. 2017;157:25-30. 30. Duffau H, Lopes M, Arthuis F, Bitar A, Sichez JP, Van Effenterre R, et al. Contribution of intraoperative electrical stimulations in surgery of low grade gliomas: a comparative study between two series without (1985-96) and with (1996-2003) functional mapping in the same institution. J Neurol Neurosurg Psychiatry. 2005;76:845-851.
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38. Rasmussen M, Bundgaard H, Cold GE. Craniotomy for supratentorial brain tumors: risk factors for brain swelling after opening the dura mater. J Neurosurg. 2004;101:621-626. 39. Mut M. Surgical treatment of brain metastasis: a review. Clin Neurol Neurosurg. 2012;114:1-8. 40. Aoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Hatano K, et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA. 2006;295:2483-2491.
symptomatic brain tumor recurrence and neurologic deficit after radiosurgery alone in patients with newly diagnosed brain metastases: results and implications. Int J Radiat Oncol Biol Phys. 2002; 52:333-338. 42. Kohutek ZA, Yamada Y, Chan TA, Brennan CW, Tabar V, Gutin PH, et al. Long-term risk of radionecrosis and imaging changes after stereotactic radiosurgery for brain metastases. J Neurooncol. 2015;125:149-156. 43. Nossek E, Matot I, Shahar T, Barzilai O, Rapoport Y, Gonen T, et al. Intraoperative seizures during awake craniotomy: incidence and consequences: analysis of 477 patients. Neurosurgery. 2013;73:135-140. 44. Gonen T, Grossman R, Sitt R, Nossek E, Yanaki R, Cagnano E, et al. Tumor location and IDH1 mutation may predict intraoperative seizures during awake craniotomy. J Neurosurg. 2014; 121:1133-1138. 45. Nossek E, Matot I, Shahar T, Barzilai O, Rapoport Y, Gonen T, et al. Failed awake craniotomy: a retrospective analysis in 424 patients undergoing craniotomy for brain tumor. J Neurosurg. 2013;118:243-249. 46. Grossman R, Nossek E, Sitt R, Hayat D, Shahar T, Barzilai O, et al. Outcome of elderly patients undergoing awake-craniotomy for tumor resection. Ann Surg Oncol. 2013;20:1722-1728.
Conflict of interest statement: This research is supported by the Singapore Ministry of Health’s National Medical Research Council under its Translational and Clinical Research Flagship Programme - Tier 1 (NMRC/TCR/016-NNI/ 2016). Received 16 June 2018; accepted 30 August 2018 Citation: World Neurosurg. (2018). https://doi.org/10.1016/j.wneu.2018.08.243 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2018 Elsevier Inc. All rights reserved.
41. Regine WF, Huhn JL, Patchell RA, St Clair WH, Strottmann J, Meigooni A, et al. Risk of
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Awake Craniotomy for Resection of Brain Metastases: A Systematic Review Tzy Harn Chua1, Angela An Qi See2,3, Beng Ti Ang2-4, Nicolas Kon Kam King2-4
-
BACKGROUND: Surgery for brain metastases aims to reduce mass effect and achieve local control through maximizing resection. There is increasing recognition that awake craniotomy (AC) is especially relevant for resection of brain metastases in eloquent areas. This study seeks to examine the neurologic outcomes of using AC for brain metastases resection.
neurologic function after the procedure showed excellent recovery. AC should be considered as a technique to optimize outcomes in brain metastases in eloquent areas.
METHODS: A systematic search for studies examining the role of AC in patients with brain metastases was conducted via PubMed without limitations on the year of publication, language, or study design, using the following search terms: (cerebral OR brain) and (metastases OR tumor) and (awake OR intraoperative OR eloquent OR supramarginal). Studies were included if patients underwent AC for resection of brain metastases and data on preand postoperative neurologic function were available.
INTRODUCTION
-
RESULTS: Seven studies published between 2001 and 2017 with 104 patients who underwent 107 ACs were identified. Gross total resection was achieved in 61% of patients, supramarginal resection was achieved in 32%, and subtotal resection was achieved in 7%. Immediately after operation, 73% of patients experienced no change or improvement in neurologic outcomes, whereas 27% experienced worsening. In the long term, 96% of those with postoperative worsening of function experienced improvements in neurologic function.
-
CONCLUSIONS: Most patients experienced improvements in neurologic function immediately after AC, and most patients that experienced short-term worsening of
-
Key words Awake craniotomy - Brain metastases - Neurologic outcomes - Recurrence - Surgical resection -
Abbreviations and Acronyms AC: Awake craniotomy DTI: Diffusion tensor imaging fMRI: Functional magnetic resonance imaging MRI: Magnetic resonance imaging SRS: Stereotactic radiosurgery WBRT: Whole brain radiation therapy
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I
ntracranial tumors are most commonly caused by brain metastases, with an estimated incidence of 8.3e14.3 per 100,000 persons.1,2 The incidence rate of hospitalization doubled from 7 to 14 patients per 100,000 persons based on data collected between 1987 and 2006.3 With the availability of more effective chemoradiotherapy and improvements in imaging modalities enabling earlier detection of metastases, the more recent incidence rates of brain metastases have been reported to be 9%e17% based on several studies, but exact incidence rates in more recent years have not been reported.4 It is well established that surgical resection of brain metastases improves both the local recurrence rate and length of survival.5 More recently, maximal resection of brain metastasis in noneloquent areas through microscopic means has also been shown to reduce the local recurrence rate.6 However, in some cases, microscopic maximal resection of tumors in eloquent areas of the brain may not be attempted under general anesthesia because of the increased concern over causing adverse neurologic outcomes. The role of awake craniotomy (AC) in resection of primary tumors has been increasingly supported by several studies,7-9 especially in terms of optimizing tumor resection and subsequent neurologic function. There is also increasing recognition in the literature that most brain metastases exhibit some evidence of infiltration similar to gliomas and are not purely well-demarcated lesions.10-13 This is
From the 1School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia; 2Department of Neurosurgery, Singapore General Hospital, Singapore; 3Department of Neurosurgery, National Neuroscience Institute, Singapore; and 4 Duke-NUS Medical School, Singapore, Singapore To whom correspondence should be addressed: Nicolas Kon Kam King, Ph.D. [E-mail: [email protected]] Citation: World Neurosurg. (2018). https://doi.org/10.1016/j.wneu.2018.08.243 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2018 Elsevier Inc. All rights reserved.
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especially relevant when trying to achieve gross total resection in eloquent areas. Despite this, there are few studies that have investigated the use of awake techniques in brain metastases surgery. The present study aims to study the utility of AC for metastases in eloquent areas. METHODS Literature Search Strategy A literature search was performed via PubMed on December 16, 2017, using a combination of the following terms as either key words or Medical Subject Headings: (cerebral OR brain) and (metastases OR tumor) and (awake OR intraoperative OR eloquent OR supramarginal). No limitations on the year of publication, language, or study design were imposed. Duplication and unrelated literature were excluded after careful scanning of titles and abstracts. After initial screening, full-text articles of the remaining literature were retrieved and assessed for eligibility criteria by 2 reviewers. Any disagreement on study eligibility was resolved through discussion with a third reviewer to reach a consensus when needed. In addition, the references of review articles and retrieved full-text articles were checked to identify other potentially eligible studies which did not turn up in the database search. Study Selection and Exclusion Criteria For a study to be included, it would have to fulfill the following criteria: 1) be published in a peer-reviewed journal, 2) have a target population of adult patients older than 18 years old of age with cerebral metastasis or metastases, 3) include patients who underwent AC for resection of tumor, and 4) have data on pre- and postoperative neurologic function. Studies on both primary and metastatic brain tumors without a separate data analysis for patients with brain metastases, review articles, and animal studies were excluded. Data Extraction A 4-phase approach including identification, screening, eligibility, and inclusion based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement14 was performed. The data extracted included mean age (years), proportion of men (%), site of primary tumor (lung, melanoma, gastrointestinal tract, renal, breast, sarcoma, adrenal, urogenital, and unknown), symptoms at presentation (weakness/paresis, seizure, speech deficits, sensory deficits, headache, gait/coordination disturbances, memory deficits, and none), use of preoperative functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI), intraoperative cortical mapping, proportion of gross total resection and subtotal/partial resection, and location of tumor (precentral, central, postcentral, temporal, parietal, parietal, frontoparietal, and periventricular). Data on preoperative radiotherapy, postoperative radiotherapy, local and distant recurrence, and survival were extracted as well. These data have been extracted for the purpose of providing sufficient baseline characteristics of individual studies that may have an impact on the primary outcome of this study. Neurologic Outcomes Neurologic outcomes were determined clinically, using scales including the Karnofsky Performance Status scale and modified Rankin Scale. Pre- and postoperative neurologic symptoms and
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function were compared. Short-term neurologic outcomes that were determined immediately after the procedure, and long-term neurologic outcomes at 3- to 6-month follow-up after the procedure were compared as well. Tumor Recurrence Local recurrence was defined as a tumor appearing at the site of resection, and distant recurrence was defined as recurrence in a location outside the site of resection. Recurrence was determined based on evidence from follow-up magnetic resonance imaging (MRI). No specific criteria were used to determine tumor recurrence. Quality Assessment The quality of evidence was assessed using a modified version of the Downs and Black checklist15 by 2 reviewers. The checklist consists of 27 questions grouped into 5 sections: reporting (10 questions); external validity (3 questions); internal validity, bias (7 questions); internal validity, confounding/selection bias (6 questions); and power (1 question). A score of 1 was given for a positive response, and a score of 0 was given for a negative or indeterminate response. Based on Gorber et al.’s method,16 a median split of the quality scores generated from the Downs and Black checklist was used to classify studies as higher or lower quality. Any disagreement was resolved through discussion with a third reviewer to reach a consensus when needed. RESULTS Study Selection, Characteristics, and Quality A total of 356 studies were identified through the PubMed search. Duplicated studies and studies that did not meet the eligibility criteria based on title and abstract were excluded. Subsequently, 28 potentially relevant full-text articles were obtained for a detailed evaluation. Then, 34 more full-text articles were identified from the reference lists of the 28 full-text articles. Finally, 7 studies with a total of 104 patients and 107 procedures met the inclusion criteria and were included (Figure 1). Of the patients, 34% were men, with a mean age of 56.0 6.8 years. In Tan and Black,17 3 patients (3%) had a reoperation, but the reason for repeat surgery was not specified. Among the 7 studies,13,17-22 1 study with 8 patients (7.7%)20 was prospective, and the rest13,17-19,21,22 with a total of 96 patients (92. 3%) were retrospective in nature. These studies presented data from patients over a period of 20 years, from July 1995 to July 2015. Two studies13,17 solely presented data on patients that underwent AC for resection of brain metastases, whereas the other studies were retrospective case series of ACs or brain metastases, and hence individual patient data were extracted from these studies. Duration of follow-up was not reported in 3 studies, and the remaining studies had a mean follow-up duration of 14.7 months (range, 4e20 months). Study characteristics are summarized in Table 1. The methodologic quality of each included study was assessed with the modified Downs and Black checklist.15 The median quality score of the studies in our sample was 13 (range, 11e14) of a maximum score of 28. Two studies17,21 had the highest methodologic quality with a score of 14, whereas 4 studies13,18,20,22 had a score of 13; Shinoura et al.19 had the lowest methodologic quality with a score of 11.
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SYSTEMATIC REVIEW OF AWAKE CRANIOTOMY FOR BRAIN METASTASES
Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart for study selection.
Study Population and Clinical Presentation Baseline characteristics are summarized in Table 2. The most common brain metastases involving eloquent areas in the overall series originated from the lungs (47%), followed by melanoma
(17%) and the breast (11%). At presentation, 42 patients (40%) had weakness or paresis of upper or lower limbs, 26 (25%) had seizures, and 15 (14%) had speech deficits, whereas 7% were asymptomatic. Preoperative fMRI and DTI were done in patients
Table 1. Study Characteristics Study
Country
Study Period
Type
Number of Patients with Brain Metastases (%)
Follow-Up (Months)
United States
1995e2000
Retrospective
21 (100)
12
United States
1999e2004
Retrospective
15 (88)
16.2
Shinoura et al., 2011
Japan
2004e2008
Retrospective
14 (67)
NR
Spena et al., 201320
Italy
2008e2010
Prospective
8 (47)
4e20
17
Tan and Black, 2001
18
Weil and Losner, 2005
19
Kamp et al., 201513
Germany
2009e2013
Retrospective
34 (100)
15.8 1.5
Joswig et al., 201621
Switzerland
2014e2015
Retrospective
3 (14)
NR
Spain
2003e2013
Retrospective
9 (27)
NR
22
Sanmillan et al., 2017 NR, not reported.
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for 3 studies.19,20,22 Patients were selected for AC based on the proximity of the tumor to eloquent cortex on preoperative MRI scans. About 68% of brain metastases (50/73) were found in the precentral region. There were 38 patients (52%) with precentral tumors from 3 studies which investigated only patients with tumors in the motor
areas18,19,22 and 12 patients from other studies, making a total of 50 patients with tumors in the precentral region. Other tumor locations included the central region (11%), postcentral region (11%), parietal area (4%), frontoparietal area (3%), temporal area (1%), and periventricular area (1%).
Table 2. Patient Characteristics Tan and Black, 200117
Weil and Losner, 200518
Shinoura et al., 201119
Spena et al., 201320
Kamp et al., 201513
Joswig et al., 201621
64 8.9
57 10.3
58 9.8
51 9.0
60 (33e83)*
43 4.2
NR
56
67
40
36
NR
29
0
NR
34
10 (48)
3 (23)
NR
NR
19 (56)
2 (66)
NR
34 (47)
Melanoma
5 (24)
2 (15)
NR
NR
5 (15)
0 (0)
NR
12 (17)
Gastrointestinal tract
2 (10)
0 (0)
NR
NR
4 (12)
0 (0)
NR
6 (8)
Renal
1 (5)
1 (8)
NR
NR
0 (0)
0 (0)
NR
2 (3)
Breast
1 (5)
4 (31)
NR
NR
5 (15)
1 (33)
NR
11 (11)
Sarcoma
1 (5)
0 (0)
NR
NR
0 (0)
0 (0)
NR
1 (1)
Adrenal
0 (0)
1 (8)
NR
NR
0 (0)
0 (0)
NR
1 (1)
Characteristic Mean age SD (years) Male (%)
Sanmillan et al., 201722
Overall
Primary tumor Lung
Urogenital
0 (0)
0 (0)
NR
NR
1 (3)
0 (0)
NR
1 (1)
Unknown
1 (5)
4 (31)
NR
NR
0 (0)
0 (0)
NR
5 (7)
Symptoms at presentation Weakness/paresis
16 (76)
14 (93)
NR
1 (13)
5 (15)
3 (100)
3 (33)
40 (38)
Seizure
9 (43)
4 (27)
NR
0 (0)
7 (21)
1 (33)
5 (56)
25 (24)
Speech deficits
6 (29)
0 (0)
NR
2 (25)
7 (21)
0 (0)
0 (0)
14 (13)
Sensory deficits
3 (14)
0 (0)
NR
2 (25)
0 (0)
0 (0)
0 (0)
5 (5)
Headache
3 (14)
0 (0)
NR
1 (13)
0 (0)
1 (33)
1 (11)
6 (6)
Gait/coordination disturbances
0 (0)
0 (0)
NR
0 (0)
4 (12)
0 (0)
0 (0)
4 (4)
Memory deficits
0 (0)
0 (0)
NR
0 (0)
3 (9)
0 (0)
0 (0)
3 (3)
None
6 (18)
7 (7)
0 (0)
0 (0)
NR
2 (25)
0 (0)
0 (0)
Preoperative fMRI
NR
NR
Yes
Yes
NR
NR
Yes
Preoperative DTI
NR
NR
Yes
Yes
NR
NR
Yes
Precentral
8 (33)
15 (100)
14 (100)
4 (50)
NR
0 (0)
9 (100)
Central
8 (33)
0 (0)
0 (0)
0 (0)
NR
0 (0)
0 (0)
Location of tumor 50 (68) 8 (11)
Postcentral
5 (21)
0 (0)
0 (0)
3 (38)
NR
0 (0)
0 (0)
8 (11)
Temporal (nondominant)
1 (4)
0 (0)
0 (0)
0 (0)
NR
0 (0)
0 (0)
1 (1)
Parietal
1 (4)
0 (0)
0 (0)
0 (0)
NR
2 (66)
0 (0)
3 (4)
Frontoparietal
0 (0)
0 (0)
0 (0)
1 (12)
NR
1 (33)
0 (0)
2 (3)
Periventricular
1 (4)
0 (0)
0 (0)
0 (0)
NR
0 (0)
0 (0)
1 (1)
Values are number of cases (%) or as otherwise indicated. NR, not reported; fMRI, functional magnetic resonance imaging; DTI, diffusion tensor imaging. *Figure in parentheses represent the range. Standard deviation was not reported in the original article.
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SYSTEMATIC REVIEW OF AWAKE CRANIOTOMY FOR BRAIN METASTASES
Surgical Technique All patients underwent sedation with intravenous sedative agents and received local anesthetic prior to craniotomy. Stereotactic neuronavigation was used to identify the tumor in 5 studies.17-20,22 Intraoperative MRI was used in 13% of patients in Tan and Black.17 Two studies13,21 did not state the use of neuronavigation. Surgeries in most of the studies13,18-20,22 were carried out as awake surgery in an asleep-awake-asleep protocol, except for 2 studies which used either a sedated-awake-sedated protocol17 or a sedated-awake-asleep protocol.21 Cortical stimulation was performed in all patients except 5 patients (17%) in Tan and Black17 and 1 patient (7%) in Shinoura et al.19 In Tan and Black,17 identification of sensory and motor cortices was achieved through the anesthesiologist’s observation of any movements and the patient’s self-reporting of sensory or motor symptoms. Speech and language areas were identified by observing for speech arrest and stimulation-evoked speech errors. Weil and Lonser18 did not mention how intraoperative deficits were identified. In Shinoura et al.,19 patients were continuously observed for any abnormal movements by the neurosurgeons. In Spena et al.,20 the patient was asked to perform several language tasks, including reading and object naming, and to report any numbness. Patients were observed for changes in speech, motor, and sensory function in Kamp et al.13 In Joswig et al.,21 a speech and language pathology assistant assessed the performance of sensory, motor, and language testing. Patients in Sanmillan et al.22 were observed for speech arrest and language function via a counting task and picture-naming task, respectively, followed by a finger-to-thumb task, bimanual hand coordination task, and verb generation task to assess the function of the supplementary motor area. The extent of resection was confirmed by contrast-enhanced MRI in 6 studies.13,17,18,20-22 The use of postoperative MRI was not stated in Shinoura et al.19 Postoperative MRI was performed within 24 hours of surgery in Weil and Lonser,18 immediately after operation in Spena et al.,20 and within 72 hours of surgery in Kamp et al.13 Tan and Black,17 Joswig et al.,21 and Sanmillan et al.22 did not specify when postoperative MRI was performed. Ultrasound was also used to confirm gross total resection in Weil and Lonser.18 Gross total resection was attempted in all tumors. Resection was terminated if the patient became symptomatic during resection or when functional areas identified on cortical mapping contained the tumor. Out of 107 procedures, gross total resection was achieved in 65 patients (61%), whereas supramarginal resection was achieved in 34 patients (32%) in Kamp et al.,13 which refers to gross resection of the metastasis and a further removal or approximately 5 mm of the surrounding tissue.13 In the 8 patients with subtotal resection, resection in 2 patients was stopped based on postoperative MRI,17 whereas resection in 6 patients19 was halted when the motor function did not recover over the 5 minutes after the procedure was paused based on the presentation of symptoms. Neurologic Outcomes Neurologic outcomes are summarized in Table 3. All studies reported short-term neurologic outcomes that were determined immediately after the operation. All but 1 study19 reported long-
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term neurologic outcomes that were determined at 3e6 months after the operation. Intraoperative seizures were reported in 2 patients (10%) in Tan and Black,17 whereas 10 out of 14 patients (71%) in Shinoura et al.19 experienced intraoperative deterioration of motor function. Among the 10 patients that experienced intraoperative deterioration of motor function in Shinoura et al.,19 motor function recovered within 5 minutes after the procedure was paused. Immediately after the operation, 76 out of 104 patients (73%) experienced no change, improvements or complete resolution in their neurologic symptoms. At 3e6 months after the operation, 23 out of 24 patients (96%) who had temporary immediate postoperative worsening of neurologic symptoms improved. A permanent neurologic deficit (acquired during the surgery) was sustained in 1 patient (1%).17 Adjuvant Treatment Out of 70 patients, 59 (84%) received postoperative radiotherapy in the form of whole brain radiation therapy (WBRT), whereas 1 patient received stereotactic radiosurgery (SRS). Five patients in Weil and Lonser18 received radiotherapy prior to treatment with surgical resection of the brain metastases. Tumor Recurrence and Survival Tumor recurrence data were only available in 3 studies.13,17,18 Among the 3 studies with a total of 70 patients, there was an overall recurrence rate of 35% (n ¼ 24), a local recurrence rate of 9% (n ¼ 6), a distant recurrence rate of 19% (n ¼ 13), and a combined local and distant recurrence rate of 7% (n ¼ 5). Data on survival could only be obtained from 2 studies. Tan and Black17 reported a median survival of 16.2 months, whereas Weil and Lonser18 reported a median survival of 12 months. Mean follow-up duration among the 3 studies was 14.7 2.3 months. DISCUSSION Our systematic review has several key findings that are of importance in the resection of brain metastases. Neurologic function improved or was not changed in 73% of all patients after the operation, while 27% of the patients experiencing a worsening of neurologic function. Out of 24 patients who experienced worsening immediately after operation, 96% improved and only 1 patient sustained a permanent neurologic deficit from the surgery. AC has also maximized the extent of surgical resection, with 93% achieving gross total or supramarginal resection and only 7% achieving subtotal resection, which is a key factor in influencing the local recurrence rate.6 Local recurrence rates (9%) are also similar to historical local recurrence rates (8%) in brain tumor resections under general anesthesia.5 Our findings suggest that AC could be a safe procedure that can be undertaken when resecting brain metastases in eloquent areas, with rates of transient and permanent neurologic deficits comparable with other studies23-29 that explored the role of AC in a heterogeneous group including both primary and metastatic tumors. Transient neurologic deficits are common immediately after the procedure, but few patients remain symptomatic permanently. This highlights the key role of awake technique with intraoperative
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Table 3. Immediate and 3- to 6-Month Postoperative Neurologic Outcomes Neurologic Outcomes Improved or resolved immediately postoperative
Tan and Weil and Shinoura Spena Kamp Joswig Sanmillan Black, 200117 Losner, 200518 et al., 201119 et al., 201320 et al., 201513 et al., 201621 et al., 201722 Overall 7 (33)
14 (93)
3 (21)
2 (24)
No change immediately postoperative
3 (14)
0 (0)
7 (50)
3 (38)
*
0 (0)
0 (0)
Persistent or worsened immediately postoperative
11 (53)
1 (7)
4 (29)
3 (38)
5 (15)
2 (66)
2 (22)
28 (27)
10 (91)
1 (100)
NR
3 (100)
5 (100)
2 (100)
2 (100)
23 (96)
1 (9)
0 (0)
NR
0 (0)
0 (0)
0 (0)
0 (0)
1 (4)
Improved or resolved at 3e6 months postoperative Permanent deficit
*
1 (33)
7 (78)
76 (73)*
Values are number of cases (%). NR, not reported. *One study reported 29 patients as improved or no change immediately post-op, but there was insufficient information to separate them into the individual categories.
mapping.30 Performing intraoperative mapping under awake conditions is necessary for tumors located in eloquent areas that require the patient to execute tasks such as speech function. For other areas such as the motor areas, intraoperative cortical stimulation under general anesthesia is an alternative.31 With that said, performing intraoperative mapping under awake conditions is still relevant because there is increasing recognition that an execution of a motor function represents muscle contraction, along with a combination of sensory feedback and higher cortical functions,32 which can only be appreciated under awake conditions. Furthermore, intraoperative brain mapping and monitoring require dedicated and specialized equipment and workforce, which may not be available in all centers worldwide. Hence, AC remains a safe and good option at a lower price point. A meta-analysis33 looking at the role of intraoperative brain mapping in the management of gliomas has also concluded that intraoperative brain mapping, usually done with the patient awake,34 resulted in lower rates of postoperative permanent neurologic deficits when compared with patients that did not undergo intraoperative brain mapping (3.4% vs. 8.3%, respectively). They also noted a higher proportion of patients that underwent intraoperative brain mapping developed early severe deficits compared with those that did not undergo intraoperative brain mapping (36.0% vs. 11.3%, respectively). Our current series compares favorably with this meta-analysis33 in terms of permanent neurologic deficits (1.0% in this study vs. 3.4%) and early postoperative deficits (27.0% in this study vs. 36.0%), which is suggestive that AC may even be safer in brain metastases. Preoperative fMRI and DTI are often performed to allow surgical planning in resecting lesions in eloquent areas. Although both imaging modalities have been found to provide useful preoperative information in terms of the proximity between the tumor and functional areas,35 fMRI only correlated with 92.3% of sensorimotor cortex mapping,35 and DTI is limited by brain shift during surgery.36 We have identified 3 studies that reported the use of both fMRI and DTI prior to performing AC.19,20,22 Both Spena et al.20 and
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Sanmillan et al.22 recognized and acknowledged the limitations of both imaging modalities that were previously mentioned. Although Shinoura et al.19 recognized the limitations of these 2 modalities, they found that fMRI was the most reliable modality for localizing the primary motor area in patients with tumors in this area and localization of the primary motor area on the contralateral side can still provide useful information about the affected side. Immediate postoperative neurologic deficits after AC are largely because of cerebral edema, damage to deep white matter tracts, and ischemia as a result of vascular injury.37 A diagnosis of brain metastases is also significantly associated with a higher risk of intraoperative brain swelling,38 which may account for intraoperative seizures or worsening of neurologic deficits. In a study of 309 patients that underwent AC for both primary and metastatic tumors near eloquent areas, intraoperative neurologic deficits were found to be significantly associated with a higher rate of worsened neurologic outcome at 1 month,26 which is consistent with our findings of the single patient that sustained a permanent neurologic deficit that was acquired during the procedure. Historically, the overall recurrence rate in brain metastases resected under general anesthesia with postoperative radiotherapy has been reported to be 20%, with a local recurrence rate of 8%, a local and distant recurrence rate of 12%, and a distant recurrence rate of 8%, with a median follow-up of 10 months.5 In a review of studies looking at the outcomes of patients that underwent asleep craniotomy for brain metastases, the authors reported local recurrence rates of 10%e59% at 1e2 years.39 We found a comparable local recurrence rate of 9% with AC for the resection of brain metastases. Alternative options in the management of brain metastases located in eloquent regions include SRS and WBRT. However, recurrence rates have been reported to be 46.8% in patients that underwent both SRS and WBRT, whereas that for SRS alone ranged from 47%e76.4%.40,41 In addition, SRS and WBRT have higher toxicity to patients compared with SRS alone and are associated with a higher rate of radiation necrosis.42 We found a lower overall recurrence rate of 35% for AC for the resection of brain metastases than reported for SRS and WBRT.
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SYSTEMATIC REVIEW OF AWAKE CRANIOTOMY FOR BRAIN METASTASES
Therefore, surgical resection with AC may confer an advantage in reducing recurrence rates without compromising neurologic function in the long term in brain metastases. It must however be acknowledged that AC has risks and complications. In particular, the risk of intraoperative seizure has been reported to be higher in patients that underwent AC for resection of intra-axial brain tumors,43 and the risk of intraoperative seizure has been associated with tumors located in certain brain regions, including the supplementary motor area.44 The occurrence of intraoperative seizure is important because it is associated with procedure failure, reduced rate of gross total resection, and higher incidence of short-term postoperative motor and speech deterioration.43,45 Additionally, the length of stay may differ depending on the age of the patients, and elderly patients may have a longer length of stay,46 which may be related to these patients’ tolerability of the procedure. The decision to perform AC in this group of patients needs to be considered prudently. Limitations of our systematic review include the retrospective nature of most studies and the marked heterogeneity among the studies. Our study has also highlighted the low number of studies currently available and the absence of studies directly comparing awake surgery with asleep surgery in the resection of brain metastases in eloquent areas. The primary outcome in our systematic review was pre- and postoperative neurologic function, and as such, the inclusion criterion of studies reporting pre- and postoperative neurologic function may have excluded studies reporting findings on our secondary outcomes, including the extent of resection, recurrence rates, and survival. However, this is the first
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systematic review investigating the role of AC in the resection of brain metastases in eloquent regions, and support of maximizing resection through AC is emerging over the last few years. AC may be insufficiently studied in resecting metastases, and this systematic review provides preliminary evidence for AC as possibly a safe and useful option in resecting metastases in eloquent areas. Although no specific inferences can be made, this systematic review seems to suggest that awake surgery may lead to better surgical outcomes in patients undergoing resection of brain metastases. CONCLUSIONS To our knowledge, this is the first systematic review examining the role of AC in brain metastases. We found that immediately after operation, 73% of the patients improved or had no change whereas 27% experienced transient worsening of neurologic function. However, follow-up in the long term revealed that 96% of the patients who had experienced worsening function in the short term, experienced an improvement in neurologic function. In addition, the recurrence rates in these patients were found to be comparable or lower than those reported in patients who received the current standard of care. There is likely to be a role for AC in maximizing resection. In metastatic tumors located in eloquent areas, AC should be considered as a technique to optimize outcomes. Use of AC has additional value over standard craniotomy. Further studies are required to assess the impact of AC for surgical resection of brain metastases.
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Conflict of interest statement: This research is supported by the Singapore Ministry of Health’s National Medical Research Council under its Translational and Clinical Research Flagship Programme - Tier 1 (NMRC/TCR/016-NNI/ 2016). Received 16 June 2018; accepted 30 August 2018 Citation: World Neurosurg. (2018). https://doi.org/10.1016/j.wneu.2018.08.243 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2018 Elsevier Inc. All rights reserved.
41. Regine WF, Huhn JL, Patchell RA, St Clair WH, Strottmann J, Meigooni A, et al. Risk of
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