Selective Excision of Metastatic Brain Tumors Originating in the Motor Cortex With Preservation of Function
http://www.100md.com
《临床肿瘤学》
the Brain Tumor Institute, Cleveland Clinic Foundation, Cleveland, OH
Department of Neurosurgery, Vanderbilt University School of Medicine, Nashville, TN
the Surgical Neurology Branch, National Institutes of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
ABSTRACT
PATIENTS AND METHODS: Seventeen consecutive patients with metastasis within the primary motor cortex underwent selective microsurgical tumor resection. Operative, hospital, neuroimaging, and follow-up information was reviewed.
RESULTS: There were 10 women and seven men (mean age, 54.3 years) who underwent 17 operations for symptomatic brain metastases. Motor cortex was identified and tumor (mean volume, 10.2 cm3) was completely resected in all patients. Three patients had transient or reversible complications. Karnofsky performance scores improved in 16 of 17 patients at 4 weeks postoperatively, with a mean improvement of 1.8 grades compared with preoperative scores (P < .05). Overall survival of 16 patients with distant follow-up (> 6 months or until death) averaged 10.6 ± 4.4 months, with nine of 16 (56%) assessable patients surviving 1 year or longer. Survival of these 16 patients, by recursive partitioning analysis (RPA), was 11.2, 13.3, and 6.7 months for RPA classes I, II, and III, respectively. The cause of death in 14 of 15 patients who have died was progressive systemic disease; in one patient it was a combination of systemic and distant CNS disease progression. There were no local CNS recurrences.
CONCLUSION: Complete microsurgical resection of metastatic tumors in the primary motor cortex is feasible and efficacious, results in a sustained improvement in performance outcomes, and permits satisfactory long-term survival.
INTRODUCTION
Uncertainty exists regarding optimal treatment for patients with metastasis in eloquent cortical areas (language, vision, and sensorimotor areas). Several studies have considered this issue as part of larger series reporting surgical treatment of brain tumors and have suggested that surgical resection may be feasible, with acceptable outcomes.1-3,18-29 No study, however, has focused on metastatic tumors located directly within the primary motor cortex (PMC) or reported results for surgical resection. Furthermore, while several groups have suggested the utility of SR to treat metastatic lesions in eloquent cortex or deep brain areas, no reports of its use, with or without WBI, have examined SR's role in the treatment of metastases in the PMC.9-17
We present an analysis of a consecutive series of 17 patients with metastatic tumors located in the PMC in whom microneurosurgical resection was performed. We review presentation, surgical and hospital characteristics, as well as short- and long-term outcomes, including sorting by recursive partitioning analysis (RPA), to demonstrate that selective, microneurosurgical resection of tumors is a safe, effective, and valuable method to treat patients with brain metastasis in the PMC.
PATIENTS AND METHODS
Each patient underwent surgery for a symptomatic metastasis in the PMC. Fifteen patients had solitary metastases. One patient (patient 16 in Tables 1 and 2) had a second lesion (volume, 10.0 cm3) removed from the contralateral parietal lobe at the same surgery. Patient 17 had two additional, symptomatic lesions—in the ipsilateral anterior frontal lobe (volume, 45 cm3) and the ipsilateral occipital lobe (volume, 7.7 cm3)—removed at the same surgery as the motor lesion. Magnetic resonance (MR) imaging, without and with contrast, was performed before and within 24 hours of surgery. Preoperative MR images were used for frameless stereotactic guidance of craniotomy placement and tumor localization. Patient information was obtained from the hospital chart; neuroimaging, operative, and anesthetic records; review of hospital nursing and discharge records; and by written or telephone contact with patients, as needed, for distant follow-up. This work was conducted as part of studies approved by the institutional review boards at Vanderbilt University School of Medicine (Nashville, TN), the National Institutes of Health (Bethesda, MD), and the Cleveland Clinic (Cleveland, OH). Patient characteristics and outcomes are summarized in Tables 1 and 2.
Surgical and Cortical Mapping Techniques
Fifteen of the 17 patients underwent craniotomy using local anesthetic, intravenous sedation, and cortical mapping.30,31 Two patients elected craniotomy under general anesthesia, with localization of sensorimotor cortex using evoked potentials. These patients received a general anesthetic using a nitrous oxide, oxygen, and narcotic technique, according to standard methods. All patients received a local field or circumferential scalp block with 0.25% bupivacaine mixed 50:50 with 1% lidocaine with 1:100,000 epinephrine.
For the 15 patients undergoing awake craniotomy, cortical mapping was performed as previously described.27,31 In brief, an Ojemann cortical stimulator (Radionics, Burlington, MA) delivers a biphasic, square-wave pulse current. Initial settings were 0.5 mA with a pulse frequency of 60 Hz, and a single pulse duration of 1 ms. The lowest setting to elicit spontaneous motor activity in the contralateral hemibody was identified (generally from 2 to 6 mA). During resection, stimulation of the subcortical white matter identified proximity to the pyramidal tracts. Stimulation was performed to identify the PMC; to identify the safest corridor to the tumor, especially if it lay more than 1 cm subcortically (a transcortical v trans-sulcal approach); and to confirm anatomic integrity of the motor pathways during and after tumor resection. In the two patients undergoing craniotomy under general anesthesia, intraoperative somatosensory evoked potential mapping was used to localize the sensory and motor cortex on the brain's surface, as previously described.27 Frameless stereotactic guidance aided identification of the PMC and tumor. Ultrasound was used to outline the tumor and confirm gross total resection.
Patient characteristics were obtained from the operative records, including the nursing, anesthetic, and operative reports. In cases of discrepancy, the average of these values was used. Operative time and blood loss calculations were inclusive of all 20 tumors removed (see data on patients 16 and 17). Length of stay in a monitored nursing unit, whether in the recovery room or the intensive care unit, and length of hospitalization from the start of surgery to discharge, were recorded (nine patients were same-day admissions and eight patients were inpatients).
Complications were surgical if they occurred within 30 days or, if later than 30 days, were a direct result of surgical intervention. Complications were transient if they resolved within 30 days of surgery or definitive management, or prolonged if they persisted to the last follow-up or death. Metastatic brain tumor recurrence was defined as local if tumor recurred at the operative site, or distant if it occurred at a CNS site distinct from the surgical site. Failure was defined by failure to respond to therapy or by mortality due to failure at that site, whether it was local, elsewhere within the CNS (distant), or outside the CNS (systemic).
Patient Evaluation and Outcomes
Patients were generally mobilized within 6 to 8 hours of surgery. Patients were seen at approximately 1 and 4 weeks after surgery, then at 3-month intervals, with repeat MR examinations every 3 months. Additional neuroimaging was obtained if CNS-related signs or symptoms developed. Systemic cancer care was managed by the patient's oncologist(s).
Patients were divided into Radiation Therapy Oncology Group RPA classes in accordance with the criteria of Gaspar et al32-33 Class I consisted of patients with Karnofsky performance scores (KPS) of at least 70, age younger than 65 years, with controlled primary disease, and no evidence of extracranial metastasis. RPA class III patients had KPS scores less than 70. Class II includes all other patients. KPS scores were calculated for the immediate preoperative period and for the score at follow-up, usually at 4 weeks after surgery. Survival statistics overall, and by RPA class, were calculated only for patients 1 to 15 and 17 (Tables 1 and 2), for whom distant follow-up (> 6 months) status, including until death, were available. A one-sided Student's t test was applied, as indicated, to determine statistical significance.
RESULTS
All patients were symptomatic at the time of presentation, with weakness in 17 and focal motor seizures in four. Lesions caused hand and arm weakness in nine patients, leg weakness in one patient, both upper and lower extremity weakness in six patients, and facial weakness in four patients (alone in one patient and in combination with weakness elsewhere in three patients). Four tumors, two of which were melanomas, were associated with hemorrhage and an exacerbation of symptoms before surgery. Four patients had previously been treated with WBI or focused, high-intensity or stereotactic radiosurgery for metastatic tumors, of which three in the motor strip continued to grow despite radiation. A fifth patient had previously had the motor tumor subtotally resected, then treated with WBI, followed by stereotactic radiosurgery for persistent growth, all at an outside institution; there had been persistent growth, with a progressive motor deficit.
Fifteen patients underwent awake craniotomy, with cortical mapping, whereas two patients elected craniotomy under general anesthesia, with evoked potential mapping, to delineate the sensorimotor cortex. The PMC was identified at surgery in all 17 patients. Tumors were found to lie discretely within the following motor regions: arm, six; hand and wrist, five; face, three; and leg, three. Average tumor volume was 10.2 ± 5.0 cm3 (range, 1.5 to 18 cm3). Operative time averaged 117.1 ± 37.8 minutes (range, 70 to 210 minutes), with a blood loss of 122.1 ± 73.9 mL (range, 50 to 250 mL). Patients spent 15.9 ± 2.8 hours (range, 12 to 20 hours) postoperatively in a monitored, intensive care setting and the average hospital length of stay, including operative time, was 49.6 ± 24.8 hours (range, 24 to 96 hours). Excluding the six patients with significant preoperative deficits, whose hospitalizations were lengthened to permit admission to a rehabilitation facility, the average total length of stay was 32.4 ± 8.0 hours (range, 24 to 54 hours).
Tumors were completely resected in all 17 patients, as confirmed by postoperative MR scans. Three patients had transient peri- or postoperative complications: one patient (patient 3) experienced mild worsening of nondominant hand weakness (from 4+/5 to 4–/5), which resolved in 1 week; one patient (patient 16) had a single, self-limited, focal motor seizure 36 hours after surgery; and one patient (patient 14) developed leg weakness due to an intracranial abscess after Gliadel wafer placement, which became symptomatic approximately 6 weeks after surgery. The abscess was removed and the patient's weakness improved to baseline level by 3 months after surgery. Preoperative seizures in four patients did not recur after surgery and required no additional distant therapy; in the one patient (patient 16) with a postoperative seizure, an anticonvulsant was administered, with no sequelae.
KPS before surgery were 71.8 ± 11.8 (range, 40 to 90) and at follow-up at 4 weeks after surgery were 89.4 ± 10.3 (range, 60 to 100); this was a statistically significant improvement (P < .04). Sixteen patients improved with surgery, whereas one patient (patient 14), at 6 weeks, was worse, although that patient improved to preoperative baseline at 3 months. Improvement (n = 16 patients) in postoperative KPS score was one level (10 points on the KPS scale) in seven patients, two levels in six patients, three levels in one patient, four levels in one patient, and five levels in one patient. There were no perioperative deaths.
At distant follow-up, 15 patients have died and two (patients 15 and 16) are alive with no evidence of disease at 12 and 6 months, respectively. Eleven patients received WBI postoperatively and 12 received additional therapy(ies) for their primary tumor and/or non-CNS metastatic disease. The mean survival in the 16 patients with more than 6-month follow-up (or who have died) is 10.6 ± 4.4 months (range, 1.5 to 17 months); median survival is 12 months. Nine of 16 (56%) assessable patients have survived 1 year or longer after surgery. Fourteen of the 15 patients known to have died have died as a result of progressive systemic disease, including all four patients who presented with an unknown primary. One patient (patient 14) died as a result of progression of both systemic and distant CNS disease. Patients with synchronous brain metastases or unknown primaries (n = 6) fared worse than patients with metachronous disease (n = 10; excluding patient 16), with mean survivals of 7.6 ± 3.9 months compared with 12.4 ± 1.4 months, respectively (P < .05).
Using Radiation Therapy Oncology Group RPA of the 16 patients with distant follow-up, five patients were grade 1, six patients were grade 2, and five patients were grade 3. Mean survivals were as follows: 11.1 ± 1.1 months, 13.3 ± 3.9 months, and 6.7 ± 4.6 months, for RPA classes I, II, and III, respectively (P < .05, for comparison between class I and class III, and class II and class III; P value nonsignificant, when comparing classes I and II).
No patient experienced disease recurrence at the site of microsurgical resection. Two patients (patients 9 and 14) developed new, nonresectable, initially asymptomatic, distant CNS metastasis 3 to 9 months after surgery, as identified by surveillance MR imaging; both were treated with SR, which controlled the lesions until death in patient 9. However, there was progression at these sites in patient 14, which contributed, along with progressive systemic disease, to death. A third patient (patient 12) developed four distant CNS metastases 6 months after surgery. This patient received repeat surgery for two symptomatic (12 cm3 each), hemorrhagic tumors, and SR for the smaller, asymptomatic lesions. This patient died as a result of the systemic effects of metastatic melanoma and treatment-related bone marrow depletion, with thrombocytopenia. A final patient (patient 17), who presented with dense upper extremity hemiparesis and lower extremity hemiplegia, made a complete and persisting neurologic recovery, but died 6 weeks later as a result of rapid involvement of the lungs by metastatic cancer.
DISCUSSION
Surgical resection and radiotherapy have been the mainstays of treatment of brain metastases, principally in concert.4-6 Two randomized trials have demonstrated for solitary metastases that surgical resection, followed by postoperative WBI, results, on average, in a 4- to 6-month survival advantage over either modality alone, with improvement in the quality of life and a significant reduction in local recurrence rates.4-6,34
The advent of SR has added to the options available to patients with cerebral metastases.7-17 SR delivers a single, high dose of radiation to a defined volume of tissue, with radiation drop-off within a few millimeters of the target, especially when the lesion is small and a single isocenter is used. A recent study showed that SR with WBI is superior to WBI alone, with survivals of 6.5 v 4.9 months, respectively.17
One potential advantage of SR, compared with surgery, is that it may be used to treat lesions in any area of the brain, including lesions in the deep gray matter and brainstem. However, no randomized trials comparing SR (with or without WBI) with surgery and WBI have been completed, although retrospective, multi-institutional studies suggest that the results may be equivalent.7,9,10 Rates of transient, new, or worsened neurologic deficits range from 5% to 15% with SR; the risk of permanent neurologic deficit may be as high as 5%, and the incidence of symptomatic radiation necrosis, requiring operative intervention, may occur in 5% of patients.9-17 Complications may be more common for lesions in eloquent areas of the brain, for larger or eccentrically shaped lesions, or for those tumors that require multiple isocenters.9,10,12,13 In addition, SR may be contraindicated in patients with significant edema, brain shift, and mass effect.
Although a few studies have noted that both surgery and SR represent feasible options to treat lesions in eloquent brain, none have examined or defined optimal treatment of brain metastases located in the PMC. Most reports of outcome with SR focus on tumors of one or two histologic types, without stratification for location of tumor; and no studies report quality of life or outcome measures related to the site of tumor within the PMC.
Several surgical reports have analyzed craniotomy for tumors, both gliomas and metastases, located in and around the sensorimotor cortex.18-28,35,36 Ebeling et al25 reported 50 patients with tumors in eloquent regions of the brain, including several in the motor and premotor cortex, of which nine were metastasis. Motor deficits were found postoperatively in 34% of all patients, without stratification for tumor type; mild preoperative motor deficits mostly resolved after surgery. Tobler and Stanley22 described 14 patients with metastasis within eloquent cortex, including premotor, motor, sensory, motor, and receptive speech and vision centers, with a neurologic complication rate of 14% and an average hospital stay of 4.5 days; one tumor recurred at the operative site (7%). Cedzich et al23 reported 99 patients, including 12 with metastasis, who underwent surgery for lesions in and around the sensorimotor region. New neurologic deficits were seen in nearly 40% of patients, with 24% suffering permanent loss of neurologic function. Duffau et al24,28 analyzed their results in 60 patients with lesions in eloquent brain cortex, including patients with metastasis, in whom two of nine (22%) had a temporary motor deficit after surgery. Keles et al27 studied 294 patients with perirolandic gliomas and found new motor deficits in 20.4% of all patients, a rate that decreased to 7.6% in patients in whom motor mapping was successful. Other groups have published similar reports, usually without differentiating between the PMC and other eloquent areas of the brain or between gliomas and metastases, with rates of transient neurologic complications of 10% to 25% and permanent rates of neurologic compromise of 5% to 15%.20,21,25 Complication rates may be higher in surgery for gliomas than metastasis, given that the former are intrinsic tumors that tend to invade normal white matter, whereas metastases tend to be circumscribed. Perioperative mortality has been rare, usually less than 1%, with average hospital stays of 3 to 5 days.20-23,35,36
Two recent studies, by Sawaya et al18 and by Tan and Black,19 examined surgery for metastases in greater detail. In a review of 400 consecutive craniotomies for glial and metastatic tumor in 327 patients, Sawaya et al18 found that surgery for metastases was associated with a lower major complication rate (6%) than surgery for gliomas (11%), although the estimated rates of both major non-neurologic and neurologic complications for lesions in eloquent regions of the brain were nearly identical. This study did not discriminate between tumors located in motor or other critical brain structures, nor did it provide long-term outcome data for the patients with metastatic tumors.18
Tan and Black19 examined 49 patients who underwent 55 craniotomies for tumor, 23 in critical brain regions, of which three were located in the central frontal gyrus, presumably the PMC. Gross total resection was accomplished in 92% of the lesions in critical brain. Thirteen of 39 patients (33%) with preoperative deficits were transiently worse after surgery and 20% of patients overall (symptomatic and asymptomatic) had a neurologic deficit after surgery; however, 92% of all patients regained their preoperative functional (KPS) status at distant follow-up. Tumor recurrence in the CNS occurred in 19 patients (38.7%) at distant follow-up (median, 16.2 months)—solely at the site of resection in seven patients (16%), only at distant sites in four patients (9%), and at both sites in seven patients (16%). Median hospitalization was 3 days and overall median survival was 16.2 months, with the best results in patients in RPA class II (22.9 months).19
In this report, we focused on patients with lesions located specifically within the PMC. Lesions in this area of the brain present several problems because even small tumors (1.5 cm3 in one patient reported here) can be symptomatic, whereas the potential for neurologic complications, whether surgery or SR are used, may be more daunting than in other areas of the brain. There are no reports of using SR for isolated PMC lesions, and many of these patients were referred by radiation oncologists who preferred not to use SR for these lesions. Two patients (patients 11 and 14) had been treated with SR, and one patient (patient 13) had been treated with high-intensity focused radiation (20 Gy over 5 days) without effect but with worsening neurologic status. Similarly, previous surgical reports, as detailed above, have not focused on metastases, although recent series, using modern microneurosurgical technique, stereotactic guidance, and cortical mapping methods, have reported that it is feasible to remove lesions in eloquent cortex, with permanent rates of neurologic compromise of 5% to 15%.18-29,35,36
We demonstrate that selective microsurgical excision of metastatic tumors can be performed with preservation or enhancement of neurologic function, with meaningful increases in quality of life, and can lead to improved survival compared with WBI or SR. All tumors were completely resected and there have been no local recurrences. Sixteen (94.1%) patients were symptomatically improved by the surgery by 4 weeks postoperatively and the final patient improved by 3 months; the average improvement in KPS at 1 month postoperatively was 1.8 grades (18 score points), which persisted throughout long-term follow-up. Patients with metachronous tumors fared better than patients with synchronous tumors.
No patient in this series suffered a permanent neurologic or systemic complication—features that are likely a combination of cortical mapping to delineate areas of motor function and, in 15 patients (88%), awake craniotomy, which has been suggested to result in fewer CNS and systemic complications. After an awake craniotomy, patients are mobilized early after surgery, which may prevent complications and which may permit safe, early discharge, as seen in this and other studies.20,30 Furthermore, awake craniotomy, used as a common tool in the operative armamentarium, appears to permit surgical resection of metastatic tumors as quickly as that for tumors removed under general anesthesia, as has been shown previously.19,20,30 This permits a decrease in operative and hospitalization use and expenses. Combined with an average discharge time of 36 hours from the start of surgery, the potential cost savings accrued to SR is likely minimized, although this was not our focus.30
Although this study does not directly address the treatment of multiple lesions, some or all of which may affect the PMC, our results in patients 16 and 17, and previous studies, suggest that up to three lesions may safely be resected at one surgery, with no significant increase in morbidity; surgery may improve long-term control of CNS disease and distant outcome.18,36 All the patients were symptomatic, although the small size of several tumors suggests that asymptomatic patients may be treated similarly. This is a series of consecutive patients referred for surgical resection, which may introduce bias, although patients were selected for surgery using standard criteria: stability of systemic disease; presence of symptoms due to edema and mass effect; or the need, in patients with an unknown primary, to obtain a diagnosis. The mixed nature of the population makes this a potentially more informative study because it more closely represents the population of patients with lesions in the PMC who present for oncologic care. Although this may represent a nonrandom population of patients, the technique of selective resection, with motor mapping, can be adapted in most centers where a collaborative effort of surgeons, anesthesiologists, and other clinicians interested in this approach exists.
In summary, microneurosurgical resection of metastatic tumors located in the PMC, with electrophysiological mapping, is a safe and effective therapy. It may be done in the face of prior therapy, including ionizing radiation. Both small (1.5 cm3) and large (18 cm3) lesions may be removed safely, with minimal morbidity, and with good expectation of symptomatic, neurologic improvement and for long-term, local control.
Authors' Disclosures of Potential Conflicts of Interest
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Department of Neurosurgery, Vanderbilt University School of Medicine, Nashville, TN
the Surgical Neurology Branch, National Institutes of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
ABSTRACT
PATIENTS AND METHODS: Seventeen consecutive patients with metastasis within the primary motor cortex underwent selective microsurgical tumor resection. Operative, hospital, neuroimaging, and follow-up information was reviewed.
RESULTS: There were 10 women and seven men (mean age, 54.3 years) who underwent 17 operations for symptomatic brain metastases. Motor cortex was identified and tumor (mean volume, 10.2 cm3) was completely resected in all patients. Three patients had transient or reversible complications. Karnofsky performance scores improved in 16 of 17 patients at 4 weeks postoperatively, with a mean improvement of 1.8 grades compared with preoperative scores (P < .05). Overall survival of 16 patients with distant follow-up (> 6 months or until death) averaged 10.6 ± 4.4 months, with nine of 16 (56%) assessable patients surviving 1 year or longer. Survival of these 16 patients, by recursive partitioning analysis (RPA), was 11.2, 13.3, and 6.7 months for RPA classes I, II, and III, respectively. The cause of death in 14 of 15 patients who have died was progressive systemic disease; in one patient it was a combination of systemic and distant CNS disease progression. There were no local CNS recurrences.
CONCLUSION: Complete microsurgical resection of metastatic tumors in the primary motor cortex is feasible and efficacious, results in a sustained improvement in performance outcomes, and permits satisfactory long-term survival.
INTRODUCTION
Uncertainty exists regarding optimal treatment for patients with metastasis in eloquent cortical areas (language, vision, and sensorimotor areas). Several studies have considered this issue as part of larger series reporting surgical treatment of brain tumors and have suggested that surgical resection may be feasible, with acceptable outcomes.1-3,18-29 No study, however, has focused on metastatic tumors located directly within the primary motor cortex (PMC) or reported results for surgical resection. Furthermore, while several groups have suggested the utility of SR to treat metastatic lesions in eloquent cortex or deep brain areas, no reports of its use, with or without WBI, have examined SR's role in the treatment of metastases in the PMC.9-17
We present an analysis of a consecutive series of 17 patients with metastatic tumors located in the PMC in whom microneurosurgical resection was performed. We review presentation, surgical and hospital characteristics, as well as short- and long-term outcomes, including sorting by recursive partitioning analysis (RPA), to demonstrate that selective, microneurosurgical resection of tumors is a safe, effective, and valuable method to treat patients with brain metastasis in the PMC.
PATIENTS AND METHODS
Each patient underwent surgery for a symptomatic metastasis in the PMC. Fifteen patients had solitary metastases. One patient (patient 16 in Tables 1 and 2) had a second lesion (volume, 10.0 cm3) removed from the contralateral parietal lobe at the same surgery. Patient 17 had two additional, symptomatic lesions—in the ipsilateral anterior frontal lobe (volume, 45 cm3) and the ipsilateral occipital lobe (volume, 7.7 cm3)—removed at the same surgery as the motor lesion. Magnetic resonance (MR) imaging, without and with contrast, was performed before and within 24 hours of surgery. Preoperative MR images were used for frameless stereotactic guidance of craniotomy placement and tumor localization. Patient information was obtained from the hospital chart; neuroimaging, operative, and anesthetic records; review of hospital nursing and discharge records; and by written or telephone contact with patients, as needed, for distant follow-up. This work was conducted as part of studies approved by the institutional review boards at Vanderbilt University School of Medicine (Nashville, TN), the National Institutes of Health (Bethesda, MD), and the Cleveland Clinic (Cleveland, OH). Patient characteristics and outcomes are summarized in Tables 1 and 2.
Surgical and Cortical Mapping Techniques
Fifteen of the 17 patients underwent craniotomy using local anesthetic, intravenous sedation, and cortical mapping.30,31 Two patients elected craniotomy under general anesthesia, with localization of sensorimotor cortex using evoked potentials. These patients received a general anesthetic using a nitrous oxide, oxygen, and narcotic technique, according to standard methods. All patients received a local field or circumferential scalp block with 0.25% bupivacaine mixed 50:50 with 1% lidocaine with 1:100,000 epinephrine.
For the 15 patients undergoing awake craniotomy, cortical mapping was performed as previously described.27,31 In brief, an Ojemann cortical stimulator (Radionics, Burlington, MA) delivers a biphasic, square-wave pulse current. Initial settings were 0.5 mA with a pulse frequency of 60 Hz, and a single pulse duration of 1 ms. The lowest setting to elicit spontaneous motor activity in the contralateral hemibody was identified (generally from 2 to 6 mA). During resection, stimulation of the subcortical white matter identified proximity to the pyramidal tracts. Stimulation was performed to identify the PMC; to identify the safest corridor to the tumor, especially if it lay more than 1 cm subcortically (a transcortical v trans-sulcal approach); and to confirm anatomic integrity of the motor pathways during and after tumor resection. In the two patients undergoing craniotomy under general anesthesia, intraoperative somatosensory evoked potential mapping was used to localize the sensory and motor cortex on the brain's surface, as previously described.27 Frameless stereotactic guidance aided identification of the PMC and tumor. Ultrasound was used to outline the tumor and confirm gross total resection.
Patient characteristics were obtained from the operative records, including the nursing, anesthetic, and operative reports. In cases of discrepancy, the average of these values was used. Operative time and blood loss calculations were inclusive of all 20 tumors removed (see data on patients 16 and 17). Length of stay in a monitored nursing unit, whether in the recovery room or the intensive care unit, and length of hospitalization from the start of surgery to discharge, were recorded (nine patients were same-day admissions and eight patients were inpatients).
Complications were surgical if they occurred within 30 days or, if later than 30 days, were a direct result of surgical intervention. Complications were transient if they resolved within 30 days of surgery or definitive management, or prolonged if they persisted to the last follow-up or death. Metastatic brain tumor recurrence was defined as local if tumor recurred at the operative site, or distant if it occurred at a CNS site distinct from the surgical site. Failure was defined by failure to respond to therapy or by mortality due to failure at that site, whether it was local, elsewhere within the CNS (distant), or outside the CNS (systemic).
Patient Evaluation and Outcomes
Patients were generally mobilized within 6 to 8 hours of surgery. Patients were seen at approximately 1 and 4 weeks after surgery, then at 3-month intervals, with repeat MR examinations every 3 months. Additional neuroimaging was obtained if CNS-related signs or symptoms developed. Systemic cancer care was managed by the patient's oncologist(s).
Patients were divided into Radiation Therapy Oncology Group RPA classes in accordance with the criteria of Gaspar et al32-33 Class I consisted of patients with Karnofsky performance scores (KPS) of at least 70, age younger than 65 years, with controlled primary disease, and no evidence of extracranial metastasis. RPA class III patients had KPS scores less than 70. Class II includes all other patients. KPS scores were calculated for the immediate preoperative period and for the score at follow-up, usually at 4 weeks after surgery. Survival statistics overall, and by RPA class, were calculated only for patients 1 to 15 and 17 (Tables 1 and 2), for whom distant follow-up (> 6 months) status, including until death, were available. A one-sided Student's t test was applied, as indicated, to determine statistical significance.
RESULTS
All patients were symptomatic at the time of presentation, with weakness in 17 and focal motor seizures in four. Lesions caused hand and arm weakness in nine patients, leg weakness in one patient, both upper and lower extremity weakness in six patients, and facial weakness in four patients (alone in one patient and in combination with weakness elsewhere in three patients). Four tumors, two of which were melanomas, were associated with hemorrhage and an exacerbation of symptoms before surgery. Four patients had previously been treated with WBI or focused, high-intensity or stereotactic radiosurgery for metastatic tumors, of which three in the motor strip continued to grow despite radiation. A fifth patient had previously had the motor tumor subtotally resected, then treated with WBI, followed by stereotactic radiosurgery for persistent growth, all at an outside institution; there had been persistent growth, with a progressive motor deficit.
Fifteen patients underwent awake craniotomy, with cortical mapping, whereas two patients elected craniotomy under general anesthesia, with evoked potential mapping, to delineate the sensorimotor cortex. The PMC was identified at surgery in all 17 patients. Tumors were found to lie discretely within the following motor regions: arm, six; hand and wrist, five; face, three; and leg, three. Average tumor volume was 10.2 ± 5.0 cm3 (range, 1.5 to 18 cm3). Operative time averaged 117.1 ± 37.8 minutes (range, 70 to 210 minutes), with a blood loss of 122.1 ± 73.9 mL (range, 50 to 250 mL). Patients spent 15.9 ± 2.8 hours (range, 12 to 20 hours) postoperatively in a monitored, intensive care setting and the average hospital length of stay, including operative time, was 49.6 ± 24.8 hours (range, 24 to 96 hours). Excluding the six patients with significant preoperative deficits, whose hospitalizations were lengthened to permit admission to a rehabilitation facility, the average total length of stay was 32.4 ± 8.0 hours (range, 24 to 54 hours).
Tumors were completely resected in all 17 patients, as confirmed by postoperative MR scans. Three patients had transient peri- or postoperative complications: one patient (patient 3) experienced mild worsening of nondominant hand weakness (from 4+/5 to 4–/5), which resolved in 1 week; one patient (patient 16) had a single, self-limited, focal motor seizure 36 hours after surgery; and one patient (patient 14) developed leg weakness due to an intracranial abscess after Gliadel wafer placement, which became symptomatic approximately 6 weeks after surgery. The abscess was removed and the patient's weakness improved to baseline level by 3 months after surgery. Preoperative seizures in four patients did not recur after surgery and required no additional distant therapy; in the one patient (patient 16) with a postoperative seizure, an anticonvulsant was administered, with no sequelae.
KPS before surgery were 71.8 ± 11.8 (range, 40 to 90) and at follow-up at 4 weeks after surgery were 89.4 ± 10.3 (range, 60 to 100); this was a statistically significant improvement (P < .04). Sixteen patients improved with surgery, whereas one patient (patient 14), at 6 weeks, was worse, although that patient improved to preoperative baseline at 3 months. Improvement (n = 16 patients) in postoperative KPS score was one level (10 points on the KPS scale) in seven patients, two levels in six patients, three levels in one patient, four levels in one patient, and five levels in one patient. There were no perioperative deaths.
At distant follow-up, 15 patients have died and two (patients 15 and 16) are alive with no evidence of disease at 12 and 6 months, respectively. Eleven patients received WBI postoperatively and 12 received additional therapy(ies) for their primary tumor and/or non-CNS metastatic disease. The mean survival in the 16 patients with more than 6-month follow-up (or who have died) is 10.6 ± 4.4 months (range, 1.5 to 17 months); median survival is 12 months. Nine of 16 (56%) assessable patients have survived 1 year or longer after surgery. Fourteen of the 15 patients known to have died have died as a result of progressive systemic disease, including all four patients who presented with an unknown primary. One patient (patient 14) died as a result of progression of both systemic and distant CNS disease. Patients with synchronous brain metastases or unknown primaries (n = 6) fared worse than patients with metachronous disease (n = 10; excluding patient 16), with mean survivals of 7.6 ± 3.9 months compared with 12.4 ± 1.4 months, respectively (P < .05).
Using Radiation Therapy Oncology Group RPA of the 16 patients with distant follow-up, five patients were grade 1, six patients were grade 2, and five patients were grade 3. Mean survivals were as follows: 11.1 ± 1.1 months, 13.3 ± 3.9 months, and 6.7 ± 4.6 months, for RPA classes I, II, and III, respectively (P < .05, for comparison between class I and class III, and class II and class III; P value nonsignificant, when comparing classes I and II).
No patient experienced disease recurrence at the site of microsurgical resection. Two patients (patients 9 and 14) developed new, nonresectable, initially asymptomatic, distant CNS metastasis 3 to 9 months after surgery, as identified by surveillance MR imaging; both were treated with SR, which controlled the lesions until death in patient 9. However, there was progression at these sites in patient 14, which contributed, along with progressive systemic disease, to death. A third patient (patient 12) developed four distant CNS metastases 6 months after surgery. This patient received repeat surgery for two symptomatic (12 cm3 each), hemorrhagic tumors, and SR for the smaller, asymptomatic lesions. This patient died as a result of the systemic effects of metastatic melanoma and treatment-related bone marrow depletion, with thrombocytopenia. A final patient (patient 17), who presented with dense upper extremity hemiparesis and lower extremity hemiplegia, made a complete and persisting neurologic recovery, but died 6 weeks later as a result of rapid involvement of the lungs by metastatic cancer.
DISCUSSION
Surgical resection and radiotherapy have been the mainstays of treatment of brain metastases, principally in concert.4-6 Two randomized trials have demonstrated for solitary metastases that surgical resection, followed by postoperative WBI, results, on average, in a 4- to 6-month survival advantage over either modality alone, with improvement in the quality of life and a significant reduction in local recurrence rates.4-6,34
The advent of SR has added to the options available to patients with cerebral metastases.7-17 SR delivers a single, high dose of radiation to a defined volume of tissue, with radiation drop-off within a few millimeters of the target, especially when the lesion is small and a single isocenter is used. A recent study showed that SR with WBI is superior to WBI alone, with survivals of 6.5 v 4.9 months, respectively.17
One potential advantage of SR, compared with surgery, is that it may be used to treat lesions in any area of the brain, including lesions in the deep gray matter and brainstem. However, no randomized trials comparing SR (with or without WBI) with surgery and WBI have been completed, although retrospective, multi-institutional studies suggest that the results may be equivalent.7,9,10 Rates of transient, new, or worsened neurologic deficits range from 5% to 15% with SR; the risk of permanent neurologic deficit may be as high as 5%, and the incidence of symptomatic radiation necrosis, requiring operative intervention, may occur in 5% of patients.9-17 Complications may be more common for lesions in eloquent areas of the brain, for larger or eccentrically shaped lesions, or for those tumors that require multiple isocenters.9,10,12,13 In addition, SR may be contraindicated in patients with significant edema, brain shift, and mass effect.
Although a few studies have noted that both surgery and SR represent feasible options to treat lesions in eloquent brain, none have examined or defined optimal treatment of brain metastases located in the PMC. Most reports of outcome with SR focus on tumors of one or two histologic types, without stratification for location of tumor; and no studies report quality of life or outcome measures related to the site of tumor within the PMC.
Several surgical reports have analyzed craniotomy for tumors, both gliomas and metastases, located in and around the sensorimotor cortex.18-28,35,36 Ebeling et al25 reported 50 patients with tumors in eloquent regions of the brain, including several in the motor and premotor cortex, of which nine were metastasis. Motor deficits were found postoperatively in 34% of all patients, without stratification for tumor type; mild preoperative motor deficits mostly resolved after surgery. Tobler and Stanley22 described 14 patients with metastasis within eloquent cortex, including premotor, motor, sensory, motor, and receptive speech and vision centers, with a neurologic complication rate of 14% and an average hospital stay of 4.5 days; one tumor recurred at the operative site (7%). Cedzich et al23 reported 99 patients, including 12 with metastasis, who underwent surgery for lesions in and around the sensorimotor region. New neurologic deficits were seen in nearly 40% of patients, with 24% suffering permanent loss of neurologic function. Duffau et al24,28 analyzed their results in 60 patients with lesions in eloquent brain cortex, including patients with metastasis, in whom two of nine (22%) had a temporary motor deficit after surgery. Keles et al27 studied 294 patients with perirolandic gliomas and found new motor deficits in 20.4% of all patients, a rate that decreased to 7.6% in patients in whom motor mapping was successful. Other groups have published similar reports, usually without differentiating between the PMC and other eloquent areas of the brain or between gliomas and metastases, with rates of transient neurologic complications of 10% to 25% and permanent rates of neurologic compromise of 5% to 15%.20,21,25 Complication rates may be higher in surgery for gliomas than metastasis, given that the former are intrinsic tumors that tend to invade normal white matter, whereas metastases tend to be circumscribed. Perioperative mortality has been rare, usually less than 1%, with average hospital stays of 3 to 5 days.20-23,35,36
Two recent studies, by Sawaya et al18 and by Tan and Black,19 examined surgery for metastases in greater detail. In a review of 400 consecutive craniotomies for glial and metastatic tumor in 327 patients, Sawaya et al18 found that surgery for metastases was associated with a lower major complication rate (6%) than surgery for gliomas (11%), although the estimated rates of both major non-neurologic and neurologic complications for lesions in eloquent regions of the brain were nearly identical. This study did not discriminate between tumors located in motor or other critical brain structures, nor did it provide long-term outcome data for the patients with metastatic tumors.18
Tan and Black19 examined 49 patients who underwent 55 craniotomies for tumor, 23 in critical brain regions, of which three were located in the central frontal gyrus, presumably the PMC. Gross total resection was accomplished in 92% of the lesions in critical brain. Thirteen of 39 patients (33%) with preoperative deficits were transiently worse after surgery and 20% of patients overall (symptomatic and asymptomatic) had a neurologic deficit after surgery; however, 92% of all patients regained their preoperative functional (KPS) status at distant follow-up. Tumor recurrence in the CNS occurred in 19 patients (38.7%) at distant follow-up (median, 16.2 months)—solely at the site of resection in seven patients (16%), only at distant sites in four patients (9%), and at both sites in seven patients (16%). Median hospitalization was 3 days and overall median survival was 16.2 months, with the best results in patients in RPA class II (22.9 months).19
In this report, we focused on patients with lesions located specifically within the PMC. Lesions in this area of the brain present several problems because even small tumors (1.5 cm3 in one patient reported here) can be symptomatic, whereas the potential for neurologic complications, whether surgery or SR are used, may be more daunting than in other areas of the brain. There are no reports of using SR for isolated PMC lesions, and many of these patients were referred by radiation oncologists who preferred not to use SR for these lesions. Two patients (patients 11 and 14) had been treated with SR, and one patient (patient 13) had been treated with high-intensity focused radiation (20 Gy over 5 days) without effect but with worsening neurologic status. Similarly, previous surgical reports, as detailed above, have not focused on metastases, although recent series, using modern microneurosurgical technique, stereotactic guidance, and cortical mapping methods, have reported that it is feasible to remove lesions in eloquent cortex, with permanent rates of neurologic compromise of 5% to 15%.18-29,35,36
We demonstrate that selective microsurgical excision of metastatic tumors can be performed with preservation or enhancement of neurologic function, with meaningful increases in quality of life, and can lead to improved survival compared with WBI or SR. All tumors were completely resected and there have been no local recurrences. Sixteen (94.1%) patients were symptomatically improved by the surgery by 4 weeks postoperatively and the final patient improved by 3 months; the average improvement in KPS at 1 month postoperatively was 1.8 grades (18 score points), which persisted throughout long-term follow-up. Patients with metachronous tumors fared better than patients with synchronous tumors.
No patient in this series suffered a permanent neurologic or systemic complication—features that are likely a combination of cortical mapping to delineate areas of motor function and, in 15 patients (88%), awake craniotomy, which has been suggested to result in fewer CNS and systemic complications. After an awake craniotomy, patients are mobilized early after surgery, which may prevent complications and which may permit safe, early discharge, as seen in this and other studies.20,30 Furthermore, awake craniotomy, used as a common tool in the operative armamentarium, appears to permit surgical resection of metastatic tumors as quickly as that for tumors removed under general anesthesia, as has been shown previously.19,20,30 This permits a decrease in operative and hospitalization use and expenses. Combined with an average discharge time of 36 hours from the start of surgery, the potential cost savings accrued to SR is likely minimized, although this was not our focus.30
Although this study does not directly address the treatment of multiple lesions, some or all of which may affect the PMC, our results in patients 16 and 17, and previous studies, suggest that up to three lesions may safely be resected at one surgery, with no significant increase in morbidity; surgery may improve long-term control of CNS disease and distant outcome.18,36 All the patients were symptomatic, although the small size of several tumors suggests that asymptomatic patients may be treated similarly. This is a series of consecutive patients referred for surgical resection, which may introduce bias, although patients were selected for surgery using standard criteria: stability of systemic disease; presence of symptoms due to edema and mass effect; or the need, in patients with an unknown primary, to obtain a diagnosis. The mixed nature of the population makes this a potentially more informative study because it more closely represents the population of patients with lesions in the PMC who present for oncologic care. Although this may represent a nonrandom population of patients, the technique of selective resection, with motor mapping, can be adapted in most centers where a collaborative effort of surgeons, anesthesiologists, and other clinicians interested in this approach exists.
In summary, microneurosurgical resection of metastatic tumors located in the PMC, with electrophysiological mapping, is a safe and effective therapy. It may be done in the face of prior therapy, including ionizing radiation. Both small (1.5 cm3) and large (18 cm3) lesions may be removed safely, with minimal morbidity, and with good expectation of symptomatic, neurologic improvement and for long-term, local control.
Authors' Disclosures of Potential Conflicts of Interest
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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