Key Points
Question
Is neurosurgical resection of brain metastases associated with unique patterns of tumor spread in the era of adjuvant stereotactic radiation?
Findings
In this cohort study of 1188 patients, those with brain metastases managed with neurosurgical resection and stereotactic radiation vs radiation alone were more likely to develop pachymeningeal seeding. Durable salvage of pachymeningeal seeding was uncommon, but a small percentage of patients achieved sustained disease control with radiotherapeutic approaches.
Meaning
Pachymeningeal seeding beyond the adjuvant stereotactic radiation field represents a substantial oncologic event in patients undergoing neurosurgical resection of a brain metastasis and warrants further evaluation in clinical studies.
This cohort study assesses the association and incidence of pachymeningeal seeding after neurosurgical resection in patients with brain metastases treated with adjuvant stereotactic radiation.
Abstract
Importance
Neurosurgical resection represents an important management strategy for patients with large, symptomatic brain metastases and increasingly is followed by stereotactic radiation as opposed to whole-brain radiation. Whether neurosurgical resection is associated with tumor spread beyond the resection site and adjuvant stereotactic radiation field remains unknown.
Objective
To characterize the association and incidence of pachymeningeal seeding with neurosurgical resection in patients with brain metastases treated with adjuvant stereotactic radiation.
Design, Setting, and Participants
Retrospective cohort study of a consecutive sample of patients with newly diagnosed brain metastases managed with neurosurgical resection and stereotactic radiation (n = 318) vs radiation alone (n = 870) between 2001 and 2015.
Main Outcomes and Measures
Incidence of pachymeningeal seeding (dural and/or outer arachnoid) and leptomeningeal disease in patients treated with neurosurgical resection and stereotactic radiation vs radiation alone and the risk factors and outcomes associated with pachymeningeal seeding in patients treated with neurosurgical resection followed by stereotactic radiation.
Results
In 1188 patients with newly diagnosed brain metastases, 133 men and 185 women (mean [SD] age, 58.9 [11.5] years) underwent neurosurgical resection. Resection was found to be associated with pachymeningeal seeding (36 of 318 patients vs 0 of 870 patients; P < .001) but not leptomeningeal disease (hazard ratio [HR], 1.14; 95% CI, 0.73-1.77; P = .56). In total, 36 (8.4%) of 428 operations were complicated by pachymeningeal seeding, with a higher incidence noted with resection of previously irradiated vs unirradiated metastases (HR, 2.39; 95% CI, 1.25-4.57; P = .008). Patients with pachymeningeal seeding had relatively low rates of subsequent development of new brain metastases and leptomeningeal disease (8 [16%] of 51 and 6 [13%] of 48, respectively). Among patients with pachymeningeal seeding, neurologic death primarily owing to progressive pachymeningeal disease accounted for 26 (72%) of 36 deaths, but when treated with salvage radiation, 49.1% of patients survived 1 year or longer.
Conclusions and Relevance
In the era of omission of adjuvant whole-brain radiation after neurosurgical resection, pachymeningeal seeding beyond the stereotactic radiation field represents a notable oncologic event that often proves difficult to salvage. However, in some patients, disease control can be achieved with radiotherapeutic approaches.
Introduction
Brain metastases are common in patients with advanced systemic malignant neoplasms.1 Neurosurgical resection represents an important treatment option for patients with symptomatic or large brain metastases.2,3 Traditionally, adjuvant whole-brain radiotherapy (WBRT) was the standard of care for the adjuvant management of patients undergoing resection of a brain metastasis.4 However, among patients with a limited number of brain metastases, recently published randomized clinical trials have demonstrated poorer quality of life and neurocognitive function when adjuvant WBRT is used and as a result, stereotactic radiation of the cavity is now more commonly used.5,6,7,8
Omission of WBRT from adjuvant management paradigms may result in unique patterns of intracranial recurrence because microscopic tumor cells potentially dispersed during the operation may grow into radiographically detectable lesions at distant intracranial sites, which would have been treated by WBRT. Previous studies on this topic are few in number; most investigations have focused on postsurgical leptomeningeal disease as the outcome of interest, but results have been conflicting9,10,11,12 in part owing to inconsistent definitions of leptomeningeal disease.13 We sought to determine whether patterns of intracranial recurrence are different in patients who undergo resection of a brain metastasis followed by adjuvant stereotactic radiation of the cavity compared with patients treated with radiation alone to identify the incidence, risk factors, and outcomes associated with propagation of oncologic disease beyond the postoperative stereotactic radiation field. Our hypothesis was that resection of a brain metastasis would be associated with a different pattern of distant meningeal recurrence than conventional leptomeningeal disease, with a unique natural history and potential salvage treatment options.
Methods
Patient Identification and Clinical Characteristics
The Department of Radiation Oncology at Brigham and Women’s Hospital/Dana-Farber Cancer Institute maintains a database of patients with newly diagnosed brain metastases treated between 2001 and 2015. When the database was initially constructed, we identified patients who had neurosurgical resection of at least 1 brain metastasis that was not followed by WBRT to facilitate a dedicated study relating to patterns of recurrence after craniotomy in this population. This study was approved by the Dana-Farber/Harvard Cancer Center Institutional Review Board, and patient written informed consent was waived. Among patients who underwent magnetic resonance imaging–based follow-up (N = 1188), 318 patients underwent resection of at least 1 brain metastasis followed by stereotactic radiation in the absence of adjuvant WBRT, whereas 870 patients never underwent resection of a brain metastasis during their disease course and received radiation alone. Indications for surgery included tumors larger than 3 to 4 cm in maximal unidimensional size, rapidly growing tumors, or tumors causing neurologic symptomatology despite treatment with steroids. Stereotactic radiation of the postoperative cavity was generally administered as a 25- to 30-Gy dose in 5 fractions, with a planning target volume margin of 0 to 2 mm; smaller cavities were treated with a 15- to 20-Gy dose in 1 fraction. All data collection was undertaken by 2 radiation oncologists (D. N. C. and A. A. A.) specializing in tumors of the central nervous system, and data analyses were performed from July to September 2018.
Imaging Assessment
All-brain magnetic resonance imaging studies throughout a patient’s entire disease course were fused by 2 radiation oncologists using Mim version 6.8.3 (Mim Software, Inc) to ensure the consistency of evaluation. We examined 2 patterns of distant intracranial recurrence: (1) leptomeningeal disease, which was defined as new oncologic disease in the leptomeninges typically seen as subarachnoid enhancement in the cranial nerves, cisterns, folia of the cerebellum, or cortical sulci14 (Figure 1A), and (2) pachymeningeal seeding, which was defined as nodular, enhancing tumors stemming from the pachymeninges (dura and/or outer arachnoid) with no involvement of the overlying calvarium to suggest bony involvement with secondary extension into the pachymeninges14 (Figure 1B). Among patients who underwent neurosurgical resection, a recurrence was only considered pachymeningeal if it extended 1 cm beyond the planning target volume of the stereotactic field.
Figure 1. Axial T1-Weighted Postcontrast Magnetic Resonance Images of Leptomeningeal Disease and Pachymeningeal Seeding .
Figures show enhancement (arrowheads) along the cerebellar folia (A) and the cerebellar folia and supratentorial sulci (B) in the setting of leptomeningeal disease. In the setting of pachymeningeal seeding, nodular enhancement (arrowheads) of the right tentorium and dural surface of right temporal lobe (C) and of the dural surface of left occipital and temporal lobe (D) is visible.
Statistical Analysis
We first assessed the occurrence of leptomeningeal disease and pachymeningeal seeding in patients who underwent neurosurgical resection (n = 318) compared with those who did not undergo resection (n = 870) using Kaplan-Meier curves and log-rank test, as well as univariable Cox regression. The leptomeningeal disease analysis excluded 21 patients for whom a definitive assessment regarding leptomeningeal disease could not be made. We then evaluated the incidence, risk factors, and outcomes associated with pachymeningeal seeding after resection. Baseline continuous patient characteristics in patients who did or did not develop pachymeningeal seeding were compared with the t test (normally distributed continuous covariates) or the Wilcoxon rank sum test (nonnormally distributed continuous covariates). The χ2 test or Fisher exact test was used for comparisons of categorical covariates.
The incidence of postsurgical pachymeningeal seeding was computed by dividing the number of patients with pachymeningeal seeding (n = 36) by the total number of neurosurgical resections (n = 428). Multivariable Cox regression was used to assess risk factors for pachymeningeal seeding after resection using the following covariates: maximal unidimensional size at resection (continuous), prior radiation of the tumor being resected vs no prior radiation (binary), and primary cancer histologic findings (categorical: non–small cell lung cancer, breast cancer, melanoma, other). Because the same patient could have multiple resections, we accounted for intrapatient correlations using a sandwich estimator. Once a patient had displayed pachymeningeal seeding, we did not evaluate further resections for this outcome measure. Only pachymeningeal seeding diagnosed from 2001 to 2015 was included in the incidence and/or risk factor analysis given that the brain metastasis database (which was used for the denominator of the incidence analysis) included data through December 31, 2015.
Among patients with pachymeningeal seeding, including those diagnosed in 2016 to 2017, we characterized development of new brain metastases, leptomeningeal disease, local failure (in pachymeningeal tumors after salvage radiation), distant pachymeningeal seeding, and neurologic death using Kaplan-Meier curves, log-rank tests, and univariable Cox regression. Neurologic death was defined by marked radiographic progression in the brain accompanied by corresponding neurologic symptomatology in the absence of systemic disease progression and/or systemic symptoms of a life-threatening nature. The assumption of proportional hazards was tested and verified. The median follow-up in surviving patients was 2.39 years. Statistical analyses were performed using SAS software (version 9.4, SAS Institute).
Results
Leptomeningeal Disease and Pachymeningeal Seeding After Neurosurgical Resection
Baseline characteristics in the 1188 patients with brain metastases, as stratified by those who underwent neurosurgical resection (n = 318; 133 men and 185 women; mean [SD] age, 58.9 [11.5] years) vs those who did not undergo resection (n = 870), are displayed in the eTable in the Supplement. Patients who underwent surgery were more likely than those who did not undergo surgery to present with fewer brain metastases at diagnosis (median, 1 vs 2; P < .001), have undergone fewer prior chemotherapy regimens for metastatic disease (median, 0 vs 0; P < .001), have differences in primary disease site and/or histologic findings, have a lower recursive partitioning analysis (RPA) class (class 1, 17.3% vs 6.7%; P < .001), have lower rates of extracranial disease (58.5% vs 76.1%; P < .001), have lower rates of progressive and/or newly diagnosed extracranial disease (51.6% vs 70.9%; P < .001), and have lower rates of presentation with seizures at diagnosis of an intracranial malignant tumor (4.7% vs 10.8%; P < .001). No other significant differences were noted between the 2 cohorts.
Patients with brain metastases who underwent neurosurgical resection vs those who did undergo resection displayed no significant difference in development of leptomeningeal disease (hazard ratio [HR], 1.14; 95% CI, 0.73-1.77; P = .56) (Figure 2A). Development of pachymeningeal seeding was seen only in patients undergoing neurosurgical resection (36 of 318 vs 0 of 870; P < .001) (Figure 2B).
Figure 2. Kaplan-Meier Curves With Associated Log-Rank Test for Freedom From Leptomeningeal Disease and Pachymeningeal Seeding.
Patients treated with neurosurgical resection (red) vs without neurosurgical resection (blue).
Incidence and Risk Factors Associated With Pachymeningeal Seeding
Of the 428 individual neurosurgical resections for brain metastases performed in the cohort analyzed for incidence, 36 resections had evidence of pachymeningeal seeding, representing an incidence of 8.4%. The incidence of pachymeningeal seeding following resection was 13.7% (28 of 205 patients) and 3.6% (8 of 223 patients) in patients with controlled vs uncontrolled or newly diagnosed extracranial disease at diagnosis, respectively. The median time to detection of pachymeningeal seeding after resection among patients who developed this complication was 4.67 months. Baseline characteristics in the 318 patients who underwent neurosurgical resection, as stratified by subsequent development of pachymeningeal seeding vs no development of seeding, are displayed in Table 1. There were no significant differences between patients with seeding vs without seeding in terms of age, sex, race, marital status, Charlson Comorbidity Index, number of brain metastases present at diagnosis, number of prior chemotherapy regimens for metastatic disease, and neurologic symptoms at diagnosis of intracranial malignancy vs no neurologic symptoms. In addition, there were no significant differences between the 2 groups in terms of primary tumor site or histologic findings (Table 1). Patients who developed pachymeningeal seeding after surgery were more likely than those who did not develop pachymeningeal seeding to have a Karnofsky performance score between 90 and 100 (27 [75.0%] of 36 patients vs 136 [48.2%] of 282 patients, P = .003), harbor lower rates of progressive/newly diagnosed extracranial disease (8 [22.2%] of 36 vs 156 [55.3%] of 282, P < .001), have a lower RPA class (class 1, 11 [30.6%] of 36 vs 44 [15.6%] of 282; P = .006), and present with seizures at diagnosis of intracranial malignancy (6 [16.7%] of 36 vs 9 [3.2%] of 282, P = .003). Multivariable Cox regression on a per metastasis level revealed that prior radiation (HR, 2.39; 95% CI, 1.25-4.57; P = .008) was significantly associated with pachymeningeal seeding after resection in a model also containing maximal unidimensional size prior to resection and primary disease histology.
Table 1. Baseline Characteristics of 428 Patients With and Without Pachymeningeal Seeding After Neurosurgical Resection.
| Characteristic | No. (%) | P Value | |
|---|---|---|---|
| Pachymeningeal Seeding (n = 36) | No Pachymeningeal Seeding (n = 282) | ||
| Patient characteristic at diagnosis of brain metastases | |||
| Age, mean (SD) | 60.8 (10.4) | 58.7 (11.6) | .32 |
| Sex | .98 | ||
| Male | 15 (41.7) | 118 (41.8) | |
| Female | 21 (58.3) | 164 (58.2) | |
| Race | .40 | ||
| White | 30 (83.3) | 250 (88.7) | |
| Other | 5 (13.9) | 27 (9.6) | |
| Unknown | 1 (2.8) | 5 (1.8) | |
| Marital status | .44 | ||
| Married | 22 (61.1) | 196 (69.5) | |
| Other | 14 (38.9) | 82 (29.1) | |
| Unknown | 0 | 4 (1.4) | |
| KPS | .003 | ||
| 60-80 | 9 (25.0) | 146 (51.8) | |
| 90-100 | 27 (75.0) | 136 (48.2) | |
| Charlson Comorbidity Indexa | .44 | ||
| 0-1 | 27 (75.0) | 190 (67.4) | |
| 2-6 | 9 (25.0) | 92 (32.6) | |
| Brain metastases, median (IQR), No. | 1 (1-2) | 1 (1-3) | .48 |
| Prior chemotherapy regimens for metastatic disease, median (IQR), No. | 0 (0-1) | 0 (0-1) | .91 |
| Primary cancer | .15 | ||
| Breast | 6 (16.7) | 52 (18.4) | |
| Lung | 17 (47.2) | 89 (31.6) | |
| Melanoma | 4 (11.1) | 72 (25.5) | |
| Other | 9 (25.0) | 69 (24.5) | |
| Presence of extracranial disease | 11 (30.6) | 175 (62.1) | <.001 |
| Progressive extracranial disease including patients with newly diagnosed cancer and extracranial metastases | 8 (22.2) | 156 (55.3) | <.001 |
| RPA class | .006 | ||
| 1 | 11 (30.6) | 44 (15.6) | |
| 2 | 22 (61.1) | 229 (81.2) | |
| 3 | 1 (2.8) | 8 (2.8) | |
| Unknown | 2 (5.6) | 1 (0.4) | |
| Neurologic symptoms | 25 (69.4) | 163 (57.8) | .21 |
| Seizure | 6 (16.7) | 9 (3.2) | .003 |
| Characteristics of brain metastases at the time of surgery | |||
| Receipt of prior radiationb | 17 (47.2) | 152 (38.8) | .37 |
| Unidimensional size of metastasis preoperatively, median (IQR), mmb | 27.8 (21.2-36.5) | 28.0 (20.1-37.6) | .96 |
Abbreviations: IQR, interquartile range; KPS, Karnofsky performance status; RPA, recursive partitioning analysis.
Excludes diagnosis of metastatic cancer so as not to inflate all scores by 6 points.
Denominator was based on the total number of neurosurgical resections (n = 428).
Clinical Course After Pachymeningeal Seeding
Development of pachymeningeal disease (n = 53 patients) was associated with a high rate of neurological death (Figure 3); of 36 patients with pachymeningeal disease who died, 26 (72%) died of neurologic disease progression. Rates of leptomeningeal failure and new metastases within the brain parenchyma were relatively low among patients who developed pachymeningeal seeding, with an incidence of 13% (6 of 48 evaluable patients) and 16% (8 of 51 evaluable patients), respectively. Local or distant pachymeningeal progression after salvage radiation was common, occurring in 50% of patients (n= 22 of 44 evaluable patients). The median survival from the time of diagnosis of pachymeningeal disease was 11.1 months.
Figure 3. Kaplan-Meier Curve for Freedom From Neurologic Death in Patients Who Developed Pachymeningeal Seeding .
Time zero refers to the date of diagnosis of pachymeningeal seeding.
Intracranial management and outcomes among patients with pachymeningeal seeding are presented in Table 2. Most patients with pachymeningeal seeding were treated with salvage radiation; stereotactic radiation of the involved pachymeningeal sites or WBRT was performed. Use of stereotactic radiation was associated with improved all-cause mortality compared with WBRT (HR, 0.49; 95% CI, 0.23-1.02; P = .06) (eFigure 1 in the Supplement) although the extent to which confounding by indication influences this association remains unclear. Among patients with pachymeningeal seeding who received salvage radiation, overall survival was not considerably different in patients with controlled vs uncontrolled or newly diagnosed extracranial disease (eFigure 2 in the Supplement).
Table 2. Intracranial Management and Outcomes in 53 Patients With Postsurgical Pachymeningeal Disease.
| Management Strategy and Outcomes | Patients, No. (%) (n = 53) |
|---|---|
| WBRT | 18 (34.0) |
| Stereotactic radiation | 26 (49.1) |
| Systemic therapy without radiation | 6 (11.3) |
| Supportive care | 3 (5.7) |
| Development of parenchymal metastases after diagnosis of pachymeningeal seedinga | 8 (15.7) |
| Development of leptomeningeal disease after diagnosis of pachymeningeal seedingb | 6 (12.5) |
| Further pachymeningeal recurrence following initial treatment of pachymeningeal seeding | |
| Local pachymeningeal failurec | 16 (37.2) |
| Distant pachymeningeal failured | 12 (27.3) |
Abbreviation: WBRT, whole-brain radiation.
Denominator excluding patients with missing data is 51.
Denominator excluding patients with missing data is 48.
Denominator excluding patients with missing data is 43.
Denominator excluding patients with missing data is 44.
Discussion
In this study, we described and quantified pachymeningeal seeding beyond the adjuvant stereotactic radiation field15 as a unique pattern of intracranial progression in patients undergoing neurosurgical resection for a brain metastasis. Receipt of prior radiation is a key risk factor for this phenomenon. Concerningly, pachymeningeal seeding occurs most frequently in patients with absent and/or controlled extracranial disease and among patients with RPA class 1 disease (ie, those who have an otherwise favorable prognosis), which is likely owing to the lower competing risk of systemic progression or death, and therefore represents a marked prognostic turn with significant clinical consequences for such patients. In patients who develop pachymeningeal failure, neurologic death represents a key cause of patient mortality. However, unlike with leptomeningeal disease, some patients with pachymeningeal failure can undergo salvage treatment and remain disease free for prolonged periods.
Pachymeningeal seeding after neurosurgical resection is likely an underreported phenomenon for 2 reasons. First, prior investigations may not have distinguished pachymeningeal from leptomeningeal disease.13,16 Second, until recently, WBRT represented the standard postoperative radiotherapeutic management modality; the efficacy of WBRT in treating micrometastatic disease likely mitigated development of pachymeningeal seeding in many patients.17 However, management paradigms shifted after publication of the North Central Cancer Treatment Group trial (N107/CEC 3)7 in which patients with a limited number of brain metastases who underwent neurosurgical resection were randomized to WBRT or radiosurgery of the cavity. Cavity radiosurgery was shown to yield considerably better neurocognitive function and quality-of-life outcomes, with no difference in survival rates. However, local control was worse with cavity radiosurgery7; it is possible that some recurrences were pachymeningeal in nature, although such details are not available.
Further examination of neurosurgical techniques that can decrease the incidence of pachymeningeal seeding warrant investigation. Radiotherapeutically, it would be difficult to design a stereotactic radiation field that covers all of the at-risk dura because pachymeningeal seeding in this study occurred at a margin exceeding 1.0 cm beyond the cavity, and often exceeded the margin by a considerable distance.15 However, investigations of additional radiotherapeutic measures to reduce the incidence of pachymeningeal seeding, such as preoperative radiation, are being conducted in multiple prospective studies (NCT01252797, NCT03398694, NCT02514915). It is important that such studies distinguish pachymeningeal dissemination as a unique form of intracranial recurrence, one that is separate from leptomeningeal disease.
Our results suggest that discussion of WBRT should be considered in patients with resection of a single brain metastasis, particularly if extracranial disease is absent and the competing risk of systemic death is thereby lower. Such management paradigms are supported by a randomized clinical trial conducted in Poland that demonstrated a survival benefit with WBRT among patients with a single resected brain metastasis.18 However, it should be noted that most randomized studies have not identified a survival benefit with adjuvant WBRT, and quality of life and/or neurocognitive function is likely better if WBRT is omitted. Among patients with extracranial systemic disease (ie, a substantial competing risk) and a limited number of brain metastases who have undergone neurosurgical resection, stereotactic radiation of the cavity seems more prudent than WBRT.5,6,7,8
The optimal salvage strategy for patients with pachymeningeal seeding remains unknown, but radiation plays a key role in management of such patients. We did not observe rates of dissemination into the brain parenchyma and leptomeninges that warranted routine use of WBRT, especially given the adverse effects of WBRT and that the higher dose of stereotactic radiation might provide more durable local control of tumors that are often inherently aggressive. Conversely, new pachymeningeal seeding can occur over time and stereotactic fields may overlap with prior courses of radiation over short periods, leading to radiation necrosis.19,20 Further investigation of the optimal treatment of patients with pachymeningeal seeding is warranted.
Limitations
Our study should be considered in the context of its limitations. Because all data stemmed from a single institution, it is unclear whether our results are generalizable to all institutions given possible differences in patient populations, treatment selection algorithms, surgical techniques, radiation approaches, and posttreatment monitoring plans. Second, the small size of our cohort renders it difficult to assess the optimal salvage strategy for patients with pachymeningeal seeding. Third, some patients who underwent neurosurgical resection and cavity radiation required WBRT for intracranial recurrences that developed in the postoperative period, which may have blunted the development of pachymeningeal metastases; our results may therefore underestimate the incidence of pachymeningeal seeding after resection. Finally, our data do not permit us to determine why certain patients develop pachymeningeal seeding while most patients do not.
Conclusions
Our study suggests that pachymeningeal seeding after neurosurgical resection and cavity radiation represents a distinct pattern of intracranial failure. Receipt of prior radiation is associated with an increased risk of pachymeningeal seeding after resection. Given that the standard practice in many institutions is stereotactic radiation of the cavity after surgical resection, further investigation into mechanisms to prevent pachymeningeal seeding are warranted. In addition, delineation of optimal radiotherapeutic management of patients who develop pachymeningeal seeding would be prudent.
eTable 1 Baseline Characteristics of Patients Who Underwent Neurosurgical Resection for a Brain Metastasis Versus Those Who Did Not
eFigure 1. Kaplan-Meier Curve With Associated Log-Rank Test for Overall Survival Among Patients With Pachymeningeal Seeding Who Received Salvage Stereotactic Radiation (blue) vs Those Who Received Salvage Whole Brain Radiation (red)
eFigure 2. Kaplan-Meier Curve With Associated Log-Rank Test for Overall Survival Among Patients With Pachymeningeal Seeding Who Received Salvage Radiation With Controlled (blue) vs Progressive/Newly Diagnosed (red) Extracranial Disease
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Supplementary Materials
eTable 1 Baseline Characteristics of Patients Who Underwent Neurosurgical Resection for a Brain Metastasis Versus Those Who Did Not
eFigure 1. Kaplan-Meier Curve With Associated Log-Rank Test for Overall Survival Among Patients With Pachymeningeal Seeding Who Received Salvage Stereotactic Radiation (blue) vs Those Who Received Salvage Whole Brain Radiation (red)
eFigure 2. Kaplan-Meier Curve With Associated Log-Rank Test for Overall Survival Among Patients With Pachymeningeal Seeding Who Received Salvage Radiation With Controlled (blue) vs Progressive/Newly Diagnosed (red) Extracranial Disease