- Email: [email protected]
Postsurgical Cavity Evolution After Brain Metastasis Resection: How Soon Should Postoperative Radiosurgery Follow?
Original Article
Postsurgical Cavity Evolution After Brain Metastasis Resection: How Soon Should Postoperative Radiosurgery Follow? Rajal A. Patel1, Derrick Lock3, Irene B. Helenowski4, James P. Chandler2, Sean Sachdev1, Matthew C. Tate2, Tim J. Kruser1
BACKGROUND: Postoperative stereotactic radiosurgery (SRS) to the cavity after resection of brain metastases improves local control. We hypothesized that significant cavity constriction would occur from the immediate postoperative period to the time of SRS and aimed to elucidate optimal treatment timing.
-
METHODS: We retrospectively reviewed 79 consecutive patients with 85 resection cavities treated with SRS after gross total resection of a brain metastasis. Preoperative lesion, immediate postoperative cavity, and cavity at the time of SRS were contoured for each patient. Factors influencing cavity size and interval cavity change were analyzed.
-
RESULTS: Median immediate postoperative cavity volume was 7.5 cm3, and median SRS cavity volume was 8.7 cm3. Median time from surgery to SRS was 20 days. Median volumetric cavity change was an increase of 28%. Of cavities, 34 (40%) increased in size >2 cm3, whereas only 8 cavities (9%) decreased in size >2 cm3; 43 cavities (51%) had £2 cm3 change. The largest postoperative cavities experienced the smallest percentage cavity change in the time interval to SRS (Spearman correlation L0.32, P [ 0.003).
-
CONCLUSIONS: Cavity size after brain metastasis resection increased a median of 28% from immediate
-
Key words - Brain metastases - Cavity - Postoperative - Stereotactic Radiosurgery Abbreviations and Acronyms BM: Brain metastasis LC: Local control LR: Local recurrence MRI: Magnetic resonance imaging SRS: Stereotactic radiosurgery Vlesion: Preoperative lesion volume Vpostop: Immediate postoperative cavity volume VSRS: Cavity volume at time of stereotactic radiosurgery WBRT: Whole-brain radiotherapy
WORLD NEUROSURGERY -: ---, - 2017
postoperative scan to time of SRS. Greater than 90% of postoperative cavities either increased >2 cm3 or remained within 2 cm3 of their immediate postoperative cavity volume. Early postoperative SRS within 2e3 weeks may be appropriate to minimize cavity growth. Delaying postoperative SRS beyond 3 weeks in hopes of significant cavity contraction is not warranted.
INTRODUCTION
S
urgical resection for patients presenting with a single brain metastasis (BM) has been shown to improve overall survival while establishing a pathologic diagnosis.1 In addition, select patients who present with multiple BMs may benefit from resection if there are symptomatic, dominant lesions. In either case, whole-brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS) after resection of a BM has been proven to improve local control (LC) at the resection cavity, with WBRT additionally decreasing the risk of developing distant BMs.1-4 Nonetheless, many institutions have started using postoperative SRS to the surgical cavity as an alternative to WBRT, owing to the lack of benefit for postoperative WBRT on overall survival and the potential neurocognitive toxicity associated with WBRT.5-8 SRS has demonstrated high rates of surgical cavity LC when used in the postoperative setting in multiple trials and
From the Departments of 1Radiation Oncology and 2Neurological Surgery, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago; 3Rosalind Franklin University of Medicine and Science, North Chicago; and 4Division of Biostatistics, Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA To whom correspondence should be addressed: Rajal A. Patel, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2017). https://doi.org/10.1016/j.wneu.2017.10.159 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2017 Elsevier Inc. All rights reserved.
www.WORLDNEUROSURGERY.org
E1
ORIGINAL ARTICLE RAJAL A. PATEL ET AL.
CAVITY DYNAMICS BEFORE POSTOPERATIVE RADIOSURGERY
retrospective series.9-11 Consistently, these studies have shown a significant correlation between increasing preoperative lesion size and local recurrence (LR) rates.9,10 Another study demonstrated increased LR rates with increasing cavity size.12 The increased LR rates may be attributed to the correlation between large preoperative lesions resulting in large postoperative cavities that are often treated with lower SRS doses.3,9,13 The timing of postoperative SRS has been evaluated in multiple retrospective reports with conflicting conclusions; some studies have recommended SRS within 1e2 weeks of surgery,14,15 whereas a contradictory study recommended delaying SRS for >1 month to allow for cavity constriction.16 Given these inconsistencies in the literature to date, we examined cavity dynamics after resection of BMs to determine what factors influenced cavity size and interval cavity change to instruct treatment timing for postoperative cavity SRS. MATERIALS AND METHODS Study Population Following institutional review board approval, 100 consecutive patients who had received SRS to a surgical cavity before 2015 were reviewed. All patients must have had a gross total resection of BM and not have undergone previous WBRT or SRS to an adjacent area. Patients were excluded if they developed a LR before SRS, if they had evidence of dural-based metastases without frank parenchymal invasion, if preoperative imaging was not available, or if immediate postoperative imaging was inadequate to evaluate the baseline surgical cavity. Ultimately, 79 patients and 85 cavities were included in our analysis. Surgery All patients underwent surgical resection by a neurosurgeon a National Cancer InstituteeDesignated Cancer Center. Gross total resection was defined as removal of all visible tumor per surgical documentation and no evidence of definitive residual tumor on postoperative imaging. Per institutional practice, patients were discharged on a 1-week dexamethasone taper after surgery and therefore were not on steroids at the time of SRS. Imaging and Volumes All patients underwent magnetic resonance imaging (MRI) before resection as well as postoperative imaging within 72 hours following surgery. Postoperative imaging consisted of MRI in 76 patients and computed tomography in 3 patients. A doubledose contrast MRI scan was obtained the morning of SRS treatment for every patient. All MRI scans included a precontrast T1-weighted image and postcontrast T1-weighted image and were interpreted by a board-certified neuroradiologist. Using the postcontrast T1-weighted image (and in select cases computed tomography images with contrast), contours of the preoperative lesion volume (Vlesion), the immediate postoperative cavity volume (Vpostop), and the cavity volume at time of stereotactic radiosurgery (VSRS) were manually contoured using MIM Software Version 6.6.12 (MIM Software Inc., Cleveland, Ohio, USA). Contours for both Vpostop and VSRS included the cavity without any additional margin. Each lesion, immediate postoperative cavity, and cavity at the time of SRS was contoured by a single observer, limiting
E2
www.SCIENCEDIRECT.com
Table 1. Patient Characteristics Characteristics
Value
Number of patients
79
Mean age, years
61
Median KPS score
90
Sex Male
38 (48%)
Female
41 (52%)
Number of cavities
85
Primary tumor type Lung
35 (41%)
Breast
15 (18%)
Melanoma
15 (18%)
Renal cell
9 (11%)
Gastrointestinal
7 (8%)
Gynecologic
2 (2%)
Soft tissue sarcoma
2 (2%)
Histology Adenocarcinoma Squamous cell carcinoma Melanoma
46 (54%) 4 (5%) 15 (18%)
Clear cell
7 (8%)
Neuroendocrine
4 (5%)
Undifferentiated
4 (5%)
Other
5 (6%)
Lesion location Frontal
30 (35%)
Temporal
9 (11%)
Parietal
17 (20%)
Occipital
12 (14%)
Cerebellum
17 (20%)
KPS, Karnofsky performance scale.
observer variability. The target for SRS was the cavity plus a 0- to 2-mm expansion, based on the preference of the treating physician, but this target volume is not reported and was not an endpoint of this study. All patients underwent single-fraction postoperative SRS with the Leskell Gamma Knife Perfexion System (Elekta AB, Stockholm, Sweden). Statistical Analysis Cavity change in cubic centimeters was calculated using the formula VSRS Vpostop. The percent cavity change from postoperative imaging to SRS was calculated using the formula 100 $ [(VSRS Vpostop)/Vpostop]. The percent change from
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2017.10.159
ORIGINAL ARTICLE RAJAL A. PATEL ET AL.
CAVITY DYNAMICS BEFORE POSTOPERATIVE RADIOSURGERY
Table 2. Cavity and Tumor Volumes Stratified by Cavity Change Cavity Change from Immediate Postoperative to SRS Decreased >2 cm3
Number (%)
Vlesion, cm3, Median (Range)
Preoperative Lesion Size, cm, Median (Range)
Vpostop, cm3, Median (Range) 12.1 (7.7e34.2)
8 (9)
9.7 (6.7e47.0)
3.0 (1.7e4.9)
Change 2 cm3
43 (51)
10.7 (0.4e108.6)
2.9 (1.0e6.9)
6.7 (0.2e101.1)
Increased >2 cm3
34 (40)
14.8 (1.6e77.5)
3.5 (1.4e6.3)
7.5 (0.4e34.4)
VSRS, cm3, Median (Range) 5.9 (3.7e10.7) 5.5 (0.4e102.5) 18.8 (2.7e57.5)
SRS, stereotactic radiosurgery; Vlesion, preoperative lesion volume; Vpostop, immediate postoperative cavity volume; VSRS, cavity volume at time of stereotactic radiosurgery.
preoperative lesion volume to immediate postoperative imaging cavity volume was calculated using the formula 100 $ [(Vpostop Vlesion)/Vlesion]. Cavities were further stratified based on an increase or decrease in cavity size 2 cm3 from Vpostop to VSRS based on the analysis by Jarvis et al.15 Correlation analyses were performed using the Wilcoxon rank sum test, Kruskal-Wallis test, Fisher exact test, and Spearman correlation. RESULTS Patient Characteristics We analyzed 79 patients and 85 individually treated cavities. The median time between surgical resection and SRS was 20 days (range, 5e44 days). The median age of patients was 61 years; 52% of patients were women. Of cavities, 41% were metastatic from primary lung carcinoma, 18% were metastatic from primary breast carcinoma, and 18% were metastatic from melanoma. The most common metastatic histology was adenocarcinoma, accounting for 54% of resected lesions. Supratentorial location accounted for 80% of resected lesions. Patient characteristics are summarized in Table 1. Volume and Cavity Change The median Vlesion was 11.5 cm3 (range, 0.4e108.6 cm3), and the median preoperative lesion diameter was 3.3 cm (range, 1.0e6.9 cm) in maximal dimension. The median Vpostop was 7.5 cm3 (range, 0.2e101.1 cm3), and the median VSRS was 8.7 cm3 (range, 0.4e102.5 cm3). From immediate postoperative imaging to MRI at the time of SRS, 59 cavities (69%) increased in size and 26 cavities (31%) decreased in size. The median volumetric cavity change from Vpostop to VSRS was a 28% increase in cavity size with a median increase of 1.5 cm3. Of cavities, 34 (40%) increased in size >2 cm3, whereas only 8 (9%) decreased in size >2 cm3; 43 cavities (51%) had 2 cm3 change (Table 2).
Of preoperative lesions, 45 were 3 cm in maximal dimension with a median Vlesion of 23.5 cm3 (range, 0.4e108.6 cm3). The cavities resulting from these lesions demonstrated a median Vpostop of 10.0 cm3 (range, 1.1e101.1 cm3) with a median volumetric decrease of 58.5%. From the time of postoperative imaging to SRS, these cavities increased a median of 1.8 cm3 (range, 7.4 to 27.8 cm3) and had a median percentage increase of 27.2%. Forty preoperative lesions were <3 cm in maximal dimension with a median Vlesion of 6.8 cm3 (range, 0.7e30.2 cm3). The cavities resulting from these lesions were also smaller than the tumor volumes after surgery, with a median Vpostop of 4.6 cm3 (range, 0.2e34.2 cm3) and median volumetric decrease of 8.6%. From the time of postoperative imaging to SRS, these cavities increased a median of 1.4 cm3 (range, 30.5 to 19.6 cm3) and had a median percentage increase of 39.5% (Table 3). Univariate Analysis Time to SRS was not significantly associated with whether cavities showed an increase or decrease in size (P ¼ 0.16) (Figure 1). Other factors analyzed that were not significantly associated with whether cavities increased or decreased in size included Vlesion, Vpostop, sex, primary tumor site, histology, BM location, performance status, and age. However, Vpostop was negatively correlated with percent cavity change (Spearman correlation 0.32, P ¼ 0.003) (Figure 2). Thus, small postoperative cavities had the greatest relative size increase at the time of SRS. DISCUSSION Postoperative SRS to the surgical cavity has been widely adopted as an alternative to WBRT to improve LC at the cavity while minimizing the risk of neurocognitive toxicity.5-8 Although LC rates are similar between postoperative SRS and WBRT, many
Table 3. Cavity and Tumor Volumes Stratified by Preoperative Lesion Size
Number (%)
Vlesion, cm3, Median (Range)
Vpostop, cm3, Median (Range)
Lesion Change from Vlesion to Vpostop, Median (Range)
VSRS, cm3, Median (Range)
Cavity Change from Vpostop to VSRS, Median (Range)
3
45 (53)
23.5 (0.4e108.6)
10.0 (1.1e101.1)
58.5% (90 to 486)
12.8 (1.4e102.5)
27.3% (62 to 587)
<3
40 (47)
6.8 (0.7e30.2)
4.6 (0.2e34.2)
8.6% (85 to 343)
5.2 (0.4e34.4)
39.5% (89 to 647)
Preoperative Lesion Size, cm
Vlesion, preoperative lesion volume; Vpostop, immediate postoperative cavity volume; VSRS, cavity volume at time of stereotactic radiosurgery.
WORLD NEUROSURGERY -: ---, - 2017
www.WORLDNEUROSURGERY.org
E3
ORIGINAL ARTICLE CAVITY DYNAMICS BEFORE POSTOPERATIVE RADIOSURGERY
700
700
600
600
500 400 300
Spearman Correlaon -0.15, p=0.16
200 100 0
0
5
10
15
20
25
30
35
40
45
50
-100 -200
500 400 300
Spearman Correlaon -0.32, p=0.003
200 100 0 -100
0
20
40
60
80
100
120
-200 -300
Interval between surgery and SRS (days)
Figure 1. Percent cavity change based on time. SRS, stereotactic radiosurgery; Vpostop, immediate postoperative cavity volume; VSRS, cavity volume at time of stereotactic radiosurgery.
studies have demonstrated increased LR rates for large preoperative lesions that consequently result in large surgical cavities prescribed a lower SRS dose.3,9,13 A phase II trial evaluating the efficacy of postoperative SRS to the surgical cavity found an overall 1-year LC rate of 85%. Within this cohort, the cavities resulting from a preoperative lesion >3 cm had elevated 1-year LR rates of 39%, whereas cavities with a preoperative lesion <3 cm had a 1-year LR rate of 7.5%.9 This trend toward decreased LC with larger tumors was also demonstrated in a recently presented phase III prospective randomized trial comparing postoperative SRS with observation for resected BMs.3 Cavities with a preoperative lesion 2.5 cm had a 1-year LR of 9%, and cavities with a preoperative lesion 2.6 cm had a 1-year LR rate of 57%. We evaluated lesion and cavity dynamics stratified by preoperative lesion size. The volumes of cavities resulting from preoperative lesions 3 cm were significantly smaller than the preoperative tumor volume (median volumetric decrease of 58.5%), whereas preoperative lesions <3 cm had associated cavities that were only minimally smaller than the preoperative tumor volume (median volumetric decrease of 8.6%). This demonstrates that some large lesions may result in cavities highly amenable to SRS, whereas small tumors are associated with cavities more reliably similar to the preoperative tumor size. Three studies have been published examining how surgical cavities evolve over time and if this change should influence timing of SRS. One series reviewed 68 cavities from 63 patients treated with surgical resection and postoperative SRS.14 Similar to our results, the authors found no association between time from surgery and cavity volume change, suggesting that the cavity volume did not significantly change during the time range examined (0e33 days). Therefore, they suggested there is no benefit to delaying SRS longer than 1e2 weeks after surgery. Another analysis of 41 patients demonstrated that 47% of cavities remained stable (defined as a change of <2 cm3 between immediate postoperative cavity volume and SRS cavity volume), whereas 23% of cavities decreased in size >2 cm3, and 30% of cavities increased in size by >2 cm3.15 The authors
E4
Percent Cavity Change from Vpostop to VSRS
Percent Cavity Change from Vpostop to VSRS
RAJAL A. PATEL ET AL.
www.SCIENCEDIRECT.com
Immediate Postoperave Cavity Volume in mL (Vpostop)
Figure 2. Percent cavity change based on immediate postoperative cavity volume. Vpostop, immediate postoperative cavity volume; VSRS, cavity volume at time of stereotactic radiosurgery.
concluded that delaying SRS after surgery does not offer the benefit of cavity collapse in most patients, and most cavities remain stable or increase in size. Our results further support these conclusions. Finally, Shah et al.16 conducted a review of 21 patients; median time between imaging was longer than other series at 39 days. Of 21 cavities, 19 decreased in size, with a mean reduction of 43%. The authors also found significantly greater cavity constriction for patients with >1 month to time of SRS imaging (mean 61% reduction in volume) compared with patients with <1 month to time of SRS imaging. Eleven patients (52%) had evidence of tumor progression within the resection cavity. Despite this concerning finding, the authors advocated for delaying SRS for >1 month to allow for cavity constriction. We found that most cavities increased in size from postoperative MRI to the time of SRS with a median volumetric cavity increase of 28%. In our series of 85 cavities, 40% of cavities increased >2 cm3, and 51% of cavities remained within 2 cm3 of their postoperative volume. The increase in cavity volume over time is contrary to our initial hypothesis and counterintuitive. A reduction in surrounding parenchymal edema may contribute to the increasing cavity volume in the majority of cavities, whereas the minority of cavities that decreased in size may be related to ongoing decompression of the normal brain parenchyma. Compared with the findings of Atalar et al.14 and Jarvis et al.,15 we observed a greater percentage of cavities to have enlarged in the interval between postresection imaging and the time of SRS. In contrast to the study by Shah et al.,16 significant cavity constriction was not demonstrated. Growing cavity size argues against delaying SRS to our median treatment time of 3 weeks, as larger cavities may be less amenable to adequate dose delivery. Furthermore, delaying SRS may lead to higher rates of gross tumor recurrence before SRS (as in the Shah et al. study16), which may compromise local control further. A previous review of patients undergoing postoperative SRS for BM resection demonstrated significantly increased LR rates when postoperative SRS was extended beyond 3 weeks time.17
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2017.10.159
ORIGINAL ARTICLE RAJAL A. PATEL ET AL.
CAVITY DYNAMICS BEFORE POSTOPERATIVE RADIOSURGERY
Our findings suggest that the largest decrease in target volume occurs as a result of surgical intervention. However, after resection, there is overall cavity growth, with small postoperative cavities experiencing the most percentage growth and large postoperative cavities experiencing minimal cavity volume change. This finding highlights the likely futility in hoping that large cavities will significantly collapse over time and become better radiosurgery targets. This study was inherently limited by its retrospective nature with all patients treated at a single center. The interval between resection and postoperative SRS was neither uniform nor predefined in our patient population. Similar to the other 3 studies examining this issue, MRI was performed postoperatively and at the time of SRS only; MRI scans in the intervening period would
REFERENCES 1. 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. 2. Kocher M, Soffietti R, Abacioglu U, Villà S, Fauchon F, Baumert BG, et al. Adjuvant wholebrain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol. 2011;29:134-141. 3. Mahajan A, Ahmed S, Li J, McAleer MF, Weinberg J, Brown PD, et al. Postoperative stereotactic radiosurgery versus observation for completely resected brain metastases: results of a prospective randomized study. Int J Radiat Oncol Biol Phys. 2016;96(2 suppl):S2. 4. Patchell RA, Tibbs PA, Regine WF, Dempsey RJ, Mohiuddin M, Kryscio RJ, et al. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA. 1998;280: 1485-1489. 5. Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth DG, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. 2009;10: 1037-1044.
more fully elucidate the timing of cavity evolution and could be the focus of further prospective efforts. CONCLUSIONS Cavity size after BM resection increased a median of 28% from the immediate postoperative period to the time of SRS. Larger postoperative cavities had less volumetric change compared with smaller cavities. Greater than 90% of postoperative cavities either increased >2 cm3 or remained within 2 cm3 of their immediate postoperative cavity volume. Postoperative SRS within 2e3 weeks may be appropriate, as delaying postoperative treatment beyond 3 weeks in hopes of significant cavity contraction is not supported by this analysis.
Appropriateness Criteria: single brain metastasis. Curr Probl Cancer. 2010;34:162-174. 8. Aoyama H, Tago M, Kato N, Toyoda T, Kenjyo M, Hirota S, et al. Neurocognitive function of patients with brain metastasis who received either whole brain radiotherapy plus stereotactic radiosurgery or radiosurgery alone. Int J Radiat Oncol Biol Phys. 2007;68:1388-1395.
15. Jarvis LA, Simmons NE, Bellerive M, Erkmen K, Eskey CJ, Gladstone DJ, et al. Tumor bed dynamics after surgical resection of brain metastases: implications for postoperative radiosurgery. Int J Radiat Oncol Biol Phys. 2012;84:943-948.
9. Brennan C, Yang TJ, Hilden P, Zhang Z, Chan K, Yamada Y, et al. A phase 2 trial of stereotactic radiosurgery boost after surgical resection for brain metastases. Int J Radiat Oncol Biol Phys. 2014; 88:130-136.
16. Shah JK, Potts MB, Sneed PK, Aghi MK, McDermott MW. Surgical cavity constriction and local progression between resection and adjuvant radiosurgery for brain metastases. Cureus. 2016;8: e575.
10. Hartford AC, Paravati AJ, Spire WJ, Li Z, Jarvis LA, Fadul CE, et al. Postoperative stereotactic radiosurgery without whole-brain radiation therapy for brain metastases: potential role of preoperative tumor size. Int J Radiat Oncol Biol Phys. 2013;85: 650-655.
17. Iorio-Morin C, Masson-Côté L, Ezahr Y, Blanchard J, Ebacher A, Mathieu D. Early Gamma Knife stereotactic radiosurgery to the tumor bed of resected brain metastasis for improved local control. J Neurosurg. 2014;121:69-74.
11. Jensen CA, Chan MD, McCoy TP, Bourland JD, deGuzman AF, Ellis TL, et al. Cavity-directed radiosurgery as adjuvant therapy after resection of a brain metastasis. J Neurosurg. 2011;114:1585-1591.
Conflict of interest statement: T.J. Kruser has served as a consultant for Varian Medical Systems, Inc., and on an advisory board for Abbvie Inc. Neither of these relationships pertains to this manuscript. The other authors have no conflict of interest to disclose. Abstract was presented at the American Society of Radiation Oncology Annual Meeting, September 24e27, 2017, in San Diego, California.
12. Eaton BR, LaRiviere MJ, Kim S, Prabhu RS, Patel K, Kandula S, et al. Hypofractionated radiosurgery has a better safety profile than single fraction radiosurgery for large resected brain metastases. J Neurooncol. 2015;123:103-111.
6. Tsao M, Xu W, Sahgal A. A meta-analysis evaluating stereotactic radiosurgery, whole-brain radiotherapy, or both for patients presenting with a limited number of brain metastases. Cancer. 2012;118:2486-2493.
13. Brown PD, Ballman KV, Cerhan J, Anderson SK, Carrero XW, Whitton AC, et al. N107C/CEC.3: a phase III trial of post-operative stereotactic radiosurgery (SRS) compared with whole brain radiotherapy (WBRT) for resected metastatic brain disease. Int J Radiat Oncol Biol Phys. 2016;96:937.
7. Suh JH, Videtic GM, Aref AM, Germano I, Goldsmith BJ, Imperato JP, et al. ACR
14. Atalar B, Choi CY, Harsh GR 4th, Chang SD, Gibbs IC, Adler JR, et al. Cavity volume dynamics
WORLD NEUROSURGERY -: ---, - 2017
after resection of brain metastases and timing of postresection cavity stereotactic radiosurgery. Neurosurgery. 2013;72:180-185 [discussion: 185].
Received 29 June 2017; accepted 28 October 2017 Citation: World Neurosurg. (2017). https://doi.org/10.1016/j.wneu.2017.10.159 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2017 Elsevier Inc. All rights reserved.
www.WORLDNEUROSURGERY.org
E5
Postsurgical Cavity Evolution After Brain Metastasis Resection: How Soon Should Postoperative Radiosurgery Follow? Rajal A. Patel1, Derrick Lock3, Irene B. Helenowski4, James P. Chandler2, Sean Sachdev1, Matthew C. Tate2, Tim J. Kruser1
BACKGROUND: Postoperative stereotactic radiosurgery (SRS) to the cavity after resection of brain metastases improves local control. We hypothesized that significant cavity constriction would occur from the immediate postoperative period to the time of SRS and aimed to elucidate optimal treatment timing.
-
METHODS: We retrospectively reviewed 79 consecutive patients with 85 resection cavities treated with SRS after gross total resection of a brain metastasis. Preoperative lesion, immediate postoperative cavity, and cavity at the time of SRS were contoured for each patient. Factors influencing cavity size and interval cavity change were analyzed.
-
RESULTS: Median immediate postoperative cavity volume was 7.5 cm3, and median SRS cavity volume was 8.7 cm3. Median time from surgery to SRS was 20 days. Median volumetric cavity change was an increase of 28%. Of cavities, 34 (40%) increased in size >2 cm3, whereas only 8 cavities (9%) decreased in size >2 cm3; 43 cavities (51%) had £2 cm3 change. The largest postoperative cavities experienced the smallest percentage cavity change in the time interval to SRS (Spearman correlation L0.32, P [ 0.003).
-
CONCLUSIONS: Cavity size after brain metastasis resection increased a median of 28% from immediate
-
Key words - Brain metastases - Cavity - Postoperative - Stereotactic Radiosurgery Abbreviations and Acronyms BM: Brain metastasis LC: Local control LR: Local recurrence MRI: Magnetic resonance imaging SRS: Stereotactic radiosurgery Vlesion: Preoperative lesion volume Vpostop: Immediate postoperative cavity volume VSRS: Cavity volume at time of stereotactic radiosurgery WBRT: Whole-brain radiotherapy
WORLD NEUROSURGERY -: ---, - 2017
postoperative scan to time of SRS. Greater than 90% of postoperative cavities either increased >2 cm3 or remained within 2 cm3 of their immediate postoperative cavity volume. Early postoperative SRS within 2e3 weeks may be appropriate to minimize cavity growth. Delaying postoperative SRS beyond 3 weeks in hopes of significant cavity contraction is not warranted.
INTRODUCTION
S
urgical resection for patients presenting with a single brain metastasis (BM) has been shown to improve overall survival while establishing a pathologic diagnosis.1 In addition, select patients who present with multiple BMs may benefit from resection if there are symptomatic, dominant lesions. In either case, whole-brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS) after resection of a BM has been proven to improve local control (LC) at the resection cavity, with WBRT additionally decreasing the risk of developing distant BMs.1-4 Nonetheless, many institutions have started using postoperative SRS to the surgical cavity as an alternative to WBRT, owing to the lack of benefit for postoperative WBRT on overall survival and the potential neurocognitive toxicity associated with WBRT.5-8 SRS has demonstrated high rates of surgical cavity LC when used in the postoperative setting in multiple trials and
From the Departments of 1Radiation Oncology and 2Neurological Surgery, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago; 3Rosalind Franklin University of Medicine and Science, North Chicago; and 4Division of Biostatistics, Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA To whom correspondence should be addressed: Rajal A. Patel, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2017). https://doi.org/10.1016/j.wneu.2017.10.159 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2017 Elsevier Inc. All rights reserved.
www.WORLDNEUROSURGERY.org
E1
ORIGINAL ARTICLE RAJAL A. PATEL ET AL.
CAVITY DYNAMICS BEFORE POSTOPERATIVE RADIOSURGERY
retrospective series.9-11 Consistently, these studies have shown a significant correlation between increasing preoperative lesion size and local recurrence (LR) rates.9,10 Another study demonstrated increased LR rates with increasing cavity size.12 The increased LR rates may be attributed to the correlation between large preoperative lesions resulting in large postoperative cavities that are often treated with lower SRS doses.3,9,13 The timing of postoperative SRS has been evaluated in multiple retrospective reports with conflicting conclusions; some studies have recommended SRS within 1e2 weeks of surgery,14,15 whereas a contradictory study recommended delaying SRS for >1 month to allow for cavity constriction.16 Given these inconsistencies in the literature to date, we examined cavity dynamics after resection of BMs to determine what factors influenced cavity size and interval cavity change to instruct treatment timing for postoperative cavity SRS. MATERIALS AND METHODS Study Population Following institutional review board approval, 100 consecutive patients who had received SRS to a surgical cavity before 2015 were reviewed. All patients must have had a gross total resection of BM and not have undergone previous WBRT or SRS to an adjacent area. Patients were excluded if they developed a LR before SRS, if they had evidence of dural-based metastases without frank parenchymal invasion, if preoperative imaging was not available, or if immediate postoperative imaging was inadequate to evaluate the baseline surgical cavity. Ultimately, 79 patients and 85 cavities were included in our analysis. Surgery All patients underwent surgical resection by a neurosurgeon a National Cancer InstituteeDesignated Cancer Center. Gross total resection was defined as removal of all visible tumor per surgical documentation and no evidence of definitive residual tumor on postoperative imaging. Per institutional practice, patients were discharged on a 1-week dexamethasone taper after surgery and therefore were not on steroids at the time of SRS. Imaging and Volumes All patients underwent magnetic resonance imaging (MRI) before resection as well as postoperative imaging within 72 hours following surgery. Postoperative imaging consisted of MRI in 76 patients and computed tomography in 3 patients. A doubledose contrast MRI scan was obtained the morning of SRS treatment for every patient. All MRI scans included a precontrast T1-weighted image and postcontrast T1-weighted image and were interpreted by a board-certified neuroradiologist. Using the postcontrast T1-weighted image (and in select cases computed tomography images with contrast), contours of the preoperative lesion volume (Vlesion), the immediate postoperative cavity volume (Vpostop), and the cavity volume at time of stereotactic radiosurgery (VSRS) were manually contoured using MIM Software Version 6.6.12 (MIM Software Inc., Cleveland, Ohio, USA). Contours for both Vpostop and VSRS included the cavity without any additional margin. Each lesion, immediate postoperative cavity, and cavity at the time of SRS was contoured by a single observer, limiting
E2
www.SCIENCEDIRECT.com
Table 1. Patient Characteristics Characteristics
Value
Number of patients
79
Mean age, years
61
Median KPS score
90
Sex Male
38 (48%)
Female
41 (52%)
Number of cavities
85
Primary tumor type Lung
35 (41%)
Breast
15 (18%)
Melanoma
15 (18%)
Renal cell
9 (11%)
Gastrointestinal
7 (8%)
Gynecologic
2 (2%)
Soft tissue sarcoma
2 (2%)
Histology Adenocarcinoma Squamous cell carcinoma Melanoma
46 (54%) 4 (5%) 15 (18%)
Clear cell
7 (8%)
Neuroendocrine
4 (5%)
Undifferentiated
4 (5%)
Other
5 (6%)
Lesion location Frontal
30 (35%)
Temporal
9 (11%)
Parietal
17 (20%)
Occipital
12 (14%)
Cerebellum
17 (20%)
KPS, Karnofsky performance scale.
observer variability. The target for SRS was the cavity plus a 0- to 2-mm expansion, based on the preference of the treating physician, but this target volume is not reported and was not an endpoint of this study. All patients underwent single-fraction postoperative SRS with the Leskell Gamma Knife Perfexion System (Elekta AB, Stockholm, Sweden). Statistical Analysis Cavity change in cubic centimeters was calculated using the formula VSRS Vpostop. The percent cavity change from postoperative imaging to SRS was calculated using the formula 100 $ [(VSRS Vpostop)/Vpostop]. The percent change from
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2017.10.159
ORIGINAL ARTICLE RAJAL A. PATEL ET AL.
CAVITY DYNAMICS BEFORE POSTOPERATIVE RADIOSURGERY
Table 2. Cavity and Tumor Volumes Stratified by Cavity Change Cavity Change from Immediate Postoperative to SRS Decreased >2 cm3
Number (%)
Vlesion, cm3, Median (Range)
Preoperative Lesion Size, cm, Median (Range)
Vpostop, cm3, Median (Range) 12.1 (7.7e34.2)
8 (9)
9.7 (6.7e47.0)
3.0 (1.7e4.9)
Change 2 cm3
43 (51)
10.7 (0.4e108.6)
2.9 (1.0e6.9)
6.7 (0.2e101.1)
Increased >2 cm3
34 (40)
14.8 (1.6e77.5)
3.5 (1.4e6.3)
7.5 (0.4e34.4)
VSRS, cm3, Median (Range) 5.9 (3.7e10.7) 5.5 (0.4e102.5) 18.8 (2.7e57.5)
SRS, stereotactic radiosurgery; Vlesion, preoperative lesion volume; Vpostop, immediate postoperative cavity volume; VSRS, cavity volume at time of stereotactic radiosurgery.
preoperative lesion volume to immediate postoperative imaging cavity volume was calculated using the formula 100 $ [(Vpostop Vlesion)/Vlesion]. Cavities were further stratified based on an increase or decrease in cavity size 2 cm3 from Vpostop to VSRS based on the analysis by Jarvis et al.15 Correlation analyses were performed using the Wilcoxon rank sum test, Kruskal-Wallis test, Fisher exact test, and Spearman correlation. RESULTS Patient Characteristics We analyzed 79 patients and 85 individually treated cavities. The median time between surgical resection and SRS was 20 days (range, 5e44 days). The median age of patients was 61 years; 52% of patients were women. Of cavities, 41% were metastatic from primary lung carcinoma, 18% were metastatic from primary breast carcinoma, and 18% were metastatic from melanoma. The most common metastatic histology was adenocarcinoma, accounting for 54% of resected lesions. Supratentorial location accounted for 80% of resected lesions. Patient characteristics are summarized in Table 1. Volume and Cavity Change The median Vlesion was 11.5 cm3 (range, 0.4e108.6 cm3), and the median preoperative lesion diameter was 3.3 cm (range, 1.0e6.9 cm) in maximal dimension. The median Vpostop was 7.5 cm3 (range, 0.2e101.1 cm3), and the median VSRS was 8.7 cm3 (range, 0.4e102.5 cm3). From immediate postoperative imaging to MRI at the time of SRS, 59 cavities (69%) increased in size and 26 cavities (31%) decreased in size. The median volumetric cavity change from Vpostop to VSRS was a 28% increase in cavity size with a median increase of 1.5 cm3. Of cavities, 34 (40%) increased in size >2 cm3, whereas only 8 (9%) decreased in size >2 cm3; 43 cavities (51%) had 2 cm3 change (Table 2).
Of preoperative lesions, 45 were 3 cm in maximal dimension with a median Vlesion of 23.5 cm3 (range, 0.4e108.6 cm3). The cavities resulting from these lesions demonstrated a median Vpostop of 10.0 cm3 (range, 1.1e101.1 cm3) with a median volumetric decrease of 58.5%. From the time of postoperative imaging to SRS, these cavities increased a median of 1.8 cm3 (range, 7.4 to 27.8 cm3) and had a median percentage increase of 27.2%. Forty preoperative lesions were <3 cm in maximal dimension with a median Vlesion of 6.8 cm3 (range, 0.7e30.2 cm3). The cavities resulting from these lesions were also smaller than the tumor volumes after surgery, with a median Vpostop of 4.6 cm3 (range, 0.2e34.2 cm3) and median volumetric decrease of 8.6%. From the time of postoperative imaging to SRS, these cavities increased a median of 1.4 cm3 (range, 30.5 to 19.6 cm3) and had a median percentage increase of 39.5% (Table 3). Univariate Analysis Time to SRS was not significantly associated with whether cavities showed an increase or decrease in size (P ¼ 0.16) (Figure 1). Other factors analyzed that were not significantly associated with whether cavities increased or decreased in size included Vlesion, Vpostop, sex, primary tumor site, histology, BM location, performance status, and age. However, Vpostop was negatively correlated with percent cavity change (Spearman correlation 0.32, P ¼ 0.003) (Figure 2). Thus, small postoperative cavities had the greatest relative size increase at the time of SRS. DISCUSSION Postoperative SRS to the surgical cavity has been widely adopted as an alternative to WBRT to improve LC at the cavity while minimizing the risk of neurocognitive toxicity.5-8 Although LC rates are similar between postoperative SRS and WBRT, many
Table 3. Cavity and Tumor Volumes Stratified by Preoperative Lesion Size
Number (%)
Vlesion, cm3, Median (Range)
Vpostop, cm3, Median (Range)
Lesion Change from Vlesion to Vpostop, Median (Range)
VSRS, cm3, Median (Range)
Cavity Change from Vpostop to VSRS, Median (Range)
3
45 (53)
23.5 (0.4e108.6)
10.0 (1.1e101.1)
58.5% (90 to 486)
12.8 (1.4e102.5)
27.3% (62 to 587)
<3
40 (47)
6.8 (0.7e30.2)
4.6 (0.2e34.2)
8.6% (85 to 343)
5.2 (0.4e34.4)
39.5% (89 to 647)
Preoperative Lesion Size, cm
Vlesion, preoperative lesion volume; Vpostop, immediate postoperative cavity volume; VSRS, cavity volume at time of stereotactic radiosurgery.
WORLD NEUROSURGERY -: ---, - 2017
www.WORLDNEUROSURGERY.org
E3
ORIGINAL ARTICLE CAVITY DYNAMICS BEFORE POSTOPERATIVE RADIOSURGERY
700
700
600
600
500 400 300
Spearman Correlaon -0.15, p=0.16
200 100 0
0
5
10
15
20
25
30
35
40
45
50
-100 -200
500 400 300
Spearman Correlaon -0.32, p=0.003
200 100 0 -100
0
20
40
60
80
100
120
-200 -300
Interval between surgery and SRS (days)
Figure 1. Percent cavity change based on time. SRS, stereotactic radiosurgery; Vpostop, immediate postoperative cavity volume; VSRS, cavity volume at time of stereotactic radiosurgery.
studies have demonstrated increased LR rates for large preoperative lesions that consequently result in large surgical cavities prescribed a lower SRS dose.3,9,13 A phase II trial evaluating the efficacy of postoperative SRS to the surgical cavity found an overall 1-year LC rate of 85%. Within this cohort, the cavities resulting from a preoperative lesion >3 cm had elevated 1-year LR rates of 39%, whereas cavities with a preoperative lesion <3 cm had a 1-year LR rate of 7.5%.9 This trend toward decreased LC with larger tumors was also demonstrated in a recently presented phase III prospective randomized trial comparing postoperative SRS with observation for resected BMs.3 Cavities with a preoperative lesion 2.5 cm had a 1-year LR of 9%, and cavities with a preoperative lesion 2.6 cm had a 1-year LR rate of 57%. We evaluated lesion and cavity dynamics stratified by preoperative lesion size. The volumes of cavities resulting from preoperative lesions 3 cm were significantly smaller than the preoperative tumor volume (median volumetric decrease of 58.5%), whereas preoperative lesions <3 cm had associated cavities that were only minimally smaller than the preoperative tumor volume (median volumetric decrease of 8.6%). This demonstrates that some large lesions may result in cavities highly amenable to SRS, whereas small tumors are associated with cavities more reliably similar to the preoperative tumor size. Three studies have been published examining how surgical cavities evolve over time and if this change should influence timing of SRS. One series reviewed 68 cavities from 63 patients treated with surgical resection and postoperative SRS.14 Similar to our results, the authors found no association between time from surgery and cavity volume change, suggesting that the cavity volume did not significantly change during the time range examined (0e33 days). Therefore, they suggested there is no benefit to delaying SRS longer than 1e2 weeks after surgery. Another analysis of 41 patients demonstrated that 47% of cavities remained stable (defined as a change of <2 cm3 between immediate postoperative cavity volume and SRS cavity volume), whereas 23% of cavities decreased in size >2 cm3, and 30% of cavities increased in size by >2 cm3.15 The authors
E4
Percent Cavity Change from Vpostop to VSRS
Percent Cavity Change from Vpostop to VSRS
RAJAL A. PATEL ET AL.
www.SCIENCEDIRECT.com
Immediate Postoperave Cavity Volume in mL (Vpostop)
Figure 2. Percent cavity change based on immediate postoperative cavity volume. Vpostop, immediate postoperative cavity volume; VSRS, cavity volume at time of stereotactic radiosurgery.
concluded that delaying SRS after surgery does not offer the benefit of cavity collapse in most patients, and most cavities remain stable or increase in size. Our results further support these conclusions. Finally, Shah et al.16 conducted a review of 21 patients; median time between imaging was longer than other series at 39 days. Of 21 cavities, 19 decreased in size, with a mean reduction of 43%. The authors also found significantly greater cavity constriction for patients with >1 month to time of SRS imaging (mean 61% reduction in volume) compared with patients with <1 month to time of SRS imaging. Eleven patients (52%) had evidence of tumor progression within the resection cavity. Despite this concerning finding, the authors advocated for delaying SRS for >1 month to allow for cavity constriction. We found that most cavities increased in size from postoperative MRI to the time of SRS with a median volumetric cavity increase of 28%. In our series of 85 cavities, 40% of cavities increased >2 cm3, and 51% of cavities remained within 2 cm3 of their postoperative volume. The increase in cavity volume over time is contrary to our initial hypothesis and counterintuitive. A reduction in surrounding parenchymal edema may contribute to the increasing cavity volume in the majority of cavities, whereas the minority of cavities that decreased in size may be related to ongoing decompression of the normal brain parenchyma. Compared with the findings of Atalar et al.14 and Jarvis et al.,15 we observed a greater percentage of cavities to have enlarged in the interval between postresection imaging and the time of SRS. In contrast to the study by Shah et al.,16 significant cavity constriction was not demonstrated. Growing cavity size argues against delaying SRS to our median treatment time of 3 weeks, as larger cavities may be less amenable to adequate dose delivery. Furthermore, delaying SRS may lead to higher rates of gross tumor recurrence before SRS (as in the Shah et al. study16), which may compromise local control further. A previous review of patients undergoing postoperative SRS for BM resection demonstrated significantly increased LR rates when postoperative SRS was extended beyond 3 weeks time.17
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2017.10.159
ORIGINAL ARTICLE RAJAL A. PATEL ET AL.
CAVITY DYNAMICS BEFORE POSTOPERATIVE RADIOSURGERY
Our findings suggest that the largest decrease in target volume occurs as a result of surgical intervention. However, after resection, there is overall cavity growth, with small postoperative cavities experiencing the most percentage growth and large postoperative cavities experiencing minimal cavity volume change. This finding highlights the likely futility in hoping that large cavities will significantly collapse over time and become better radiosurgery targets. This study was inherently limited by its retrospective nature with all patients treated at a single center. The interval between resection and postoperative SRS was neither uniform nor predefined in our patient population. Similar to the other 3 studies examining this issue, MRI was performed postoperatively and at the time of SRS only; MRI scans in the intervening period would
REFERENCES 1. 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. 2. Kocher M, Soffietti R, Abacioglu U, Villà S, Fauchon F, Baumert BG, et al. Adjuvant wholebrain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol. 2011;29:134-141. 3. Mahajan A, Ahmed S, Li J, McAleer MF, Weinberg J, Brown PD, et al. Postoperative stereotactic radiosurgery versus observation for completely resected brain metastases: results of a prospective randomized study. Int J Radiat Oncol Biol Phys. 2016;96(2 suppl):S2. 4. Patchell RA, Tibbs PA, Regine WF, Dempsey RJ, Mohiuddin M, Kryscio RJ, et al. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA. 1998;280: 1485-1489. 5. Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth DG, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. 2009;10: 1037-1044.
more fully elucidate the timing of cavity evolution and could be the focus of further prospective efforts. CONCLUSIONS Cavity size after BM resection increased a median of 28% from the immediate postoperative period to the time of SRS. Larger postoperative cavities had less volumetric change compared with smaller cavities. Greater than 90% of postoperative cavities either increased >2 cm3 or remained within 2 cm3 of their immediate postoperative cavity volume. Postoperative SRS within 2e3 weeks may be appropriate, as delaying postoperative treatment beyond 3 weeks in hopes of significant cavity contraction is not supported by this analysis.
Appropriateness Criteria: single brain metastasis. Curr Probl Cancer. 2010;34:162-174. 8. Aoyama H, Tago M, Kato N, Toyoda T, Kenjyo M, Hirota S, et al. Neurocognitive function of patients with brain metastasis who received either whole brain radiotherapy plus stereotactic radiosurgery or radiosurgery alone. Int J Radiat Oncol Biol Phys. 2007;68:1388-1395.
15. Jarvis LA, Simmons NE, Bellerive M, Erkmen K, Eskey CJ, Gladstone DJ, et al. Tumor bed dynamics after surgical resection of brain metastases: implications for postoperative radiosurgery. Int J Radiat Oncol Biol Phys. 2012;84:943-948.
9. Brennan C, Yang TJ, Hilden P, Zhang Z, Chan K, Yamada Y, et al. A phase 2 trial of stereotactic radiosurgery boost after surgical resection for brain metastases. Int J Radiat Oncol Biol Phys. 2014; 88:130-136.
16. Shah JK, Potts MB, Sneed PK, Aghi MK, McDermott MW. Surgical cavity constriction and local progression between resection and adjuvant radiosurgery for brain metastases. Cureus. 2016;8: e575.
10. Hartford AC, Paravati AJ, Spire WJ, Li Z, Jarvis LA, Fadul CE, et al. Postoperative stereotactic radiosurgery without whole-brain radiation therapy for brain metastases: potential role of preoperative tumor size. Int J Radiat Oncol Biol Phys. 2013;85: 650-655.
17. Iorio-Morin C, Masson-Côté L, Ezahr Y, Blanchard J, Ebacher A, Mathieu D. Early Gamma Knife stereotactic radiosurgery to the tumor bed of resected brain metastasis for improved local control. J Neurosurg. 2014;121:69-74.
11. Jensen CA, Chan MD, McCoy TP, Bourland JD, deGuzman AF, Ellis TL, et al. Cavity-directed radiosurgery as adjuvant therapy after resection of a brain metastasis. J Neurosurg. 2011;114:1585-1591.
Conflict of interest statement: T.J. Kruser has served as a consultant for Varian Medical Systems, Inc., and on an advisory board for Abbvie Inc. Neither of these relationships pertains to this manuscript. The other authors have no conflict of interest to disclose. Abstract was presented at the American Society of Radiation Oncology Annual Meeting, September 24e27, 2017, in San Diego, California.
12. Eaton BR, LaRiviere MJ, Kim S, Prabhu RS, Patel K, Kandula S, et al. Hypofractionated radiosurgery has a better safety profile than single fraction radiosurgery for large resected brain metastases. J Neurooncol. 2015;123:103-111.
6. Tsao M, Xu W, Sahgal A. A meta-analysis evaluating stereotactic radiosurgery, whole-brain radiotherapy, or both for patients presenting with a limited number of brain metastases. Cancer. 2012;118:2486-2493.
13. Brown PD, Ballman KV, Cerhan J, Anderson SK, Carrero XW, Whitton AC, et al. N107C/CEC.3: a phase III trial of post-operative stereotactic radiosurgery (SRS) compared with whole brain radiotherapy (WBRT) for resected metastatic brain disease. Int J Radiat Oncol Biol Phys. 2016;96:937.
7. Suh JH, Videtic GM, Aref AM, Germano I, Goldsmith BJ, Imperato JP, et al. ACR
14. Atalar B, Choi CY, Harsh GR 4th, Chang SD, Gibbs IC, Adler JR, et al. Cavity volume dynamics
WORLD NEUROSURGERY -: ---, - 2017
after resection of brain metastases and timing of postresection cavity stereotactic radiosurgery. Neurosurgery. 2013;72:180-185 [discussion: 185].
Received 29 June 2017; accepted 28 October 2017 Citation: World Neurosurg. (2017). https://doi.org/10.1016/j.wneu.2017.10.159 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2017 Elsevier Inc. All rights reserved.
www.WORLDNEUROSURGERY.org
E5