Discovery of additional brain metastases on the day of stereotactic radiosurgery: risk factors and outcomes

CLINICAL ARTICLE J Neurosurg 126:1756 1763, 2017 Discovery of additional brain metastases on the day of stereotactic radiosurgery: risk factors and outcomes Michael A. Garcia, MD, MS, 1 Ann Lazar, PhD, MS, 2 Sai Duriseti, PhD, MD, 1 David R. Raleigh, MD, PhD, 1 Christopher P. Hess, MD, PhD, 3,4 Shannon E. Fogh, MD, 1 Igor J. Barani, MD, 1 Jean L. Nakamura, MD, 1 David A. Larson, MD, PhD, 1 Philip Theodosopoulos, MD, 5 Michael McDermott, MD, 5 Penny K. Sneed, MD, 1 and Steve Braunstein, MD, PhD 1 Departments of 1 Radiation Oncology, 2 Epidemiology and Biostatistics, 3 Radiology & Biomedical Imaging, 4 Neurology, and 5 Neurological Surgery, University of California, San Francisco, California OBJECTIVE High-resolution double-dose gadolinium-enhanced Gamma Knife (GK) radiosurgery-planning MRI (GK MRI) on the day of GK treatment can detect additional brain metastases undiagnosed on the prior diagnostic MRI scan (dmri), revealing increased intracranial disease burden on the day of radiosurgery, and potentially necessitating a reevaluation of appropriate management. The authors identified factors associated with detecting additional metastases on GK MRI and investigated the relationship between detection of additional metastases and postradiosurgery patient outcomes. METHODS The authors identified 326 patients who received GK radiosurgery at their institution from 2010 through 2013 and had a prior dmri available for comparison of numbers of brain metastases. Factors predictive of additional brain metastases on GK MRI were investigated using logistic regression analysis. Overall survival was estimated by Kaplan-Meier method, and postradiosurgery distant intracranial failure was estimated by cumulative incidence measures. Multivariable Cox proportional hazards model and Fine-Gray regression modeling assessed potential risk factors of overall survival and distant intracranial failure, respectively. RESULTS The mean numbers of brain metastases (SD) on dmri and GK MRI were 3.4 (4.2) and 5.8 (7.7), respectively, and additional brain metastases were found on GK MRI in 48.9% of patients. Frequencies of detecting additional metastases for patients with 1, 2, 3 4, and more than 4 brain metastases on dmri were 29.5%, 47.9%, 55.9%, and 79.4%, respectively (p < 0.001). An index brain metastasis with a diameter greater than 1 cm on dmri was inversely associated with detecting additional brain metastases, with an adjusted odds ratio of 0.57 (95% CI 0.4 0.9, p = 0.02). The median time between dmri and GK MRI was 22 days (range 1 88 days), and time between scans was not associated with detecting additional metastases. Patients with additional brain metastases did not have larger total radiosurgery target volumes, and they rarely had an immediate change in management (abortion of radiosurgery or addition of whole-brain radiation therapy) due to detection of additional metastases. Patients with additional metastases had a higher incidence of distant intracranial failure than those without additional metastases (p = 0.004), with an adjusted subdistribution hazard ratio of 1.4 (95% CI 1.0 2.0, p = 0.04). Significantly worse overall survival was not detected for patients with additional brain metastases on GK MRI (log-rank p = 0.07), with the relative adjusted hazard ratio of 1.07, (95% CI 0.81 1.41, p = 0.65). CONCLUSIONS Detecting additional brain metastases on GK MRI is strongly associated with the number of brain metastases on dmri and inversely associated with the size of the index brain metastasis. The discovery of additional brain metastases at time of GK radiosurgery is very unlikely to lead to aborting radiosurgery but is associated with a higher incidence of distant intracranial failure. However, there is not a significant difference in survival. CLASSIFICATION OF EVIDENCE Type of question: prognostic; study design: retrospective cohort trial; evidence: Class IV. https://thejns.org/doi/abs/10.3171/2016.4.jns152319 KEY WORDS brain metastases; stereotactic radiosurgery; MRI; distant intracranial failure; survival; gadolinium; oncology ABBREVIATIONS dmri = diagnostic MRI; GK = Gamma Knife; GK MRI = GK radiosurgery planning MRI; HR = hazard ratio; IRSPGR = inversion recovery spoiled gradient recalled; OR = odds ratio; SHR = subdistribution HR; SRS = stereotactic radiosurgery; UCSF = University of California, San Francisco; WBRT = whole-brain radiation therapy. SUBMITTED October 5, 2015. ACCEPTED April 14, 2016. INCLUDE WHEN CITING Published online July 1, 2016; DOI: 10.3171/2016.4.JNS152319. 1756 J Neurosurg Volume 126 June 2017 AANS, 2017

Discovering new brain metastases on day of radiosurgery Brain metastases are a significant cause of morbidity and mortality among cancer patients. 12,24 The incidence of brain metastases has risen over the past 2 decades, and this increase has been attributed to increased utilization of brain MRI, 1,15 improved systemic oncological therapies, 20 and a rise in incidence of cancer diagnoses in an aging population. 21,27 Advancements in MRI technology and the development of specific protocols aimed at detecting brain metastases have led to improved diagnostic sensitivity and quantification of brain metastases. 10,25,26 The specific number of brain metastases on diagnostic MRI (dmri) impacts management approaches and the potential treatment-associated toxicities. 23 Stereotactic radiosurgery (SRS), is widely used for the primary treatment of a limited number of brain metastases and in the salvage setting after wholebrain radiation. 3,12,14,22 Over the last decade it has become more common to use SRS alone as the up-front therapy for more extensive intracranial disease (greater than 4 brain metastases), although this practice remains controversial. 4,18,19 Prospective data suggest that the use of SRS for 5 10 brain metastases is not associated with worse overall survival compared with SRS for 2 4 metastases. 28 An advantage of Gamma Knife SRS is the ability to quantify intracranial disease burden on the day of SRS on the basis of frame-fixed Gamma Knife (GK) planning MRI (GK MRI). The utilization of high-resolution thinsliced GK MRI, delayed administration of contrast agent, and use of a greater dose of contrast agent have all led to greater sensitivity for the detection of brain metastases. 5,10,13,25,29 The identification of additional intracranial disease on the day of SRS can pose a management dilemma and possibly lead to aborting SRS in favor of wholebrain radiation therapy (WBRT). Three studies reviewing cases from the 1990s and early 2000s demonstrated that patients with multiple brain metastases identified on dmri are at risk for having additional metastases discovered on GK MRI, 5,6,16 although the majority of patients in these studies had a low intracranial disease burden (1 2 brain metastases) on dmri. At our institution, we commonly perform GK SRS for patients referred with multiple brain metastases on dmri. Here, we report our experience with finding additional brain metastases on GK MRI in the modern radiosurgical era (reviewing cases involving patients treated from 2010 through 2013). We describe patient characteristics associated with the discovery of additional brain metastases at the time of GK SRS, as well as the potential impact of additional metastases on distant intracranial failure and overall survival. Methods Patients We retrospectively reviewed 350 consecutive cases involving patients treated with GK SRS for brain metastases at the University of California, San Francisco (UCSF), from January 2010 through December 2013. All SRS procedures were performed using the Perfexion Leksell GK system. Of the 350 patients, 326 had a GK MRI with double-dose gadolinium (0.2 mmol/kg gadopentetate dimeglumine, Magnevist) as well as a prior dmri with single-dose CLASSIFICATION OF EVIDENCE Type of Question Prognostic Study Design Retrospective Cohort Trial Evidence Class IV Garcia and colleagues present data from a single-institution, retrospective cohort study describing an association between number of brain metastases on the initial diagnostic brain MRI scan (dmri), and detecting additional brain metastases on the Gamma Knife planning MRI (GK MRI). This study provides Class IV evidence that detecting additional brain metastases on the GK MRI is strongly associated with increasing numbers of brain metastases on the original dmri and is weakly and inversely associated with size of the largest brain metastasis on the dmri > 1 cm. The authors found no association between overall survival and the detection of additional brain metastases on the GK MRI, but the study was underpowered to detect such a difference. The authors also ask a prognostic question about whether the detection of additional brain metastases on the GK MRI is associated with poorer overall survival. No such association was demonstrated, but the study was underpowered to detect such a difference. For this latter question, the authors study possesses nearly all of the characteristics of a high-quality prognostic trial (clearly and prospectively defined primary outcome and inclusion and exclusion criteria, a broad spectrum of patients, at least 80% of patients for whom both the risk factor and the outcome are measured). Multivariate analysis was used to account for differences between groups, and the outcome measure (survival) is largely objective, making the lack of masked assessment less critical. Thus, even though data collection was retrospective, with respect to this question, the authors study provides Class II evidence and illustrates that a single study can ask multiple questions (even different types of questions therapeutic, diagnostic, prognostic) and provide different levels of evidence for each. gadolinium (0.1 mmol/kg gadolinium) available for comparison of numbers of metastases (24 of the 350 patients either had no dmri, had CT-based SRS planning due to MRI contraindication, or received single-dose gadolinium due to renal impairment). Patient baseline characteristics (including age, sex, cancer histology, performance status, prognosis based on the Graded Prognostic Assessment, number of metastases identified on the dmri and GK MRI scans, and total volume of metastases treated) were recorded from the radiation oncologists consultation notes, the referring providers notes, and GK SRS procedure notes. Clinical follow-up data were available for 268 patients. Imaging follow-up data (radiology reports for brain MRI scans from UCSF and outside institutions) were available for 238 patients. Vital status was known for 317 patients. All patients provided informed consent for treatment, and this retrospective review was approved by our institutional review board. Diagnostic MRI At our institution, all patients who are referred for consideration for GK SRS are screened for appropriateness of J Neurosurg Volume 126 June 2017 1757

M. A. Garcia et al. SRS at a multidisciplinary GK conference, during which the images and report from the most recent dmri are reviewed by members of the neuroradiology, neurosurgery, and radiation oncology services. It is during this conference that the number of brain metastases is agreed upon and is documented in the radiation oncology consultation note. The numbers of metastases on dmri were gathered from these consultation notes. In addition, radiology reports were reviewed to acquire technical MRI protocol data. All patients had dmri with T1- and T2-weighted sequences and a single dose of gadolinium for contrast enhancement. MRI field strength (1.5 T or 3 T) and slice thickness were recorded. In the case of postoperative resection cavity SRS (13.4%), the resection cavity or cavities were counted as individual metastases. The index lesion was defined as the largest brain metastasis on the dmri scan. MRI for GK SRS Planning The GK MRI was performed after a neurological surgeon placed a Leksell stereotactic frame under local anesthesia. The MRI was performed using a 1.5- or 3-T scanner. A double dose of gadopentetate dimeglumine (0.2 mmol/kg body weight) was administered intravenously 10 minutes before acquisition of a 3D coronal inversion recovery spoiled gradient recalled (IRSPGR) acquisition sequence with 1.5 mm 1.2 mm 1.1 mm voxels (TR 34 msec, TE 4.7 msec, FOV 30 22 mm, matrix 256 192, flip angle 70, 1.5 mm slices, scan time 7 10 minutes). The axial and coronal postcontrast IRSPGR images were used to determine the number of brain metastases and SRS target delineation in all cases. After acquisition of the GK MRI, a neuroradiologist, neurological surgeon, and radiation oncologist compared the images from the GK MRI to the dmri and agreed on the final number of metastases to be targeted by SRS. The final number of metastases was used to determine whether additional brain metastases were present on GK MRI as compared with preradiosurgery dmri. Gamma Knife SRS Procedure All patients were treated with single-fraction GK SRS. Electronic SRS treatment summaries and operative reports were accessed on our institution s electronic medical record system to record volumetric measurements of all SRS-treated brain metastases, number of metastases treated, and treatment-related decisions made at time of GK SRS (including proceeding with SRS, aborting the procedure if the intracranial disease burden was determined to be unacceptably high, or treating just a subset of metastases with subsequent WBRT). Statistics Logistic regression analyses of detection of additional brain metastases on GK MRI were generated to assess the association with baseline patient characteristics prior to SRS treatment among the 326 available cases. Odds ratios (ORs) and corresponding 95% confidence intervals for each baseline patient characteristic were assessed for statistical significance based on a univariate logistic regression analysis. The 2 factors that were statistically significant on univariate analysis were number of brain metastases on dmri and size of the index brain metastasis on dmri. Thus, multivariable logistic regression analyses were conducted to evaluate the relationships of these 2 factors with detection of additional brain metastases, controlling for each as a potential confounder. A paired 2-sample t-test was used to compare the mean number of brain metastases on dmri with the mean number of metastases treated by SRS, pairing dmri and the GK MRI brain metastasis count of each patient. An endpoint of this investigation was post-srs freedom from distant intracranial failure (developing new brain metastases outside the previous SRS target volumes). All 238 patients who had brain MRI imaging follow-up were included in this analysis. Time to distant intracranial failure was defined as the time from the first SRS at UCSF until distant intracranial failure, the event of interest, or death (all causes), a competing event. Patients were censored at the end of brain MRI follow-up. Cumulative incidence curves were plotted and compared by the detection of additional brain metastases using Gray s test. 7,8 The Fine and Gray competing-risks regression model was used to assess each potential risk factor individually. The final model was developed by including all of the risk factors that were statistically significant in the univariate analysis. These included detection of additional brain metastases, number of brain metastases on the dmri, systemic disease burden (no extracranial disease, controlled extracranial disease, or uncontrolled extracranial disease), Graded Prognostic Assessment prognosis, and prior intracranial treatment (surgery, SRS, WBRT). The subdistribution hazard ratio (SHR) and corresponding 95% CI from the multivariable Fine and Gray 7 model are presented. Overall survival was also an endpoint considered among the 317 patients with known vital status. Overall survival was defined as the time from the first SRS at UCSF until the date of death. Patients were censored at time of last clinic follow-up or last brain MRI, whichever came last. Kaplan-Meier curves were plotted and compared by the detection of additional brain metastases using a log-rank test. Cox proportional hazards models assessed each potential factor individually, and the identified factors that reached statistical significance (detection of additional brain metastases, systemic disease burden, number of brain metastases on dmri, and SRS treatment volume) were included in the multivariable model. The adjusted hazard ratio (HR) and corresponding 95% CI are presented from this multivariable model. The proportional hazards assumption was assessed using a standard approach based on the Cox extended model (i.e., time-dependent covariates). The R CRAN cmprsk package and SAS version 9.4 were used to generate the analyses, and 2-sided p values less than 0.05 were considered statistically significant. Results Patient Baseline Characteristics We identified 326 patients with 1531 brain metastases treated at UCSF with GK SRS from January 2010 through December 2013 who had both a GK MRI and prior dmri scan for comparison of numbers of brain metastases. The median time between the dmri and GK MRI scans was 22 days (range 1 88 days). The median patient age was 1758 J Neurosurg Volume 126 June 2017

Discovering new brain metastases on day of radiosurgery 60.7 years (range 23.0 97.7 years). At SRS consultation, 35.8% of patients had neurological symptoms. Extracranial metastases were present in 82.8% of patients, and the primary tumor was controlled in 71.5%. The majority of patients (60.4%) had no prior intracranial treatment before their SRS treatment at our institution, and the remainder had either single or multimodality intracranial treatment, including 21.5% with prior resection, 16.3% with previous WBRT, and 8.0% with linear accelerator based SRS or SRS performed outside our institution. Baseline patient characteristics at the time of SRS are summarized in Table 1. The most common cancer histologies were non small cell lung cancer (33.4%), breast (24.2%), melanoma (21.8%), and renal cell carcinoma (5.2%). Detection of Additional Brain Metastases on GK MRI Among all patients, additional brain metastases were discovered at a frequency of 48.9% on GK MRI, and detection of additional metastases did not vary among the different histological cancer subtypes. The mean volume of new brain metastases discovered on GK MRI was 0.08 cm 3 (range 0.01 1.41 cm 3 ). The frequencies of detecting additional brain metastases for patients with 1, 2, 3 4, and more than 4 brain metastases on dmri were 29.5%, 47.9%, 55.9%, and 79.4%, respectively (adjusted OR 1.28, 95% CI 1.16 1.42, p < 0.001) (Fig. 1 upper). An index brain metastasis larger than 1 cm in diameter on dmri was inversely associated with detecting additional brain metastases (adjusted OR 0.57, 95% CI 0.36 0.91, p = 0.017) (Fig. 1 lower). The length of time between scans was not associated with additional brain metastases on GK MRI (p = 0.47), even among patients with extracranial metastases (p = 0.6) and uncontrolled primary tumors (p = 0.4). Other factors not found to be associated with detecting additional brain metastases included prior intracranial therapies (including WBRT, resection, or SRS), prior or current systemic therapies, dmri slice thickness, and dmri field strength (Table 2). Impact of Additional Brain Metastases on SRS Management and Outcome Significantly more metastases were targeted with SRS than would have been anticipated by the dmri, with the mean number (SD) of metastases targeted by SRS being 4.68 (5.61) compared with 3.38 metastases (4.23) seen on dmri (mean difference 1.30, 95% CI 0.53 2.06, p < 0.001). However, patients with additional brain metastases did not have a significantly larger mean total SRS-target volume compared with patients without additional brain metastases (5.4 vs 4.5 cm 3, p = 0.22). There were no cases of leptomeningeal disease diagnosed on GK MRI. No new neurological symptoms could be attributed to the finding of new brain metastases on GK MRI. A total of 4 patients developed new neurological symptoms within the time interval between dmri and GK MRI. Of these patients, 3 developed headaches and 1 had a short episode of wordfinding difficulty. All new brain metastases among these 4 patients were under 1 cm 3. None of these lesions were associated with new edema on the GK MRI. The patient with the episode of word-finding difficulty had 1 new TABLE 1. Patient characteristics at GK SRS consultation Characteristic Value* Total no. of patients 326 Patient age Median, yrs (range) 60.7 (23.0 97.7) <40 27 (8.2) 40 59 119 (36.5) 60 69 112 (34.4) 70 68 (20.9) Sex Male 142 (43.6) Female 184 (56.4) Prognosis based on Graded Prognostic Assessment 3 5 mos 88 (26.9) 6 8 mos 126 (38.7) 9 11 mos 40 (12.3) 12 14 mos 15 (4.6) 15 mos 26 (7.9) Unknown 31 (9.5) Extracranial metastases Yes 270 (82.8) No 55 (16.9) Unknown 4 (0.3) Primary tumor controlled Yes 233 (71.5) No 92 (28.2) Unknown 1 (0.3) Neurological symptoms Yes 117 (35.8) No 206 (63.2) Unknown 3 (0.9) Prior WBRT Yes 53 (16.3) No 273 (83.7) Systemic therapy at time of radiosurgical consultation Yes 116 (35.6) No 207 (63.5) Unknown 3 (0.9) Prior brain metastasis resection Yes 70 (21.5) No 256 (78.5) Prior radiosurgery Yes 26 (8.0) No 300 (92.0) * Values are number of patients (%) unless otherwise indicated. brain metastasis in the superior right frontal lobe measuring 0.08 cm 3. Among the 159 patients who were found to have additional brain metastases, 1 patient had an increase of more than 3-fold (from 6 to 20) in the number of brain metas- J Neurosurg Volume 126 June 2017 1759

M. A. Garcia et al. FIG. 1. Frequency of detecting additional brain metastases (abm) on the GK MRI scan is associated with the number of brain metastases on dmri (upper) and inversely associated with the size of the index brain metastasis on dmri (lower). Error bars represent 95% confidence intervals. tases detected on GK MRI, and GK SRS was aborted in favor of WBRT in this case. Four patients with additional brain metastases had only a subset of the detected brain metastases treated by SRS and subsequently underwent WBRT. The median duration of imaging follow-up was 13.2 months (range 0.6 57.0 months). Patients with additional metastases on GK MRI had a higher incidence of distant intracranial failure compared with those without additional metastases (p = 0.004, Fig. 2), with an adjusted SHR of 1.4 (95% CI 1.0 1.9, p = 0.04). The median overall survival among all patients was 10.6 months. Overall survival following SRS for patients with additional brain metastases detected on GK MRI was 8.4 months compared with 12.6 months if no additional metastases were detected, although the log-rank test (p = 0.07) and adjusted HR of 1.07 (95% CI 0.81 1.41, p = 0.65) did not indicate a statistically significant difference (Fig. 3). Discussion Growing evidence demonstrates the feasibility and toxicity advantages of SRS alone, omitting WBRT, for patients with a limited number of brain metastases both after diagnosis 2,3,9,17,22 and in the salvage setting. 19 There is also interest in using SRS alone for more extensive intracranial disease. 18 Recent prospective data from Yamamoto and colleagues show that survival of patients treated with SRS TABLE 2. Odds ratios for detection of additional brain metastases Characteristic OR (95% CI)* p Value Patient age (per yr) 1.0 (0.98 1.02) 0.80 Male sex 1.62 (0.99 2.7) 0.06 Extracranial metastases present 1.40 (0.78 2.5) 0.26 Neurological symptoms present 0.87 (0.55 1.36) 0.53 Prior WBRT delivered 1.45 (0.8 2.6) 0.22 Primary tumor controlled 0.91 (0.56 1.47) 0.69 Systemic therapy at time of SRS 1.17 (0.73 1.86) 0.52 Prior brain metastasis resection 0.63 (0.37 1.09) 0.10 Prior SRS delivered 2.10 (0.9 4.8) 0.09 Time btwn dmri & GK MRI (per day) 0.99 (0.98 1.01) 0.47 Index metastasis on dmri >1 cm 0.57 (0.36 0.91) 0.017 No. of metastases on dmri (per metastasis) 1.28 (1.16 1.42) 0.001 * ORs (95% CIs) are based on univariate logistic regression analysis of additional brain metastases. Boldface type indicates statistical significance. Adjusted OR. without WBRT for 5 10 brain metastases is similar to the survival of those treated for 2 4 metastases. 28 Three studies reviewing low-intracranial-disease-burden cases involving patients with mean numbers of brain metastases of 1 and 2 on dmri who were treated with SRS between 1998 and 2006 found that a higher number of brain metastases on dmri is associated with more risk of additional brain metastases at SRS. 5,6,16 Detection of additional metastases on the day of SRS can impact radiosurgical management, and patients are counseled on the possibility of aborting SRS in favor of WBRT. As there appears to be a shift toward treating a higher number of metastases by SRS without WBRT over the past decade, 4,18 we sought to identify risk factors for detecting additional brain metastases in the modern radiosurgical setting. To our knowledge, the present study is the first to investigate the impact that additional brain metastases on GK MRI may have on radiosurgical management and distant intracranial failure. Risk Factors for Detecting Additional Brain Metastases Our patients had a mean of 3.4 brain metastases on dmri scan, more than the patients in the studies by Donahue, 5 Patel, 16 and Engh. 6 Additional brain metastases were detected in 48.9% of our patients at SRS. Our data corroborate that the number of brain metastases identified on dmri is strongly associated with detecting additional metastases at SRS, and we show an 80% risk of discovering additional metastases at the time of SRS for patients with 5 or more brain metastases identified on dmri. The length of time between dmri and GK MRI was not associated with detecting additional brain metastases, which was also shown by Engh et al. 6 Furthermore, in our study the presence of extracranial metastasis, uncontrolled primary tumor, and concurrent systemic therapy was not associated with detecting additional brain metastases. Considering these findings together, it is more likely that MRI technique differences between the dmri 1760 J Neurosurg Volume 126 June 2017

Discovering new brain metastases on day of radiosurgery FIG. 2. Distant intracranial failure with death as a competing risk. Patients with additional brain metastases (abm detected) and patients with no additional brain metastases (no abm detected) are listed with number of events; distant intracranial failure (DF) or death. Patients were censored at last brain MRI if distant intracranial failure or death did not occur. *A total of 13 patients with additional brain metastases detected were censored. **A total of 21 patients without additional brain metastases detected were censored. Figure is available in color online only. and GK MRI account for detection of a greater number of brain metastases on the day of SRS rather than metastatic seeding during the relatively short period between dmri and GK MRI scans. Thinner slice thickness 13 and a higher dosage of gadolinium 25 are established techniques for increasing sensitivity of brain metastases at the time of SRS, and we employ both of these methods at our institution. In addition, Kushnirsky and colleagues recently showed improved sensitivity of brain metastasis detection with delayed contrast enhancement (10 15 minutes). 10 All patients in our study received delayed contrast enhancement (10 minutes) as part of our GK MRI institutional protocol. The combination of thin slice thickness, double-dose gadolinium, and delayed contrast enhancement likely contributes to the high frequency of additional brain metastases detected within our patient cohort. Of note, the numbers of brain metastases on both the dmri and GK MRI were determined using a multidisciplinary approach with mem- FIG. 3. Kaplan-Meier results for overall survival stratified by additional brain metastases (abm detected) versus no additional brain metastases (no abm detected). Figure is available in color online only. J Neurosurg Volume 126 June 2017 1761

M. A. Garcia et al. bers of the neuroradiology, neurosurgery, and radiation oncology services as part of our institutional radiosurgical workflow. We are the first to show that a larger index brain metastasis on dmri is associated with decreased frequency of detecting additional brain metastases. This is somewhat of a surprising finding for which we do not yet have a biological explanation. It is possible that patients with larger and fewer brain metastases have good systemic disease control, established after initial metastatic seeding of the brain. However, systemic therapy and disease control were not associated with a lower rate of detecting additional brain metastases. The clinical significance of the inverse relationship between brain metastasis size and the detection of additional brain metastases at SRS is uncertain. But, there may be added confidence that a patient with a single brain metastasis greater than 1 cm in diameter may have a lower risk of having additional metastases discovered at the time of SRS. Our patient population included patients with diverse cancer histological types, with the most common being non small cell lung cancer, breast cancer, melanoma, and renal cell carcinoma. Histology was not associated with detection of additional metastases on GK MRI. This is in contrast to the findings of Engh and colleagues, who demonstrated a higher risk of detecting new metastases for patients with non small cell lung cancer (frequency of 37%) and a low risker for those with melanoma (0 of 11 patients). 6 Our cohort included a larger proportion of patients known to have more than 1 brain metastasis before the GK MRI, which appears to put patients with all histological tumor types at such a higher risk of detection of new brain metastases (49% in our patient cohort compared with 29% in the study by Engh et al.) that differences among histological types may no longer be significant. We did not evaluate the specific molecular subtypes within each primary tumor histological type, but it is important to note that some molecular subtypes may play a role in intracranial disease course as well as in the response to targeted systemic therapies. 11 However, our data do not suggest that imaging findings at SRS or patient outcomes after treatment differ among groups of patients with different tumor histological types. Impact of Additional Brain Metastases on Radiosurgical Management Although additional brain metastases were detected in nearly half of our patients (n = 159), only 1 case was aborted in favor of whole-brain radiation. Four other patients had WBRT added to their disease management due to a large increase in brain metastases. The mean total target volume was not significantly different among patients with and without additional metastases detected on GK MRI. Though patients with multiple brain metastases on dmri should be counseled on the high likelihood of finding additional brain metastases, our findings indicate that detection of additional metastases is very unlikely to change management on the day of SRS. Indeed, the management of multiple brain metastases discovered at the time of SRS varies depending on institutional criteria and practice. In general, at our institution we tend to abort the procedure in favor of WBRT if there is a doubling in the number of metastases resulting in more than 20 brain metastases in a patient with no prior WBRT. Impact of Additional Brain Metastases on Distant Intracranial Failure and Overall Survival To our knowledge, this study is the first to evaluate distant intracranial failure among patients with additional brain metastases detected at SRS. Using the adjusted model to control for intracranial and systemic disease burden, patients with additional metastases at SRS had a higher incidence of distant intracranial failure than patients without additional metastases. It may be that finding additional brain metastases represents a high state of intracranial disease burden, such that there is a high probability of intracranial microscopic metastases not captured by the high-resolution GK MRI scan, which cannot be targeted radiosurgically. Undetectable microscopic disease is a possible explanation for the fact that randomized trials have shown improved distant intracranial failure with adding WBRT to SRS, 2,9 although the lack of survival benefit seen in these trials, along with added neurocognitive toxicity, 3 argues against the addition of WBRT. 18 Patel and colleagues showed worse survival among patients with additional metastases on GK MRI (median survival of 12.1 months if no additional metastases vs 6.9 months if additional metastases). 16 Although patients in our cohort had a higher intracranial disease burden (a mean of 3.4 brain metastases on dmri vs 1 in Patel s study), we did not detect a statistically significant overall survival difference even with a larger sample size (317 vs 133 patients). The median duration of survival among patients found to have additional brain metastases at SRS was 8.4 months compared with 12.6 months among patients without additional metastases, but this difference was not statistically significant after adjusting for intracranial and systemic disease burden. Other baseline patient characteristics were similar, although our cohort included a few patients with a Karnofsky Performance Status score lower than 70 (Patel excluded these patients). The lack of overall survival difference may be due to improvements in systemic therapies 11 and intracranial salvage therapies over the last 2 decades. Study Limitations The limitations of our study include the inherent selection bias present in all single-institution retrospective studies. All patients treated with SRS at our institution are screened at a multidisciplinary conference based on imaging, history, and performance status and thus likely represent a subpopulation of patients with brain metastases. However, the large numbers of patients (326) and treated brain metastases (1531) in our cohort adds to the generalizability for patients treated with radiosurgery for brain metastases. Conclusions A larger number of known brain metastases at the time of radiosurgical consultation is associated with a high probability of discovering additional brain metastases on the day of GK SRS, but this finding is very unlikely to result in aborting the procedure. Patients in whom additional brain metastases are detected have a higher incidence of distant 1762 J Neurosurg Volume 126 June 2017

Discovering new brain metastases on day of radiosurgery intracranial failure than patients without additional metastases. However, the lack of statistically significant impact on survival may support the use of radiosurgery without WBRT among patients with a larger number of brain metastases. References 1. Akeson P, Larsson EM, Kristoffersen DT, Jonsson E, Holtås S: Brain metastases comparison of gadodiamide injectionenhanced MR imaging at standard and high dose, contrastenhanced CT and non-contrast-enhanced MR imaging. Acta Radiol 36:300 306, 1995 2. Aoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Hatano K, et al: Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 295:2483 2491, 2006 3. 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Author Contributions Conception and design: Garcia, Braunstein. Acquisition of data: Garcia, Duriseti, Sneed, Braunstein. Analysis and interpretation of data: Garcia, Lazar, Raleigh, Hess, Nakamura, Larson, Sneed, Braunstein. Drafting the article: Garcia, Lazar, Duriseti, Raleigh, Hess, Sneed, Braunstein. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Garcia. Statistical analysis: Garcia, Lazar, Sneed, Braunstein. Administrative/technical/material support: Duriseti. Study supervision: Garcia, Sneed, Braunstein. Correspondence Michael A. Garcia, Department of Radiation Oncology, University of California, San Francisco, 1600 Divisadero St., Ste. H1031, San Francisco, CA 94143-1078. email: michael.garcia@ ucsf.edu. J Neurosurg Volume 126 June 2017 1763