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Charu Singh, Jack M. Qian, James B. Yu and Veronica L. Chiang

OBJECTIVE

Concurrent use of anti-PD-1 therapies with stereotactic radiosurgery (SRS) have been shown to be beneficial for survival and local lesional control in melanoma patients with brain metastases. It is not known, however, if immunotherapy (IT) confers the same outcome advantage in lung cancer patients with brain metastases treated with SRS.

METHODS

The authors retrospectively reviewed 85 non–small cell lung cancer (NSCLC) patients with brain metastases who were treated with SRS between January 2006 and December 2016. Thirty-nine PD-L1 antibody–positive patients received anti-PD-1 therapy with SRS (IT group) and 46 patients received chemotherapy (CT) with SRS (CT group). Results were obtained using chi-square, Kaplan-Meier, and Mann-Whitney U tests and Cox regression analyses.

RESULTS

Median survival following first radiosurgical treatment in the whole study group was 11.6 months (95% CI 8–15.5 months). Median survival times in the IT group and CT group were 10 months (95% CI 8.3–13.2 months) and 11.6 months (95% CI 7.7–15.6 months), respectively (p = 0.23). A Karnofsky Performance Status (KPS) score < 80 (p = 0.001) and lung-specific molecular marker Graded Prognostic Assessment (lungmol GPA) score < 1.5 (p = 0.02) were found to be predictive of worse survival.

Maximal percent lesional shrinkage and time to maximal shrinkage were not significantly different between the CT and IT groups. Of the lesions for which a complete response occurred, 94.8% had pre-SRS volumes < 500 mm3. The amount of lesion shrinkage and time to maximal shrinkage were not different between the IT and CT groups for lesions with volumes < 500 mm3. However, in lesions with volume > 500 mm3, 90% of lesions shrank after radiosurgery in the IT group compared with 47.8% in the CT group (p = 0.001). Median times to initial response and times to maximal shrinkage were faster in the IT group than in the CT group: initial response 49 days (95% CI 33.7–64.3 days) versus 84 days (95% CI 28.1–140 days), p = 0.001; maximal response 105 days (95% CI 59–150 days) versus 182 days (95% CI 119.6–244 days), p = 0.12.

CONCLUSIONS

Unlike patients with melanoma, patients with NSCLC with brain metastases undergoing SRS showed no significant benefit—either in terms of survival or total amount of lesional response—when anti-PD-1 therapies were used. However, in lesions with volume > 500 mm3, combining SRS with IT may result in a faster and better volumetric response which may be particularly beneficial in lesions causing mass effect or located in neurologically critical locations.

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Rovel J. Colaco, Pierre Martin, Harriet M. Kluger, James B. Yu and Veronica L. Chiang

OBJECT

Radiation necrosis (RN), or its imaging equivalent, treatment-related imaging changes (TRIC), is an inflammatory reaction to high-dose radiation in the brain. The authors sought to investigate the hypothesis that immunotherapy increases the risk of developing RN/TRIC after stereotactic Gamma Knife (GK) radiosurgery for brain metastases.

METHODS

A total of 180 patients who underwent GK surgery for brain metastases between 2006 and 2012 were studied. The systemic therapy they received was classified as cytotoxic chemotherapy (CT), targeted therapy (TT), or immunotherapy (IT). The timing of systemic therapy in relation to GK treatment was also recorded. Logistic regression was used to calculate the odds of developing RN according to type of systemic therapy received.

RESULTS

The median follow-up time was 11.7 months. Of 180 patients, 39 (21.7%) developed RN/TRIC. RN/TRIC rates were 37.5% (12 of 32) in patients who received IT alone, 16.9% (14 of 83) in those who received CT only, and 25.0% (5 of 20) in those who received TT only. Median overall survival was significantly longer in patients who developed RN/TRIC (23.7 vs 9.9 months, respectively). The RN/TRIC rate was increased significantly in patients who received IT alone (OR 2.40 [95% CI 1.06–5.44]; p = 0.03), whereas receipt of any CT was associated with a lower risk of RN/TRIC (OR 0.38 [95% CI 0.18–0.78]; p = 0.01). The timing of development of RN/TRIC was not different between patients who received IT and those who received CT.

CONCLUSIONS

Patients who receive IT alone may have an increased rate of RN/TRIC compared with those who receive CT or TT alone after stereotactic radiosurgery, whereas receiving any CT may in fact be protective against RN/TRIC. As the use of immunotherapies increases, the rate of RN/TRIC may be expected to increase compared with rates in the chemotherapy era.

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Veronica L. Chiang, Phillipe Gailloud, Kieran J. Murphy, Daniele Rigamonti and Rafael J. Tamargo

Object. The routine use of intraoperative angiography as an aid in the surgical treatment of aneurysms is uncommon. The advantages of the ability to visualize residual aneurysm or unintended occlusion of parent vessels intraoperatively must be weighed against the complications associated with repeated angiography and prolonged vascular access. The authors reviewed the results of their routine use of intraoperative angiography to determine its safety and efficacy.

Methods. Prospectively gathered data from all aneurysm cases treated surgically between January 1996 and June 2000 were reviewed. A total of 303 operations were performed in 284 patients with aneurysms; 24 patients also underwent postoperative angiography. Findings on intraoperative angiographic studies prompted reexploration and clip readjustment in 37 (11%) of the 337 aneurysms clipped. Angiography revealed parent vessel occlusion in 10 cases (3%), residual aneurysm in 22 cases (6.5%), and both residual lesion and parent vessel occlusion in five cases (1.5%). When compared with subsequent postoperative imaging, false-negative results were found on two intraoperative angiograms (8.3%) and a false-positive result was found on one (4.2%). Postoperative angiograms obtained in both false-negative cases revealed residual anterior communicating artery aneurysms. Both of these aneurysms also subsequently rebled, requiring reoperation. In the group that underwent intraoperative angiography, in 303 operations eight patients (2.6%) suffered complications, of which only one was neurological.

Conclusions. In the surgical treatment of intracranial aneurysms, the use of routine intraoperative angiography is safe and helpful in a significant number of cases, although it does not replace careful intraoperative inspection of the surgical field.

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Veronica L. Chiang, Michel Torbey, Daniele Rigamonti and Michael A. Williams

✓ The authors report an unusual case of a patient with low-pressure hydrocephalus and a ventriculopleural shunt, in whom routine respiratory management performed using positive-pressure ventilation caused shunt obstruction and coma. While the patient received positive-pressure ventilation with external cerebrospinal fluid (CSF) drainage at subatmospheric pressure, the ventricles returned to normal size and the coma rapidly reversed. After the authors' recognition of the effect of positive-pressure ventilation on intrapleural pressure and ventriculopleural shunt function, and the subsequent removal of positive-pressure ventilation, CSF flow through the shunt resumed and the patient's coma resolved.

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L. Dade Lunsford, Veronica Chiang, John R. Adler, Jason Sheehan, William Friedman and Douglas Kondziolka

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Henry S. Park, Elyn H. Wang, Charles E. Rutter, Christopher D. Corso, Veronica L. Chiang and James B. Yu

OBJECT

Single-fraction stereotactic radiosurgery (SRS) is a crucial component in the management of limited brain metastases from non-small cell lung cancer (NSCLC). Intracranial SRS has traditionally been delivered using a frame-based Gamma Knife (GK) platform, but stereotactic modifications to the linear accelerator (LINAC) have made an alternative approach possible. In the absence of definitive prospective trials comparing the efficacy and toxicities of treatment between the 2 techniques, nonclinical factors (such as technology accessibility, costs, and efficiency) may play a larger role in determining which radiosurgery system a facility may choose to install. To the authors’ knowledge, this study is the first to investigate national patterns of GK SRS versus LINAC SRS use and to determine which factors may be associated with the adoption of these radiosurgery systems.

METHODS

The National Cancer Data Base was used to identify patients > 18 years old with NSCLC who were treated with single-fraction SRS to the brain between 2003 and 2011. Patients who received “SRS not otherwise specified” or who did not receive a radiotherapy dose within the range of 12–24 Gy were excluded to reduce the potential for misclassification. The chi-square test, t-test, and multivariable logistic regression analysis were used to compare potential demographic, clinicopathologic, and health care system predictors of GK versus LINAC SRS use, when appropriate.

RESULTS

This study included 1780 patients, among whom 1371 (77.0%) received GK SRS and 409 (23.0%) underwent LINAC SRS. Over time, the proportion of patients undergoing LINAC SRS steadily increased, from 3.2% in 2003 to 30.8% in 2011 (p < 0.001). LINAC SRS was adopted more rapidly by community versus academic facilities (overall 29.2% vs 17.2%, p < 0.001). On multivariable analysis, 4 independent predictors of increased LINAC SRS use emerged, including year of diagnosis in 2008–2011 versus 2003–2007 (adjusted OR [AOR] 2.04, 95% CI 1.52–2.73, p < 0.001), community versus academic facility type (AOR 2.04, 95% CI 1.60–2.60, p < 0.001), non-West versus West geographic location (AOR 4.50, 95% CI 2.87–7.09, p < 0.001), and distance from cancer reporting facility of < 20 versus ≥ 20 miles (AOR 1.57, 95% CI 1.21–2.04, p = 0.001).

CONCLUSIONS

GK remains the most commonly used single-fraction SRS modality for NSCLC brain metastases in the US. However, LINAC-based SRS has been rapidly disseminating in the past decade, especially in the community setting. Wide geographic variation persists in the distribution of GK and LINAC SRS cases. Further comparative effectiveness research will be needed to evaluate the impact of these shifts on SRS-related toxicities, local control, and survival, as well as treatment costs and efficiency.

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Jonathan P. S. Knisely, James B. Yu, Jaclyn Flanigan, Mario Sznol, Harriet M. Kluger and Veronica L. S. Chiang

Object

A prospectively collected cohort of 77 patients who underwent definitive radiosurgery between 2002 and 2010 for melanoma brain metastases was retrospectively reviewed to assess the impact of ipilimumab use and other clinical variables on survival.

Methods

The authors conducted an institutional review board–approved chart review to assess patient age at the time of brain metastasis diagnosis, sex, primary disease location, initial radiosurgery date, number of metastases treated, performance status, systemic therapy and ipilimumab history, whole-brain radiation therapy (WBRT) use, follow-up duration, and survival at the last follow-up. The Diagnosis-Specific Graded Prognostic Assessment (DSGPA) score was calculated for each patient based on performance status and the number of brain metastases treated.

Results

Thirty-five percent of the patients received ipilimumab. The median survival in this group was 21.3 months, as compared with 4.9 months in patients who did not receive ipilimumab. The 2-year survival rate was 47.2% in the ipilimumab group compared with 19.7% in the nonipilimumab group. The DS-GPA score was the most significant predictor of overall survival, and ipilimumab therapy was also independently associated with an improvement in the hazard for death (p = 0.03).

Conclusions

The survival of patients with melanoma brain metastases managed with ipilimumab and definitive radiosurgery can exceed the commonly anticipated 4–6 months. Using ipilimumab in a supportive treatment paradigm of radiosurgery for brain oligometastases was associated with an increased median survival from 4.9 to 21.3 months, with a 2-year survival rate of 19.7% versus 47.2%. This association between ipilimumab and prolonged survival remains significant even after adjustment for performance status without an increased need for salvage WBRT.

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Jonathan P. S. Knisely, Masaaki Yamamoto, Cary P. Gross, William A. Castrucci, Hidefumi Jokura and Veronica L. S. Chiang

Object

Oligometastatic brain metastases may be treated with stereotactic radiosurgery (SRS) alone, but no consensus exists as to when SRS alone would be appropriate. A survey was conducted at 2 radiosurgery meetings to determine which factors SRS practitioners emphasize in recommending SRS alone, and what physician characteristics are associated with recommending SRS alone for ≥ 5 metastases.

Methods

All physicians attending the 8th Biennial Congress and Exhibition of the International Stereotactic Radiosurgery Society in June 2007 and the 18th Annual Meeting of the Japanese Society of Stereotactic Radiosurgery in July 2009 were asked to complete a questionnaire ranking 14 clinical factors on a 5-point Likert-type scale (ranging from 1 = not important to 5 = very important) to determine how much each factor might influence a decision to recommend SRS alone for brain metastases. Results were condensed into a single dichotomous outcome variable of “influential” (4–5) versus “not influential” (1–3). Respondents were also asked to complete the statement: “In general, a reasonable number of brain metastases treatable by SRS alone would be, at most, ___.” The characteristics of physicians willing to recommend SRS alone for ≥ 5 metastases were assessed. Chi-square was used for univariate analysis, and logistic regression for multivariate analysis.

Results

The final study sample included 95 Gamma Knife and LINAC-using respondents (54% Gamma Knife users) in San Francisco and 54 in Sendai (48% Gamma Knife users). More than 70% at each meeting had ≥ 5 years experience with SRS. Sixty-five percent in San Francisco and 83% in Sendai treated ≥ 30 cases annually with SRS. The highest number of metastases considered reasonable to treat with SRS alone in both surveys was 50. In San Francisco, the mean and median numbers of metastases considered reasonable to treat with SRS alone were 6.7 and 5, while in Sendai they were 11 and 10. In the San Francisco sample, the clinical factors identified to be most influential in decision making were Karnofsky Performance Scale score (78%), presence/absence of mass effect (76%), and systemic disease control (63%). In Sendai, the most influential factors were the size of the metastases (78%), the Karnofsky Performance Scale score (70%), and metastasis location (68%). In San Francisco, 55% of respondents considered treating ≥ 5 metastases and 22% considered treating ≥ 10 metastases “reasonable.” In Sendai, 83% of respondents considered treating ≥ 5 metastases and 57% considered treating ≥ 10 metastases “reasonable.” In both groups, private practitioners, neurosurgeons, and Gamma Knife users were statistically significantly more likely to treat ≥ 5 metastases with SRS alone.

Conclusions

Although there is no clear consensus for how many metastases are reasonable to treat with SRS alone, more than half of the radiosurgeons at 2 international meetings were willing to extend the use of SRS as an initial treatment for ≥ 5 brain metastases. Given the substantial variation in clinicians' approaches to SRS use, further research is required to identify patient characteristics associated with optimal SRS outcomes.