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Journal of Korean Neurosurgical Society > Volume 64(2); 2021 > Article
Lee, Cho, Choi, Kong, Seol, Nam, Jung, Sun, Lee, Ahn, Ahn, Park, and Lee: Immune Checkpoint Inhibitors for Non-Small-Cell Lung Cancer with Brain Metastasis : The Role of Gamma Knife Radiosurgery

Abstract

Objective

Immune checkpoint inhibitors (ICIs) are approved for treating non-small-cell lung cancer (NSCLC); however, the safety and efficacy of combined ICI and Gamma Knife radiosurgery (GKS) treatment remain undefined. In this study, we retrospectively analyzed patients treated with ICIs with or without GKS at our institute to manage patients with brain metastases from NSCLC.

Methods

We retrospectively reviewed medical records of patients with brain metastases from NSCLC treated with ICIs between January 2015 and December 2017. Of 134 patients, 77 were assessable for brain responses and categorized into three groups as follows : group A, ICI alone (n=26); group B, ICI with concurrent GKS within 14 days (n=24); and group C, ICI with non-concurrent GKS (n=27).

Results

The median follow-up duration after brain metastasis diagnosis was 19.1 months (range, 1-77). At the last follow-up, 53 patients (68.8%) died, 20 were alive, and four were lost to follow-up. The estimated median overall survival (OS) of all patients from the date of brain metastasis diagnosis was 20.0 months (95% confidence interval, 12.5-27.7) (10.0, 22.5, and 42.1 months in groups A, B, and C, respectively). The OS was shorter in group A than in group C (p=0.001). The intracranial disease progression-free survival (p=0.569), local progression-free survival (p=0.457), and complication rates did not significantly differ among the groups. Twelve patients showed leptomeningeal seeding (LMS) during follow-up. The 1-year LMS-free rate in treated with ICI alone group (69.1%) was significantly lower than that in treated with GKS before ICI treatment or within 14 days group (93.2%) (p=0.004).

Conclusion

GKS with ICI showed no favorable OS outcome in treating brain metastasis from NSCLC. However, GKS with ICI did not increase the risk of complications. Furthermore, compared with ICI alone, GKS with ICI may be associated with a reduced incidence of LMS. Further understanding of the mechanism, which remains unknown, may help improve the quality of life of patients with brain metastasis.

INTRODUCTION

Brain metastasis, a common complication of non-small-cell lung cancer (NSCLC), has incidence rates of 30-50% and significantly affects the quality of life of patients [18,49]. The prognosis of patients with brain metastases from NSCLC is extremely poor. Without treatment, the median survival is only 1-2 months. Primary approaches to the treatment of brain metastases include whole-brain radiation therapy, surgery, and stereotactic radiosurgery (SRS) such as Gamma Knife radiosurgery (GKS). Currently, biomarker target agents have led to improved progression-free survival (PFS) and overall survival (OS) in patients with advanced NSCLC [29,33]. Biomarker target agents are a new strategy for treating NSCLC. Some studies have suggested that SRS improves OS and local control in patients with brain metastases [10,24,27,34]. However, these targeted therapies have their own limitations [38,50].
Recently, immune checkpoint inhibitors (ICIs) have been introduced for treating NSCLC. Several drugs, such as pembrolizumab and nivolumab, have been approved for treating NSCLC and malignant melanoma. For both these diseases, clinical trials have shown greater improvement in OS with ICIs than with the standard treatment [4,5,17]. However, there are only few reports on the use of ICIs for treating brain metastases from NSCLC. Although the use of SRS has improved the control of brain lesions and has prolonged survival [9], the efficacy of SRS and ICIs in patients with brain metastases from NSCLC has not been established. In this study, we retrospectively analyzed patients treated with ICIs with or without GKS at our institute to manage patients with brain metastases from NSCLC.

MATERIALS AND METHODS

The study protocol was reviewed and approved by the Institutional Review Board of Samsung Medical Center (SMC-2017-10-051) and was conducted according to the recommendations of the Declaration of Helsinki for biomedical research involving human subjects (1975).
We retrospectively reviewed medical records of patients who were prescribed ICIs (nivolumab and pembrolizumab) for treating NSCLC between January 2015 and December 2017 at our institute. In total, 622 patients were prescribed ICIs, of whom 134 were diagnosed with brain metastasis. Among the 134 patients, 57 lacked follow-up imaging until the last checkup or died and thus were excluded. We enrolled the remaining 77 patients who had follow-up imaging to assess the treatment response. The patients were categorized into three groups based on the administered medications and GKS : group A received ICI alone without GKS, group B received ICI with concurrent GKS within 14 days of prescribing ICI, and group C received ICI with non-concurrent GKS after 14 days of prescribing ICI (Fig. 1).

Medication

ICIs (pembrolizumab and nivolumab) were prescribed by neuro-oncologists. The patients received doses of 2 mg/kg pembrolizumab or 3 mg/kg nivolumab every 3 weeks infused intravenously for 30-60 minutes.

Radiosurgical technique

GKS was performed by a neurosurgeon using a Leksell Gamma Knife model Perfexion or ICON (Elekta, Stockholm, Sweden). The median marginal dose of 19 Gy (range, 12-25) at a 50% isodose of the maximum dose was prescribed.

Radiological evaluation

Radiological images obtained using brain magnetic resonance imaging (MRI) were assessed by neuro-radiologists. Local progression of intracranial lesions was defined by the radiological progression of a previously treated metastatic lesion. Intracranial disease progression was defined by the radiological progression of the intracranial condition, including local progression and development of new lesions. Leptomeningeal seeding (LMS) was defined by radiologically identified leptomeningeal progression. To rule out the pseudoprogression by radiation, perfusion images were performed on all MRI.

Statistical analysis

The patients’ demographic and clinical data are summarized using standard descriptive statistics and frequency tabulations. Fisher’s exact test was used to evaluate the differences in categorical variables, and the Kruskal-Wallis test was used to evaluate the differences in continuous variables among the groups. OS was analyzed from the date of diagnosis of brain metastasis to the date of death of the patient. Intracranial disease PFS (I-PFS) was analyzed from the date of initiating treatment with ICI to the date when the intracranial disease progression was revealed using MRI. Local PFS (L-PFS) was analyzed from the date of initiating treatment with ICI to the date when local progression was revealed using MRI. LMSPFS was analyzed from the date of initiating treatment with ICI to the date when LMS was identified. OS, I-PFS, L-PFS, and LMS-PFS were analyzed among the three groups using the log-rank test with Kaplan-Meier plots. p-values <0.05 were considered statistically significant. All analyses were performed in R version 3.4 (https://cran.r-project.org/).

RESULTS

Characteristics of patients and lesions

Seventy-seven patients were enrolled in our study. The median age of these patients was 60 years (range, 42-79) at the time of the diagnosis of brain metastasis; 55 patients were men and 22 were women. The median follow-up duration was 19.1 months (range, 1-77). At the last follow-up, 53 patients (68.8%) died, 20 were alive, and four were lost to follow-up. Adenocarcinomas were identified in 68 patients (88.3%), squamous cell carcinomas in eight (10.4%), and large cell carcinomas in one (1.3%). The mode of onset of brain metastasis was synchronous in 40 patients (51.9%) and metachronous in 37 (48.1%). Nivolumab was prescribed for 31 patients and pembrolizumab for 46 patients. The expression of programmed death-ligand 1 (PD-L1) was assessed in certain patients. The percentage of tumor cells with a level of membrane positivity of >50% was considered positive for PD-L1 protein expression. Thirty-four patients (44.2%) tested positive, 23 (29.8%) tested negative, and 20 did not undergo the evaluation. Ten patients (13.0%) underwent whole-brain radiation therapy before starting ICI treatment. During the follow-up period, 51 patients underwent GKS.
The patients were categorized into three groups based on the administered medications and GKS. Twenty-six patients were included in group A (patients received ICI alone and did not undergo GKS), 24 in group B (ICI with concurrent GKS within 14 days of prescribing ICI), and 27 in group C (ICI with non-concurrent GKS after 14 days of prescribing ICI). The number of brain lesions was counted at the time of diagnosing brain metastasis. The presence of more than 10 lesions and LMS was assigned a value of 10. The median value was 2 (range, 1-10) in all three groups. There were no statistically significant differences in the number of lesions among the three groups (p=0.068) and the patients’ Eastern Cooperative Oncology Group performance status among the three groups (p=1.000). The follow-up duration was shorter in group A than in group B or C (p<0.001). The other baseline characteristics were not statistically different among the three groups (Table 1).

Survival of patients and disease progression

The estimated median OS of all patients from the date of brain metastasis diagnosis was 20.0 months (95% confidence interval [CI], 12.5-27.7) (estimated median OS were 10.0, 22.5, and 42.1 months in groups A, B, and C, respectively). The OS was significantly shorter in group A than in group C (p=0.001). The estimated median I-PFS from the date of initiating ICI was 4.8 months (95% CI, 2.1-7.5). There were no statistically significant differences in I-PFS among the three groups (p=0.569) (estimated median I-PFS were 3.4, 4.7, and 7.9 months in groups A, B, and C, respectively). The estimated median L-PFS from the date of initiating ICI was 24.0 months (95% CI, 6.9-41.1). There were no statistically significant differences in L-PFS among the three groups (p=0.457) (L-PFS was not reached in group A; the estimated median L-PFS were 26.8 and 11.5 months in groups B and C, respectively) (Fig. 2). During the follow-up period, 53 patients experienced intracranial disease progression. LMS occurred in eight, two, and no patient in groups A, B, and C, respectively. Local treatment failures were observed in one, seven, and two patients in groups A, B, and C, respectively.

Effect of ICIs with GKS on LMS

We analyzed the effects of ICI and GKS on the development of LMS. Four patients with LMS diagnosed before starting ICI were excluded, and 73 patients were finally analyzed (24, 23, and 26 patients in groups A, B, and C, respectively). LMS occurred in eight, two, and two patients in groups A, B, and C, respectively. The duration from the initiation of ICI to the development of LMS occurred with a statistically significant difference among the three groups (p=0.015) (the 1-year LMS-free rates were 69.1%, 90.0%, and 95.7% in groups A, B, and C, respectively). The difference was more significant when analyzed from the time of the diagnosis of brain metastasis (p<0.001) (the 1-year LMS-free rates were 74.2%, 95.2%, and 100.0% in groups A, B, and C, respectively).
In group C, only two patients underwent GKS at 2 weeks after completing ICI treatment. We excluded these two patients and analyzed the data again. The results were clearer when the patients were categorized with respect to treatment with ICI alone group and treatment with GKS before ICI treatment or within 14 days. The duration from the initiation of ICI to the occurrence of LMS was statistically significant between the two groups (p=0.004) (the 1-year LMS-free rates were 69.1% and 93.2%, respectively). The duration from the diagnosis of brain metastasis to the occurrence of LMS was also statistically significant among the three groups (p<0.001) (the 1-year LMS-free rates were 74.2% and 97.9% in groups A and B, respectively). The incidence of LMS was lower when ICI was used with GKS (Fig. 3).

Complications

Adverse events were reported according to the National Cancer Institute Common Toxicity Criteria, which were examined during treatment with ICI. There was no adverse event with grade >3. Additionally, there was no case with significant morbidity or mortality related to the treatment (ICI and GKS).

DISCUSSION

ICIs have impressive and long-lasting therapeutic effects on extracranial melanomas and lung cancers. In recent studies, the use of ICI targeting programmed death (PD)-1 and PD-L1 represented a paradigm shift in the management of NSCLC. Some studies have reported significant improvements in OS or quality of life of patients with advanced NSCLC after treatment with ICI compared with those after treatment with other drugs [3-6,11,19,25,45]. The 5-year update of CA209-003 revealed the use of nivolumab in patients with advanced NSCLC resulted in a four-fold improvement in the 5-year OS compared with previous data [19]. Furthermore, in patients treated with pembrolizumab, the 5-year OS was reported to be 23.2% in the treatment-naive group and 15.5% in the pretreated group [11]. The safety of ICI combined with other drugs has also been reported to some extent [16,32]. However, the efficacy of ICI in treating brain tumors needs to be elucidated. The permeability of different drugs through the blood-brain barrier varies among patients and also varies based on the different metastatic lesions in the same patient [36]. ICIs do not directly act on tumors but activate peripheral T cells [41]. Thus, even if the blood-brain barrier is intact, T cells can access the tumor. Furthermore, although normal brain parenchyma or primary brain tumors have immunoregulatory environments with a few infiltrated lymphocytes, metastatic brain lesions have a significant number of tumor-infiltrating lymphocytes [1]. Hence, we assumed that ICIs could be effective in treating metastatic brain tumors. However, there is limited evidence regarding the efficacy of ICIs in treating brain lesions. Preliminary results suggest that ICIs are effective in treating brain metastases in certain patients with NSCLC who were treated with pembrolizumab without radiation therapy [21]. In a recent follow-up study, the response rate of brain lesions was 29.4%, along with a median OS of 8.9 months, with 31% of the patients living for >2 years [22]. Furthermore, the median PFS and OS were 5.5 and 6.5 months, respectively, when patients with brain metastasis from squamous cell lung carcinoma were treated with nivolumab [2]. Another study reported a sudden progression of brain lesions after administering ICIs [28].
The efficacy of radiosurgery with ICI remains unclear. Several reports have revealed that brain metastasis from melanoma and NSCLC has a favorable survival outcome when treated with ICI and SRS [8,30,31,40,43,46-48]; however, some studies have reported no difference in disease control or survival [12,39,42]. In a recent meta-analysis, the application of concurrent radiation along with ICI within 4 weeks showed good results with respect to 12-month OS [35,37]. Our results, however, showed no difference in survival between the concurrent- and non-concurrent-treated groups. The same results were obtained when concurrent was defined as within 2 or 4 weeks. Regarding safety issues, some studies have shown exacerbation of peritumoral edema with the concurrent use of ICI and GKS [14,30], although this was not observed in our study. According to a recently released meta-analysis, a combination of SRS and ICI did not appear to be associated with untoward rates of radionecrosis [35].
Radiation augments antitumor immune responses by releasing tumor antigens and increasing tumor mutational burden following necrosis of tumor cells, thereby causing the release of immune-stimulatory damage-associated molecular patterns. This promotes the recruitment of antigen-presenting cells to the tumor microenvironment [26,51]. Radiation increases PD-L1 expression [13,15]. This suggests that radiation increases the effectiveness of ICI therapy. Chen et al. [8] reported a reduced incidence of new brain metastasis after concurrent SRS, which was explained as a reflection of improved extracranial disease control rather than an abscopal effect. However, our results showed that compared with ICI alone, GKS along with ICI could reduce the incidence of LMS. This could not be explained by extracranial disease control solely. We report here for the first time that SRS delayed the development of LMS in patients with NSCLC treated with an ICI. LMS occurs when malignant cells spread to the cerebrospinal f luid (CSF) space [20,23]. The malignant cells can reach the CSF space via a hematogenous route through the vessels of the arachnoid or choroid plexus [7]. They can also spread from the parenchymal tumor itself while growing or during surgery. LMS develops in 3-5% of patients with advanced NSCLC [44]. LMS may involve a different metastatic process from that of parenchymal metastasis. Our previous study revealed that most patients with brain metastasis from NSCLC experienced LMS in the terminal stage, resulting in a very poor prognosis [9]. This study demonstrated that the early use of ICIs before or with GKS could reduce the incidence of LMS. Unfortunately, we could not completely identify the mechanism of these effects; however, this treatment strategy could aid in improving the quality of life of terminally ill patients with NSCLC.
Because of the retrospective design, our study had some limitations. In total, 42.5% (57/134) of the patients were excluded owing to a lack of clinical information necessary to assess intracranial response. Because they died before we could obtain additional brain imaging, we could not predict the response in these patients. In addition, in the treatment scheme, the prescription of ICI was heterogeneous in a small number of patients with a short follow-up duration. This could make generalization of our results difficult.
Recent studies on the effectiveness of ICI have been published; however, we could not determine a clear factor that could identify patients for whom ICI treatment could be effective. In addition, although many complications caused by ICIs have been reported, there were no specific complications in the current study.

CONCLUSION

The effects of ICIs on the central nervous system, previously considered an immuno-privileged area, have been reported. In this study, ICIs in combination with GKS showed no favorable OS outcome in treating patients with brain metastasis from NSCLC. However, GKS with ICI did not increase the risk of complications. Furthermore, GKS with ICI might be associated with a reduced incidence of LMS; however the exact mechanism for this remains unknown. LMS has a significant impact on the quality of life of end-of-life patients with brain metastasis. It is expected that further understanding of the mechanism may help improve the quality of life of patients with brain metastasis. Further studies are required to identify clinical and molecular predictors to improve the outcomes of patients with brain metastases from NSCLC and to provide clinically meaningful treatment options.

Notes

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

INFORMED CONSENT

This type of study does not require informed consent.

AUTHOR CONTRIBUTIONS

Conceptualization : JIL

Data curation : MHL, KRC, JWC, DSK, HJS, DHN, HAJ, JMS, SHL, JSA, MJA, KP

Formal analysis : MHL

Methodology : MHL

Project administration : JIL

Visualization : MHL

Writing - original draft : JIL

Writing - review & editing : JIL, MHL, KRC, JWC, DSK, HJS, DHN, HAJ, JMS, SHL, JSA, MJA, KP

Fig. 1.
Flow chart of the study. ICI : immune checkpoint inhibitor, GKS : Gamma Knife radiosurgery.
jkns-2020-0135f1.jpg
Fig. 2.
Survival curve according to the treatment group. A : Overall survival. B : Intracranial disease progression-free survival. C : Local progression-free survival according to the treatment group (group A, ICI alone without GKS; group B, ICI with concurrent GKS within 14 days of prescribing ICI; and group C, ICI with non-concurrent GKS after 14 days of prescribing ICI). ICI : immune checkpoint inhibitor, GKS : Gamma Knife radiosurgery.
jkns-2020-0135f2.jpg
Fig. 3.
Leptomeningeal progression-free survival curve according to the treatment group duration from the start of ICI treatment (A) and diagnosis of brain metastasis (B) to the development of leptomeningeal seeding (ICI alone without GKS, treatment with GKS before ICI treatment or within 14). ICI : immune checkpoint inhibitor, GKS : Gamma Knife radiosurgery.
jkns-2020-0135f3.jpg
Table 1.
Demographic characteristics of the patients and comparison among the Groups according to differences in the treatment scheme
Total (n=77) Group A (ICI alone, n=26) Group B (ICI and concurrent GKS, n=24) Group C (ICI and non-concurrent GKS, n=27) p-value*
Age (years) 60 (42−79) 61 (42−79) 62 (51−78) 59 (42−75) 0.507
Sex, male : female 55 : 22 17 : 9 19 : 5 19 : 8 0.568
Follow-up (months) 19.1 (1−77.0) 10.4 (1−40.0) 19.7 (1−77.0) 30.3 (7.0−67.3) <0.001
Pathology 0.400
 Adenocarcinoma 68 (88.3) 22 (84.6) 21 (87.5) 25 (92.6)
 Squamous cell carcinoma 8 (10.4) 4 (15.4) 3 (12.5) 1 (3.7)
 Large cell carcinoma 1 (1.3) 0 (0.0) 0 (0.0) 1 (3.7)
Onset 0.332
 Synchronous 40 (51.9) 11 (42.3) 12 (50.0) 17 (63.0)
 Metachronous 37 (48.1) 15 (57.7) 12 (50.0) 10 (37.0)
ECOG performance status 1.000
 0 2 (2.6) 1 (3.8) 0 (0.0) 1 (3.7)
 1 68 (88.3) 23 (88.5) 22 (91.7) 23 (85.2)
 2 7 (9.1) 2 (7.7) 2 (8.3) 3 (11.1)
Number of lesions 2 (1−10) 2 (1−10) 2 (1−9) 2 (1−10) 0.068
Number of GKS 1 (0−6) 0 2 (1−5) 2 (1−6) <0.001
WBRT prior to ICI 10 (13.0) 4 (15.4) 3 (12.5) 3 (11.1) 0.916
Medication, ICIs 0.591
 Nivolumab 31 (40.3) 9 (34.6) 9 (37.5) 13 (48.1)
 Pembrolizumab 46 (59.7) 17 (65.4) 15 (62.5) 14 (51.9)
PD-L1 0.179
 ≥50% 34 (44.2) 8 (30.8) 14 (58.3) 8 (29.6)
 <50% 23 (29.8) 12 (46.2) 7 (29.2) 8 (29.6)
 Not available 20 (26.0) 6 (23.1) 3 (12.5) 11 (40.7)

Values are presented as median (range) or number (%) unless otherwise indicated.

* p-value was analyzed by comparing the groups A, B, and C.

Kruskal-Wallis test.

Fisher's exact test.

ICI : immune checkpoint inhibitor, GKS : Gamma Knife radiosurgery, ECOG : Eastern Cooperative Oncology Group, WBRT : whole brain radiotherapy, PD-L1 : programmed death-ligand 1

References

1. Berghoff AS, Fuchs E, Ricken G, Mlecnik B, Bindea G, Spanberger T, et al : Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in patients with brain metastases. Oncoimmunology 5 : e1057388, 2016
crossref pmid
2. Bidoli P, Chiari R, Catino A, Grossi F, Noberasco C, Gelsomino F, et al : Efficacy and safety data from patients with advanced squamous NSCLC and brain metastases participating in the nivolumab Expanded Access Programme (EAP) in Italy. Ann Oncol 27(suppl 6):1228P, 2016
crossref
3. Borghaei H, Langer CJ, Gadgeel S, Papadimitrakopoulou VA, Patnaik A, Powell SF, et al : 24-month overall survival from KEYNOTE-021 cohort G: pemetrexed and carboplatin with or without pembrolizumab as firstline therapy for advanced nonsquamous non-small cell lung cancer. J Thorac Oncol 14 : 124-129, 2019
crossref pmid
4. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al : Nivolumab versus Docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373 : 1627-1639, 2015
crossref pmid pmc
5. Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, et al : Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373 : 123-135, 2015
crossref pmid pmc
6. Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al : Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol 18 : 1600-1609, 2017
crossref pmid
7. Chamberlain MC : Leptomeningeal metastasis. Curr Opin Oncol 22 : 627-635, 2010
crossref pmid
8. Chen L, Douglass J, Kleinberg L, Ye X, Marciscano AE, Forde PM, et al : Concurrent immune checkpoint inhibitors and stereotactic radiosurgery for brain metastases in non-small cell lung cancer, melanoma, and renal cell carcinoma. Int J Radiat Oncol Biol Phys 100 : 916-925, 2018
crossref pmid
9. Cho KR, Lee MH, Kong DS, Seol HJ, Nam DH, Sun JM, et al : Outcome of gamma knife radiosurgery for metastatic brain tumors derived from non-small cell lung cancer. J Neurooncol 125 : 331-338, 2015
crossref pmid
10. Choi YL, Sun JM, Cho J, Rampal S, Han J, Parasuraman B, et al : EGFR mutation testing in patients with advanced non-small cell lung cancer: a comprehensive evaluation of real-world practice in an East Asian tertiary hospital. PLoS One 8 : e56011, 2013
crossref pmid pmc
11. Chung HC, Ros W, Delord JP, Perets R, Italiano A, Shapira-Frommer R, et al : Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol 37 : 1470-1478, 2019
crossref
12. Colaco RJ, Martin P, Kluger HM, Yu JB, Chiang VL : Does immunotherapy increase the rate of radiation necrosis after radiosurgical treatment of brain metastases? J Neurosurg 125 : 17-23, 2016
crossref pmid
13. Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, et al : Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest 124 : 687-695, 2014
crossref pmid pmc
14. Diao K, Bian SX, Routman DM, Yu C, Kim PE, Wagle NA, et al : Combination ipilimumab and radiosurgery for brain metastases: tumor, edema, and adverse radiation effects. J Neurosurg 129 : 1397-1406, 2018
crossref pmid pmc
15. Dovedi SJ, Adlard AL, Lipowska-Bhalla G, McKenna C, Jones S, Cheadle EJ, et al : Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res 74 : 5458-5468, 2014
crossref pmid
16. Gadgeel SM, Stevenson JP, Langer CJ, Gandhi L, Borghaei H, Patnaik A, et al : Pembrolizumab and platinum-based chemotherapy as first-line therapy for advanced non-small-cell lung cancer: phase 1 cohorts from the KEYNOTE-021 study. Lung Cancer 125 : 273-281, 2018
crossref pmid pmc
17. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al : Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372 : 2018-2028, 2015
crossref pmid
18. Gavrilovic IT, Posner JB : Brain metastases: epidemiology and pathophysiology. J Neurooncol 75 : 5-14, 2005
crossref pmid
19. Gettinger S, Horn L, Jackman D, Spigel D, Antonia S, Hellmann M, et al : Five-year follow-up of Nivolumab in previously treated advanced nonsmall-cell lung cancer: results from the CA209-003 study. J Clin Oncol 36 : 1675-1684, 2018
crossref
20. Gleissner B, Chamberlain MC : Neoplastic meningitis. Lancet Neurol 5 : 443-452, 2006
crossref pmid
21. Goldberg SB, Gettinger SN, Mahajan A, Chiang AC, Herbst RS, Sznol M, et al : Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a nonrandomised, open-label, phase 2 trial. Lancet Oncol 17 : 976-983, 2016
crossref pmid pmc
22. Goldberg SB, Gettinger SN, Mahajan A, Herbst RS, Chiang AC, Lilenbaum R : Durability of brain metastasis response and overall survival in patients with Non-Small Cell Lung Cancer (NSCLC) treated with pembrolizumab. J Clin Oncol 36 : 2009, 2018
crossref pmid
23. Grossman SA, Krabak MJ : Leptomeningeal carcinomatosis. Cancer Treat Rev 25 : 103-119, 1999
crossref pmid
24. Harris S, Chan MD, Lovato JF, Ellis TL, Tatter SB, Bourland JD, et al : Gamma knife stereotactic radiosurgery as salvage therapy after failure of whole-brain radiotherapy in patients with small-cell lung cancer. Int J Radiat Oncol Biol Phys 83 : e53-e59, 2012
crossref pmid pmc
25. Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, et al : Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387 : 1540-1550, 2016
crossref pmid
26. Hodge JW, Guha C, Neefjes J, Gulley JL : Synergizing radiation therapy and immunotherapy for curing incurable cancers. Opportunities and challenges. Oncology (Williston Park) 22 : 1064-1084, 2008
pmid pmc
27. Johnson AG, Ruiz J, Hughes R, Page BR, Isom S, Lucas JT, et al : Impact of systemic targeted agents on the clinical outcomes of patients with brain metastases. Oncotarget 6 : 18945-18955, 2015
crossref pmid pmc
28. Kanai O, Fujita K, Okamura M, Nakatani K, Mio T : Severe exacerbation or manifestation of primary disease related to Nivolumab in non-small-cell lung cancer patients with poor performance status or brain metastases. Ann Oncol 27 : 1354-1356, 2016
crossref pmid
29. Karampeazis A, Voutsina A, Souglakos J, Kentepozidis N, Giassas S, Christofillakis C, et al : Pemetrexed versus erlotinib in pretreated patients with advanced non-small cell lung cancer: a Hellenic Oncology Research Group (HORG) randomized phase 3 study. Cancer 119 : 2754-2764, 2013
crossref pmid
30. Kiess AP, Wolchok JD, Barker CA, Postow MA, Tabar V, Huse JT, et al : Stereotactic radiosurgery for melanoma brain metastases in patients receiving ipilimumab: safety profile and efficacy of combined treatment. Int J Radiat Oncol Biol Phys 92 : 368-375, 2015
crossref pmid pmc
31. Knisely JP, Yu JB, Flanigan J, Sznol M, Kluger HM, Chiang VL : Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival. J Neurosurg 117 : 227-233, 2012
crossref pmid pmc
32. Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, et al : Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol 17 : 1497-1508, 2016
crossref pmid pmc
33. Lee HY, Ahn HK, Jeong JY, Kwon MJ, Han JH, Sun JM, et al : Favorable clinical outcomes of pemetrexed treatment in anaplastic lymphoma kinase positive non-small-cell lung cancer. Lung Cancer 79 : 40-45, 2013
crossref pmid
34. Lee MH, Kong DS, Seol HJ, Nam DH, Lee JI : The influence of biomarker mutations and systemic treatment on cerebral metastases from NSCLC treated with radiosurgery. J Korean Neurosurg Soc 60 : 21-29, 2017
crossref pmid
35. Lehrer EJ, Peterson J, Brown PD, Sheehan JP, Quiñones-Hinojosa A, Zaorsky NG, et al : Treatment of brain metastases with stereotactic radiosurgery and immune checkpoint inhibitors: an international meta-analysis of individual patient data. Radiother Oncol 130 : 104-112, 2019
crossref pmid
36. Lockman PR, Mittapalli RK, Taskar KS, Rudraraju V, Gril B, Bohn KA, et al : Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer. Clin Cancer Res 16 : 5664-5678, 2010
crossref pmid pmc
37. Lu VM, Goyal A, Rovin RA, Lee A, McDonald KL : Concurrent versus non-concurrent immune checkpoint inhibition with stereotactic radiosurgery for metastatic brain disease: a systematic review and meta-analysis. J Neurooncol 141 : 1-12, 2019
crossref
38. Magnuson WJ, Lester-Coll NH, Wu AJ, Yang TJ, Lockney NA, Gerber NK, et al : Management of brain metastases in tyrosine kinase inhibitornaïve epidermal growth factor receptor-mutant non-small-cell lung cancer: a retrospective multi-institutional analysis. J Clin Oncol 35 : 1070-1077, 2017
crossref pmid
39. Mathew M, Tam M, Ott PA, Pavlick AC, Rush SC, Donahue BR, et al : Ipilimumab in melanoma with limited brain metastases treated with stereotactic radiosurgery. Melanoma Res 23 : 191-195, 2013
crossref pmid
40. Murphy B, Walker J, Bassale S, Monaco D, Jaboin J, Ciporen J, et al : Concurrent radiosurgery and immune checkpoint inhibition. Am J Clin Oncol 42 : 253-257, 2019
crossref pmid
41. Pardoll DM : The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12 : 252-264, 2012
crossref pmid pmc
42. Patel KR, Shoukat S, Oliver DE, Chowdhary M, Rizzo M, Lawson DH, et al : Ipilimumab and stereotactic radiosurgery versus stereotactic radiosurgery alone for newly diagnosed melanoma brain metastases. Am J Clin Oncol 40 : 444-450, 2017
crossref
43. Qian JM, Yu JB, Kluger HM, Chiang VL : Timing and type of immune checkpoint therapy affect the early radiographic response of melanoma brain metastases to stereotactic radiosurgery. Cancer 122 : 3051-3058, 2016
crossref pmid pmc
44. Remon J, Le Rhun E, Besse B : Leptomeningeal carcinomatosis in non-small cell lung cancer patients: a continuing challenge in the personalized treatment era. Cancer Treat Rev 53 : 128-137, 2017
crossref pmid
45. Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, et al : Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 389 : 255-265, 2017
crossref pmid
46. Schapira E, Hubbeling H, Yeap BY, Mehan WA Jr, Shaw AT, Oh K, et al : Improved overall survival and locoregional disease control with concurrent PD-1 pathway inhibitors and stereotactic radiosurgery for lung cancer patients with brain metastases. Int J Radiat Oncol Biol Phys 101 : 624-629, 2018
crossref
47. Shepard MJ, Xu Z, Donahue J, Eluvathingal Muttikkal TJ, Cordeiro D, Hansen L, et al : Stereotactic radiosurgery with and without checkpoint inhibition for patients with metastatic non-small cell lung cancer to the brain: a matched cohort study. J Neurosurg 133 : 611-946, 2020
crossref
48. Silk AW, Bassetti MF, West BT, Tsien CI, Lao CD : Ipilimumab and radiation therapy for melanoma brain metastases. Cancer Med 2 : 899-906, 2013
crossref
49. Sørensen JB, Hansen HH, Hansen M, Dombernowsky P : Brain metastases in adenocarcinoma of the lung: frequency, risk groups, and prognosis. J Clin Oncol 6 : 1474-1480, 1988
crossref
50. Sperduto PW, Wang M, Robins HI, Schell MC, Werner-Wasik M, Komaki R, et al : A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT and SRS with temozolomide or erlotinib for non-small cell lung cancer and 1 to 3 brain metastases: Radiation Therapy Oncology Group 0320. Int J Radiat Oncol Biol Phys 85 : 1312-1318, 2013
crossref
51. Weichselbaum RR, Liang H, Deng L, Fu YX : Radiotherapy and immunotherapy: a beneficial liaison? Nat Rev Clin Oncol 14 : 365-379, 2017
crossref
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