Association of Immunotherapy With Survival Among Patients With Brain Metastases Whose Cancer Was Managed With Definitive Surgery of the Primary Tumor

IMPORTANCE Immunotherapy has shown significant control of intracranial metastases in patients with melanoma. However, the association of immunotherapy combined with other cancer treatments and overall survival (OS) of patients with brain metastases, regardless of primary tumor site, is unknown. OBJECTIVE To explore the association of immunotherapy with OS in patients with cancer and brain metastases who received definitive surgery of the primary site. DESIGN, SETTING, AND PARTICIPANTS This comparative effectiveness study included 3112 adult patients in the National Cancer Database from 2010 to 2016 with non–small cell lung cancer, breast cancer,melanoma,colorectalcancer,orkidneycancerandbrainmetastasesatthetimeofdiagnosis and who received definitive surgery of the primary site. Data analysis was conducted from March to April 2020.


Introduction
3][4][5] The most common primary tumors associated with BMs are lung cancer (40%-50%), breast cancer (15%-30%), and melanoma (5%-20%), followed by colorectal cancer (3%-8%) and kidney cancer (2%-4%). 6Brain metastases cause significant morbidity and mortality and carry a poor survival prognosis. 710] Local therapies, such as whole-brain radiation therapy (RT), stereotactic radiosurgery, and surgical resection, have been the mainstay of treatment in these patients. 11,12These local therapies are associated with neurotoxic effects and represent a significant problem. 13totoxic chemotherapy has shown limited activity in the nervous system due to its inability to cross the blood-brain barrier (BBB).With the progress in the understanding of the pathophysiology of the BBB and the development of new cytotoxic chemotherapies and targeted therapies, a renewed interest has been placed on the use of systemic treatment for BMs. 14,15Currently, there is a compelling rationale that drugs that sufficiently penetrate the BBB can evoke a clinical response in the central nervous system. 16BB2 inhibitors were associated with an objective central nervous system response rate of 74% and a median progression-free survival of 7.3 (95% CI, 6.5-8.1)months and a median overall survival (OS) of 10.5 (95% CI, 7.8-13.2) months in patients with breast cancer and BMs. 17 Epidermal growth factor receptor inhibitors were associated with 3 months improved median OS in patients with BMs from non-small cell lung cancer (12 months in targeted therapy vs 9 months in chemotherapy). 18Targeted therapies were also associated with improved OS in patients with BMs and kidney cancer or melanoma. 19,20Together, these findings suggest that targeted therapies may be useful in treating intracranial disease.
Immunotherapy has changed the treatment landscape of various malignant neoplasms and may offer an exciting opportunity for the treatment of BMs. 15 The brain was long considered as an immune-privileged organ, and it was thought that immunotherapy was ineffective in BMs because it will not cross the BBB or, when it does cross the BBB, its ability to elicit a robust immune response would be limited. 14,15However, preclinical and clinical evidence indicate that monoclonal antibodies can penetrate the BBB both in primary and metastatic brain cancer and thus could be an excellent option for the treatment of brain metastasis. 11,21 ongoing phase 2 trial of pembrolizumab among patients with BMs from melanoma or non-small cell lung cancer reported a response rate of 33% (95% CI, 14%-59%) in patients with non-small cell lung cancer and 22% (95% CI, 7%-48%) in patients with melanoma. 22A phase 2 clinical trial of patients with BMs in which participants received a combination of nivolumab and ipilimumab reported 57% intracranial clinical benefit with 56% complete or partial responses. 23[25][26][27][28] More extensive studies regarding the potential role of immunotherapy in patients with BMs who receive surgery of the primary tumor are lacking.The surgery distinction was made because the survival of patients with BMs who receive surgery of the primary site is different from those who do not receive surgery (20 vs 9 months) based on our data (Figure 1).Removing the primary tumor will significantly reduce the tumor burden, and immunotherapy may work better in a setting with minimal residual disease, when the bulk of the tumor mass has been optimally reduced.Using the data from the National Cancer Database (NCDB), we explored whether the use of immunotherapy in patients with BMs who received surgery of the primary site is associated with improved OS in patients with non-small cell lung cancer, breast cancer, melanoma, colorectal cancer, and kidney cancer.

Data Source
This was a comparative effectiveness study that used data extracted from NCDB.

Study Population
The study cohort consisted of patients with BMs aged 19 years and older who were diagnosed with the primary cancer of non-small cell lung cancer, melanoma, breast cancer, colorectal cancer, or kidney cancer between 2010 and 2016.These primary cancers account for more than 75% of BM cases.The year 2010 was chosen because this is the first year the NCDB collected information regarding BMs at the time of diagnosis.Patients who did not receive definitive surgery of the primary site and those who were missing radiation therapy, chemotherapy, and immunotherapy were excluded from the study.Patients with unknown or missing information regarding the covariates of interest were not included in the multivariable analysis.This study only includes patients with BMs who had definitive surgery of the primary cancer site.Definitive surgery refers to cancer surgery (removing primary cancer and the regional lymph nodes).Using the site-specific International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) surgery codes, patients with breast cancer with codes 20 to 80, patients with non-small cell lung cancer with codes 30 to 79, patients with melanoma with codes 30 to 60, patients with colorectal cancer with codes 30 to 80, and patients with kidney cancer with codes 30 to 80 were defined as having received definitive surgery and were included in the analysis.

End Points
The primary outcome was OS, which was calculated from the time of diagnosis of BMs to the time of death from any cause.The odds ratios for identifying the factors associated with receiving immunotherapy in the multivariable analysis were also calculated.

Factors and Covariates
The main factors were immunotherapy, immunotherapy plus chemotherapy, immunotherapy plus RT, and immunotherapy plus chemoradiation.Covariates included the patient-level variables of age, sex, and race and the demographic variables of place of residence, income, education (based on the zip code of the patient at the time of diagnosis).The treatment-related variables of insurance, treatment facility type, comorbidity score, and receipt of immunotherapy, chemotherapy, or RT were also included.

Statistical Analysis
The baseline covariates between patients with BMs who received immunotherapy and those who did not were compared.Mean, median, and range were calculated for all continuous variables, while proportions were reported for all categorical variables for those who received immunotherapy and for those who did not.Multiple logistic regression analysis was performed to identify the factors associated with receiving immunotherapy.The odds ratio was reported as the measure of association between the covariate of interest and the outcome of receiving immunotherapy.
The OS rates for those who received immunotherapy and those who did not receive immunotherapy were reported.The OS rates for immunotherapy plus RT vs RT alone, immunotherapy plus chemotherapy vs chemotherapy alone, and immunotherapy plus chemoradiation vs chemoradiation alone were also reported.Kaplan-Meier curves were used to report the median OS, and the log-rank test was used to indicate the significance of the findings.We also reported the Kaplan-Meier curves for the OS of patients who received immunotherapy combined with RT, chemotherapy, or chemoradiation.The Cox proportional hazard regression was used to report the hazard of death.The hazard ratio (HR) and its 95% CI for all the variables of interest were reported.Univariable Cox proportional analysis was performed for all the covariates of interest.Variables with a P < .15 in the univariable analysis were selected for the multivariable analysis.We performed all statistical analyses in SAS version 9.4 (SAS Institute).Statistical significance was set at P < .05,and all tests were 2-tailed.2B).

Patient and Treatment Characteristics
In the univariable Cox proportional hazard analysis (Table 2), patients who received immunotherapy had improved OS compared with their counterparts (HR, 0.73; 95% CI, 0.60-0.88;P < .001).We also found significantly improved OS among patients who received RT plus immunotherapy vs RT alone (HR, 0.66; 95% CI, 0.49-0.89;P = .006)and chemoradiation plus immunotherapy vs chemoradiation alone (HR, 0.72; 95% CI, 0.53-0.99;P = .04)(Table 3).Younger age, female sex, living in areas with median income of $35 000 or greater, receiving treatment at academic centers, having a comorbidity score of 0, receiving chemotherapy, receiving RT, and having a tumor type of non-small cell lung cancer were also associated with improved OS in the univariable analysis (Table 2).
In the multivariable analysis (Table 2) adjusted for age at diagnosis, sex, income, hospital type, comorbidity score, and receipt of chemotherapy or RT, patients who received immunotherapy had significantly improved OS compared with no immunotherapy (HR, 0.62; 95% CI, 0.51-0.76;P < .001).
Treatment with RT plus immunotherapy was associated with significantly improved OS compared with RT alone (HR, 0.59; 95% CI, 0.42-0.84;P = .003)in the multivariable analysis.Chemotherapy plus immunotherapy and chemoradiation plus immunotherapy were not associated with improved OS in the multivariable analysis (Table 3).Younger age, academic hospital type, comorbidity score of 0, receiving chemotherapy, and tumor type of non-small cell lung cancer were associated with improved OS in the multivariable analysis.

Discussion
In the current analysis, we found significant OS benefit for patients who received immunotherapy combined with RT compared with RT alone.Younger age, receiving treatment at an academic center, comorbidity score of 0, primary cancer of non-small cell lung cancer, and use of RT were associated with improved OS. Median OS was longer in patients who received RT plus immunotherapy compared with patients who only received RT alone.0][31] In the multivariable analysis in this study, we found that RT plus immunotherapy was associated with significantly improved OS compared with RT alone (HR, 0.59; 95% CI, 0.42-0.84;P = .003).Previously published studies have also investigated the association of immunotherapy combined with RT and chemotherapy with outcomes.  Most][37]  a The variables of race, education, income, place of residence, insurance status, and chemotherapy were not included in the multivariable logistic regression analysis above because each of them had a P > .15 in the univariate analysis.
[31][32][35][36][37] However, based on our knowledge, none of the previous studies included patients with non-small cell lung cancer, breast cancer, small cell lung cancer, CRC, or kidney cancer.
What is unique in our study is that we found that immunotherapy was associated with significantly improved survival in patients with BMs who received surgery of the primary site, which has not, to our knowledge, been investigated so far.The improved OS with the addition of immunotherapy to RT may indicate the synergetic or additive effect of immunotherapy with RT.The improved OS in patients who received RT plus immunotherapy may be associated with the abscopal effect of RT.9][40][41] Immunotherapy may enhance the optimal effect of the abscopal effect by increasing and improving the immune response to tumor-associated antigens, notably when the removal of the primary tumor minimizes the tumor burden.3][44] For patients with significant extracranial disease, the addition of immunotherapy may improve survival by controlling extracranial disease.
However, for those without or with minimal extracranial disease, the association of immunotherapy with survival will be mediated through the control of BMs, which will be influenced by the drug permeability of BBB.
To our knowledge, this study is the first to use an extensive database such as NCDB and to investigate the association of immunotherapy combined with chemotherapy and/or RT with the OS of patients with BMs who received definitive surgery of the primary tumor.The findings of our study, together with the results of the previously published studies of immunotherapy in patients with melanoma, warrant future clinical trials of immunotherapy combined with chemotherapy and/or RT in patients who receive definitive surgery of the primary tumor.Patients with BMs have been historically excluded from clinical trials of immunotherapy due to poor survival and fear of adverse effects.For patients with BMs who do not participate in clinical trials, proper treatment of BM still requires multidisciplinary input regarding appropriate integration from surgery, radiation, and systemic therapies.Furthermore, the quality of life of patients and long-term toxic effects should be carefully weighed when immunotherapy is recommended.Immunotherapy is not a standard-ofcare treatment in BMs outside of clinical trials.However, some patients are receiving immunotherapy.These patients may have been taking part in a clinical trial and received immunotherapy as part of a study.Patients who participate in trials are highly selected populations and usually have better prognoses.However, in our study, 83 of 170 patients (48.82%) for whom information regarding treatment facility was available were treated at academic centers, an indication that most patients may have been treated at community centers and may not have been participating in clinical trials.However, we cannot determine whether a patient was participating in a clinical trial by using the treatment facility variable.It is also possible that immunotherapy was recommended for patients who could not tolerate standard-of-care treatments or failed to show any response to standard-of-care treatments.Last but not least, immunotherapy could be recommended for patients who have exhausted many lines of standard-of-care treatments.The strength of this study is the large sample size and the inclusion of patients with various primary tumors.

Figure 1 .No
Figure 1.Overall Survival With or Without Definitive Surgery of the Primary Tumor Site 5 months regardless of what other treatments they received.Immunotherapy combined with RT improved OS by 10 months compared with those who only received RT.

Table 1 .
Immunotherapy Among Patients With Brain Metastases Whose Cancer Was Managed With Definitive SurgeryOutcomesPatients with older age, male sex, comorbidity score of 0, diagnosis in 2014 or after, and primary cancer types of breast cancer, melanoma, and CRC (vs kidney cancer) were positively associated with the use of immunotherapy in the multivariable logistic analysis.The odds ratios of the factors associated with receiving immunotherapy are provided in Patients who received immunotherapy had better OS compared with those who did not receive immunotherapy, with an age at diagnosis was 61(19-90)years.From 3112 patients analyzed, 183 (5.88%) received immunotherapy, 318 (10.22%) received chemotherapy alone, 788 (25.32%) received RT alone, and 1393 (44.76%) received chemoradiation alone.Overall, 22 patients (6.47%) received chemotherapy plus immunotherapy, 72 patients (8.37%) received RT plus immunotherapy, and 76 patients (5.17%) received chemoradiation plus immunotherapy.JAMA Network Open | Oncology

Table 1 .
Multivariable Logistic Regression Analysis of the Factors Associated With the Receipt of Immunotherapy

Table 2 .
Univariable and Multivariable Cox Proportional Regression Analysis of Factors Associated With Overall Survival a These variables were not included in the multivariable analysis because they had P > .15 in the univariable analysis.