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Figure.
Kaplan-Meier Curves Displaying Freedom From Symptomatic Necrosis as Stratified by Receipt of Immunotherapy vs No Receipt of Immunotherapy
Kaplan-Meier Curves Displaying Freedom From Symptomatic Necrosis as Stratified by Receipt of Immunotherapy vs No Receipt of Immunotherapy

Log rank P<.001.

Table.  
Baseline Patient Characteristics at Time of Diagnosis of Brain Metastases in Patients Who Did or Did Not Receive Immunotherapy
Baseline Patient Characteristics at Time of Diagnosis of Brain Metastases in Patients Who Did or Did Not Receive Immunotherapy
1.
Giglio  P, Gilbert  MR.  Cerebral radiation necrosis.  Neurologist. 2003;9(4):180-188.PubMedGoogle ScholarCrossref
2.
Chasset  F, Pages  C, Biard  L,  et al.  Single-center study under a French Temporary Authorization for Use (TAU) protocol for ipilimumab in metastatic melanoma: negative impact of baseline corticosteroids.  Eur J Dermatol. 2015;25(1):36-44.PubMedGoogle Scholar
3.
Goldberg  SB, Gettinger  SN, Mahajan  A,  et al.  Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial.  Lancet Oncol. 2016;17(7):976-983.PubMedGoogle ScholarCrossref
4.
Margolin  K, Ernstoff  MS, Hamid  O,  et al.  Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial.  Lancet Oncol. 2012;13(5):459-465.PubMedGoogle ScholarCrossref
5.
Tawbi  HA-H, Forsyth  PAJ, Algazi  AP,  et al.  Efficacy and safety of nivolumab (NIVO) plus ipilimumab (IPI) in patients with melanoma (MEL) metastatic to the brain: results of the phase II study CheckMate 204.  J Clin Oncol. 2017;35(suppl 15):9507-9507.Google Scholar
6.
Long  GV, Atkinson  V, Menzies  AM,  et al.  A randomized phase II study of nivolumab or nivolumab combined with ipilimumab in patients (pts) with melanoma brain metastases (mets): The Anti-PD1 Brain Collaboration (ABC).  J Clin Oncol. 2017;35(suppl 15):9508-9508.Google Scholar
Research Letter
August 2018

Immunotherapy and Symptomatic Radiation Necrosis in Patients With Brain Metastases Treated With Stereotactic Radiation

Author Affiliations
  • 1Department of Radiation Oncology, Dana-Farber/Brigham and Women’s Cancer Center, Harvard Medical School, Boston, Massachusetts
  • 2Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
  • 3Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
  • 4Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
JAMA Oncol. 2018;4(8):1123-1124. doi:10.1001/jamaoncol.2017.3993

Immunotherapeutic checkpoint inhibitors are commonly used in patients with melanoma, non–small cell lung cancer (NSCLC), and renal cell carcinoma (RCC), all cancers that frequently metastasize to the brain. Radiation therapy is frequently used for brain metastases because few systemic agents effectively penetrate the blood-brain barrier. The most deleterious consequence of brain-directed, stereotactic radiation is radiation necrosis—inflammation and/or injury to the brain abutting the treated tumor.1 Published literature has suggested that brain-directed stereotactic radiation in patients also receiving immunotherapy may yield beneficial, synergistic effects; however, few studies have examined radiation necrosis. We investigated the association between immunotherapy and symptomatic radiation necrosis in patients with melanoma, NSCLC, or RCC and newly diagnosed brain metastases treated with stereotactic radiation.

Methods

The institutional review board of Dana-Farber Cancer Institute approved the project and informed consent was waived. We identified 480 patients with newly diagnosed brain metastases secondary to NSCLC (n = 294), melanoma (n = 145), and RCC (n = 41) treated with stereotactic radiation at Brigham and Women’s Hospital/Dana-Farber Cancer Institute between 2001 and 2015; of these, 115 patients received immunotherapeutic checkpoint inhibitors (ipilimumab, pembrolizumab, or nivolumab) whereas 365 did not. Target tumors that were 0 to 2 cm, 2 to 3 cm, and larger than 3 cm in maximal diameter generally received 18 to 20 Gy in 1 fraction, 18 Gy in 1 fraction, and 25 to 30 Gy in 5 fractions, respectively. Patients received immunotherapy for a median of 14.3 (IQR, 8.0-31.0) weeks. Symptomatic radiation necrosis was defined as an enlarging lesion after stereotactic radiation causing neurologic symptomatology that displayed one of the following characteristics: pathology specimen showing only necrosis (if surgical resection performed) or changes consistent with necrosis on dual-phase positron emission tomography–computed tomography (PET-CT) or serial magnetic resonance imaging (MRI).

All time-to-event analyses were performed using Kaplan-Meier plots and Cox regression in SAS statistical software package (version 9.4, SAS Institute). The assumption of proportional hazards was verified. The median follow-up of surviving patients who did vs did not receive immunotherapy was 23.1 (IQR, 15.4-42.1) vs 25.1 (IQR, 15.2-34.3) months, respectively.

Results

Patient characteristics at diagnosis of brain metastases in patients who did and did not receive immunotherapy were generally well balanced (Table). Symptomatic necrosis occurred in 23 of 115 and 25 of 365 patients who did vs did not receive immunotherapy, respectively (Figure). Receipt of immunotherapy was associated with symptomatic radiation necrosis after adjustment for tumor histology (HR, 2.56; 95% CI, 1.35-4.86; P = .004); this association was especially strong in patients with melanoma (HR, 4.02; 95% CI, 1.17-13.82; P = .03). Among patients with melanoma, receipt of ipilimumab vs no immunotherapy (HR, 4.70; 95% CI, 1.36-16.19; P = .01) and programmed cell death protein 1 (PD-1) inhibition vs no immunotherapy (HR, 3.57; 95% CI, 0.94-13.53; P = .06) were associated with development of symptomatic necrosis, although the association with PD-1 inhibition was not statistically significant. Of the 23 patients who received immunotherapy and developed symptomatic necrosis, 18 (78%) were treated with dexamethasone (median duration, 1.8 months).

Discussion

Radiation necrosis significantly impacts quality of life; focal neurologic deficits are common, as are headaches, nausea, and seizures. Steroids are often given, potentially minimizing the efficacy of immunotherapy.2 Given the strong association between immunotherapy and symptomatic radiation necrosis that we observed, utilization of immunotherapy as monotherapy for treatment of brain metastases has appeal. However, intracranial response rates to immune-checkpoint monotherapy in patients with brain metastases are generally low,3,4 although concurrent ipilimumab plus nivolumab in melanoma has promise.5,6

Limitations

Limitations of our study include its retrospective nature and the small sample size, which prevented use of a propensity score matching analysis. In addition, there is potential for error in radiographic delineation of necrosis from tumor progression. However, we found high agreement between radiographic-only delineation of necrosis vs progression in patients undergoing surgery (by the senior author, A.A., blinded to the surgical results) and the surgical pathology (κ = .76).

Conclusions

We found an association between receipt of immunotherapy and symptomatic radiation necrosis in patients undergoing stereotactic radiation for brain metastases. Prospective studies are needed to better characterize the risks and benefits of combining brain-directed stereotactic radiation with immunotherapy in this population.

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Article Information

Corresponding Author: Ayal Aizer, MD, MHS, Department of Radiation Oncology, Brigham and Women’s Hospital, 75 Francis St, ASB1-L2, Boston, MA 02115 (aaaizer@partners.org).

Accepted for Publication: September 16, 2017.

Published Online: January 11, 2018. doi:10.1001/jamaoncol.2017.3993

Author Contributions: Drs Martin and Aizer had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Martin, Redig, Schoenfeld, Aizer.

Acquisition, analysis, or interpretation of data: Martin, Cagney, Catalano, Alexander, Schoenfeld, Aizer.

Drafting of the manuscript: Martin, Cagney, Catalano, Redig, Aizer.

Critical revision of the manuscript for important intellectual content: Martin, Alexander, Redig, Schoenfeld, Aizer.

Statistical analysis: Martin, Catalano, Aizer.

Administrative, technical, or material support: Martin, Cagney, Alexander, Redig, Schoenfeld, Aizer.

Study supervision: Alexander, Schoenfeld, Aizer.

Conflict of Interest Disclosures: Dr Redig reports consulting fees from Medtronic, Boehringer-Ingelheim, and Proactive Worldwide Inc. Dr Schoenfeld reports consulting and scientific advisory board fees for BMS, AstraZeneca, Nanobiotix, Tilos, Debiopharm as well as research funding from Merck and BMS. Dr Aizer reports research funding from Varian Medical Systems. No other conflicts are reported.

References
1.
Giglio  P, Gilbert  MR.  Cerebral radiation necrosis.  Neurologist. 2003;9(4):180-188.PubMedGoogle ScholarCrossref
2.
Chasset  F, Pages  C, Biard  L,  et al.  Single-center study under a French Temporary Authorization for Use (TAU) protocol for ipilimumab in metastatic melanoma: negative impact of baseline corticosteroids.  Eur J Dermatol. 2015;25(1):36-44.PubMedGoogle Scholar
3.
Goldberg  SB, Gettinger  SN, Mahajan  A,  et al.  Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial.  Lancet Oncol. 2016;17(7):976-983.PubMedGoogle ScholarCrossref
4.
Margolin  K, Ernstoff  MS, Hamid  O,  et al.  Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial.  Lancet Oncol. 2012;13(5):459-465.PubMedGoogle ScholarCrossref
5.
Tawbi  HA-H, Forsyth  PAJ, Algazi  AP,  et al.  Efficacy and safety of nivolumab (NIVO) plus ipilimumab (IPI) in patients with melanoma (MEL) metastatic to the brain: results of the phase II study CheckMate 204.  J Clin Oncol. 2017;35(suppl 15):9507-9507.Google Scholar
6.
Long  GV, Atkinson  V, Menzies  AM,  et al.  A randomized phase II study of nivolumab or nivolumab combined with ipilimumab in patients (pts) with melanoma brain metastases (mets): The Anti-PD1 Brain Collaboration (ABC).  J Clin Oncol. 2017;35(suppl 15):9508-9508.Google Scholar
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