Letters

RESEARCH LETTER Table. Baseline Patient Characteristics at Time of Diagnosis of Brain

Metastases in Patients Who Did or Did Not Receive Immunotherapy
Immunotherapy and Symptomatic Radiation
No. (%)
Necrosis in Patients With Brain Metastases No
Treated With Stereotactic Radiation Immuno- Immuno-
therapy therapy
Immunotherapeutic checkpoint inhibitors are commonly used Characteristic (n = 365) (n = 115) P Valuea
in patients with melanoma, non–small cell lung cancer Age, mean (SD), y 62 (11) 61 (11) .17
(NSCLC), and renal cell carcinoma (RCC), all cancers that fre- Sex .13
quently metastasize to the Female 166 (45) 43 (37)
brain. Radiation therapy is Male 199 (55) 72 (63)
Invited Commentary page 1116 frequently used for brain Race .04
metastases bec ause few White 313 (86) 109 (95)
Related article page 1112 systemic agents effectively African American 17 (5) 0
penetrate the blood-brain Hispanic 6 (2) 1 (1)

barrier. The most deleterious consequence of brain-directed, Asian 15 (4) 1 (1)

Other 1 (<1) 0
stereotactic radiation is radiation necrosis—inflammation
Unknown 13 (4) 4 (3)
and/or injury to the brain abutting the treated tumor.1 Pub-
Primary cancer <.001
lished literature has suggested that brain-directed stereotac-
Melanoma 73 (20) 72 (63)
tic radiation in patients also receiving immunotherapy may
NSCLC 256 (70) 38 (33)
yield beneficial, synergistic effects; however, few studies have
Renal cell carcinoma 36 (10) 5 (4)
examined radiation necrosis. We investigated the association
KPS, median (IQR) 90 (80-90) 90 (80-90) .16
between immunotherapy and symptomatic radiation necro-
Size of largest metastasis, 14 (8-22) 12 (6-22) .20
sis in patients with melanoma, NSCLC, or RCC and newly di- median (IQR), mm
agnosed brain metastases treated with stereotactic radiation. Neurologic symptoms 170 (47) 64 (57) .07
Seizures 6 (2) 2 (2) .99
Methods | The institutional review board of Dana-Farber Can- Primary cancer controlled 172 (47) 62 (54) .31
cer Institute approved the project and informed consent was Extracranial disease 290 (79) 102 (89) .03

waived. We identified 480 patients with newly diagnosed Extracranial disease sites
Lung 169 (46) 72 (63) .003
brain metastases secondary to NSCLC (n = 294), melanoma
Liver 35 (10) 24 (21) .003
(n = 145), and RCC (n = 41) treated with stereotactic radiation
Bone 69 (19) 35 (30) .01
at Brigham and Women’s Hospital/Dana-Farber Cancer Insti-
Lymph nodes 110 (30) 47 (41) .04
tute between 2001 and 2015; of these, 115 patients received
Soft tissue 47 (13) 34 (30) <.001
immunotherapeutic checkpoint inhibitors (ipilimumab,
Adrenal 37 (10) 9 (8) .59
pembrolizumab, or nivolumab) whereas 365 did not. Target
Type of initial radiation .24
tumors that were 0 to 2 cm, 2 to 3 cm, and larger than 3 cm
SRS 291 (80) 88 (77)
in maximal diameter generally received 18 to 20 Gy in 1 frac- SRT 55 (15) 16 (14)
tion, 18 Gy in 1 fraction, and 25 to 30 Gy in 5 fractions, SRS and SRT 19 (5) 11 (10)
respectively. Patients received immunotherapy for a median Systemic therapy prior to SRS/SRT 106 (29) 41 (36) .20
of 14.3 (IQR, 8.0-31.0) weeks. Symptomatic radiation necro- No. of prior systemic therapy 0 (0-1) 0 (0-1) .29
sis was defined as an enlarging lesion after stereotactic regimens, median (IQR)
Salvage whole brain radiation 95 (26) 33 (29) .63
radiation causing neurologic symptomatology that displayed after initial SRS/SRT
one of the following characteristics: pathology specimen SRS/SRT after initial SRS/SRT 127 (35) 59 (51) .002
showing only necrosis (if surgical resection performed) or
Abbreviations: IQR, interquartile range; KPS, Karnsofsky performance status;
changes consistent with necrosis on dual-phase positron NSCLC, non–small-cell lung cancer; SD, standard deviation; SRS, stereotactic
emission tomography–computed tomography (PET-CT) or radiosurgery; SRT, stereotactic radiotherapy.
serial magnetic resonance imaging (MRI). a
Baseline patient characteristics in patients who received immunotherapy vs
All time-to-event analyses were performed using Kaplan- not were compared using the t test, Wilcoxon rank sum test, and Fisher exact
test, as indicated.
Meier plots and Cox regression in SAS statistical software pack-
age (version 9.4, SAS Institute). The assumption of propor-
tional hazards was verified. The median follow-up of surviving Results | Patient characteristics at diagnosis of brain metasta-
patients who did vs did not receive immunotherapy was 23.1 ses in patients who did and did not receive immunotherapy
(IQR, 15.4-42.1) vs 25.1 (IQR, 15.2-34.3) months, respectively. were generally well balanced (Table). Symptomatic necrosis

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 Letters
Figure. Kaplan-Meier Curves Displaying Freedom From Symptomatic
Necrosis as Stratified by Receipt of Immunotherapy
vs No Receipt of Immunotherapy
1.0
Freedom From Symptomatic Necrosis
0.8
0.6
0.4
0.2
0 Ayal A. Aizer, MD, MHS
0 1
No. at risk
No immunotherapy 422 203
Immunotherapy 129 67
Log rank P<.001.
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 sympto-
matic 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 (me-
dian 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 mini-
mizing the efficacy of immunotherapy.2 Given the strong as-
sociation between immunotherapy and symptomatic radia-
tion necrosis that we observed, utilization of immunotherapy
as monotherapy for treatment of brain metastases has ap-
peal. 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 pro-
pensity score matching analysis. In addition, there is poten-
tial for error in radiographic delineation of necrosis from tu-
mor progression. However, we found high agreement between
radiographic-only delineation of necrosis vs progression in pa-
tients undergoing surgery (by the senior author, A.A., blinded
to the surgical results) and the surgical pathology (κ = .76).
1124 JAMA Oncology August 2018 Volume 4, Number 8 (Reprinted)
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Conclusions | We found an association between receipt of im-
munotherapy and symptomatic radiation necrosis in pa-
tients undergoing stereotactic radiation for brain metastases.
Prospective studies are needed to better characterize the risks
and benefits of combining brain-directed stereotactic radia-
No immunotherapy tion with immunotherapy in this population.
Allison M. Martin, BS
Immunotherapy
Daniel N. Cagney, MD
Paul J. Catalano, ScD
Brian M. Alexander, MD, MPH
Amanda J. Redig, MD, PhD
Jon D. Schoenfeld, MD, MPH
2 3 4 5 6 7 8 9 10
Time, y Author Affiliations: Department of Radiation Oncology, Dana-Farber/Brigham and
Women’s Cancer Center, Harvard Medical School, Boston, Massachusetts (Martin,
82 41 20 13 6 3 2 2 1
21 7 4 4 3 2 1 1 0 Cagney,Alexander,Schoenfeld,Aizer); Department of Biostatistics, Harvard T. H. Chan
School of Public Health, Boston, Massachusetts (Catalano); Department of
Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston,
Massachusetts (Catalano); Department of Medical Oncology, Dana-Farber Cancer
Institute, Harvard Medical School, Boston, Massachusetts (Redig).
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,andProactiveWorldwideInc.DrSchoenfeldreportsconsulting
andscientificadvisoryboardfeesforBMS,AstraZeneca,Nanobiotix,Tilos,Debiopharm
aswellasresearchfundingfromMerckandBMS.DrAizerreportsresearchfundingfrom
Varian Medical Systems. No other conflicts are reported.
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