Abstract
This study investigates the association between immunotherapy and symptomatic radiation necrosis in patients with melanoma, non–small-cell lung cancer, or renal cell carcinoma and newly diagnosed brain metastases treated with stereotactic radiation therapy.
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).
Table. Baseline Patient Characteristics at Time of Diagnosis of Brain Metastases in Patients Who Did or Did Not Receive Immunotherapy.
| Characteristic | No. (%) | P Valuea | |
|---|---|---|---|
| No Immunotherapy (n = 365) |
Immunotherapy (n = 115) |
||
| Age, mean (SD), y | 62 (11) | 61 (11) | .17 |
| Sex | .13 | ||
| Female | 166 (45) | 43 (37) | |
| Male | 199 (55) | 72 (63) | |
| Race | .04 | ||
| White | 313 (86) | 109 (95) | |
| African American | 17 (5) | 0 | |
| Hispanic | 6 (2) | 1 (1) | |
| Asian | 15 (4) | 1 (1) | |
| Other | 1 (<1) | 0 | |
| Unknown | 13 (4) | 4 (3) | |
| Primary cancer | <.001 | ||
| Melanoma | 73 (20) | 72 (63) | |
| NSCLC | 256 (70) | 38 (33) | |
| Renal cell carcinoma | 36 (10) | 5 (4) | |
| KPS, median (IQR) | 90 (80-90) | 90 (80-90) | .16 |
| Size of largest metastasis, median (IQR), mm | 14 (8-22) | 12 (6-22) | .20 |
| Neurologic symptoms | 170 (47) | 64 (57) | .07 |
| Seizures | 6 (2) | 2 (2) | .99 |
| Primary cancer controlled | 172 (47) | 62 (54) | .31 |
| Extracranial disease | 290 (79) | 102 (89) | .03 |
| Extracranial disease sites | |||
| Lung | 169 (46) | 72 (63) | .003 |
| Liver | 35 (10) | 24 (21) | .003 |
| Bone | 69 (19) | 35 (30) | .01 |
| Lymph nodes | 110 (30) | 47 (41) | .04 |
| Soft tissue | 47 (13) | 34 (30) | <.001 |
| Adrenal | 37 (10) | 9 (8) | .59 |
| Type of initial radiation | .24 | ||
| SRS | 291 (80) | 88 (77) | |
| SRT | 55 (15) | 16 (14) | |
| SRS and SRT | 19 (5) | 11 (10) | |
| Systemic therapy prior to SRS/SRT | 106 (29) | 41 (36) | .20 |
| No. of prior systemic therapy regimens, median (IQR) | 0 (0-1) | 0 (0-1) | .29 |
| Salvage whole brain radiation after initial SRS/SRT | 95 (26) | 33 (29) | .63 |
| SRS/SRT after initial SRS/SRT | 127 (35) | 59 (51) | .002 |
Abbreviations: IQR, interquartile range; KPS, Karnsofsky performance status; NSCLC, non–small-cell lung cancer; SD, standard deviation; SRS, stereotactic radiosurgery; SRT, stereotactic radiotherapy.
Baseline patient characteristics in patients who received immunotherapy vs not were compared using the t test, Wilcoxon rank sum test, and Fisher exact test, as indicated.
Figure. Kaplan-Meier Curves Displaying Freedom From Symptomatic Necrosis as Stratified by Receipt of Immunotherapy vs No Receipt of Immunotherapy.
Log rank P<.001.
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.
References
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