Ipilmumab and cranial radiation in metastatic melanoma patients: a case series and review
© Schoenfeld et al. 2015
Received: 3 September 2015
Accepted: 14 October 2015
Published: 15 December 2015
Ipilimumab improves survival in metastatic melanoma patients. This population frequently develops brain metastases, which have been associated with poor survival and are often treated with radiation. Therefore, outcomes following ipilimumab and radiation are of interest, especially given case reports and animal studies suggest combined treatment may generate abscopal responses outside the radiation field.
We reviewed sixteen consecutive melanoma patients who received 1 to 8 courses of radiation, with a sum total of 51, systematically evaluating abscopal responses by following the largest extra-cranial lesion. We also reviewed other series of patients treated with cranial radiation and ipilimumab.
Our patients received between 1 and 8 courses of cranial radiation. Four patients received radiation concurrently with ipilimumab. Median survival was 14 months, and 17 months in patients initially treated with SRS. Interestingly, after radiotherapy, there was a 2.8-fold increased likelihood that the rate of extra-cranial index lesion response improved that didn’t reach statistical significance (p = 0.07); this was more pronounced when ipilimumab was administered within three months of radiation (p < 0.01).
Our experience and review of recently published series suggest ipilimumab and cranial radiation is well tolerated and can result in prolonged survival. Timing of ipilimumab administration in relation to radiation may impact outcomes. Additionally, our results demonstrate a trend for favorable systemic response following radiotherapy worthy of further evaluation in studies powered to detect potential synergies between radiation and immunotherapy.
KeywordsMelanoma Ipilimumab Immunotherapy Radiation Abscopal effect Brain metastases Stereotactic radiosurgery
Approximately 30–50 % of metastatic melanoma patients develop brain metastases, which have historically been associated with limited survival of approximately four months . Treatment typically includes whole-brain radiation (WBRT) or stereotactic radiosurgery (SRS) . Ipilimumab has also demonstrated promise treating brain metastases in both a prospective trial  and a randomized trial including patients with intracranial disease .
Given the survival benefit associated with ipilimumab [4, 5] the combination of ipilimumab and cranial radiotherapy is of interest. Additionally, the effect of radiation and ipilimumab is intriguing given case reports and preclinical studies that suggest abscopal responses after radiation and immunotherapy [6, 7]. We sought to systematically explore this phenomenon by reviewing our experience and other recently published series describing patients treated with the combination of ipilimumab and cranial radiation.
Materials and methods
Patients and treatment
Sixteen consecutive patients with malignant melanoma were treated with ipilimumab and at least one instance of cranial radiation between 2008 and 2013 at our institution. This study was approved by our institutional review board as described in the Ackowledgments. No patient consent was required as this was a retrospective study.
Ipilimumab was generally given every three weeks for a total of four doses at a dose of either 3 mg/kg (n = 14) or 10 mg/kg (n = 2); patients achieving clinical benefit were offered maintenance therapy every twelve weeks. Cranial radiation was either WBRT or SRS. No patients received SRS as a planned boost. SRS was delivered using the Cyberknife (Accuray, Sunnvale, CA) system prescribed to the clinical tumor volume (CTV) which was equivalent to the planning tumor volume.
Evaluation of response
A multimodality team including a medical, and radiation oncologist along with a neurosurgeon regularly followed all patients at least every 3 months until death. While receiving ipilimumab, evaluation of systemic response using mWHO criteria was performed with computed tomography or magnetic resonance imaging generally after four initial cycles and then at three-month intervals unless otherwise indicated. To evaluate abscopal effect, we extracted the longest diameter of the largest extra-cranial “index” lesion from the medical record, and changes between subsequent scans were calculated. A “delta-delta” was calculated as the difference in percent change of the index lesion on the two consecutive scans performed prior to radiation therapy as compared with the difference in the consecutive scans performed pre- and post-radiation as described previously .
We calculated overall survival from the last day of the first cranial radiation course using the Kaplan-Meier method. Responses before and after radiotherapy were compared using McNemar’s and binomial tests for clustered data. Two-group exact tests for clustered data were used to explore the impact of treatment timing on response. All statistical tests were two-sided.
Patient (n = 16) and radiation treatment (n = 51) characteristics
13 (81 %)
Age at time of initial brain radiation, median (range)
57 years (40 – 85 years)
2 (13 %)
14 (88 %)
Number of ipilimumab treatments, median (range)
4 (1 – 17)
Number of radiation courses per patient, median (range)
Number of lesions irradiated
23 (45 %)
15 (29 %)
13 (25 %)
Type of radiotherapya
Whole brain radiation
5 (10 %)
46 (90 %)
Radiation Dose (Gray), median (range)
Whole brain radiation
36 Gy (20 – 36 Gy)
22 Gy (18 – 24 Gy)
Location of index lesion
Skin/subcutaneous tissue/lymph nodes
8 (26 %)
14 (45 %)
9 (29 %)
Not imaged / Unknown
Seven patients received ipilimumab before brain-directed radiation, and 5 patients began ipilimumab after radiation. Four patients received radiation at some point while undergoing ipilimumab treatment and continued ipilimumab following radiation (concurrent treatment). Among these four patients who received concurrent treatment, in one patient, both treatments were given on the same day, and in two patients, concurrent treatment occurred multiple times. Overall, ipilimumab treatment was given within 3 months of radiation in 21 instances (41 %); in the remaining 59 %, ipilimumab was administered a median of 3.5 months prior to radiation.
Sequential imaging of systemic index lesions was performed before and after radiation in 31 instances. These lesions were most commonly located in the chest (45 %, Table 1). On the subsequent scan after radiation, in 11 of these 31 instances (35 %) the index lesion decreased in size as compared with the scan preceding radiation therapy. In comparison, in 25 of these 31 instances the index lesion size was also comparable on two scans prior to radiation treatment, and only 4 (17 %) demonstrated a favorable response (p = 0.20, McNemar’s test for clustered paired data). Among the 31 instances where imaging was available before and after radiation, there were 22 instances where two consecutive scans were also performed prior to the receipt of radiotherapy. In these cases, the response rate of index lesion response improved in 50 % of instances following radiation in comparison to worsening in 18 % (p = 0.07, binomial test for clustered data). In contrast, there was no significant association between time elapsed since first ipilimumab administration and favorable kinetics (p = 0.88).
We describe our experience treating melanoma patients with cranial radiation and ipilimumab. We report a median OS greater than 1 year in 16 patients that received a total of 51 radiotherapy courses including patients who received WBRT, multiple courses for recurrent disease, and patients who received radiotherapy concurrent with ipilimumab. These results compare favorably with historical series of melanoma patients with brain metastases treated with surgery and radiotherapy that describe median OS of less than 9 months, and less than 4 months in patients treated with radiotherapy alone . Two-year OS in our series was 25 % and prolonged OS of over 50 months was observed. Similar favorable outcomes have also been seen in patients treated concurrently with ipilimumab and radiation of extra cranial lesions .
Review of studies evaluating patients treated with cranial radiation and ipilimumab
Median overall survival (mos)
Radiation necrosis requiring surgery
Kiess et al. 
1 yr OS 40–65 % depending on timing of ipi
Routine use of ppx steroids
SRS before or during ipi associated with improved OS
Knisely et al. 
2 yr OS 47 %
SRS before ipi associated with trend towards improved survival
Mathew et al. 
6 mos OS 56 %
Routine use of ppx steroids
Schoenfeld et al. (current study)
1 yr OS 54 %
No routine use of ppx steroids
SRS before ipi associated with better survival
Shoukat et al. 
1 yr OS 67 %
Tazi et al. 
2 yr OS 58 %
All patients received SRS before or during ipi
Interestingly, the two other studies that reported the shortest median OS reported routine use of prophylactic steroids at the time of SRS [10, 11]. Although data suggests that steroids administered for ipilimumab-induced immune-related adverse events do not adversely impact the efficacy of treatment, further evaluation of prophylactic steroids for asymptomatic patients may be warranted [12, 13].
Our analysis included evaluation of index systemic lesion response in relation to the timing of brain-directed radiotherapy and ipilimumab administration. Other retrospective studies have suggested radiation may be associated with a favorable systemic response in patients progressing on ipilimumab who receive radiation to a variety of sites [8, 14]. Similarly, we found that index lesions decreased in size after brain directed radiotherapy in 63 % patients who received both radiotherapy and ipilimumab within a three-month span. The limited number of patients analyzed constrained our power to detect statistically significant differences; however index lesions were approximately twice as likely to decrease in size on imaging following radiation, with the additive benefit of improved kinetics of response. Although delayed index lesion response to ipilimumab or favorable response to ipilimumab as compared to other systemic agents may partially explain these results, ipilimumab had been administered for more than three months prior to radiotherapy in 27 (53 %) of instances and there was no significant association between duration of ipilimumab and favorable kinetics.
Radiation has potential immunogenic properties [15, 16] and the combination of ipilimumab and local radiotherapy increased systemic anti-tumor responses and improved OS in a mouse model of breast carcinoma . Case reports and small studies have suggested similar radiation-stimulated immune phenomenon in humans, with the combination of radiation and ipilimumab resulting in increased antigen targeting, decreased numbers of inhibitory myeloid-derived suppressor cells, and increased levels of anti-tumor antibodies and circulating activated T-cells [6, 7, 18]. Our results add to this growing body of evidence that suggest that future studies should continue to examine the potential synergies between radiotherapy and immunotherapy.
Whole brain radiation therapy
JDS is supported in part by the Claudia Adams Barr Program for Innovative Cancer Research. This study was approved by the Dana-Farber Harvard Cancer Center Institutional Review Board which approves retrospective studies such as this conducted at Beth Israel Deaconess Medical Center.
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