ORIGINAL ARTICLE
Ipilimumab and Stereotactic Radiosurgery Versus Stereotactic Radiosurgery Alone for Newly Diagnosed Melanoma Brain Metastases Kirtesh R. Patel, MD,* Sana Shoukat, MD,w Daniel E. Oliver, BA,z Mudit Chowdhary, BA,z Monica Rizzo, MD,y David H. Lawson, MD,8 Faisal Khosa, MD,z Yuan Liu, PhD,# and Mohammad K. Khan, MD, PhD*
Background: We compared the safety and efficacy of ipilimumab and stereotactic radiosurgery (SRS) to SRS alone for newly diagnosed melanoma brain metastases (MBM). Materials and Methods: We reviewed records of newly diagnosed MBM patients treated with SRS from 2009 to 2013. The primary endpoint of overall survival (OS), and secondary endpoints of local control, distant intracranial failure, and radiation necrosis were compared using Kaplan-Meier method. Univariate and multivariate analysis were performed using the Cox proportional hazards method. Results: Fifty-four consecutive MBM patients were identified, with 20 (37.0%) receiving ipilimumab within 4 months of SRS. Ipilimumabtreated and non-ipilimumab–treated patients had similar baseline characteristics. No difference in symptomatic radiation necrosis or hemorrhage was identified between cohorts. Compared with patients in the nonipilimumab group, 1 year local control (71.4% vs. 92.3%, P = 0.40) and intracranial control (12.7% vs. 29.1%, P = 0.59) were also statistically similar. The ipilimumab cohort also had no difference in 1-year OS (37.1% vs. 38.5%, P = 0.84). Patients administered ipilimumab within 14 days of SRS had higher 1-year (42.9%) and 2-year OS (42.9%) relative to ipilimumab delivered >14 days (33.8%, 16.9%) and SRS alone (38.5%, 25.7%) but these difference were not statistically significant. Univariate analysis and multivariate analysis both confirmed single brain metastasis, controlled primary, and active systemic disease as predictors for OS. Conclusions: Use of ipilimumab within 4 months of SRS seems to be safe, with no increase in radiation necrosis or hemorrhage; however, our retrospective institutional experience with this treatment regimen was not associated with improved outcomes. Key Words: melanoma brain metastasis, stereotactic radiosurgery, ipilimumab
for metastatic melanoma patients in 2 randomized phase III.1,2 Distinct from chemotherapy or targeted agents, the survival rates stabilized after 2 years and remained durable at 5 years.3,4 These promising results led the FDA to approve anti-CTLA-4 antibody, ipilimumab, for metastatic melanoma. In both of these phase III trials with ipilimumab, patients with melanoma brain metastasis (MBM) were poorly represented: only 12.2% and 0% of patients enrolled to the ipilimumab arms had stable MBM.1,2 With up to 50% of melanoma patients developing brain metastasis (BM),5,6 a poor prognostic indicator,7 the efficacy of ipilimumab against MBM is a highly debated and clinically relevant question. Moreover, with most chemotherapies and targeted agents limited by the blood-brain barrier (BBB),8 achieving improvements in survival for MBM continues to be a challenge. To investigate the efficacy of ipilimumab on intracranial disease, Margolin et al9 conducted a prospective nonrandomized phase II trial of ipilimumab alone for untreated MBM. Although this study demonstrated intracranial response rates similar to previously reported extracranial response rates, 50% to 55% of patients did not complete therapy due to intracranial progression. Furthermore, intracranial local control (LC) rate of 29% with ipilimumab alone was lower than the 67% to 75% LC rate with stereotactic radiation therapy (SRS).10,11 With ipilimumab alone constrained by lower LC and higher intracranial progression, adding radiation is a potential treatment approach to help address these limitations.12,13 The aim of this study is to characterize the safety and efficacy of SRS when combined with ipilimumab for patients with intracranial metastases from melanoma.
(Am J Clin Oncol 2015;00:000–000)
MATERIALS AND METHODS
A
ntibodies targeting cytotoxic T-lymphocyte–associated antigen 4, a T-cell inhibitory signaling molecule, have demonstrated improvements in overall survival (OS) at 3 years
From the Departments of *Radiation Oncology; ySurgery, Division of Surgical Oncology; #Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute; Departments of wInternal Medicine; 8Hematology and Medical Oncology; zRadiology, Emory University; and zEmory University School of Medicine, Atlanta, GA. Supported by BMS. D.H.L. has served on advisory boards for Bristol-Myers Squibb (BMS). The other authors declare no conflicts of interest. Reprints: Mohammad K. Khan MD, PhD, Department of Radiation Oncology, Winship Cancer Institute, Emory University, 1365 Clifton Rd NE, Office A1312, Atlanta, GA 30322. E-mail: [email protected]. Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0277-3732/15/000-000 DOI: 10.1097/COC.0000000000000199
American Journal of Clinical Oncology
Patient Selection After receiving institutional review board approval, we identified 54 consecutive, newly diagnosed MBM patients treated with SRS alone at our institution between 2009 and 2013. Patients who had received prior whole brain radiotherapy (WBRT) were excluded. Patients treated with ipilimumab 3 mg/kg within 4 months of SRS were recorded. Patients treated with higher doses (eg, 10 mg/kg) or receiving maintenance ipilimumab were excluded. For the ipilimumab and SRS cohort, treatment sequence and the number of days between therapies were recorded.
Radiation Treatment Technical details of SRS have been previously described.14,15 In brief, SRS was performed using a linear accelerator with 6 MV photon energies. The T1 postcontrast magnetic
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American Journal of Clinical Oncology
resonance imaging (MRI) defined lesion constituted the gross tumor volume (GTV). No margin was utilized to create a clinical target volume. The GTV was expanded by 1 mm to generate the planning target volume (PTV). BM up to 20 mm in diameter were typically treated to 21 Gy, 21 to 30 mm in diameter to 18 Gy, and 31 to 40 mm in diameter to 15 Gy. Patients with large metastases cavities (typically > 40 mm in diameter) were treated with fractionated radiosurgery over 3 to 5 fractions using a frameless radiosurgery technique.16 All patients charts were reviewed for the following baseline patient characteristics at the time of initial SRS: age, sex, clinical trial enrollment, number of BM, symptomatic from BM, steroid treatment, presence of active systemic disease, primary controlled, Eastern Cooperative Group Oncology performance status (ECOG PS), Recursive Partitioning Analysis, Graded Performance Assessment (GPA) score, lactic dehydrogenase (LDH) value before SRS, prior systemic therapy, and time to next systemic therapy. Radiation treatment parameters were also recorded, including: largest dose per fraction, number of fractions, SRS to a resection cavity, cumulative GTV volume, and PTV margin. Linear acceleratorbased SRS treatment delivery methods—dynamic conformal arc therapy or intensity modulated radiosurgery—were also recorded (Table 1).
Follow-up Follow-up consisted of clinical examination and brain MRI at 4 to 6 weeks after initial SRS, and then at 3 months intervals thereafter unless clinically indicated at an earlier time point. Local recurrence (LR) was defined as the presence of new progressive nodular enhancement involving the prior lesion or resection cavity seen on brain MRI with contrast. Clinical radiation necrosis was defined on the basis of 2 radiographic features: the development of contrast-enhancing mass within prior radiation treatment fields and conventional imaging features, including soap bubble appearance17; if there was a question of the nodular enhancement representing radiation necrosis, additional functional imaging was obtained (eg, MR perfusion, brain positron emission tomography, and MR spectroscopy). Decreased perfusion and elevated lactate were interpreted as areas of necrosis, whereas increased perfusion and elevated choline were interpreted as recurrent disease. For patients with symptomatic radiation necrosis, dexamethasone steroids were typically the first treatment utilized for the SRS alone cohort; because steroids can decrease the number of lymphocytes, which are the main effects of ipilimumab, steroids were typically utilized in shorter courses, or avoided and in lieu of hyperbaric oxygen, bevacizumab, or surgery were more commonly utilized. Distant intracranial failure (DIF) was defined as presence of new enhancing lesions distinctly outside the prior SRS treatment zone. For LR and DIF analyses, patients were censored at time of last brain imaging or salvage WBRT, whichever came first. For OS, death from any cause was defined as the event, and patients were censored at time of last follow-up. For patients who were deceased or lost to follow-up at the time of our analysis, we confirmed the date of death by querying the Social Security Death Index. For patients with progressive intracranial disease, salvage intracranial treatments were recorded, including WBRT, repeat SRS, next systemic therapy, and neurosurgical resection. Decision to treat and the specifics of each treatment were at the discretion of the physician. Toxicity endpoints that were recorded included the development of radionecrosis and hemorrhage on MRI.
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TABLE 1. Baseline Patient Characteristics
Median age (y) Sex Male Female ECOG PS 0 1 Z2 No. BM 1 2-3 Z4 Active systemic disease Yes No Primary controlled Yes No RPA 1 2 3 Symptomatic at time of BM Yes No Steroids Yes No Melanoma-specific GPA 4 3 2 1 BRAF inhibitor Yes No Prior systemic therapy Yes No LDH > 200 r200 Next systemic therapy Yes No Median days to next systemic therapy Single fraction SRS Yes No Radiation to cavity Yes No Median cumulative GTV volume (cm3) Median PTV margin (mm) Radiation delivery method Dynamic conformal arc Intensity modulated radiosurgery
SRS (n = 34)
IPI and SRS (n = 20)
P
60.2
56.5
0.121
28 (82.4%) 6 (17.6%)
13 (65%) 7 (35%)
0.812
11 (32.4%) 15 (44.1%) 8 (23.5%)
9 (45%) 7 (50%) 4 (60%)
0.647
17 (50%) 12 (35.3%) 5 (14.7%)
8 (40%) 10 (50%) 2 (10%)
0.625
22 (64.7%) 12 (35.3%)
17 (85%) 3 (15%)
0.108
20 (58.8%) 14 (41.2%)
11 (55%) 9 (45%)
0.784
4 (11.8%) 28 (82.4%) 2 (5.8%)
1 (5%) 18 (90%) 1 (5%)
0.837
11 (32.4%) 23 (67.65)
2 (10.0%) 18 (90.0%)
0.1
7 (21.9%) 25 (78.1%)
1 (5.6%) 17 (94.4%)
0.231
7 16 6 5
(20.6%) (47.1%) (17.7%) (14.6%)
(25%) (30%) (35%) (10%)
0.423
4 (11.8%) 30 (88.2%)
7 (35%) 13 (65%)
0.077
17 (50%) 17 (50%)
15 (75%) 5 (25%)
0.071
11 (45.8%) 13 (54.2%)
9 (47.4%) 10 (52.6%)
0.92
29 (85.3%) 5 (14.7%) 11
15 (75%) 5 (25%) 15
0.471
34 (100%) 0 (0%)
16 (80%) 4 (20%)
0.015
10 (29.4%) 24 (70.6%) 2.66
3 (15%) 17 (85%) 1.1
0.329
1 27 (87.8%) 6 (18.2%)
5 6 7 2
1 15 (75%) 5 (25%)
0.217
0.508 0.196 0.729
Bold P values denotes statistical significant, P < 0.05. BM indicates brain metastases; ECOG PS, Eastern Cooperative Group Oncology performance status; GPA, graded prognostic analysis; GTV, gross tumor volume; LDH, lactic dehydrogenase; PS, Performance Status; PTV, planning target volume; RPA, recursive portioning analysis.
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American Journal of Clinical Oncology
Volume 00, Number 00, ’’ 2015
Ipilimumab and SRS Versus SRS
FIGURE 1. Kaplan-Meier curve illustrating the comparison of stereotactic radiosurgery (SRS) with ipilimumab (solid line) to SRS alone (dashed line) with respect to overall survival is shown.
Radiation necrosis was diagnosed as detailed above. Intracranial hemorrhage was diagnosed by utilizing diffusion weighted images and confirmed with new changes identified on T1 and T2 sequences. For patients that were symptomatic from these adverse events, interventions utilized for these adverse events were also recorded.
Statistical Analysis Patient age, ECOG PS, and number of BM were classified into categories per previously published prognostic indices.18 The number of BM was separated into categories of 1, 2 to 3, and Z4. The serum LDH level was categorized as normal or elevated.19 Univariate association with ipilimumab for categorical covariates was conducted by the w2/Fisher exact test, and by the Kruskal-Wallis/analysis of variance for numerical covariates. The univariate association with ipilimumab for each covariate was produced as follows: for categorical covariates, the contingency table along with the Fisher exact test was carried out; for numerical covariates, the mean and median along with the Kruskal-Wallis test were reported. For radiation necrosis, a competing risk model with death was utilized. The univariate survival analysis for each variable was carried out using the Cox proportional hazard model. The hazard ratio with 95% confidence interval (CI) was reported along with the log rank test P value. The multivariate analysis (MVA) was conducted by entering all variables found to be significant in the univariate model and eliminated backwards using an exclusion criterion of P value > 0.1. The Kaplan-Meier curves were produced for each time to event outcome using a log rank test P value and to provide a median survival time for each comparison group.
RESULTS Patient Characteristics Our database included 54 patients treated with SRS between 2009 and 2013. Median age for the cohort was 60.1 Copyright
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years (range, 25.6 to 89.5 y). Median imaging follow-up was 7.3 months. Of the 54 MBM patients, 20 (37.0%) patients received ipilimumab within months of SRS. Median time between ipilimumab and SRS was 40 days (range, 0 to 117 d). One patient (5%) was treated concurrently, 12 (60%) were treated with ipilimumab before SRS, and 7 (35%) were treated with ipilimumab after SRS. None of the SRS alone patients received ipilimumab before or after 4 months of SRS. Table 1 illustrates no statistically significant differences between the groups, except a higher rate of fractionated SRS for the ipilimumab cohort (20% vs. 0%, P = 0.015); the ipilimumab cohort, however, did have a trend toward higher rates of prior systemic therapy (75% vs. 50%, P = 0.071) and BRAF inhibitor treatment (35% vs. 11.8%, P = 0.077).
OS No difference in OS was identified between cohorts: 1year OS for ipilimumab and SRS group and SRS alone cohort was 37.1% and 38.5%, respectively, P = 0.84 (Fig. 1). Univariate analysis revealed single BM and single fraction SRS treatment as statistically significant predictors of improved survival; ECOG PS, active systemic disease, controlled primary, and LDH demonstrated statistical trends (Table 2). Of these factors, MVA revealed single BM (HR = 0.35; 95% CI, 0.13-0.95; P = 0.029), active systemic disease (HR = 2.78; 95% CI, 1.15-7.14; P = 0.014), and controlled extracranial primary (HR = 0.40; 95% CI, 0.19-0.82; P = 0.025) as predictors of survival. Radiation parameters, including cumulative GTV volume, PTV margin, and radiation delivery method, did not correlate with OS. Seven (35%) patients were administered ipilimumab within 14 days of SRS, whereas 13 (65%) received ipilimumab >14 days of SRS, but within 4 months. One-year and 2-year OS was 42.9% and 42.9%, respectively, in the ipilimumab within 14 days of SRS, 33.8% and 16.9%, respectively, in the ipilimumab >14 days, and 38.5% and 25.7%, respectively, in the SRS alone group (Fig. 2).
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No. Patients Hazard Ratio Log Rank P 20 34
1.07
0.839
7 12 1 34
1.18 0.97 1.85
0.924
34 20
1.64
0.154
41 13
0.9
0.789
20 22 12
0.58 1.45
0.053
25 18 11
0.56 0.3
0.03
5 46 3
2.01 3.92
0.203
13 41
1.7
0.206
8 42
1.94
0.209
12 22 13 7
0.5 0.93 0.86
0.589
39 15
2.35
0.073
31 23
0.58
0.098
11 43
0.7
0.401
32 22
1.32
0.437
20 23
0.49
0.057
13 41
0.71
50 4
0.35
0.04
7 43
1.5
0.416
1.74
0.195
The 1-year LC rate was similar between the ipilimumab and SRS and SRS alone groups (71.4% vs. 92.3%, P = 0.40). Univariate analysis revealed active systemic disease and Recursive Partitioning Analysis class 1 associated with improved LR-free survival. MVA was not performed since the small number of LRs would make the analysis not statistically meaningful. DIF rates were also not statistically different between the cohorts: median distant intracranial-free survival was 4.2 versus 3.1 months and 1-year free survival was 12.7% versus 29.1%, P = 0.592. Only single BM predicted for statistically significant DIF on univariate (HR = 0.28, P = 0.033) and MVA (HR = 0.21; 95% CI, 0.06-0.70; P = 0.023). Of the 54 patients treated with SRS alone or ipilimumab and SRS, 38 patients (70.3%) developed an intracranial recurrence after SRS. One patient developed a LR alone, 2 patients presented with LR and DIF, and 36 patients recurred with DIF only. The 3 LR were treated with surgery and postoperative SRS alone. The 2 DIF that presented with LR were also treated with SRS alone. Of the 36 DIF, 24 (66.7%) patients did not require salvage WBRT. Rates of salvage WBRT were similar between the ipilimumab, SRS cohort (5 patients, 20.0%), and the SRS alone cohort (7 patients, 20.5%).
Toxicity At 1 year, the ipilimumab and SRS cohort had a trend toward developing higher rates of radiation necrosis (30.0% vs. 20.92%, P = 0.078). Of the 17 patients who ultimately developed radiation necrosis 12 were symptomatic; 8 of these patients (66.7%) received steroids treatment only, whereas 4 required surgery (33.3%). Comparing rates of symptomatic radiation necrosis at 1 year, however, demonstrated no significant difference (15.0% vs. 14.7%, P = 1.00) between ipilimumab and nonipilimumab (Fig. 3). One year rates of hemorrhage between the ipilimumab cohort (15.%) and the nonipilimumab cohort (14.7%) demonstrated no statistical difference (P = 1.00). Median time to developing hemorrhage was 5.0 months. Overall 11 patients developed hemorrhage. Three were symptomatic from the hemorrhage, requiring steroid treatment; all 3 patients were in the nonipilimumab cohort. None of these symptomatic patients required surgical intervention.
DISCUSSION
0.383
*Because the variable was developed during the follow-up, it can no longer be treated as baseline characteristics. Therefore, to estimate the hazard ratio, the time from the origin to development of status was taken into account by treating the variables as time-varying covariates and using an extended Cox model. Bold P values denotes statistical significant, P < 0.05. BM indicates brain metastases; ECOG, Eastern Cooperative Group Oncology; GPA, graded prognostic analysis; LDH, lactic dehydrogenase; PS, Performance Status; PTV, planning target volume; RPA, recursive portioning analysis; XRT, radiation therapy.
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LC and Intracranial Failure
TABLE 2. Univariate Factors for Overall Survival Ipilimumab Yes No Treatment sequence XRT before XRT after Concurrent XRT alone Age r65 Z65 Sex Male Female ECOG 0 1 2 No. BM 1 2-3 Z4 RPA 1 2 3 Symptomatic Yes No Steroids Yes No Melanoma-specific GPA 4 3 2 1 Active systemic disease Yes No Primary controlled Yes No BRAF inhibitor Yes No Prior systemic therapy Yes No LDH > 200 < 200 Radiation to a cavity Yes No Single fraction Yes No PTV margin (mm) >1 1 Next systemic therapy* Yes No
Most chemotherapeutic agents have limited intracranial efficacy due to the BBB decreasing central nervous system penetration. Indeed, for asymptomatic BM, radiation therapy has been the standard of care.8 However even with SRS, median OS for MBM is only 6.7 months.18 By activating immune cells, which can cross the BBB and target tumors, immunotherapy is a possible novel adjuvant approach against BM.20 A case report of a MBM treated with ipilimumab provides evidence toward this hypothesis: after 7 months of ipilimumab treatment, the patient underwent neurosurgical resection, with pathology revealing a high infiltrate of CD8 + T cells and low FoxP3, T-regulatory cells.21 Support for this hypothesis however is limited given that it is a case report with only 1 patient and without controls. To investigate the hypothesis that ipilimumab may have intracranial efficacy, Margolin et al9 conducted a phase II study in melanoma patients with untreated BM. Although ipilimumab did demonstrate similar rate of intracranial
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American Journal of Clinical Oncology
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Ipilimumab and SRS Versus SRS
FIGURE 2. Kaplan-Meier curve comparing overall survival of the cohorts receiving of stereotactic radiosurgery (SRS) and ipilimumab within 14 days (solid line), SRS and ipilimumab between 15 days to 4 months (single dash), and SRS alone (double dash line).
response rates to extracranial response, 55% of patients developed intracranial progression. We therefore conducted this retrospective review comparing SRS and ipilimumab to SRS alone. In our study the majority (85%) of the ipilimumab cohort was asymptomatic, obviating the need for steroids; the median survival for these patients was of 8.0 months and 1year OS was 37.1%. These findings are similar to the experience with induction ipilimumab 10 mg/kg and maintenance, in which the asymptomatic group had a median and 1-year OS of 7.0 months and 31%, respectively. In comparison with the SRS alone cohort, ipilimumab administered within 4 months of SRS was not associated with an increase in median survival (8.0 vs. 9.1, P = 0.8391) (Fig. 1). Melanoma-specific GPA is a tool utilized to predict median survival of MBM patients. The median GPA for our SRS alone cohort was 3.0, corresponding to an expected median survival of 8.8 months. The expected survival is similar to the actual observed survival for our cohort (9.1 mo). This suggests that our ipilimumab cohort did not have significantly improved survival rather than our SRS alone cohort having higher than anticipated survival. Case reports combining high-dose, ablative radiation with concurrent ipilimumab have demonstrated durable systemic responses and higher than expected survival.22,23 Because these case reports delivered concurrent ipilimumab and radiation, one possible explanation for the no improvement in survival is that timing of therapy may be critical to maximize the synergy between SRS and radiation. The half-life of ipilimumab is 14.9 days24; furthermore, Kim et al25 demonstrated radiation-induced expression of mannose 6 phosphate receptor, a receptor critical for radiation enhanced efficacy of ipilimumab, peaks within 3 days after irradiation, and normalizes over 7 to 14 days. We, therefore investigated whether these therapies, administered within this period of biological activity, correlated with improved survival. Figure 2 illustrates that patients receiving SRS and ipilimumab within 14 days had higher 1- and 2-year OS relative to ipilimumab delivered >14 Copyright
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days of SRS or SRS alone (42.9%, 42.9% vs. 33.8%, 16.9% vs. 38.5%, 25.7%, respectively) but these difference were not statistically significant. Given the small number of patients size within the SRS delivered within 14 days (n = 7), it is most likely that any potential difference is due to small selection bias from a small sample size. In contrast to our findings, 2 other retrospective studies investigating the efficacy of SRS and ipilimumab have demonstrated improved OS when compared with SRS alone. The first study, by Knisely et al,26 demonstrated a markedly improved survival for patients receiving ipilimumab, 21.3 versus 4.9 months; furthermore, ipilimumab remained a significant predictor for OS on MVA. However, with known prognostic patient characteristics—LDH,27 active systemic disease, and primary controlled—not included in their analysis, it is unclear if these observed survival differences were due to selection bias favoring the ipilimumab group. Furthermore, the study included patients from 2002 to 2010, with many patients being treated on clinical trial; however, use of BRAF inhibitor therapy, which was also a potential clinical trial during this time period, was also not recorded and could have contributed to the improved outcomes. Silk et al28 subsequently published their institutional experience and accounted for many of these factors not included in the Knisely et al’s analysis.26 They similarly found an improved survival of 18.3 versus 5.3 months. However, better ECOG PS and BRAF inhibitor treatment was significantly more common in the ipilimumab and SRS cohort. With both clinical factors strongly predictive of survival, this may have contributed to a selection bias favoring improved outcomes in the ipilimumab cohort. Moreover, the average interval between ipilimumab and radiation was 23 weeks. Without comparing the median time to next systemic therapy in the SRS arm, this relatively large interval may introduce further selection bias favoring improved survival in ipilimumab cohort. To address these factors, we first limited our cohort to start in 2009, when patients at our institution had access to
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FIGURE 3. Competing risk model illustrating the comparison of stereotactic radiosurgery (SRS) with ipilimumab (solid line) to SRS alone (dashed line) with respect to symptomatic radiation necrosis is shown.
BRAF inhibitors in the clinical trial setting. Consequently, we found a less statistical difference in rates of BRAF inhibitor between our cohorts (35% vs. 11.8%, P = 0.077) compared with Silk and colleagues (39.4% vs. 3.1%, P < 0.001). Second, we chose to limit the ipilimumab cohort to
Ipilimumab and Stereotactic Radiosurgery Versus Stereotactic Radiosurgery Alone for Newly Diagnosed Melanoma Brain Metastases Kirtesh R. Patel, MD,* Sana Shoukat, MD,w Daniel E. Oliver, BA,z Mudit Chowdhary, BA,z Monica Rizzo, MD,y David H. Lawson, MD,8 Faisal Khosa, MD,z Yuan Liu, PhD,# and Mohammad K. Khan, MD, PhD*
Background: We compared the safety and efficacy of ipilimumab and stereotactic radiosurgery (SRS) to SRS alone for newly diagnosed melanoma brain metastases (MBM). Materials and Methods: We reviewed records of newly diagnosed MBM patients treated with SRS from 2009 to 2013. The primary endpoint of overall survival (OS), and secondary endpoints of local control, distant intracranial failure, and radiation necrosis were compared using Kaplan-Meier method. Univariate and multivariate analysis were performed using the Cox proportional hazards method. Results: Fifty-four consecutive MBM patients were identified, with 20 (37.0%) receiving ipilimumab within 4 months of SRS. Ipilimumabtreated and non-ipilimumab–treated patients had similar baseline characteristics. No difference in symptomatic radiation necrosis or hemorrhage was identified between cohorts. Compared with patients in the nonipilimumab group, 1 year local control (71.4% vs. 92.3%, P = 0.40) and intracranial control (12.7% vs. 29.1%, P = 0.59) were also statistically similar. The ipilimumab cohort also had no difference in 1-year OS (37.1% vs. 38.5%, P = 0.84). Patients administered ipilimumab within 14 days of SRS had higher 1-year (42.9%) and 2-year OS (42.9%) relative to ipilimumab delivered >14 days (33.8%, 16.9%) and SRS alone (38.5%, 25.7%) but these difference were not statistically significant. Univariate analysis and multivariate analysis both confirmed single brain metastasis, controlled primary, and active systemic disease as predictors for OS. Conclusions: Use of ipilimumab within 4 months of SRS seems to be safe, with no increase in radiation necrosis or hemorrhage; however, our retrospective institutional experience with this treatment regimen was not associated with improved outcomes. Key Words: melanoma brain metastasis, stereotactic radiosurgery, ipilimumab
for metastatic melanoma patients in 2 randomized phase III.1,2 Distinct from chemotherapy or targeted agents, the survival rates stabilized after 2 years and remained durable at 5 years.3,4 These promising results led the FDA to approve anti-CTLA-4 antibody, ipilimumab, for metastatic melanoma. In both of these phase III trials with ipilimumab, patients with melanoma brain metastasis (MBM) were poorly represented: only 12.2% and 0% of patients enrolled to the ipilimumab arms had stable MBM.1,2 With up to 50% of melanoma patients developing brain metastasis (BM),5,6 a poor prognostic indicator,7 the efficacy of ipilimumab against MBM is a highly debated and clinically relevant question. Moreover, with most chemotherapies and targeted agents limited by the blood-brain barrier (BBB),8 achieving improvements in survival for MBM continues to be a challenge. To investigate the efficacy of ipilimumab on intracranial disease, Margolin et al9 conducted a prospective nonrandomized phase II trial of ipilimumab alone for untreated MBM. Although this study demonstrated intracranial response rates similar to previously reported extracranial response rates, 50% to 55% of patients did not complete therapy due to intracranial progression. Furthermore, intracranial local control (LC) rate of 29% with ipilimumab alone was lower than the 67% to 75% LC rate with stereotactic radiation therapy (SRS).10,11 With ipilimumab alone constrained by lower LC and higher intracranial progression, adding radiation is a potential treatment approach to help address these limitations.12,13 The aim of this study is to characterize the safety and efficacy of SRS when combined with ipilimumab for patients with intracranial metastases from melanoma.
(Am J Clin Oncol 2015;00:000–000)
MATERIALS AND METHODS
A
ntibodies targeting cytotoxic T-lymphocyte–associated antigen 4, a T-cell inhibitory signaling molecule, have demonstrated improvements in overall survival (OS) at 3 years
From the Departments of *Radiation Oncology; ySurgery, Division of Surgical Oncology; #Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute; Departments of wInternal Medicine; 8Hematology and Medical Oncology; zRadiology, Emory University; and zEmory University School of Medicine, Atlanta, GA. Supported by BMS. D.H.L. has served on advisory boards for Bristol-Myers Squibb (BMS). The other authors declare no conflicts of interest. Reprints: Mohammad K. Khan MD, PhD, Department of Radiation Oncology, Winship Cancer Institute, Emory University, 1365 Clifton Rd NE, Office A1312, Atlanta, GA 30322. E-mail: [email protected]. Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0277-3732/15/000-000 DOI: 10.1097/COC.0000000000000199
American Journal of Clinical Oncology
Patient Selection After receiving institutional review board approval, we identified 54 consecutive, newly diagnosed MBM patients treated with SRS alone at our institution between 2009 and 2013. Patients who had received prior whole brain radiotherapy (WBRT) were excluded. Patients treated with ipilimumab 3 mg/kg within 4 months of SRS were recorded. Patients treated with higher doses (eg, 10 mg/kg) or receiving maintenance ipilimumab were excluded. For the ipilimumab and SRS cohort, treatment sequence and the number of days between therapies were recorded.
Radiation Treatment Technical details of SRS have been previously described.14,15 In brief, SRS was performed using a linear accelerator with 6 MV photon energies. The T1 postcontrast magnetic
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American Journal of Clinical Oncology
resonance imaging (MRI) defined lesion constituted the gross tumor volume (GTV). No margin was utilized to create a clinical target volume. The GTV was expanded by 1 mm to generate the planning target volume (PTV). BM up to 20 mm in diameter were typically treated to 21 Gy, 21 to 30 mm in diameter to 18 Gy, and 31 to 40 mm in diameter to 15 Gy. Patients with large metastases cavities (typically > 40 mm in diameter) were treated with fractionated radiosurgery over 3 to 5 fractions using a frameless radiosurgery technique.16 All patients charts were reviewed for the following baseline patient characteristics at the time of initial SRS: age, sex, clinical trial enrollment, number of BM, symptomatic from BM, steroid treatment, presence of active systemic disease, primary controlled, Eastern Cooperative Group Oncology performance status (ECOG PS), Recursive Partitioning Analysis, Graded Performance Assessment (GPA) score, lactic dehydrogenase (LDH) value before SRS, prior systemic therapy, and time to next systemic therapy. Radiation treatment parameters were also recorded, including: largest dose per fraction, number of fractions, SRS to a resection cavity, cumulative GTV volume, and PTV margin. Linear acceleratorbased SRS treatment delivery methods—dynamic conformal arc therapy or intensity modulated radiosurgery—were also recorded (Table 1).
Follow-up Follow-up consisted of clinical examination and brain MRI at 4 to 6 weeks after initial SRS, and then at 3 months intervals thereafter unless clinically indicated at an earlier time point. Local recurrence (LR) was defined as the presence of new progressive nodular enhancement involving the prior lesion or resection cavity seen on brain MRI with contrast. Clinical radiation necrosis was defined on the basis of 2 radiographic features: the development of contrast-enhancing mass within prior radiation treatment fields and conventional imaging features, including soap bubble appearance17; if there was a question of the nodular enhancement representing radiation necrosis, additional functional imaging was obtained (eg, MR perfusion, brain positron emission tomography, and MR spectroscopy). Decreased perfusion and elevated lactate were interpreted as areas of necrosis, whereas increased perfusion and elevated choline were interpreted as recurrent disease. For patients with symptomatic radiation necrosis, dexamethasone steroids were typically the first treatment utilized for the SRS alone cohort; because steroids can decrease the number of lymphocytes, which are the main effects of ipilimumab, steroids were typically utilized in shorter courses, or avoided and in lieu of hyperbaric oxygen, bevacizumab, or surgery were more commonly utilized. Distant intracranial failure (DIF) was defined as presence of new enhancing lesions distinctly outside the prior SRS treatment zone. For LR and DIF analyses, patients were censored at time of last brain imaging or salvage WBRT, whichever came first. For OS, death from any cause was defined as the event, and patients were censored at time of last follow-up. For patients who were deceased or lost to follow-up at the time of our analysis, we confirmed the date of death by querying the Social Security Death Index. For patients with progressive intracranial disease, salvage intracranial treatments were recorded, including WBRT, repeat SRS, next systemic therapy, and neurosurgical resection. Decision to treat and the specifics of each treatment were at the discretion of the physician. Toxicity endpoints that were recorded included the development of radionecrosis and hemorrhage on MRI.
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TABLE 1. Baseline Patient Characteristics
Median age (y) Sex Male Female ECOG PS 0 1 Z2 No. BM 1 2-3 Z4 Active systemic disease Yes No Primary controlled Yes No RPA 1 2 3 Symptomatic at time of BM Yes No Steroids Yes No Melanoma-specific GPA 4 3 2 1 BRAF inhibitor Yes No Prior systemic therapy Yes No LDH > 200 r200 Next systemic therapy Yes No Median days to next systemic therapy Single fraction SRS Yes No Radiation to cavity Yes No Median cumulative GTV volume (cm3) Median PTV margin (mm) Radiation delivery method Dynamic conformal arc Intensity modulated radiosurgery
SRS (n = 34)
IPI and SRS (n = 20)
P
60.2
56.5
0.121
28 (82.4%) 6 (17.6%)
13 (65%) 7 (35%)
0.812
11 (32.4%) 15 (44.1%) 8 (23.5%)
9 (45%) 7 (50%) 4 (60%)
0.647
17 (50%) 12 (35.3%) 5 (14.7%)
8 (40%) 10 (50%) 2 (10%)
0.625
22 (64.7%) 12 (35.3%)
17 (85%) 3 (15%)
0.108
20 (58.8%) 14 (41.2%)
11 (55%) 9 (45%)
0.784
4 (11.8%) 28 (82.4%) 2 (5.8%)
1 (5%) 18 (90%) 1 (5%)
0.837
11 (32.4%) 23 (67.65)
2 (10.0%) 18 (90.0%)
0.1
7 (21.9%) 25 (78.1%)
1 (5.6%) 17 (94.4%)
0.231
7 16 6 5
(20.6%) (47.1%) (17.7%) (14.6%)
(25%) (30%) (35%) (10%)
0.423
4 (11.8%) 30 (88.2%)
7 (35%) 13 (65%)
0.077
17 (50%) 17 (50%)
15 (75%) 5 (25%)
0.071
11 (45.8%) 13 (54.2%)
9 (47.4%) 10 (52.6%)
0.92
29 (85.3%) 5 (14.7%) 11
15 (75%) 5 (25%) 15
0.471
34 (100%) 0 (0%)
16 (80%) 4 (20%)
0.015
10 (29.4%) 24 (70.6%) 2.66
3 (15%) 17 (85%) 1.1
0.329
1 27 (87.8%) 6 (18.2%)
5 6 7 2
1 15 (75%) 5 (25%)
0.217
0.508 0.196 0.729
Bold P values denotes statistical significant, P < 0.05. BM indicates brain metastases; ECOG PS, Eastern Cooperative Group Oncology performance status; GPA, graded prognostic analysis; GTV, gross tumor volume; LDH, lactic dehydrogenase; PS, Performance Status; PTV, planning target volume; RPA, recursive portioning analysis.
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American Journal of Clinical Oncology
Volume 00, Number 00, ’’ 2015
Ipilimumab and SRS Versus SRS
FIGURE 1. Kaplan-Meier curve illustrating the comparison of stereotactic radiosurgery (SRS) with ipilimumab (solid line) to SRS alone (dashed line) with respect to overall survival is shown.
Radiation necrosis was diagnosed as detailed above. Intracranial hemorrhage was diagnosed by utilizing diffusion weighted images and confirmed with new changes identified on T1 and T2 sequences. For patients that were symptomatic from these adverse events, interventions utilized for these adverse events were also recorded.
Statistical Analysis Patient age, ECOG PS, and number of BM were classified into categories per previously published prognostic indices.18 The number of BM was separated into categories of 1, 2 to 3, and Z4. The serum LDH level was categorized as normal or elevated.19 Univariate association with ipilimumab for categorical covariates was conducted by the w2/Fisher exact test, and by the Kruskal-Wallis/analysis of variance for numerical covariates. The univariate association with ipilimumab for each covariate was produced as follows: for categorical covariates, the contingency table along with the Fisher exact test was carried out; for numerical covariates, the mean and median along with the Kruskal-Wallis test were reported. For radiation necrosis, a competing risk model with death was utilized. The univariate survival analysis for each variable was carried out using the Cox proportional hazard model. The hazard ratio with 95% confidence interval (CI) was reported along with the log rank test P value. The multivariate analysis (MVA) was conducted by entering all variables found to be significant in the univariate model and eliminated backwards using an exclusion criterion of P value > 0.1. The Kaplan-Meier curves were produced for each time to event outcome using a log rank test P value and to provide a median survival time for each comparison group.
RESULTS Patient Characteristics Our database included 54 patients treated with SRS between 2009 and 2013. Median age for the cohort was 60.1 Copyright
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years (range, 25.6 to 89.5 y). Median imaging follow-up was 7.3 months. Of the 54 MBM patients, 20 (37.0%) patients received ipilimumab within months of SRS. Median time between ipilimumab and SRS was 40 days (range, 0 to 117 d). One patient (5%) was treated concurrently, 12 (60%) were treated with ipilimumab before SRS, and 7 (35%) were treated with ipilimumab after SRS. None of the SRS alone patients received ipilimumab before or after 4 months of SRS. Table 1 illustrates no statistically significant differences between the groups, except a higher rate of fractionated SRS for the ipilimumab cohort (20% vs. 0%, P = 0.015); the ipilimumab cohort, however, did have a trend toward higher rates of prior systemic therapy (75% vs. 50%, P = 0.071) and BRAF inhibitor treatment (35% vs. 11.8%, P = 0.077).
OS No difference in OS was identified between cohorts: 1year OS for ipilimumab and SRS group and SRS alone cohort was 37.1% and 38.5%, respectively, P = 0.84 (Fig. 1). Univariate analysis revealed single BM and single fraction SRS treatment as statistically significant predictors of improved survival; ECOG PS, active systemic disease, controlled primary, and LDH demonstrated statistical trends (Table 2). Of these factors, MVA revealed single BM (HR = 0.35; 95% CI, 0.13-0.95; P = 0.029), active systemic disease (HR = 2.78; 95% CI, 1.15-7.14; P = 0.014), and controlled extracranial primary (HR = 0.40; 95% CI, 0.19-0.82; P = 0.025) as predictors of survival. Radiation parameters, including cumulative GTV volume, PTV margin, and radiation delivery method, did not correlate with OS. Seven (35%) patients were administered ipilimumab within 14 days of SRS, whereas 13 (65%) received ipilimumab >14 days of SRS, but within 4 months. One-year and 2-year OS was 42.9% and 42.9%, respectively, in the ipilimumab within 14 days of SRS, 33.8% and 16.9%, respectively, in the ipilimumab >14 days, and 38.5% and 25.7%, respectively, in the SRS alone group (Fig. 2).
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Patel et al
No. Patients Hazard Ratio Log Rank P 20 34
1.07
0.839
7 12 1 34
1.18 0.97 1.85
0.924
34 20
1.64
0.154
41 13
0.9
0.789
20 22 12
0.58 1.45
0.053
25 18 11
0.56 0.3
0.03
5 46 3
2.01 3.92
0.203
13 41
1.7
0.206
8 42
1.94
0.209
12 22 13 7
0.5 0.93 0.86
0.589
39 15
2.35
0.073
31 23
0.58
0.098
11 43
0.7
0.401
32 22
1.32
0.437
20 23
0.49
0.057
13 41
0.71
50 4
0.35
0.04
7 43
1.5
0.416
1.74
0.195
The 1-year LC rate was similar between the ipilimumab and SRS and SRS alone groups (71.4% vs. 92.3%, P = 0.40). Univariate analysis revealed active systemic disease and Recursive Partitioning Analysis class 1 associated with improved LR-free survival. MVA was not performed since the small number of LRs would make the analysis not statistically meaningful. DIF rates were also not statistically different between the cohorts: median distant intracranial-free survival was 4.2 versus 3.1 months and 1-year free survival was 12.7% versus 29.1%, P = 0.592. Only single BM predicted for statistically significant DIF on univariate (HR = 0.28, P = 0.033) and MVA (HR = 0.21; 95% CI, 0.06-0.70; P = 0.023). Of the 54 patients treated with SRS alone or ipilimumab and SRS, 38 patients (70.3%) developed an intracranial recurrence after SRS. One patient developed a LR alone, 2 patients presented with LR and DIF, and 36 patients recurred with DIF only. The 3 LR were treated with surgery and postoperative SRS alone. The 2 DIF that presented with LR were also treated with SRS alone. Of the 36 DIF, 24 (66.7%) patients did not require salvage WBRT. Rates of salvage WBRT were similar between the ipilimumab, SRS cohort (5 patients, 20.0%), and the SRS alone cohort (7 patients, 20.5%).
Toxicity At 1 year, the ipilimumab and SRS cohort had a trend toward developing higher rates of radiation necrosis (30.0% vs. 20.92%, P = 0.078). Of the 17 patients who ultimately developed radiation necrosis 12 were symptomatic; 8 of these patients (66.7%) received steroids treatment only, whereas 4 required surgery (33.3%). Comparing rates of symptomatic radiation necrosis at 1 year, however, demonstrated no significant difference (15.0% vs. 14.7%, P = 1.00) between ipilimumab and nonipilimumab (Fig. 3). One year rates of hemorrhage between the ipilimumab cohort (15.%) and the nonipilimumab cohort (14.7%) demonstrated no statistical difference (P = 1.00). Median time to developing hemorrhage was 5.0 months. Overall 11 patients developed hemorrhage. Three were symptomatic from the hemorrhage, requiring steroid treatment; all 3 patients were in the nonipilimumab cohort. None of these symptomatic patients required surgical intervention.
DISCUSSION
0.383
*Because the variable was developed during the follow-up, it can no longer be treated as baseline characteristics. Therefore, to estimate the hazard ratio, the time from the origin to development of status was taken into account by treating the variables as time-varying covariates and using an extended Cox model. Bold P values denotes statistical significant, P < 0.05. BM indicates brain metastases; ECOG, Eastern Cooperative Group Oncology; GPA, graded prognostic analysis; LDH, lactic dehydrogenase; PS, Performance Status; PTV, planning target volume; RPA, recursive portioning analysis; XRT, radiation therapy.
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LC and Intracranial Failure
TABLE 2. Univariate Factors for Overall Survival Ipilimumab Yes No Treatment sequence XRT before XRT after Concurrent XRT alone Age r65 Z65 Sex Male Female ECOG 0 1 2 No. BM 1 2-3 Z4 RPA 1 2 3 Symptomatic Yes No Steroids Yes No Melanoma-specific GPA 4 3 2 1 Active systemic disease Yes No Primary controlled Yes No BRAF inhibitor Yes No Prior systemic therapy Yes No LDH > 200 < 200 Radiation to a cavity Yes No Single fraction Yes No PTV margin (mm) >1 1 Next systemic therapy* Yes No
Most chemotherapeutic agents have limited intracranial efficacy due to the BBB decreasing central nervous system penetration. Indeed, for asymptomatic BM, radiation therapy has been the standard of care.8 However even with SRS, median OS for MBM is only 6.7 months.18 By activating immune cells, which can cross the BBB and target tumors, immunotherapy is a possible novel adjuvant approach against BM.20 A case report of a MBM treated with ipilimumab provides evidence toward this hypothesis: after 7 months of ipilimumab treatment, the patient underwent neurosurgical resection, with pathology revealing a high infiltrate of CD8 + T cells and low FoxP3, T-regulatory cells.21 Support for this hypothesis however is limited given that it is a case report with only 1 patient and without controls. To investigate the hypothesis that ipilimumab may have intracranial efficacy, Margolin et al9 conducted a phase II study in melanoma patients with untreated BM. Although ipilimumab did demonstrate similar rate of intracranial
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American Journal of Clinical Oncology
Volume 00, Number 00, ’’ 2015
Ipilimumab and SRS Versus SRS
FIGURE 2. Kaplan-Meier curve comparing overall survival of the cohorts receiving of stereotactic radiosurgery (SRS) and ipilimumab within 14 days (solid line), SRS and ipilimumab between 15 days to 4 months (single dash), and SRS alone (double dash line).
response rates to extracranial response, 55% of patients developed intracranial progression. We therefore conducted this retrospective review comparing SRS and ipilimumab to SRS alone. In our study the majority (85%) of the ipilimumab cohort was asymptomatic, obviating the need for steroids; the median survival for these patients was of 8.0 months and 1year OS was 37.1%. These findings are similar to the experience with induction ipilimumab 10 mg/kg and maintenance, in which the asymptomatic group had a median and 1-year OS of 7.0 months and 31%, respectively. In comparison with the SRS alone cohort, ipilimumab administered within 4 months of SRS was not associated with an increase in median survival (8.0 vs. 9.1, P = 0.8391) (Fig. 1). Melanoma-specific GPA is a tool utilized to predict median survival of MBM patients. The median GPA for our SRS alone cohort was 3.0, corresponding to an expected median survival of 8.8 months. The expected survival is similar to the actual observed survival for our cohort (9.1 mo). This suggests that our ipilimumab cohort did not have significantly improved survival rather than our SRS alone cohort having higher than anticipated survival. Case reports combining high-dose, ablative radiation with concurrent ipilimumab have demonstrated durable systemic responses and higher than expected survival.22,23 Because these case reports delivered concurrent ipilimumab and radiation, one possible explanation for the no improvement in survival is that timing of therapy may be critical to maximize the synergy between SRS and radiation. The half-life of ipilimumab is 14.9 days24; furthermore, Kim et al25 demonstrated radiation-induced expression of mannose 6 phosphate receptor, a receptor critical for radiation enhanced efficacy of ipilimumab, peaks within 3 days after irradiation, and normalizes over 7 to 14 days. We, therefore investigated whether these therapies, administered within this period of biological activity, correlated with improved survival. Figure 2 illustrates that patients receiving SRS and ipilimumab within 14 days had higher 1- and 2-year OS relative to ipilimumab delivered >14 Copyright
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days of SRS or SRS alone (42.9%, 42.9% vs. 33.8%, 16.9% vs. 38.5%, 25.7%, respectively) but these difference were not statistically significant. Given the small number of patients size within the SRS delivered within 14 days (n = 7), it is most likely that any potential difference is due to small selection bias from a small sample size. In contrast to our findings, 2 other retrospective studies investigating the efficacy of SRS and ipilimumab have demonstrated improved OS when compared with SRS alone. The first study, by Knisely et al,26 demonstrated a markedly improved survival for patients receiving ipilimumab, 21.3 versus 4.9 months; furthermore, ipilimumab remained a significant predictor for OS on MVA. However, with known prognostic patient characteristics—LDH,27 active systemic disease, and primary controlled—not included in their analysis, it is unclear if these observed survival differences were due to selection bias favoring the ipilimumab group. Furthermore, the study included patients from 2002 to 2010, with many patients being treated on clinical trial; however, use of BRAF inhibitor therapy, which was also a potential clinical trial during this time period, was also not recorded and could have contributed to the improved outcomes. Silk et al28 subsequently published their institutional experience and accounted for many of these factors not included in the Knisely et al’s analysis.26 They similarly found an improved survival of 18.3 versus 5.3 months. However, better ECOG PS and BRAF inhibitor treatment was significantly more common in the ipilimumab and SRS cohort. With both clinical factors strongly predictive of survival, this may have contributed to a selection bias favoring improved outcomes in the ipilimumab cohort. Moreover, the average interval between ipilimumab and radiation was 23 weeks. Without comparing the median time to next systemic therapy in the SRS arm, this relatively large interval may introduce further selection bias favoring improved survival in ipilimumab cohort. To address these factors, we first limited our cohort to start in 2009, when patients at our institution had access to
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FIGURE 3. Competing risk model illustrating the comparison of stereotactic radiosurgery (SRS) with ipilimumab (solid line) to SRS alone (dashed line) with respect to symptomatic radiation necrosis is shown.
BRAF inhibitors in the clinical trial setting. Consequently, we found a less statistical difference in rates of BRAF inhibitor between our cohorts (35% vs. 11.8%, P = 0.077) compared with Silk and colleagues (39.4% vs. 3.1%, P < 0.001). Second, we chose to limit the ipilimumab cohort to
