Abstract
This study examines the treatment of patients with metastatic melanoma receiving multisite radiotherapy with in conjunction with immunotherapy.
Over the past decade, the treatment of advanced melanoma has been enriched by several new immunotherapies, such as immune checkpoint inhibitors for cytotoxic T–lymphocyte-associated antigen 4 (CTLA-4) or programmed cell death 1 (PD-1). However, a considerable proportion of patients do not respond to these drugs, and new strategies are needed. Among them, the use of checkpoint inhibitors with concomitant radiotherapy appears relevant. The rationale is that the tumor killing can increase tumor antigen in the bloodstream, favoring antigen presentation leading to an immunogenic response to tumor cells outside of the radiation field, defined as the abscopal effect. Results of this strategy have mostly been reported for the treatment of brain metastasis with stereotactic ablative radiotherapy (SABR) and anti–PD-1, ipilimumab, or anti–programmed cell death ligand 1 (PD-L1). Data concerning extracerebral irradiation and data analyzing the impact of irradiation of several tumor sites with immunotherapy are scarce. To irradiate several tumor sites could indeed increase the diversity of antigen presentation and thus increase the probability of response.
Methods
In this study we describe the treatment of metastatic melanoma patients receiving multisite radiotherapy with immunotherapy. All patients signed written informed consent. Institutional review board approval was waived by the Department for Clinical Research and Innovation, University Hospital of Nice, France, because it is a retrospective study and all data used were fully deidentified. No patients were compensated.
Statistical comparisons were 2-sided and performed using χ2 and log-rank tests for censored data. The Mann-Whitney test was used for median comparisons among quantitative data. Participants were irradiated for a minimum of 2 metastastic lesions, with either a local curative intent (oligometastatic patients: SABR group) or with a palliative and/or symptomatic intent using 3-dimensional conformal radiotherapy (3DCRT group).
Results
The detailed features of the patients and treatment are presented in Table 1. Forty-six metastatic lesions (brain, n = 9; liver, n = 3; spinal cord/spine, n = 4; muscle, n = 2; bone, n = 10; skin, n = 2; lung, n = 7; cauda equina/spine, n = 2; retroperitoneum, n = 1; adrenal, n = 1; and lymph node, n = 5) in 15 patients were irradiated. The median age was 57.1 years (range, 48.9-81.4 years). Of 15 patients, 11 (73%) were men. Five patients were treated with SABR (n = 19 metastatic tumors), and 10 (n = 27 metastatic tumors) were treated with 3DCRT. The median number of tumor sites treated was 2 (range, 2-8).
Table 1. Patient Demographics and Treatment Characteristics.
| Characteristic | Total Population (n = 15 Patients, 46 Metastatic Tumors) | SABR Group (n = 5 Patients, 19 Metastatic Tumors) | 3DCRT Group (n = 10 Patients, 27 Metastatic Tumors) | P Valuea |
|---|---|---|---|---|
| Age, median (range), y | 57.1 (48.9-81.4) | 57.1 (56.1-66.5) | 60.1 (48.9-81.4) | >.99 |
| Metastasis status, No. of patients (%) | ||||
| M1A | 1 (7) | 0 | 1 (10) | .50 |
| M1B | 1 (7) | 0 | 1 (10) | |
| M1C | 13 (87) | 5 (100) | 8 (80) | |
| Brain metastasis, No. of patients (%) | ||||
| Yes | 6 (40) | 3 (60) | 3 (30) | .20 |
| No | 9 (60) | 2 (40) | 7 (70) | |
| Lactate dehydrogenase | ||||
| ULN, median (range) | 0.96 (0.53-3.27) | 0.91 (0.9-1.01) | 0.99 (0.53-3.27) | .50 |
| ≤ULN, No. (%) | 8 (62) | 5 (56) | 3 (75) | |
| >ULN, No. (%) | 5 (38) | 4 (44) | 1 (25) | |
| Missing, No. | 2 | 1 | 1 | |
| Previous therapies, No. of patients (%) | ||||
| None | 8 (53) | 3 (60) | 5 (50) | >.99 |
| Previous chemotherapy | 3 (20) | 1 (20) | 2 (20) | |
| BRAF inhibitor | 2 (13) | 0 | 2 (20) | |
| BRAF + MEK inhibitor | 2 (13) | 1 (20) | 1 (10) | |
| Type of concomitant immunotherapy, No. of tumors (%) | ||||
| Ipilimumab | 6 (13) | 4 (22) | 2 (7) | .20 |
| Nivolumab | 21 (46) | 6 (33) | 15 (54) | |
| Pembrolizumab | 19 (41) | 8 (44) | 11 (39) | |
| BRAF status, No. (%) | ||||
| Wild type | 11 (73) | 4 (80) | 7 (70) | .60 |
| Mutated (V600E) | 4 (27) | 1 (20) | 3 (30) | |
| Performance status at time of irradiation, No. of patients (%)b | ||||
| 0 | 9 (64) | 5 (100) | 4 (44) | .03 |
| 1 | 5 (36) | 0 | 5 (56) | |
| Missing data, No. | 1 | 0 | 1 | |
| GTV, median (range), mL | 10.2 (1-329.5) | 4.2 (1-26.2) | 31.2 (1-329.5) | .01 |
| Total dose, median (range), Gy | 18 (5-35) | 20 (18-35) | 18 (5-30) | <.001 |
| No. of sessions, median (range) | 3 (1-7) | 1 (1-7) | 3 (1-5) | .30 |
| Dose per session, median (range), Gy | 6 (3-20) | 18 (5-20) | 6 (3-8) | <.001 |
Abbreviations: 3DCRT, 3-dimensional conformal radiotherapy; GTV, gross tumor volume; SABR, stereotactic ablative radiotherapy; ULN, upper limit normal.
Statistical comparisons were performed using χ2 test and Mann-Whitney test for median comparisons among qualitative and quantitative data, respectively.
Eastern Cooperative Oncology Group.
Regarding safety outcomes, we did not see any grade 4 (G4) to G5 toxic effects. The most common adverse events were of G1 to G2, including asthenia (6 patients; 2 G3 lasting for 2 weeks, 1 G2, and 3 G1), headache (1 patient, G1), pruritus (4 patients, G1), nausea (4 patients, G1), hypothyroidism (2 patients, G1), diffuse pain (1 patient, G1), alopecia (1 patient, G2), vitiligo (3 patients, G1), cough (1 patient, G1), dyspnea (1 patient, G1), and right frontal brain radionecrosis with left limb paresthesia (1 patient, G2). The 3 patients with vitiligo achieved a tumor response. More importantly, for 1 of these patients a complete response was observed, and the vitiligo developed in the radiation field before it extended to the eyelashes and eyebrows. No cases of adrenal insufficiency, hypophysitis, or colitis were reported. Six patients had no toxic effects to report.
Regarding efficacy (Table 2), with a median follow-up of 14.1 months (range, 1.6-19.8 months) from radiotherapy, the 6-month and 1-year progression-free survival (PFS) and overall survival rates (from radiotherapy) were 71.8% and 46.2% and 77.9% and 58.4%, respectively. Notably, 5 patients received radiotherapy after failure of immunotherapy while maintaining immunotherapy treatment (2 patients with nivolumab, 3 with pembrolizumab). For these patients, we did not observe abscopal effect, but tumor stabilization and/or response was reported for 13 (93%) of 14 irradiated metastatic tumors (median PFS, 4.8 months). In this study there was no difference of local control or survival between the SABR and the 3D group, although radiation dose was much higher in the SABR group, and this is despite the oligometastatic profile of SABR patients.
Table 2. Tumor Response and Survival.
| Variable | Total Population (n = 15 Patients, 46 Metastatic Tumors) | SABR Group (n = 5 Patients, 19 Metastatic Tumors) | 3DCRT Group (n = 10 Patients, 27 Metastatic Tumors) | P Valuea |
|---|---|---|---|---|
| Best local response, No. of tumors (%) | ||||
| Complete response | 15 (34.9) | 8 (47.1) | 7 (26.9) | .20 |
| Partial response | 2 (4.7) | 1 (5.9) | 1 (3.8) | |
| Stabilized disease | 18 (41.9) | 4 (23.5) | 14 (53.8) | |
| Progression | 8 (18.6) | 4 (23.5) | 4 (15.4) | |
| Missing data, No. | 3 | 2 | 1 | |
| Local control, No. of relapses (%) | ||||
| 6 mo | 9 (78) | 4 (75) | 5 (79) | .90 |
| 12 mo | 13 (63) | 5 (68) | 8 (55) | |
| Missing data, No. | 3 | 2 | 1 | |
| Progression-free survival, No. of progressions (%) | ||||
| 6 mo | 4 (72) | 1 (80) | 3 (67) | .60 |
| 12 mo | 7 (46) | 3 (40) | 4 (50) | |
| Overall survival, No. of deaths (%) | ||||
| 6 mo | 3 (78) | 1 (80) | 2 (76) | .90 |
| 12 mo | 5 (58) | 2 (60) | 3 (57) |
Abbreviations: 3DCRT, 3-dimensional conformal radiotherapy; SABR, stereotactic ablative radiotherapy.
Statistical comparisons were performed using log-rank test for censored data.
Discussion
This study shows that concurrent multisite radiotherapy with checkpoint inhibitors can have positive clinical outcomes in metastatic melanoma and is associated with a low-grade toxic effects profile. Prospective studies with larger samples of patients are needed to confirm the interest of this combination. The translational focus on immunologic markers appears necessary to improve patient selection for future clinical applications. This will be tested within the ongoing NCT02799901 phase 2 trial.
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