Purpose/Objective(s): Prior case reports and preclinical studies have suggested that combined radiotherapy and immunotherapy may generate tumor responses outside the radiation treatment field (the “abscopal effect”). However, the frequency of this phenomenon and the radiation parameters associated with its occurrence are relatively unexplored. We aimed to systemically evaluate out-of-field responses following radiotherapy in a large cohort of patients with metastatic melanoma who had been also been treated with the CTLA-4 inhibitor ipilimumab.
Materials/Methods: We retrospectively reviewed records from 91 consecutive patients with metastatic melanoma who were treated with ipilimumab and radiation therapy at our institution. These 91 patients received a total of 208 courses of palliative radiation treatment between October 2007 and June 2014. Overall survival was calculated from the date patients were diagnosed with metastatic melanoma using the Kaplan-Meier method. We reviewed radiographic imaging before and after each course of radiotherapy, and the largest “index” lesion outside the radiation treatment field was identified. The difference in the largest diameters of the index lesions were calculated comparing the pre- and post- radiation treatment imaging studies as well as two consecutive imaging studies performed immediately prior to radiotherapy. A favorable response was defined as any decrease in the size of the index lesion. We compared the number of favorable responses before and after radiation therapy using McNemar's test. We also calculated the difference in response on the two imaging studies prior to radiation as compared to before and after radiation therapy by calculating the difference between the percent changes in index lesion diameter (“delta-delta”), and analyzed the significance of these differences using the binomial test. Finally, we used Pearson's chi-squared test to assess associations between radiation treatment parameters and changes in response rate.
Results: Patient median survival was 19 months (IQR: 11-48 months, median follow up 17 months), with 5-year survival of 22%. There were 116 radiotherapy courses identified with available data from at least two consecutive imaging studies prior to initiation of radiation as well as a single post-radiation study. Index lesions shrank in 10 instances prior to radiation therapy (9%) as compared with 29 instances (25%) after radiation therapy; in 22 of these 29 instances (76%) the index lesion had been increasing in size prior to radiotherapy (p<0.001). Radiotherapy was also associated with an improved rate of index lesion response (delta-delta) in 65% of cases (p=0.004). A radiation fraction size ≤3 Gy was associated with an improved rate of index lesion response as compared with hypofractionated treatment including stereotactic radiosurgery and stereotactic body radiotherapy (78% favorable as compared with 52%, p=0.016).
Conclusions: Our systematic review of metastatic melanoma patients treated with the combination of radiotherapy and ipilimumab suggests that a subset of patients may have more favorable out-of-field responses following treatment with radiation. Interestingly, we found that smaller radiation fraction sizes (≤3 Gy/fraction) were associated with a more favorable change in response. If confirmed, these results may have important ramifications for the design of future trials that seek to combine radiation and immunotherapy to maximize the likelihood of achieving an abscopal effect.
Citation Format: Ravi A. Chandra, Tyler J. Wilhite, Tracy A. Balboni, Alexander Spektor, Andrea K. Ng, Frank Stephen Hodi, Jr., Jonathan D. Schoenfeld. A systematic evaluation of abscopal responses following radiation therapy in patients with metastatic melanoma treated with ipilimumab. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A20.
- ©2015 American Association for Cancer Research.