The Association of Radiation Dose-Fractionation and Immunotherapy Use With Overall Survival in Metastatic Melanoma Patients

Shang-Jui Wang,Rahul R Parikh,Sharad Goyal,Eric Miller,Ann W Silk,John Byun,Joseph Weiner,Zorimar Rivera-Nunez,Dukagjin Blakaj,Sachin R Jhawar

doi:10.7759/cureus.8767

Abstract

ObjectiveMetastatic melanoma patients often receive palliative radiotherapy (RT) and immunotherapy (IT). However, the immunological interplay between RT dose-fractionation and IT is uncertain, and the optimal treatment strategy using RT and IT in metastatic melanoma remains unclear. Our main objective was to examine the effect of RT dose-fractionation on overall survival (OS).MethodsUsing the National Cancer Database (NCDB), we classified metastatic melanoma patients who received palliative RT into two dose-fractionation groups - conventionally fractionated RT (CFRT; <5 Gy/fraction) and hypofractionated RT (HFRT: ≥5 Gy/fraction) - with or without IT. Survival analysis was performed using the Cox regression model, Kaplan-Meier method, and propensity-score matching (PSM).ResultsA total of 5,281 metastatic melanoma patients were included, with a median follow-up of 5.9 months. The three-year OS was highest in patients who received HFRT+IT [37.3% (95% CI: 31.1-43.5)] compared to those who received HFRT alone [19.0% (95% CI: 16.2-21.9)], CFRT+IT [17.6 (95%CI: 13.9-21.6)], or CFRT alone [8.6% (95%CI: 7.6-9.7); p<0.0001]. The magnitude of OS benefit with the use of IT was greater in those who received HFRT (18.3%) compared with those who received CFRT (9.0%) (p<0.0001). The addition of IT to HFRT, compared to CFRT, was associated with greater OS benefit in patients treated with RT to the brain and soft tissue/visceral (STV) sites. On PSM analysis, HFRT+IT was associated with improved three-year OS compared to other treatments.ConclusionMetastatic melanoma patients who received HFRT+IT was associated with the greatest OS benefit. Our findings warrant further prospective evaluation as to whether higher RT dose-per-fraction improves clinical outcomes in metastatic melanoma patients receiving IT.

Highlights

Melanoma is the first malignancy in which immunotherapy (IT) has gained widespread use in the metastatic setting
The three-year overall survival (OS) was highest in patients who received hypofractionated RT (HFRT)+IT [37.3%] compared to those who received HFRT alone [19.0%], conventionally fractionated RT (CFRT)+IT [17.6 (95%CI: 13.9-21.6)], or CFRT alone [8.6% (95%CI: 7.6-9.7); p
The addition of IT to HFRT, compared to CFRT, was associated with greater OS benefit in patients treated with RT to the brain and soft tissue/visceral (STV) sites

Summary

Introduction

Melanoma is the first malignancy in which immunotherapy (IT) has gained widespread use in the metastatic setting. Immune checkpoint inhibitors such as anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) and antiprogrammed cell death-1 (PD-1) antibodies, which are considered first-line therapies in patients with metastatic melanoma, can reverse the immunosuppressive effects exerted by cancer cells and promote antitumor immunity [1,2,3,4]. RT has been demonstrated to induce immune-modulation through a variety of mechanisms, including increased presentation of antigens, the release of pro-inflammatory cytokines and molecules, upregulation of death receptors and ligands, and neoantigen formation [6].

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