Radiotherapy for Melanoma: More than DNA Damage

Abstract

Despite its reputation as a radioresistant tumour, there is evidence to support a role for radiotherapy in patients with melanoma and we summarise current clinical practice. Melanoma is a highly immunogenic tumour and in this era of immunotherapy, there is renewed interest in the potential of irradiation, not only as an adjuvant and palliative treatment, but also as an immune stimulant. It has long been known that radiation causes not only DNA strand breaks, apoptosis, and necrosis, but also immunogenic modulation and cell death through the induction of dendritic cells, cell adhesion molecules, death receptors, and tumour-associated antigens, effectively transforming the tumour into an individualised vaccine. This immune response can be enhanced by the application of clinical hyperthermia as evidenced by randomised trial data in patients with melanoma. The large fraction sizes used in cranial radiosurgery and stereotactic body radiotherapy are more immunogenic than conventional fractionation, which provides additional radiobiological justification for these techniques in this disease entity. Given the immune priming effect of radiotherapy, there is a strong but complex biological rationale and an increasing body of evidence for synergy in combination with immune checkpoint inhibitors, which are now first-line therapy in patients with recurrent or metastatic melanoma. There is great potential to increase local control and abscopal effects by combining radiotherapy with both immunotherapy and hyperthermia, and a combination of all three modalities is suggested as the next important trial in this refractory disease.

Figure 1

Schematic of the potential costimulation of the immune system by radiotherapy, immune therapy, and hyperthermia.

Figure 2

Complete clinical response of cutaneous malignant melanoma metastases three months following irradiation with 3 x 9 Gy with 80kV combined with weekly superficial hyperthermia.

Figure 3

Complete clinical response of a cutaneous melanoma metastatic cervical lymph node conglomerate that developed during systemic therapy with nivolumab and ipilimumab, two months following irradiation with 12 x 3 Gy with 6MV over 3 weeks, combined with twice-weekly superficial hyperthermia.