Localized Low-Dose Radiotherapy for Follicular Lymphoma: History, Clinical Results, Mechanisms of Action, and Future Outlooks

The extreme radiosensitivity of indolent lymphomas was reported in the early years of radiotherapy (RT). The efficacy of low-dose total body irradiation (1.5–2 Gy) was particularly demonstrative. Higher doses were considered appropriate for localized disease. The optimal (or conventional) dose of curative RT derived from the early studies was determined to be 30–35 Gy. Nevertheless, in older series addressing the tumoricidal radiation dose in non-Hodgkin's lymphomas, investigators noted that a significant number of "nodular" lymphomas were controlled with a dose of <22 Gy for >3 years. The idea of reintroducing localized low-dose radiotherapy (LDRT) for indolent non-Hodgkin's lymphomas came from a clinical observation. The first study showing the high efficacy of LDRT (4 Gy in two fractions of 2 Gy within 3 days) in selected patients with chemoresistant, indolent, non-Hodgkin's lymphomas was published in 1994. Since this first report, at least eight series of patients treated with localized LDRT have been published, showing a 55% complete response rate in irradiated sites, with a median duration of 15–42 months. How LDRT induces lymphoma cell death remains partly unknown. However, some important advances have recently been reported. Localized LDRT induces an apoptosis of follicular lymphoma cells. This apoptotic cell death elicits an immune response mediated by macrophages and dendritic cells. Follicular lymphoma is probably an ideal model to explore these mechanisms. This review also discusses the future of LDRT for follicular lymphoma. The extreme radiosensitivity of indolent lymphomas was reported in the early years of radiotherapy (RT). The efficacy of low-dose total body irradiation (1.5–2 Gy) was particularly demonstrative. Higher doses were considered appropriate for localized disease. The optimal (or conventional) dose of curative RT derived from the early studies was determined to be 30–35 Gy. Nevertheless, in older series addressing the tumoricidal radiation dose in non-Hodgkin's lymphomas, investigators noted that a significant number of "nodular" lymphomas were controlled with a dose of <22 Gy for >3 years. The idea of reintroducing localized low-dose radiotherapy (LDRT) for indolent non-Hodgkin's lymphomas came from a clinical observation. The first study showing the high efficacy of LDRT (4 Gy in two fractions of 2 Gy within 3 days) in selected patients with chemoresistant, indolent, non-Hodgkin's lymphomas was published in 1994. Since this first report, at least eight series of patients treated with localized LDRT have been published, showing a 55% complete response rate in irradiated sites, with a median duration of 15–42 months. How LDRT induces lymphoma cell death remains partly unknown. However, some important advances have recently been reported. Localized LDRT induces an apoptosis of follicular lymphoma cells. This apoptotic cell death elicits an immune response mediated by macrophages and dendritic cells. Follicular lymphoma is probably an ideal model to explore these mechanisms. This review also discusses the future of LDRT for follicular lymphoma.