We read with great interest the brief report by Meyer et al, “Tissue TGF-β expression following conventional radiotherapy and pulsed low-dose-rate radiation”.Citation1 Pulse Reduced (-low) Dose Rate Radiotherapy (PRDR) is delivered using conventional radiotherapy linear accelerators but at a much slower rate. Typically taking ∼45 minutes compared with ∼5 minutes using conventional techniques, 0.2 Gy pulses interspaced with 3 min intervals is given until the total prescribed dose is delivered. PRDR was developed following the observation that normal tissue may initiate DNA repair at lower amounts of damage compared with malignant cells. In theory, DNA damage could accumulate exclusively in the tumor cells while repair would be exclusive to the normal tissues.Citation2 Clinically, this may reduce both acute and late side effects of radiotherapy while maintaining tumor cell killing. Promising results from small clinical trials have been seen in the re-irradiation setting of chest walls,Citation3 glioblastoma,Citation4 and other cancers. Currently there is an ongoing clinical trial assessing its impact on overall survival when combined with Avastin in recurrent glioblastoma (NCT01743950).
In this brief report the authors demonstrate a potential mechanism for the decreased acute and long-term toxicities observed with PRDR. Transforming growth factor β (TGF-β) is associated with late radiation toxicities including necrosis and pneumonitis.Citation5 The authors hypothesize that PRDR may reduce TGF-β in tissues and may explain the clinically observed decrease in toxicity. In a murine model system the authors demonstrate significant reduction in inflammatory response following PLDR compared with conventional fractionated radiotherapy in bone marrow, small intestine, lungs and pancreases. In addition, this increase in TGF-β was observed quite early following radiotherapy at 14 d despite the commonly held belief this is a late effect occurring after months.Citation5 This is an interesting finding as it suggests a mechanism for the observed clinical benefits of PLDR as well as being hypothesis generating into other aspects of the tumor-host response that may differ between conventional radiotherapy and PLDR.
We have been interested in the impact of TGF-β on acute and late side effects of radiotherapy, as well as the potentially immunosuppressive nature of TGF-β for T-cell function and recruitment. These results support further clinical trials using this technique in areas where pneumonitis or necrosis is of particular concern. In addition, it suggests other work is needed to determine if PLDR may enhance T-cell function in tumors by decreasing the immune inhibitory effects of TGF-β.Citation6 These results may not only have important implications for decreasing the side effects of radiotherapy, but may enhance the effects of the native immune response to tumors or enhance immune modulating agents currently under investigation.
Disclosure of potential conflicts of interest
No potential conflicts of interest were disclosed.
Acknowledgment
We thank the Ludwig Center for metastasis research for its generous support.
References
- Meyer JE, Wakif ES. Tissue TGF-beta expression following conventional radiotherapy and pulsed low-dose-rate radiation. Cell Cycle 2017; 16(12):1171-1174; PMID:28486014; https://doi.org/10.1080/15384101.2017.1317418
- Tome WA, Howard SP. On the possible increase in local tumour control probability for gliomas exhibiting low dose hyper-radiosensitivity using a pulsed schedule. Br J Radiol 2007; 80(949):32-7; PMID:16945935; https://doi.org/10.1259/bjr/15764945
- Richards GM, Tomé WA, Robins HI, Stewart JA, Welsh JS, Mahler PA, Howard SP. Pulsed reduced dose-rate radiotherapy: a novel locoregional retreatment strategy for breast cancer recurrence in the previously irradiated chest wall, axilla, or supraclavicular region. Breast Cancer Res Treat 2009; 114(2):307-13; https://doi.org/10.1007/s10549-008-9995-3
- Cannon GM, Tomé WA, Robins HI, Howard SP. Pulsed reduced dose-rate radiotherapy: case report: a novel re-treatment strategy in the management of recurrent glioblastoma multiforme. J Neurooncol 2007; 83(3):307-11; PMID:17252184; https://doi.org/10.1007/s11060-007-9329-z
- Hallahan DE, Haimovitz-Friedman A, Kufe DW, Fuks Z, Weichselbaum RR. The role of cytokines in radiation oncology. Important Adv Oncol 1993; 71-80; PMID:8505057
- Schoenhals JE, Skrepnik T, Selek U, Cortez MA, Li A, Welsh JW. Optimizing radiotherapy with immunotherapeutic approaches. Adv Exp Med Biol 2017; 995:53-71; PMID:28321812