Local Tumor Control and Normal Tissue Toxicity of Pulsed Low-Dose Rate Radiotherapy for Recurrent Lung Cancer

Abstract

Objectives:This study investigates (1) local tumor control and (2) normal tissue toxicity of pulsed low-dose rate radiotherapy (PLDR) for recurrent lung cancer.Methods:For study 1, nude mice were implanted with A549 tumors and divided into the following 3 groups: (1) control (n = 10), (2) conventional radiotherapy (RT; n = 10), and (3) PLDR (n = 10). Tumor-bearing mice received 2 Gy daily dose for 2 consecutive days. Weekly magnetic resonance imaging was used for tumor growth monitoring. For study 2, 20 mice received 8 Gy total body irradiation either continuously (n = 10) or 40 × 0.2 Gy pulses with 3-minute intervals (n = 10).Results:For study 1, both conventional RT and PLDR significantly inhibited the growth of A549 xenografts compared with the control group (>35% difference in the mean tumor volume; P < .05). The PLDR results were slightly better than conventional RT (8% difference in the mean tumor volume; P > .05). For study 2, the average weight was 20.94 ± 1.68 g and 25.69 ± 1.27 g and the survival time was 8 days and 12 days for mice treated with conventional RT and PLDR (P < .05), respectively.Conclusion:This study showed that PLDR could control A549 tumors as effectively as conventional RT, and PLDR induced much less normal tissue toxicity than conventional RT. Thus, PLDR would be a good modality for recurrent lung cancers.Advances in Knowledge:This article reports our results of an in vivo animal investigation of PLDR for the treatment of recurrent cancers, which may not be eligible for treatment because of the dose limitations on nearby healthy organs that have been irradiated in previous treatments. This was the first in vivo study to quantify the tumor control and normal tissue toxicities of PLDR using mice with implanted tumors, and our findings provided evidence to support the clinical trials that employ PLDR treatment techniques.

Tissue TGF-β expression following conventional radiotherapy and pulsed low-dose-rate radiation

“…In accordance with what has been previously published we observed histopathological signs of reduced toxicity in mice following PLDR when compared with equivalent doses of CRT 5 ( Fig. 1).…”

“…Male balb/c mice were subjected to the same total physical doses of whole-body radiation using 2 different radiation delivery protocols 5 according to an approved Fox Chase Cancer Center and Temple Health Institutional Animal Care and Use Committee protocol. Conventional radiotherapy (CRT) was delivered as a single dose of 8 Gy whereas PLDR involved delivery in 40 fractions of 0.2 Gy separated by 3 minutes.…”

“…The technique is based on 3 observations: low dose hyper-radiosensitivity, evidence of a transition dose beyond which DNA damage repair is triggered, and the observation of improved DNA damage repair for normal tissue at low dose rates. [5][6][7][8][9][10] The theory is that tumor cells have a higher dose threshold to initiate DNA repair than normal tissues.…”

Use of Pulsed Low–Dose Rate Radiotherapy in Refractory Malignancies

“…PLDR not only exerts increased tumor control capacity but also favors normal tissue sparing and the preservation of vascular network. In the lung cancer murine model, Zhang et al found that PLDR could control tumors as effectively as the conventional radiotherapy but results in much less normal tissue toxicities than the conventional radiotherapy [5] . The preclinical study demonstrated that the combination of PLDR and temozolomide was associated with increased vascularization and fewer degenerating neurons compared with standard fractionated treatment plus temozolomide [2] .…”

Understanding the pluses of pulses

“…Accordingly, spreading the total doses into short, low-dose pulses been shown to effectively limit tissue toxicity and minimize complications. 1,2 Although PLDR has been validated in pre-clinical and clinical studies, the molecular basis of reduced necrosis and preserved normal tissue integrity has remained unclear.…”