Local Tumor Control and Normal Tissue Toxicity of Pulsed Low-Dose Rate Radiotherapy for Recurrent Lung Cancer: An In Vivo Animal Study

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.

Keywords: A549 xenograft model; normal tissue toxicity; pulsed low-dose rate radiotherapy (PLDR); total body irradiation (TBI); tumor growth.

Figure 1.

The experiment setup and procedures for the tumor control experiment and total body irradiation experiment.

Figure 2.

Top: Weekly magnetic resonance (MR) images of A549 tumors after the radiation treatment (W1 is the treatment week). Bottom: the average tumor volumes for the control mice (CON), and the mice received 4 Gy conventional radiotherapy (RT) and pulsed low-dose rate radiotherapy (PLDR).

Figure 3.

The average weight of mice in the conventional radiotherapy (RT)group and the pulsed low-dose rate radiotherapy (PLDR) group. The mice in the conventional RT group received continuous 8 Gy TBI treatment and the mice in the PLDR group received 8 Gy total body irradiation (TBI) in 40 × 0.2 Gy pulses with 3-minute intervals.

Figure 4.

The survival time of mice in the conventional radiotherapy (RT) group and the pulsed low-dose rate radiotherapy (PLDR) group. The mice in the conventional RT group received continuous 8 Gy TBI treatment and the mice in the PLDR group received 8 Gy TBI in 40 × 0.2 Gy pulses with 3-minute intervals.

Figure 5.

The morphological abnormalities of spleen in 3 groups. Compared to the control group (A, ×100 and D, ×200), the degree of atrophy in the spleen was mild to moderate in the pulsed low-dose rate radiotherapy (PLDR) group (B, ×100 and E, ×200), but severe in the conventional radiotherapy (RT) group (C, ×100 and F, ×200).

Figure 6.

The morphological abnormalities of bone marrow in 3 groups. Compared to the control group (A, ×100 and D, × 200), the degree of atrophy in the bone marrow was mild to moderate in the pulsed low-dose rate radiotherapy (PLDR) group (B, ×100 and E, ×200), but severe in the conventional radiotherapy (RT) group (C, ×100 and F, ×200).