Decreasing Irradiated Rat Lung Volume Changes Dose-Limiting Toxicity From Early to Late Effects

Purpose

Technological developments in radiation therapy result in smaller irradiated volumes of normal tissue. Because the risk of radiation therapy-induced toxicity generally depends on irradiated volume, changing volume could change the dose-limiting toxicity of a treatment. Recently, in our rat model, we found that early radiation-induced lung dysfunction (RILD) was closely related to irradiated volume dependent vascular remodeling besides inflammation. The exact relationship between early and late RILD is still unknown. Therefore, in this preclinical study we investigated the dose-volume relationship of late RILD, assessed its dependence on early and late pathologies and studied if decreasing irradiated volume changed the dose-limiting toxicity.

Methods and Materials

A volume of 25%, 32%, 50%, 63%, 88%, or 100% of the rat lung was irradiated using protons. Until 26 weeks after irradiation, respiratory rates were measured. Macrovascular remodeling, pulmonary inflammation, and fibrosis were assessed at 26 weeks after irradiation. For all endpoints dose-volume response curves were made. These results were compared to our previously published early lung effects.

Results

Early vascular remodeling and inflammation correlated significantly with early RILD. Late RILD correlated with inflammation and fibrosis, but not with vascular remodeling. In contrast to the early effects, late vascular remodeling, inflammation and fibrosis showed a primarily dose but not volume dependence. Comparison of respiratory rate increases early and late after irradiation for the different dose-distributions indicated that with decreasing irradiated volumes, the dose-limiting toxicity changed from early to late RILD.

Conclusions

In our rat model, different pathologies underlie early and late RILD with different dose-volume dependencies. Consequently, the dose-limiting toxicity changed from early to late dysfunction when the irradiated volume was reduced. In patients, early and late RILD are also due to different pathologies. As such, new radiation techniques reducing irradiated volume might change the dose-limiting toxicity of the radiation therapy treatment.

Introduction

Radiation therapy plays a pivotal role in the treatment of thoracic cancers. Unfortunately, radiation-induced lung dysfunction (RILD) is a potentially life-threatening and dose-limiting side effect of thoracic irradiation and thus the risk should be minimized (1).

Traditionally, RILD is divided into an early inflammatory phase known as “radiation pneumonitis” and a later fibroproductive phase referred to as “lung fibrosis.” Clinically significant symptomatic early RILD occurs in approximately 5% to 50%, 5% to 10%, and 1% to 5% of patients irradiated for cancers of the lung, mediastinal lymphatics, and breast, respectively 2, 3.

Accurate prediction of the development of RILD is of great importance for treatment optimization. However, controversy exists about which dosimetric parameter(s) optimally predict RILD (4). Moreover, only models predicting early RILD are described. Because new advances in therapies will lead to a longer life expectancy of cancer patients, the occurrence of late radiation-induced normal tissue toxicity will become more relevant. Besides, technological developments in radiation therapy result in smaller irradiated volumes of normal tissue. Changing the irradiated volume could change the dose-limiting toxicity of a treatment.

In our rat model, early and late RILD occurs as a bi-phasic increase in breathing rates and histopathological changes (5). Morphologically, distinct types of lung injury can be observed: vascular remodeling, inflammation and fibrosis (6). Recently, we found that in concert with inflammation, vascular remodeling played a major role in the cause of early RILD 7, 8. It was shown that lung irradiation induced early vascular remodeling resulting in pulmonary hypertension and right ventricle hypertrophy eventually leading to cardiopulmonary dysfunction 7, 9.

The relationship between early RILD with its dependence on irradiation dose and volume and late RILD is still unknown. Therefore, in this preclinical study, we investigated the dose-volume relationship of late RILD, assessed its dependence on early and late pathologies and studied if decreasing irradiated volume could change the dose-limiting toxicity.