Prevention and treatment of radiotherapy-induced side effects

Abstract

Radiotherapy remains a mainstay of cancer treatment, being used in roughly 50% of patients. The precision with which the radiation dose can be delivered is rapidly improving. This precision allows the more accurate targeting of radiation dose to the tumor and reduces the amount of surrounding normal tissue exposed. Although this often reduces the unwanted side effects of radiotherapy, we still need to further improve patients' quality of life and to escalate radiation doses to tumors when necessary. High-precision radiotherapy forces one to choose which organ or functional organ substructures should be spared. To be able to make such choices, we urgently need to better understand the molecular and physiological mechanisms of normal tissue responses to radiotherapy. Currently, oversimplified approaches using constraints on mean doses, and irradiated volumes of normal tissues are used to plan treatments with minimized risk of radiation side effects. In this review, we discuss the responses of three different normal tissues to radiotherapy: the salivary glands, cardiopulmonary system, and brain. We show that although they may share very similar local cellular processes, they respond very differently through organ-specific, nonlocal mechanisms. We also discuss how a better knowledge of these mechanisms can be used to treat or to prevent the effects of radiotherapy on normal tissue and to optimize radiotherapy delivery.

Keywords: brain; cardiopulmonary system; dose distribution; normal tissue effects; salivary gland.

Fig. 1

A schematic of the cellular and tissue responses of the salivary gland to radiotherapy over time. (Left panel) The left panel depicts a model of a salivary gland and shows the structure of the acinus, which when enlarged features the different cell types it is composed of. (Right panel) The early and late responses of salivary gland tissue to radiotherapy. The early response (which occurs within hours or days) is completely different mechanistically to the late response. The early response is too rapid to be explained by mitotic failure or related cell death and seems to be due to failure of vasculature function, parasympathetic nerve function, acinar cell signal transduction, and possibly inflammation and acinar cell apoptosis (which is limited, depending on the experimental model used). The later effects (which occur > 30 days after radiotherapy) result from acinar cell loss, which coincides with chronic inflammation and fibrosis. Depending on the radiotherapy dose used, some morphological recovery might follow, as shown by the appearance of acinar cell clusters.

Fig. 2

A schematic of the side effects of radiotherapy on the cardiopulmonary system over time. Shown are the cellular, tissue, and organ responses over time in the tissues of the lung and heart. The loss and dysfunction of lung vascular ECs are the first visible forms of damage in the irradiated lung. This is followed by acute inflammation and, depending on the dose, the first signs of fibrosis. These local processes are aggravated by loss of diastolic function if the heart is irradiated concomitantly. In the subsequent months, lung damage progresses and features chronic inflammation and function‐limiting fibrosis. The resulting dyspnea might resolve at later time points by compensatory inflation of nonirradiated parts of the lung. The adequacy of this compensatory response, however, depends on the irradiated lung volume. In addition, cardiac irradiation might also lead to later onset cardiac failure.

Fig. 3

A schematic of the cellular and tissue responses of the brain to radiotherapy over time. Radiation causes multiple effects in the brain, including vascular damage, neurogenesis decline, white matter damage, and neuronal damage. Within hours after irradiation, cell death, largely via apoptosis, occurs in ECs, progenitor cells, and neuroblasts of the SVZ and SGZ, and in OPCs. Neurons exhibit abnormal glutamate signaling and synaptic function relatively early after irradiation, alongside alterations in dendritic spines and morphology. These early responses are followed by an inflammatory response that is characterized by the release of cytokines, and the reactivity of astrocytes and microglial cells. This inflammatory response can contribute to both early and late effects that affect different cell types and their interactions.