Thoracic Radiation Normal Tissue Injury

https://doi.org/10.1016/j.semradonc.2017.04.009Get rights and content

Thoracic malignancies are often a difficult group of tumors to treat definitively as the radiation doses needed to achieve a high probability for tumor control are often associated with high rates of radiation-induced toxicities. The lungs are particularly radiosensitive and are susceptible to radiation pneumonitis in the acute and subacute settings and pulmonary fibrosis in the late setting. Acute esophagitis is common and affects patient quality of life. Beyond acute pericarditis, late cardiac toxicities are increasingly being recognized as clinically relevant when delivering thoracic radiotherapy and can affect overall survival. This review details the common and dose-limiting acute and late toxicities associated with thoracic radiation therapy. As radiation-induced toxicities are often amplified with concurrent chemotherapy, this article focuses on the toxicities associated with irradiation for lung cancer, the most common thoracic malignancy, which is often treated with multimodality therapy. The management of radiation-induced toxicities and the changing patterns of toxicities with advanced radiation delivery modalities are also described.

Introduction

Thoracic malignancies are a heterogenous group of cancers that included non–small cell lung cancer (NSCLC), small cell lung cancer (SCLC), esophageal cancer, thymoma, thymic carcinoma, and malignant pleural mesothelioma, as well as lymphomas and more rare tumors such as thoracic sarcomas and paragangliomas. Lung cancer is by far the most common thoracic malignancy in both developed and developing countries,1 and it is the leading cause of death among all malignancies, with an estimated 222,500 new cases and 155,870 deaths expected in the United States in 2017.2

Over 85% of patients with lung cancer are histologically classified as having NSCLC, and approximately 15% of patients with NSCLC present with localized disease that is confined to their primary tumor site.3 Among these patients, surgery has been considered the standard treatment modality for curative-intent therapy. However, owing to the high proportion of patients who are determined to be medically inoperable, largely due to comorbidities or advanced age,4, 5 radiation therapy has had an entrenched position as a curative-intent modality for nonoperable patients.

With local control and overall survival rates with conventionally fractionated radiotherapy for stage I NSCLC inferior to that with surgery, there was great interest in assessing first hypofractionation6 and then stereotactic body radiation therapy (SBRT).7, 8 Given the excellent local control rates and early high rates of survival, SBRT, also termed stereotactic ablative radiotherapy, has recently emerged as a potential alternative to surgery in medical operable patients with stage I NSCLC,9, 10 as well as an option for early-stage SCLC.11

The remainder of patients with nonmetastatic NSCLC and SCLC present with nodal metastases or more advanced primary tumors. These patients with NSCLC are considered to have locally advanced disease, whereas those with SCLC are considered to have limited-stage disease. For each of these groups, the standard-of-care treatment is concurrent chemoradiation. A primary study to define this standard for locally advanced NSCLC (LA-NSCLC) was the Radiation Therapy Oncology Group (RTOG) 94-10 trial.12 In that trial, 610 patients were randomized into the following 3 arms: (1) sequential cisplatin and vinblastine followed by radiation therapy to 63 Gy in 34 daily fractions (sequential arm), (2) concurrent cisplatin and vinblastine and radiation therapy to 63 Gy in 34 daily fractions (concurrent arm), and (3) concurrent cisplatin plus etoposide and hyperfractionated radiotherapy to 69.6 Gy in 58 twice-daily fractions (hyperfractionated arm). This landmark study demonstrated improved overall survival in the concurrent arm compared with the sequential arm (17.0 months vs 14.6 months). For limited-stage SCLC (LS-SCLC), the Japanese Cooperative Oncology Group randomized 231 patients to sequential vs concurrent chemotherapy (cisplatin and etoposide) and radiation therapy (45 Gy in 1.5 Gy twice-daily fractions).13 Concurrent therapy had numerically improved median survival (27.2 months vs 19.7 months). Although both studies provide a strong rationale for concurrent chemoradiation, both studies also demonstrated increased rates of toxicities with concurrent compared with sequential chemoradiation.

In this article, I describe the common and the dose-limited toxicities associated with radiation therapy for thoracic malignancies, with a focus on the toxicities of concurrent chemoradiation for lung cancer. Both acute and late toxicities are detailed. I also describe the management of radiation toxicities and the changing patterns of toxicities with advanced radiation delivery modalities such as SBRT, intensity-modulated radiation therapy (IMRT), and proton therapy.

Section snippets

Radiation Pneumonitis

Radiation pneumonitis, an inflammation of the normal lung tissues from radiation therapy, is a dose-limiting toxicity of thoracic radiation therapy. In hours to days after the initiation of irradiation to the lungs, acute inflammation predominates and is manifested by hyperemia, increased capillary permeability, leukocytic infiltration, and cytokine release of factors such as tumor necrosis factor-α, interleukin-6, and interleukin-1α. Subsequent exudative alveolitis and sustained acute

Pulmonary Fibrosis

The aforementioned cascade of acute lung parenchymal changes from irradiation can lead to chronic parenchymal damage. In fact, distinguishing between the resolution of acute pneumonitis and the development of late fibrosis is often not possible to be made clinically, and these 2 entities may constitute a continuous spectrum of radiation-induced lung toxicities or the development of radiation pneumonitis may increase the risk for the development of radiation fibrosis.48, 49

The mechanism of

Advanced Radiotherapy Techniques and Toxicity Implications

Since the publication of several sentinel chemoradiation trials for LA-NSCLC, LS-SCLC, and esophageal cancer that defined the expected rates of toxicities from therapy, multiple advances have been made to radiotherapy delivery that may now allow for lower toxicity rates in the modern era. IMRT is perhaps the most prominent and important such advance. By using inverse-planned computer algorithms to generate highly conformal irradiation dose distributions, IMRT can allow for substantial

Conclusions

Thoracic malignancies are a heterogeneous but difficult group of tumors to treat with radiation therapy, and treatment-induced toxicities are common and potentially life threatening. Factors associated with radiation pneumonitis and radiation esophagitis are relatively well defined, whereas there exists a knowledge gap as to the exact toxicities, mechanisms, and factors associated with the development of treatment-related cardiac toxicities. SBRT has emerged as a standard approach for

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