History and Epidemiology

Radiation-induced lung injury (RILI) is a common complication of radiation therapy, which is a vital part of the treatment for lung, esophageal, and other thoracic cancers, as well as hematologic malignancies.¹ RILI can develop acutely as radiation pneumonitis (RP) and chronically in the form of radiation-induced pulmonary fibrosis (RIF). Radiation therapy has been used as a cancer treatment since the beginning of the 1900s but may cause adverse effects such as pulmonary fibrosis lung injury.^{2, 3}

RIF lung injury can be split into two types: classical RP and sporadic RP.⁴ Classical RP is an injury confined to the affected area that often leads to fibrosis. Sporadic RP affects a larger area than the tissue that was originally exposed to radiation and can lead to bilateral lymphocytic alveolitis, or inflammation of the lung tissue.⁴

Etiology and Risk Factors of Radiation-Induced Lung Injury

The population at risk is significant, as most patients with thoracic and breast malignancies undergo radiation therapy.² External beam radiation therapy (EBRT), either alone or with chemotherapy and surgery, is standard cancer treatment, with more than half of cancer patients receiving radiotherapy.^{5, 6}Advances in radiation delivery techniques has lowered the occurrence of RILI over time.²

Risk factors include the volume of lung irradiated, the dose of radiation received, whether induction chemotherapy was used prior to radiation, whether there was a prior thoracic radiation, a history of smoking, and pulmonary conditions such as COPD and interstitial lung disease.¹

Radiation-Induced Lung Injury Prognosis

Radiation causes damage to rapidly proliferating tumor cells and normal tissues in nearby organs within the radiation field. The radiosensitivity of individual cells will determine the adverse effect ionizing radiation has on healthy tissues.⁵ Lung tissue is among the most sensitive tissues to ionizing radiation. Its susceptibility to radiation damage limits the positive effect radiotherapy can have in lung cancer treatment.¹

The primary mechanisms that cause RILI are direct DNA damage and the generation of reactive oxygen species (ROS), along with upregulation of several cytokines, which induces fibroblast collagen deposition.¹ DNA damage can lead to altered gene expression and immediate release of growth factors such as transforming growth factor ß (TGF-ß), platelet-derived growth factor (PDGF), and interleukin 1 (IL-1). ROS can modify protein expression and produce hydroxyl radicals that cause DNA damage.

Radiation-induced pulmonary fibrosis can adversely affect the prognosis of cancer patients. The various anatomic sites and types of tissue in the lungs can cause a polymorphic clinical presentation of RIF.⁶ It may result in thickening of the skin and induration, limited joint mobility, muscle atrophy and contracture, mucosal fibrosis, lymphedema, fistula, ulceration, and hollow organ stenosis. Reactions like these can be extremely painful.⁶

Radiation-Induced Lung Injury Diagnosis & Presentation

Accurate diagnosis and quantification of radiation-induced pulmonary fibrosis and radiation pneumonitis are crucial to pursuing the most effective treatment method. Clinical diagnosis of radiation-induced lung injury is often complicated by the presence of various non-specific signs and symptoms commonly seen in patients, as well as by other conditions, such as malignancy, infection, and cardiogenic pulmonary edema. Symptoms caused by acute radiation pneumonitis typically develop around 4 to 12 weeks following radiation, whereas symptoms of fibrotic radiation pneumonitis develop after 6 to 12 months.

Non-specific signs and symptoms include tachypnea, cyanosis, crackles or pleural rub under thorax examination, chest pain, and malaise.⁷ Thoracic radiation can cause less common but severe symptoms such as hypoxemia and respiratory failure. Symptoms that are less frequent include airway obstruction, bronchitis, respiratory infections, and fevers.

Diagnostic Workup/Physical Examination Findings

Radiation-induced lung injury symptoms include dry cough, shortness of breath, chest pain, and fever.⁸ In severe cases it can lead to respiratory failure and death. Radiation therapy can cause density changes in the lung parenchyma, which can be monitored by a computed tomography (CT) scan.¹ CT monitoring is an important factor in diagnostics when the patient shows no signs or symptoms. For patients experiencing symptoms like cough and dyspnea, causes other than RILI should be considered because in up to 45% of patients, these symptoms are due to a different cause.¹

Diagnosis of radiation-induced lung injury is often made by using a clinical assessment and radiological findings.⁷ Pulmonary function tests are mainly used to evaluate lung function status during radiotherapy, and are a useful predictive tool to avoid complications or limit toxicity from radiation exposure. Reduced baseline mechanical function can be measured by spirometry and plethysmography. Additionally, the diffusion lung capacity of carbon monoxide test (DLCO) can be used as a predictive factor for radiation pneumonitis by flagging gas exchange abnormalities.⁷

When a physical examination is conducted, common signs of RILI include pleural friction rub, moist rales, and signs of consolidation.⁷In cases of both RP and radiation-induced pulmonary fibrosis, chronic pulmonary insufficiency, possibly leading to lung failure, can occur if the volume of damage in the lung is large enough. Pulmonary insufficiency can also lead to pulmonary.²

Differential Diagnosis

A chest X-ray is an initial test used to examine radiation pneumonitis but findings with imaging after radiation injury can mimic other etiologies.⁷ The extent of RP damage can vary depending on the radiological image that is observed. Imaging can display scarce patchy lesions within the irradiated field due to fading of the pulmonary vasculature.⁷ Newer diagnostic techniques such as VMAT and IMRT can deliver lower doses of radiation during diagnosis.¹CT imaging and pulmonary function tests can also be used as diagnostic tools for cases of RILI.⁹

Differential diagnoses include infection, thromboembolic disease, drug-induced pneumonitis, spread of underlying malignancy, cardiac failure, and exacerbation of chronic pulmonary diseases, such as COPD, heart failure, and interstitial lung disease.²

Radiation-Induced Lung Injury Treatment

Treatment of acute pneumonitis depends on clinical severity of the injury.² Currently, corticosteroids, azathioprine, and cyclosporin A are used as initial treatments for RP.⁴Severe cases of lung parenchyma, an effect of radiation therapy, are treated with corticosteroids with mostly fast improvement and recovery. Ambroxol and angiotensin-converting enzyme inhibitors have also been used as additional drugs to prevent or attenuate pneumonitis.⁴

Additional drugs are being considered for clinical use to treat radiation-induced pulmonary fibrosis including nintedanib, a multiple tyrosine kinase inhibitor, and pirfenidone, a TGF-β inhibitor, after they exhibited anti-inflammatory and anti-fibrotic effects in experimental murine irradiation models.⁴Exposure to the triggering agent at any time during treatment can lead to the development of radiation recall pneumonitis (RRP), an acute inflammatory response in a formerly irradiated lung after systemic antineoplastic agents have been administered.⁷

This article originally appeared on Pulmonology Advisor

References

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Radiation-Induced Lung Injury