Radiation pneumonitis and pulmonary fibrosis in non–small-cell lung cancer: Pulmonary function, prediction, and prevention

Although radiotherapy improves locoregional control and survival in patients with non-small-cell lung cancer, radiation pneumonitis is a common treatment-related toxicity. Many pulmonary function tests are not significantly altered by pulmonary toxicity of irradiation, but reductions in Dl_co, the diffusing capacity of carbon monoxide, are more commonly associated with pneumonitis. Several patient-specific factors (e.g. age, smoking history, tumor location, performance score, gender) and treatment-specific factors (e.g. chemotherapy regimen and dose) have been proposed as potential predictors of the risk of radiation pneumonitis, but these have not been consistently demonstrated across different studies. The risk of radiation pneumonitis also seems to increase as the cumulative dose of radiation to normal lung tissue increases, as measured by dose-volume histograms. However, controversy persists about which dosimetric parameter optimally predicts the risk of radiation pneumonitis, and whether the volume of lung or the dose of radiation is more important. Radiation oncologists ought to consider these dosimetric factors when designing radiation treatment plans for all patients who receive thoracic radiotherapy. Newer radiotherapy techniques and technologies may reduce the exposure of normal lung to irradiation. Several medications have also been evaluated for their ability to reduce radiation pneumonitis in animals and humans, including corticosteroids, amifostine, ACE inhibitors or angiotensin II type 1 receptor blockers, pentoxifylline, melatonin, carvedilol, and manganese superoxide dismutase-plasmid/liposome. Additional research is warranted to determine the efficacy of these medications and identify nonpharmacologic strategies to predict and prevent radiation pneumonitis.

Introduction

Clinical treatment guidelines recommend the use of radiotherapy in patients with locally advanced non-small-cell lung cancer (NSCLC), good performance status, and adequate pulmonary function (1). Conventionally fractionated radiotherapy for NSCLC consists of 1.8–2.0 Gy fractions given once daily for 5 days each week to a total dose of 60 Gy or more. This treatment strategy is associated with improved locoregional control and survival (2), but radiation-induced lung toxicity such as radiation pneumonitis and pulmonary fibrosis is common. Radiation pneumonitis usually develops in the first few weeks to months after radiotherapy is initiated and consists of symptomatic changes such as cough, shortness of breath, and fever, with or without changes in pulmonary function tests (PFTs). Pulmonary fibrosis is the permanent scarring of lung tissue that occurs more gradually (over months to years) in response to the initial tissue injury and leads to permanent impairment of oxygen transfer.

The incidence of moderate to severe radiation pneumonitis ranges from roughly 10% to 20% with radiotherapy or chemoradiotherapy (3), but its reported incidence has varied widely in clinical studies for several reasons. The type of radiotherapy and the presence or absence of neoadjuvant, adjuvant, concurrent, or consolidation chemotherapy may influence the risk of radiation pneumonitis.

Underreporting of radiotherapy-induced pneumonitis is likely, particularly in retrospective studies, because the nonspecific symptoms of acute pneumonitis (shortness of breath and cough, with or without mild fever) may be erroneously attributed to another cardiovascular or respiratory disorder. Furthermore, patients may be asymptomatic but still have radiographic evidence of radiation pneumonitis, and this population is not reported in retrospective analyses. Even in prospective trials that include acute toxicity end points, patients are not always assessed for the presence of radiation pneumonitis (4, 5). Finally, some analyses include patients who expire early (i.e., before it is reasonable to assume they could have developed radiation pneumonitis) in the denominator of patients “at risk,” thereby artificially reducing the true estimated incidence of radiation pneumonitis.

The morbidity and mortality directly attributable to radiation-induced lung toxicity are difficult to distinguish from the clinical consequences of NSCLC itself and the underlying cardiorespiratory conditions in these patients. The major consequence of radiation pneumonitis is shortness of breath, which leads to diminished quality of life and reduced activities of daily living. These are particularly important sequelae in patients with locally advanced lung cancer, who usually undergo treatment to reduce symptoms rather than to increase life span. Mild to moderate symptomatic radiation pneumonitis may resolve with symptomatic treatment such as inhaled corticosteroid therapy (6). Severe radiation pneumonitis is associated with significantly lower survival than mild or absent radiation pneumonitis (7), and the mortality rate associated with severe radiation pneumonitis may approach 50% (8). Consequently, one analysis determined that 2.3% of all patients who received thoracic radiotherapy or chemoradiotherapy for advanced cancer died of radiation pneumonitis (9), corresponding to approximately 1 in 43 patients.

Emerging clinical evidence suggests that identifying patients at risk of radiation pneumonitis, modifying radiotherapy treatment to minimize doses to normal lung tissue, and using radioprotective therapy may reduce the incidence and severity of radiation pneumonitis, potentially increasing the dose of radiotherapy that can be administered to NSCLC tumors. The objective of this review was to briefly summarize recent findings that might influence how practicing radiation oncologists predict and prevent radiation pneumonitis. The pathophysiology, etiology, and radiographic diagnosis of radiation pneumonitis are not discussed in this review, and the reader is referred to other papers for excellent summaries of these topics (10, 11, 12, 13).

This review begins with a summary of clinical studies that evaluated the correlations between PFTs and radiation pneumonitis, because these tests are frequently used as surrogate end points for the presence and severity of radiation pneumonitis. The next sections describe studies that evaluated patient-specific and treatment-specific risk factors for radiation pneumonitis, with particular attention to the use of dose-volume histograms (DVHs) and various dosimetric parameters that are used to estimate risk; this section is followed by a brief review of potential biochemical detection markers for radiation pneumonitis. The remaining sections of the review describe how the risk of radiation pneumonitis might be influenced by evolving radiotherapy treatment strategies; also discussed is preliminary evidence that cytoprotective medications might reduce radiation pneumonitis.