Preliminary result of definitive radiotherapy in patients with non-small cell lung cancer who have underlying idiopathic pulmonary fibrosis: comparison between X-ray and proton therapy

Surgical resection is the standard of care in the treatment of patients with early-stage non-small cell lung cancer (NSCLC). However, a significant number (30–60%) of patients are medically inoperable due to the reasons including; old age, poor performance status, medical co-morbidities, and inadequate cardio-pulmonary function. Patients deemed unsuitable for surgery are often referred for definitive radiation therapy (RT). For the patients with poor pulmonary function or pulmonary diseases such as interstitial lung disease (ILD), even RT can result in significant complications; however, no universally accepted criteria to define patient suitability for RT have been described.

Pulmonary toxicity is one of the most common treatment-related complications after RT, and can affect the morbidity and mortality of patients with lung cancer [1‐4]. Severe pulmonary toxicity occurs at a rate of 1.5–20% in patients who undergo stereotactic body radiation therapy (SBRT) or at a rate of 5.0–25% after conventionally fractionated RT [5]. Several studies suggest that idiopathic pulmonary fibrosis (IPF) increases the risk of serious, sometimes life-threatening, treatment-related pulmonary complications such as acute exacerbation of IPF and/or pneumonia following RT [6‐8]. Recently, a few clinical results suggest that proton therapy can be performed more safely in patients with IPF than surgery or X-ray treatment [9‐11]. However, the role of proton therapy for these vulnerable patients to reduce the incidence of severe RT-related pulmonary complications is still unclear.

Proton therapy for lung cancer patients has started from January 2016 at authors’ institution. Herein, we present the preliminary result of early-stage lung cancer patients who had underlying IPF and were treated with definitive RT, focusing on the comparison between X-ray and proton therapy.

IPF is a pulmonary disease associated with a dismal prognosis. The median survival of patients with IPF ranges from 2.5 years to 3.5 years and the 5-year survival ranges between 20 and 40% [13]. The condition can be acutely exacerbated by a range of triggering factors, including infection, surgery, and RT. Yamashita et al. [6] demonstrated that severe pulmonary toxicity was observed in nine out of thirteen patients with IPF after SBRT, and seven of these cases were fatal. The presence of IPF shadow on CT was found to correlate well with the severe pulmonary toxicity. However, there was no correlation between the DVH parameters and the severe pulmonary toxicity. This may imply that even a small volume of RT including SBRT is not safe. Accordingly, they suggested that pre-screening for an IPF pattern on CT should be performed before SBRT in patients with lung cancer and underlying IPF. Lee et al. [7] evaluated the relationship between interstitial lung changes in the pre-radiotherapy CT and symptomatic pulmonary toxicity. The risk of pulmonary toxicity grade ≥ 2, ≥3, or ≥ 4 was higher in patients with interstitial lung change than patients without (grade 2, 15.6 to 46.7%, p = 0.03; grade 3, 4.4 to 40%, p = 0.002; grade 4, 4.4 to 33.3%, p = 0.008). Four out of the five patients with grade 5 pulmonary toxicity had diffuse interstitial changes on pre-radiotherapy CT. Recently, Ono et al. [9] reported the clinical results of proton RT in patients with IPF. The cumulative incidence of pulmonary toxicity was 19.8%, including one case of treatment-related death. This study was the first report on the incidence of pulmonary toxicity after proton RT in IPF patients. They showed that grade 4 or 5 pulmonary toxicity occurred at a rate of 6.3%, which was lower than that reported in previous studies with X-ray treatment. This result suggests that proton RT may reduce the incidence of life-threatening pulmonary complications in patients with IPF compared to that with X-ray irradiation.

Current study has several limitations. First, it is a retrospective analysis and there may be some selection biases. Second, the sample size is too small to show a statistical significance of difference between the two groups. Despite the lack of statistical significance due to small number of cases, our preliminary analysis is the first one to directly compare X-ray and proton therapy for lung cancer patients with IPF, and shows a promising result that is concordant with previous studies (summarized in Table 5). Although patients that received proton therapy had poorer diffusing capacity and higher GAP stages compared to X-ray, the incidence of severe treatment-related pulmonary complications was observed less frequently in the proton group (40.9% in X-ray vs. 12.5% in proton), and the incidence of treatment-related death occurred in four patients (18.2%) treated with X-ray (Fig. 3) but none with proton therapy. In addition, patients treated with proton therapy showed a tendency of better overall one-year survival compared to X-ray. Especially, proton therapy showed significantly increased survival outcomes compared to X-ray in patients with higher GAP stage (II and III) subgroups (1-year OS rate; 50.0% versus 26.4%, p = 0.036). These promising results with proton therapy may be because proton therapy could affect a smaller lung volume than X-ray irradiation. However, there were no statistically significant differences in the dosimetric factors of the patients, including MLD, V₅, V₁₀ and V₂₀ of lung although CTV was significantly larger in the proton RT group. We hope our ongoing prospective study with a large number of patients and systematic evaluation of pre- and post-treatment lung functions could confirm the benefit of proton therapy for patients with severely compromised pulmonary function and/or IPF.

Our retrospective analysis showed that RT is associated with serious treatment-related complications in patients with IPF. Proton therapy may be helpful to reduce these acute and fatal pulmonary complications in these vulnerable patients. Currently, a phase 2 prospective trial with proton RT in patients with severely compromised pulmonary function and/or IPF is ongoing at authors’ institution.