After Institutional Review Board approval (#2018–08-108), we retrospectively reviewed the medical records of 264 patients with stage I-II NSCLC treated with definitive RT alone at Samsung Medical Center from January 2010 to October 2017. They were determined to be unsuitable for surgery due to various reasons including old age, poor pulmonary function, and poor performance status. All the diagnosis of underlying pulmonary diseases was confirmed by experienced pulmonologists (H.Y.P. and H.S.Y.). Among these, patients who had no underlying pulmonary disease (65 patients, 24.6%) or other than IPF, such as chronic obstructive pulmonary disease (COPD; 152, 57.6%) or combined pulmonary fibrosis and emphysema (CPFE; 17, 6.4%) were excluded. Ultimately, 30 patients (11.4%) that had underlying IPF were analyzed in the current study. The RT technique (X-ray or proton therapy) was selected individually by the discretion of radiation oncologists. Most of all, patients with severely compromised pulmonary function and/or underlying disease, such as COPD, CPFE, and IPF, were mainly treated with proton therapy. And large tumor size and multiple lesions were also considered. In this study, X-ray and proton RT were delivered to 22 (73.3%) and eight (26.7%) patients, respectively. Treatment-related complications and survival outcomes were compared between X-ray and proton therapy.
Diagnostic and staging scheme for lung cancer and IPF
All tumors were staged based on the seventh edition of the American Joint Committee on Cancer tumor staging criteria. Tumor assessment consisted of complete history taking, physical examination, complete blood counts, chemistry profiles, pulmonary function test (PFT), chest X-ray, computed tomography (CT) scan of the chest and upper abdomen, whole-body 18F-fluorodeoxyglucose positron emission tomography with CT (FDG-PET-CT) scan, and magnetic resonance imaging of the brain as a routine staging work-up. The PFT including both spirometry and diffusing capacity were performed before treatment. Detailed measurements included (1) forced expiratory volume in one second (FEV1), (2) forced vital capacity (FVC), (3) ratio of the two volumes (FEV1/FVC), (4) diffusing capacity of the lung for carbon monoxide (DLCO), and (5) DLCO divided by alveolar ventilation (DLCO/VA). For the diagnosis of IPF, the presence of a typical radiological pattern, which is the coarse reticulation with honeycombing appearance in peripheral and predominantly basal lung area, was seen on high-resolution CT (HRCT). Spirometry typically revealed a reduction in the vital capacity and DLCO. The patients with IPF also showed oxygen desaturation with a six-minute walk test. The GAP model, including four baseline variables (sex, age, and two lung physiology variables; FVC and DLCO) was used for IPF staging .
The gross tumor volume (GTV) was delineated under the lung window setting. The internal target volume (ITV) was delineated following four-dimensional CT with consideration of respiratory tumor motion. The clinical target volume (CTV) was generated with a 5 mm expansion of the GTVs in all directions, and was then modified considering the adjacent anatomic structures. The planning target volume (PTV) was generated with 5 mm expansion of the CTVs. The percentage volume of lung receiving ≥20 Gy (V20) of the lung was tried to be kept ≤35% and the mean lung dose was ≤20 Gy. Maximum doses to the spinal cord and esophagus were not to exceed 45 Gy and 60 Gy, respectively. The prescription policy was to deliver at least 97% of the prescribed dose to 95% of the CTVs.
Treatment planning for X-ray, Pinnacle treatment planning system, version 9.2 (Royal Phillips Electronics, Miami, FL) was used to calculate the dose distributions, and two different dose-fractionation schedules were used to deliver 60 Gy in either 20 fractions over 4 weeks or 15 fractions over 3 weeks. The biologically equivalent doses at α/β of 10 Gy (BED10) were 78 Gy and 84 Gy, respectively. Dose selection depended on the location, size, and geometry of the tumor in relation to the esophagus. If the shortest distance between the CTV margin and the esophagus was ≥1.5 cm, 60 Gy in 15 fractions was preferred to 60 Gy in 20 fractions. For SBRT for small size and peripherally located tumors, 60 Gy in 4 fractions was delivered. Eleven patients were treated with SBRT, 10 with 3-dimensional conformal RT (3DCRT), and one with intensity-modulated RT (IMRT) as it was difficult to safely cover the whole disease extent while satisfying the dose-volume constraints using the 3DCRT technique.
Treatment planning for proton, RayStation treatment planning system, version 6.2 (Raysearch Laboratories AB, Stockholm, Sweden) was used. Line scanning method was used for the proton therapy in all patients with the proton therapy system at our institute (Sumitomo, Japan). Six patients were treated with stereotactic body proton therapy (SBPT, 60–64 CcGE in 4–8 fractions) and two with intensity-modulated proton therapy (IMPT, 60 CcGE in 20 fractions).
Physical examination, blood tests, chest CT scan, and/or PET-CT were performed every 3 months for 2 years after RT and then every 6 months thereafter to detect disease progression during follow-up. Revised Response Evaluation Criteria In Solid Tumors (RECIST) guidelines (Version 1.1) were used for tumor response evaluation. Treatment-related pulmonary complications, excluding infection-related cases, were evaluated using the Common Terminology Criteria for Adverse Events version 4.0.
Overall survival (OS) was defined as the time from the start date of the RT until the date of death from any cause or the latest documented follow-up. The 1-year rate of OS was calculated using the Kaplan–Meier method and was compared using the log-rank test. Factors that were thought to be relevant were entered into a Cox proportional hazard regression analysis to account for potential confounding factors and to determine independent prognostic factors. To compare the clinical characteristics and dose-volume parameters, Chi-square or Fisher’s exact test was used to assess categorical variables and independent-sample t test was used to assess continuous variables. A p value< 0.05 was regarded as statistically significant in two-tailed tests. Statistical analysis was performed using SPSS software, standard version 24.0 (IBM Corporation, Armonk, NY, USA).