Changes in Pulmonary Function Following Single-Fraction Carbon Ion Radiotherapy: A Retrospective Analysis

Changes in Pulmonary Function Following Single-Fraction Carbon Ion Radiotherapy: A Retrospective Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Changes in Pulmonary Function Following Single-Fraction Carbon Ion Radiotherapy: A Retrospective Analysis Ryo Karita, Mio Nakajima, Teruaki Mizobuchi, Satoshi Ikeda, Kayoko Ohnishi, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8791044/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background With the increasing incidence of lung cancer and the aging population in Japan, the demand for carbon-ion radiotherapy (CIRT) as a minimally invasive treatment for lung cancer has increased. Although there are reports on pulmonary function after surgery or stereotactic body radiotherapy, the effect of CIRT on pulmonary function remains unclear. We aimed to elucidate the impact of CIRT on pulmonary function and evaluate the safety of CIRT for interstitial pneumonia (IP) by comparing changes in pulmonary function between patients with and without IP. Methods We enrolled 102 patients who underwent single-fraction CIRT (50 Gy [relative biological effectiveness]) for untreated lung cancer (including clinically diagnosed cases) and pre- and post-CIRT pulmonary function tests between June 2011 and November 2017. Clinical factors including dosimetric parameters that affect pulmonary function after CIRT, such as the mean lung dose (MLD) and the percentage of lung volume receiving > 5 Gy (V5) and > 20 Gy (V20), were also evaluated to determine the calculated dose-volume histogram. Results Pulmonary function decreased after CIRT. Comparison between the non-IP and IP groups shows that the respective median rates of change were − 4.91% vs -8.41% for percent predicted vital capacity ( p = 0.007), -4.35% vs -9.90% for percent predicted force vital capacity ( p = 0.036), -6.31% vs -10.5% for percent predicted forced expiratory volume in 1 s ( p = 0.035), and − 4.51% vs -9.93% for percent predicted diffusing capacity of the lung for carbon monoxide (%DLCO) ( p = 0.083). Significant weak negative correlations were observed among the rates of change in %DLCO, V20 ( p = 0.012), and MLD ( p = 0.023). Conclusions Pulmonary function declined after CIRT. This decline was more pronounced in patients with IP than in those without IP. lung cancer carbon-ion therapy pulmonary function Figures Figure 1 Figure 2 1. Background Surgery is the standard of care for early-stage non-small cell lung cancer (NSCLC) [ 1 ]. However, given the increasing number of elderly patients with multiple comorbidities, the demand for alternative minimally invasive therapies for lung cancer is also increasing. Stereotactic body radiotherapy (SBRT) has been established as a standard alternative treatment for patients with medically inoperable peripheral early-stage NSCLC, demonstrating favorable local control and safety profiles [ 2 ]. Carbon-ion radiotherapy (CIRT), a type of particle therapy using carbon ions, was first used clinically at our hospital. Categorized as particle therapy alongside proton beam therapy, CIRT has a high relative biological effectiveness (RBE) and provides superior dose conformality compared with photon therapy. These properties allow the delivery of curative doses to the target lesion while minimizing radiation exposure to the surrounding normal tissues [ 3 – 5 ]. For early-stage lung cancer, CIRT has been demonstrated to reduce toxicity to the lungs and adjacent organs compared to conventional photon radiotherapy, while maintaining favorable local control rates [ 3 ]. Radiotherapy for patients complicated with interstitial pneumonia (IP) is of particular concern, as it carries the risk of acute exacerbation (AE) of IP and further deterioration of pulmonary function. SBRT is associated with a high risk of radiation pneumonitis and AE in these patients. Given the potential fatal outcomes, SBRT is frequently considered a contraindication in this population [ 6 ]. Conversely, CIRT has emerged as a relatively safe and effective treatment modality for patients with comorbid IP. Indeed, a Japanese multi-institutional study reported a remarkably low incidence of Grade ≥ 2 radiation pneumonitis (3.3%) in patients with stage I NSCLC and comorbid IP [ 7 ]. Although longitudinal changes in pulmonary function after surgery or SBRT have been well documented, there are few data regarding the specific impact of CIRT on pulmonary function. This study aimed to elucidate the effects of CIRT on pulmonary function in patients with untreated lung cancer. Furthermore, we aimed to evaluate the safety of CIRT for IP by comparing the longitudinal trends in pulmonary function between patients with and without IP. This study provides valuable information regarding the determination of treatment indications and management of post-treatment pulmonary function. 2. Methods 2.1 Patients Population This single-center retrospective cohort study included patients who underwent CIRT for untreated lung cancer (including clinically diagnosed cases) at our institution between June 2011 and November 2017. Patients who were treated with a single-fraction protocol of 50 Gy and underwent pulmonary function tests (PFTs) before and after CIRT were included. We analyzed the clinical factors, including pre- and post-CIRT pulmonary function. Treatment-related adverse events were assessed according to the Common Terminology Criteria for Adverse Events version 5.0. We also investigated the correlations between changes in pulmonary function and dose-volume histogram (DVH) parameters, specifically gross tumor volume (GTV), mean lung dose (MLD), and the percentage of lung volume receiving > 5 Gy (V5), > 10 Gy (V10), and > 20 Gy (V20). IP was diagnosed based on high-resolution CT findings and clinical history. Patients were evaluated by a multidisciplinary team of thoracic surgeons, radiation oncologists, and pulmonologists. 2.2 Carbon-Ion Radiotherapy Planning The details of CIRT planning and delivery at our institution have been described previously [ 4 , 8 ]. The carbon ion dose was calculated by multiplying the physical dose by the RBE and was expressed in Gy (RBE). A fixed dose of 50 Gy was delivered in a single fraction via 2–4 fixed ports. Treatment planning was performed using four-dimensional computed tomography with 1–2- mm slice intervals. The GTV containing the lung tumor was contoured within the lung window. The clinical target volume was defined by adding a 0.5–1.0 cm margin to the GTV. Furthermore, to expand the three-dimensional treatment planning technique into four dimensions, a planning target volume (PTV) was created by adding a setup margin of 2–3 mm. The total dose was prescribed to the isocenter and adjusted such that the 95% isodose line covered the PTV. Dose constraints for organs at risk were established based on previous clinical trials [ 8 ] and strictly adhered to the spinal cord (maximum point dose; D max ) < 10 Gy, esophagus (dose to the hottest 0.2 cc; D 0.2cc ) < 10 Gy, and main bronchus (D 2cc ) < 30 Gy. No specific dose constraints were defined for the lungs. 2.3 Pulmonary Function Tests Pulmonary function tests were performed before and after CIRT to evaluate the following parameters: vital capacity (VC), forced expiratory volume in 1 s (FEV 1.0 ), FEV 1.0 /forced vital capacity (FVC) ratio, diffusing capacity of the lung for carbon monoxide (DLCO), percent predicted VC (%VC), percent predicted FVC (%FVC), percent predicted FEV 1.0 (%FEV 1.0 ), and percent predicted DLCO (%DLCO). 2.4 Statistical Analysis Statistical analyses were performed using R version 4.4.2 (The R Foundation for Statistical Computing, Vienna, Austria) and RStudio version 2025.05.1 + 513 (Posit Software, PBC, Boston, MA, USA). The Wilcoxon signed-rank test was used to compare the pulmonary function values before and after CIRT. The Mann–Whitney U test was used to compare the absolute change and rates of change in pulmonary function between patients with and without IP. Spearman’s rank correlation coefficient was used to evaluate the association between the rate of change in pulmonary function and the DVH parameters. Statistical significance was set at p < 0.05. 3. Results 3.1 Patient Characteristics Patient characteristics are summarized in Table 1 . The study cohort included 39 females and 63 males, with a median age of 76 years (range, 42–91 years). The performance statuses were 0 in 80 patients, 1 in 20 patients, and 2 in 2 patients. IP was observed in 15 patients. The pathological types included adenocarcinoma (n = 40), squamous cell carcinoma (n = 18), and NSCLC (n = 3); 41 cases were clinically diagnosed. The median tumor diameter was 23 mm (range, 8.0–66 mm). Grade ≥ 3 adverse events were observed in three patients. The median interval between the pre- and post-CIRT PFTs was 212 days (range, 168–906 days). Table 1 Patient characteristics Category N = 102 Value Sex, female/male 39/63 Age (years) 76 (42–91) Performance status, 0/1/2 80/20/2 Smoking, pack-year 0 (0–150) IP, yes/no 15/87 Pathological diagnosis, adenocarcinoma/squamous cell carcinoma/NSCLC/clinical diagnosis 40/18/3/41 Tumor size (mm) 23 (8.0–66) Adverse events≧G3, yes/no 3/99 Time to PFTs after CIRT (days) 212 (168–906) Follow-up period (days) 2415 (369–4530) Continuous variables are expressed as median with range IP, interstitial pneumonia; NSCLC, non-small cell lung carcinoma; PFTs, pulmonary function tests; CIRT, carbon-ion radiotherapy 3.2 DVH Parameters The DVH data are presented in Table 2 . The median GTV was 5.48 cm 3 (range, 0.13–55.3 cm 3 ). The median GTV maximum and minimum doses were 50.7 Gy (range, 49.9–52.2 Gy) and 49.0 Gy (range, 39.5–49.8 Gy), respectively. The MLD was 2.63 Gy (range, 1.02–5.54 Gy). The median V5, V10, and V20 were 8.90% (range, 3.84–22.7%), 7.16% (range, 1.93–19.5%), and 4.90% (range, 1.94–12.8%), respectively. Table 2 DVH parameters Category N = 102 Value GTV volume (cm 3 ) 5.48 (0.13–55.3) GTV maximum dose (Gy) 50.7 (49.9–52.2) GTV minimum dose (Gy) 49.0 (39.5–49.8) MLD (Gy) 2.63 (1.02–5.54) V5 (%) 8.90 (3.84–22.7) V10 (%) 7.16 (1.93–19.5) V20 (%) 4.90 (1.94–12.8) Continuous variables are expressed as median with range DVH, dose volume histograms; GTV, gross tumor volume; Gy, Gray; MLD, mean lung dose; V5, percentage of lung volume receiving > 5 Gy; V10, percentage of lung volume receiving > 10 Gy; V20, percentage of lung volume receiving > 20 Gy 3.3 Changes in Pulmonary Function The changes in pulmonary function before and after CIRT are shown in Table 3 . Significant decreases were observed in VC, %VC, FVC, %FVC, FEV 1.0 , %FEV 1.0 ( p < 0.001), DLCO ( p = 0.001), and %DLCO ( p = 0.003) after CIRT. However, no significant changes were observed in FEV 1.0 /FVC ( p = 0.169). Table 3 Changes in pulmonary function pre- and post-CIRT Category N = 102 pre-CIRT post-CIRT P -value VC (L) 2.66 (1.32–4.42) 2.55 (1.05–4.18) < 0.001 %VC (%) 96.8 (49.7–145) 92.7 (46.1–139) < 0.001 FVC (L) 2.50 (1.09–4.38) 2.36 (1.00–4.28) < 0.001 %FVC (%) 85.3 (47.3–133) 81.2 (43.6–123) < 0.001 FEV 1.0 (L) 1.81 (0.59–3.52) 1.74 (0.61–3.46) < 0.001 %FEV 1.0 (%) 83.4 (31.1–122) 79.2 (28.0–123) < 0.001 FEV 1.0 /FVC (%) 74.5 (31.9–92.0) 73.9 (29.4–96.5) 0.169 DLCO (mL/min/mmHg) 11.9 (1.58–28.7) 10.6 (1.97–26.9) 0.001 %DLCO (%) 81.2 (16.0–227) 77.5 (20.2–193) 0.003 Continuous variables are expressed as median with range CIRT, carbon-ion radiotherapy; VC, vital capacity; %VC, percent predicted VC; FVC, forced vital capacity; %FVC, percent predicted FVC; FEV 1.0 , forced expiratory volume in 1 second; %FEV 1.0 , percent predicted FEV 1.0 ; DLCO, diffusing capacity of the lung for carbon monoxide; %DLCO, percent predicted DLCO 3.4 Comparison between Patients with IP and without IP Table 4 shows a comparison of pretreatment pulmonary function between patients with and without IP. No significant differences were observed in VC, FVC, %FVC, FEV 1.0 , %FEV 1.0 , or FEV 1.0 /FVC ratio. However, %VC, DLCO, and %DLCO were significantly lower in patients with IP (n = 15) than in those without IP (n = 87). No significant differences were observed in DVH parameters between the groups (Table 5 ). Table 4 Comparison of pre-CIRT pulmonary function between patients complicated with IP and those without IP. Category non-IP N = 87 IP N = 15 P -value VC (L) 2.65 (1.32–4.42) 2.74 (1.45–3.86) 0.791 %VC (%) 98.1 (49.7–145) 90.6 (65.0–131) 0.043 FVC (L) 2.50 (1.09–4.38) 2.70 (1.40–3.41) 0.723 %FVC (%) 85.5 (47.3–133) 81.8 (58.6 − 110) 0.243 FEV 1.0 (L) 1.78 (0.59–3.52) 1.92 (1.22–2.78) 0.372 %FEV 1.0 (%) 84.0 (31.1–122) 79.5 (56.4–108) 0.828 FEV 1.0 /FVC (%) 74.2 (31.9–92.0) 77.4 (65.1–90.0) 0.199 DLCO (mL/min/mmHg) 12.2 (1.58–28.7) 8.47 (3.39–16.2) 0.005 %DLCO (%) 85.0 (16.0–227) 53.4 (28.7–95.9) 0.001 Continuous variables are expressed as median with range CIRT, carbon-ion radiotherapy; IP, interstitial pneumonia; VC, vital capacity; %VC, percent predicted VC; FVC, forced vital capacity; %FVC, percent predicted FVC; FEV 1.0 , forced expiratory volume in 1 second; %FEV 1.0 , percent predicted FEV 1.0 ; DLCO, diffusing capacity of the lung for carbon monoxide; %DLCO, percent predicted DLCO Table 5 Comparison of DVH parameters between patients complicated with IP and those without IP. Category non-IP N = 87 IP N = 15 P -value GTV volume (cm 3 ) 5.26 (0.13–55.3) 6.12 (1.77–49.6) 0.688 GTV maximum dose (Gy) 50.7 (49.9–52.2) 50.9 (50.0–51.8) 0.313 GTV minimum dose (Gy) 49.1 (39.5–49.8) 48.9 (48.5–49.7) 0.08 MLD (Gy) 2.59 (1.02–5.54) 3.01 (1.75–5.09) 0.59 V5 (%) 8.81 (3.84–22.7) 9.97 (5.46–18.6) 0.698 V10 (%) 7.01 (1.93–19.5) 8.55 (4.99–14.7) 0.549 V20 (%) 4.82 (1.94–12.8) 6.21 (3.48–10.4) 0.414 Continuous variables are expressed as median with range DVH, dose volume histograms; IP, interstitial pneumonia; GTV, gross tumor volume; Gy, Gray; MLD, mean lung dose; V5, percentage of lung volume receiving > 5 Gy; V10, percentage of lung volume receiving > 10 Gy; V20, percentage of lung volume receiving > 20 Gy Table 6 shows the pre- and post-CIRT pulmonary function for each group. In both groups, all parameters significantly decreased after treatment, except FEV 1.0 /FVC. The absolute change and rate of change in pulmonary function for patients with and without IP are summarized in Table 7. Patients with IP exhibited significantly greater declines than those without IP in terms of absolute changes in VC, %VC, FVC, FEV 1.0 , and %FEV 1.0 . Similarly, the rates of change in VC, %VC, FVC, %FVC, FEV 1.0 , and %FEV 1.0 were significantly lower in the IP group (Fig. 1). No significant differences were observed between the two groups in terms of changes in FEV 1.0 /FVC, DLCO, and %DLCO. 3.5 Correlation between Pulmonary Function and DVH Parameters Spearman’s rank correlation analysis showed significant negative correlations between the rate of change in %DLCO and V20 ( p = 0.012) and MLD ( p = 0.023; Fig. 2). In contrast, no statistically significant correlations were found between the rates of change in %VC, %FVC, or %FEV 1.0 and any DVH parameter. 4. Discussion This study investigated the effects of CIRT on pulmonary function. Significant declines were observed in major pulmonary function parameters after CIRT. The rate of change was approximately − 5% in patients without IP, whereas it was approximately − 10% in patients complicated with IP across all parameters, indicating a tendency toward a greater decline in pulmonary functions in patients complicated with IP. Significant negative correlations were observed between the rate of change in %DLCO and several DVH parameters, such as V20 ( p = 0.012) and MLD. Stone et al. reported that in 127 patients treated with SBRT (48–60 Gy in 4–5 fractions), the percentage changes in pulmonary function at one year were − 4.1% for FEV 1.0 , − 5.7% for FVC, and − 5.2% for DLCO [ 9 ]. Furthermore, a systematic review by Niezink et al. on SBRT for lung cancer and chemoradiotherapy for lung or esophageal cancer demonstrated that the decline in DLCO after radiotherapy was more pronounced than that in FEV 1.0 [ 10 ]. In our study, the rate of change in %DLCO was the most substantial among patients complicated with IP, which is consistent with the previous findings. Regarding the comparison with surgery, Macke et al. reported that following segmentectomy for stage I NSCLC, the declines in %FEV 1.0 and %DLCO were − 4.3% and − 3.6%, respectively, for 1–2 segment resections, and − 8.2% and − 5.9%, respectively, for 3–5 segment resections [ 11 ]. The decline in pulmonary function observed after CIRT in our study is comparable to that reported for segmentectomy, particularly resembling the decline rates seen after 1–2 segment resections. Additionally, in a study on wedge resection, VC recovered to near-preoperative levels 12 months postoperatively, but FEV 1.0 did not return to baseline [ 12 ]. Tane et al. reported that postoperative pulmonary function was significantly better preserved with segmentectomy than with lobectomy [ 13 ]. Conversely, Suzuki et al. reported no significant difference in pulmonary function between segmentectomy and lobectomy 6 months postoperatively, suggesting potential compensatory changes following lobectomy [ 14 ]. Fuzhi et al. demonstrated that the recovery of pulmonary function after lung cancer surgery varies depending on the surgical invasiveness and extent of resection. Although recovery occurs within 6–12 months, it generally does not reach preoperative levels [ 15 ]. Based on these surgical outcome comparisons, the influence of CIRT on pulmonary function seems acceptable. Patients complicated with IP are at high risk of AE across a wide range of treatment modalities, including surgery, chemotherapy, immunotherapy, and radiotherapy, which may lead to fatal outcomes [ 16 ]. Regarding SBRT, the incidence of Grade ≥ 2 radiation pneumonitis in patients complicated with IP ranges from 19% to 50% [ 17 ], with a high risk of Grade ≥ 3 toxicity reported at 10%–38.9% [ 17 , 18 ]. In contrast, a multi-institutional study by Okano et al. investigating CIRT for NSCLC patients complicated with IP reported a Grade ≥ 2 radiation pneumonitis incidence of 3.3%–12% [ 7 , 19 ], representing a lower incidence compared with SBRT. Furthermore, lung V20 has been identified as a significant predictive factor for overall survival [ 19 ]. The more pronounced decline in pulmonary function observed in patients complicated with IP in the current study suggests that CIRT-induced lung tissue damage exacerbates pre-existing fibrosis and inflammation associated with IP, thereby imposing an additional burden on pulmonary function. Given that IP is a known risk factor for radiation pneumonitis, it has been suggested that its impact is similarly reflected in pulmonary function outcomes following CIRT. In this study, Spearman’s rank correlation analysis revealed significant negative correlations between DVH parameters (specifically V20 and MLD) and the rate of change in %DLCO. Previous reports on radiotherapy have suggested that radiation-induced lung injury, dependent on irradiation volume, contributes to a decline in DLCO [ 20 ]. Our findings were consistent with these observations. Yamamoto et al. reported that DLCO and DLCO/alveolar volume exhibit strong correlations with the low-dose region of the lungs, suggesting that DLCO may possess higher radiosensitivity than other pulmonary function parameters [ 21 ]. Similarly, a systematic review by Niezink et al. noted that the decline in DLCO was more pronounced than that in FEV 1.0 , which is consistent with the results of a previous review [ 10 ]. This suggests that radiation-induced pulmonary microvascular damage may contribute to the reduction in DLCO. However, no clear correlations were observed between the parameters related to ventilatory function, such as VC and FEV 1.0 . This may be attributed to the fact that pulmonary function decline is influenced by multiple factors beyond dose distribution, including individual pulmonary reserves and the status of pre-existing lung diseases. This study has several limitations. First, this was a single-center study with a retrospective design; therefore, inherent biases may exist. Second, nearly half of the cases were diagnosed clinically rather than pathologically. Furthermore, the IP classification was based on clinical findings, which may have been insufficient. To address this issue, treatment indications and strategies were thoroughly discussed by our institutional cancer board before the initiation of therapy. Third, the relatively small sample size might have limited the statistical reliability of our results. Fourth, the median interval for posttreatment pulmonary function testing was approximately 7 months (212 days), which is insufficient to evaluate long-term longitudinal changes in pulmonary function. Previous studies on SBRT have reported continued declines in FEV 1.0 and FVC even at 24 months post-treatment [ 9 ]. Therefore, long-term follow-up is necessary for CIRT. Future research should aim to overcome these limitations through prospective cohort studies, long-term follow-ups of pulmonary function, and detailed multivariate analyses. Such efforts are warranted to identify the factors influencing pulmonary function after CIRT and to establish evidence for formulating optimized treatment plans tailored to individual patients. Abbreviations NSCLC non-small cell lung cancer SBRT stereotactic body radiotherapy CIRT carbon-ion radiotherapy RBE relative biological effectiveness IP interstitial pneumonia AE acute exacerbation PFTs pulmonary function tests DVH dose-volume histogram GTV gross tumor volume MLD mean lung dose V5 percentage of lung volume receiving > 5 Gy V10 percentage of lung volume receiving > 10 Gy V20 percentage of lung volume receiving > 20 Gy PTV planning target volume VC vital capacity FVC forced vital capacity FEV 1.0 forced expiratory volume in 1 s DLCO diffusing capacity of the lung for carbon monoxide %VC percent predicted VC %FVC percent predicted FVC %FEV 1.0 percent predicted FEV 1.0 %DLCO percent predicted DLCO Declarations Ethics approval and consent to participate The study was conducted in accordance with the principles of the Declaration of Helsinki and its amendments. This study was approved by the Institutional Review Board of our institution (Approval No. N23-023). The requirement for written informed consent from each patient was waived due to the retrospective design of the study. Consent for publication Not applicable Availability of data and materials The dataset supporting the findings of this study are available from the QST Hospital, but restrictions apply to the availability of these data owing to patient privacy; therefore, they are not publicly available. However, the data are available from Ryo Karita ( [email protected] ) or Mio Nakajima ( [email protected] ) upon reasonable request and with permission from the QST Hospital. Competing interests The authors declare that they have no competing interests. Funding No funding sources to declare. Authors' contributions Conception, design, collection, and assembly of data: R Karita, M Nakajima. Supervision: H Ishikawa. Provision of study materials or patients: R Karita, Mio Nakajima, H Ishikawa. Data analysis and interpretation: R Karita. Manuscript writing: All authors. 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Table 6 and 7 Table 6 and 7 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table6.docx Table7.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 30 Mar, 2026 Reviews received at journal 23 Mar, 2026 Reviewers agreed at journal 25 Feb, 2026 Reviews received at journal 19 Feb, 2026 Reviewers agreed at journal 10 Feb, 2026 Reviewers invited by journal 09 Feb, 2026 Editor assigned by journal 05 Feb, 2026 Submission checks completed at journal 05 Feb, 2026 First submitted to journal 04 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8791044","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":588735122,"identity":"c368b68d-3208-4bfd-8817-4eb612924350","order_by":0,"name":"Ryo Karita","email":"","orcid":"","institution":"National Institutes for Quantum Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Ryo","middleName":"","lastName":"Karita","suffix":""},{"id":588735123,"identity":"be34f28d-21f5-4713-8071-74dda18e81e5","order_by":1,"name":"Mio Nakajima","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9klEQVRIiWNgGAWjYFACNgYGCQMQg7GB4QNMUIJYLYwzYIoJaoEBZh5CikHAnP1Y4geLgm3yDGKHGx/blNXVMfAvPsBguQO3FsuetMMSEga3DRukE5uNc84dlmCQeJbAIHkGtxaDA+kNIC2MQC1t0rltB4BazhgwSLbh0XL+efMPoBZ7sBbLtjoitNxIOwayJRGshbGNWYKBv4eQlmdpFkAtyW1Avxj2nDss2SbBlnAAr1/Opxnflvhz27ZfOv3hgx9ldfz8/IcPPpbEE2IgwAyKC0j0AEk2iQSGw5IN+LUwwtMJWCP/AQbGjwS0jIJRMApGwYgCAJNITNLXP5chAAAAAElFTkSuQmCC","orcid":"","institution":"National Institutes for Quantum Science and Technology","correspondingAuthor":true,"prefix":"","firstName":"Mio","middleName":"","lastName":"Nakajima","suffix":""},{"id":588735127,"identity":"64c7d093-bf6e-4065-b887-a5a68405a744","order_by":2,"name":"Teruaki Mizobuchi","email":"","orcid":"","institution":"Social Welfare Organization Saiseikai Imperial Gift Foundation, Chibaken Saiseikai Narashino Hospital","correspondingAuthor":false,"prefix":"","firstName":"Teruaki","middleName":"","lastName":"Mizobuchi","suffix":""},{"id":588735128,"identity":"b6698ae0-02be-4103-85cf-0076e68b3731","order_by":3,"name":"Satoshi Ikeda","email":"","orcid":"","institution":"Kansai Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Satoshi","middleName":"","lastName":"Ikeda","suffix":""},{"id":588735133,"identity":"638c387a-625d-4f18-b23a-e82ed5f6cb16","order_by":4,"name":"Kayoko Ohnishi","email":"","orcid":"","institution":"International University of Health and Welfare","correspondingAuthor":false,"prefix":"","firstName":"Kayoko","middleName":"","lastName":"Ohnishi","suffix":""},{"id":588735134,"identity":"331bd6ab-9587-4336-9b30-19781f0a7e56","order_by":5,"name":"Hidemi Suzuki","email":"","orcid":"","institution":"Chiba University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hidemi","middleName":"","lastName":"Suzuki","suffix":""},{"id":588735135,"identity":"6c7eec47-c1c3-4847-bdd0-ba6381d4eec3","order_by":6,"name":"Hitoshi Ishikawa","email":"","orcid":"","institution":"National Institutes for Quantum Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Hitoshi","middleName":"","lastName":"Ishikawa","suffix":""}],"badges":[],"createdAt":"2026-02-05 01:23:40","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8791044/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8791044/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102745943,"identity":"ab969e3e-4d51-44d6-98d0-27f3a99e1091","added_by":"auto","created_at":"2026-02-16 08:54:51","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":4847487,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of the change rate in pulmonary function between patients with and without IP.\u003c/p\u003e\n\u003cp\u003ePatients with IP exhibited significantly greater declines in %VC (A), %FVC (B), and %FEV\u003csub\u003e1.0\u003c/sub\u003e (C) than those without IP. No significant difference was observed between the two groups in terms of %DLCO (D).\u003c/p\u003e\n\u003cp\u003eIP, interstitial pneumonia; %VC, percent predicted vital capacity; %FVC, percent predicted forced vital capacity; %FEV\u003csub\u003e1.0\u003c/sub\u003e, percent predicted forced expiratory volume in 1 s; %DLCO, percent predicted diffusing capacity of the lungs for carbon monoxide.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8791044/v1/8187894241715ac7bd98708b.png"},{"id":102441862,"identity":"9b43a0a0-6b87-4ff4-91e2-94c13a2433e7","added_by":"auto","created_at":"2026-02-11 17:00:42","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":5656733,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelation analysis between %DLCO and DVH parameters.\u003c/p\u003e\n\u003cp\u003eSpearman’s rank correlation analysis revealed significantly weak negative correlations between the change rates of %DLCO, V20, and MLD.\u003c/p\u003e\n\u003cp\u003e%DLCO, percent predicted diffusing capacity of the lung for carbon monoxide; DVH, dose volume histograms; V20, percentage of lung volume receiving \u0026gt; 20 Gy; MLD, mean lung dose\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8791044/v1/e946ae242e4f9f8edbaa7dee.png"},{"id":102751651,"identity":"43bab043-bfbd-436a-a2aa-cf8fa4a577ef","added_by":"auto","created_at":"2026-02-16 09:26:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":10466617,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8791044/v1/faf22a9a-a4d3-48df-ab80-0c4afabbe418.pdf"},{"id":102441859,"identity":"7462fa58-03f9-44d5-9181-2a61675ba168","added_by":"auto","created_at":"2026-02-11 17:00:42","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":22395,"visible":true,"origin":"","legend":"","description":"","filename":"Table6.docx","url":"https://assets-eu.researchsquare.com/files/rs-8791044/v1/e982f338f1452bccfeb521bf.docx"},{"id":102745647,"identity":"f7a3da50-64a3-4fa9-a4cc-94baca03b321","added_by":"auto","created_at":"2026-02-16 08:53:05","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":22234,"visible":true,"origin":"","legend":"","description":"","filename":"Table7.docx","url":"https://assets-eu.researchsquare.com/files/rs-8791044/v1/6b4b5c5a66d5bee5f227074e.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Changes in Pulmonary Function Following Single-Fraction Carbon Ion Radiotherapy: A Retrospective Analysis","fulltext":[{"header":"1. Background","content":"\u003cp\u003eSurgery is the standard of care for early-stage non-small cell lung cancer (NSCLC) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. However, given the increasing number of elderly patients with multiple comorbidities, the demand for alternative minimally invasive therapies for lung cancer is also increasing. Stereotactic body radiotherapy (SBRT) has been established as a standard alternative treatment for patients with medically inoperable peripheral early-stage NSCLC, demonstrating favorable local control and safety profiles [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCarbon-ion radiotherapy (CIRT), a type of particle therapy using carbon ions, was first used clinically at our hospital. Categorized as particle therapy alongside proton beam therapy, CIRT has a high relative biological effectiveness (RBE) and provides superior dose conformality compared with photon therapy. These properties allow the delivery of curative doses to the target lesion while minimizing radiation exposure to the surrounding normal tissues [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. For early-stage lung cancer, CIRT has been demonstrated to reduce toxicity to the lungs and adjacent organs compared to conventional photon radiotherapy, while maintaining favorable local control rates [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRadiotherapy for patients complicated with interstitial pneumonia (IP) is of particular concern, as it carries the risk of acute exacerbation (AE) of IP and further deterioration of pulmonary function. SBRT is associated with a high risk of radiation pneumonitis and AE in these patients. Given the potential fatal outcomes, SBRT is frequently considered a contraindication in this population [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Conversely, CIRT has emerged as a relatively safe and effective treatment modality for patients with comorbid IP. Indeed, a Japanese multi-institutional study reported a remarkably low incidence of Grade\u0026thinsp;\u0026ge;\u0026thinsp;2 radiation pneumonitis (3.3%) in patients with stage I NSCLC and comorbid IP [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough longitudinal changes in pulmonary function after surgery or SBRT have been well documented, there are few data regarding the specific impact of CIRT on pulmonary function. This study aimed to elucidate the effects of CIRT on pulmonary function in patients with untreated lung cancer. Furthermore, we aimed to evaluate the safety of CIRT for IP by comparing the longitudinal trends in pulmonary function between patients with and without IP. This study provides valuable information regarding the determination of treatment indications and management of post-treatment pulmonary function.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Patients Population\u003c/h2\u003e \u003cp\u003eThis single-center retrospective cohort study included patients who underwent CIRT for untreated lung cancer (including clinically diagnosed cases) at our institution between June 2011 and November 2017. Patients who were treated with a single-fraction protocol of 50 Gy and underwent pulmonary function tests (PFTs) before and after CIRT were included.\u003c/p\u003e \u003cp\u003eWe analyzed the clinical factors, including pre- and post-CIRT pulmonary function. Treatment-related adverse events were assessed according to the Common Terminology Criteria for Adverse Events version 5.0. We also investigated the correlations between changes in pulmonary function and dose-volume histogram (DVH) parameters, specifically gross tumor volume (GTV), mean lung dose (MLD), and the percentage of lung volume receiving\u0026thinsp;\u0026gt;\u0026thinsp;5 Gy (V5), \u0026gt; 10 Gy (V10), and \u0026gt;\u0026thinsp;20 Gy (V20).\u003c/p\u003e \u003cp\u003eIP was diagnosed based on high-resolution CT findings and clinical history. Patients were evaluated by a multidisciplinary team of thoracic surgeons, radiation oncologists, and pulmonologists.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Carbon-Ion Radiotherapy Planning\u003c/h2\u003e \u003cp\u003eThe details of CIRT planning and delivery at our institution have been described previously [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The carbon ion dose was calculated by multiplying the physical dose by the RBE and was expressed in Gy (RBE). A fixed dose of 50 Gy was delivered in a single fraction via 2\u0026ndash;4 fixed ports.\u003c/p\u003e \u003cp\u003eTreatment planning was performed using four-dimensional computed tomography with 1\u0026ndash;2- mm slice intervals. The GTV containing the lung tumor was contoured within the lung window. The clinical target volume was defined by adding a 0.5\u0026ndash;1.0 cm margin to the GTV. Furthermore, to expand the three-dimensional treatment planning technique into four dimensions, a planning target volume (PTV) was created by adding a setup margin of 2\u0026ndash;3 mm. The total dose was prescribed to the isocenter and adjusted such that the 95% isodose line covered the PTV.\u003c/p\u003e \u003cp\u003eDose constraints for organs at risk were established based on previous clinical trials [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] and strictly adhered to the spinal cord (maximum point dose; D\u003csub\u003emax\u003c/sub\u003e)\u0026thinsp;\u0026lt;\u0026thinsp;10 Gy, esophagus (dose to the hottest 0.2 cc; D\u003csub\u003e0.2cc\u003c/sub\u003e)\u0026thinsp;\u0026lt;\u0026thinsp;10 Gy, and main bronchus (D\u003csub\u003e2cc\u003c/sub\u003e)\u0026thinsp;\u0026lt;\u0026thinsp;30 Gy. No specific dose constraints were defined for the lungs.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Pulmonary Function Tests\u003c/h2\u003e \u003cp\u003ePulmonary function tests were performed before and after CIRT to evaluate the following parameters: vital capacity (VC), forced expiratory volume in 1 s (FEV\u003csub\u003e1.0\u003c/sub\u003e), FEV\u003csub\u003e1.0\u003c/sub\u003e /forced vital capacity (FVC) ratio, diffusing capacity of the lung for carbon monoxide (DLCO), percent predicted VC (%VC), percent predicted FVC (%FVC), percent predicted FEV\u003csub\u003e1.0\u003c/sub\u003e (%FEV\u003csub\u003e1.0\u003c/sub\u003e), and percent predicted DLCO (%DLCO).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Statistical Analysis\u003c/h2\u003e \u003cp\u003eStatistical analyses were performed using R version 4.4.2 (The R Foundation for Statistical Computing, Vienna, Austria) and RStudio version 2025.05.1\u0026thinsp;+\u0026thinsp;513 (Posit Software, PBC, Boston, MA, USA). The Wilcoxon signed-rank test was used to compare the pulmonary function values before and after CIRT. The Mann\u0026ndash;Whitney U test was used to compare the absolute change and rates of change in pulmonary function between patients with and without IP. Spearman\u0026rsquo;s rank correlation coefficient was used to evaluate the association between the rate of change in pulmonary function and the DVH parameters. Statistical significance was set at \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Patient Characteristics\u003c/h2\u003e \u003cp\u003ePatient characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The study cohort included 39 females and 63 males, with a median age of 76 years (range, 42\u0026ndash;91 years). The performance statuses were 0 in 80 patients, 1 in 20 patients, and 2 in 2 patients. IP was observed in 15 patients. The pathological types included adenocarcinoma (n\u0026thinsp;=\u0026thinsp;40), squamous cell carcinoma (n\u0026thinsp;=\u0026thinsp;18), and NSCLC (n\u0026thinsp;=\u0026thinsp;3); 41 cases were clinically diagnosed. The median tumor diameter was 23 mm (range, 8.0\u0026ndash;66 mm). Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 adverse events were observed in three patients. The median interval between the pre- and post-CIRT PFTs was 212 days (range, 168\u0026ndash;906 days).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCategory N\u0026thinsp;=\u0026thinsp;102\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eValue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex, female/male\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39/63\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76 (42\u0026ndash;91)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePerformance status, 0/1/2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80/20/2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking, pack-year\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0\u0026ndash;150)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIP, yes/no\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15/87\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePathological diagnosis,\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eadenocarcinoma/squamous cell carcinoma/NSCLC/clinical diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40/18/3/41\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor size (mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (8.0\u0026ndash;66)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdverse events≧G3, yes/no\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3/99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime to PFTs after CIRT (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e212 (168\u0026ndash;906)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFollow-up period (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2415 (369\u0026ndash;4530)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eContinuous variables are expressed as median with range\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eIP, interstitial pneumonia; NSCLC, non-small cell lung carcinoma; PFTs, pulmonary function tests; CIRT, carbon-ion radiotherapy\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.2 DVH Parameters\u003c/h2\u003e \u003cp\u003eThe DVH data are presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The median GTV was 5.48 cm\u003csup\u003e3\u003c/sup\u003e (range, 0.13\u0026ndash;55.3 cm\u003csup\u003e3\u003c/sup\u003e). The median GTV maximum and minimum doses were 50.7 Gy (range, 49.9\u0026ndash;52.2 Gy) and 49.0 Gy (range, 39.5\u0026ndash;49.8 Gy), respectively. The MLD was 2.63 Gy (range, 1.02\u0026ndash;5.54 Gy). The median V5, V10, and V20 were 8.90% (range, 3.84\u0026ndash;22.7%), 7.16% (range, 1.93\u0026ndash;19.5%), and 4.90% (range, 1.94\u0026ndash;12.8%), respectively.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDVH parameters\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCategory N\u0026thinsp;=\u0026thinsp;102\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eValue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGTV volume (cm\u003csup\u003e3\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.48 (0.13\u0026ndash;55.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGTV maximum dose (Gy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e50.7 (49.9\u0026ndash;52.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGTV minimum dose (Gy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e49.0 (39.5\u0026ndash;49.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMLD (Gy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.63 (1.02\u0026ndash;5.54)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eV5 (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8.90 (3.84\u0026ndash;22.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eV10 (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7.16 (1.93\u0026ndash;19.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eV20 (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.90 (1.94\u0026ndash;12.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eContinuous variables are expressed as median with range\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eDVH, dose volume histograms; GTV, gross tumor volume; Gy, Gray; MLD, mean lung dose; V5, percentage of lung volume receiving\u0026thinsp;\u0026gt;\u0026thinsp;5 Gy; V10, percentage of lung volume receiving\u0026thinsp;\u0026gt;\u0026thinsp;10 Gy; V20, percentage of lung volume receiving\u0026thinsp;\u0026gt;\u0026thinsp;20 Gy\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Changes in Pulmonary Function\u003c/h2\u003e \u003cp\u003eThe changes in pulmonary function before and after CIRT are shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Significant decreases were observed in VC, %VC, FVC, %FVC, FEV\u003csub\u003e1.0\u003c/sub\u003e, %FEV\u003csub\u003e1.0\u003c/sub\u003e (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), DLCO (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), and %DLCO (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003) after CIRT. However, no significant changes were observed in FEV\u003csub\u003e1.0\u003c/sub\u003e /FVC (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.169).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eChanges in pulmonary function pre- and post-CIRT\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCategory N\u0026thinsp;=\u0026thinsp;102\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003epre-CIRT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003epost-CIRT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVC (L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.66 (1.32\u0026ndash;4.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.55 (1.05\u0026ndash;4.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e%VC (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e96.8 (49.7\u0026ndash;145)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e92.7 (46.1\u0026ndash;139)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFVC (L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.50 (1.09\u0026ndash;4.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.36 (1.00\u0026ndash;4.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e%FVC (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e85.3 (47.3\u0026ndash;133)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e81.2 (43.6\u0026ndash;123)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFEV\u003csub\u003e1.0\u003c/sub\u003e (L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.81 (0.59\u0026ndash;3.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.74 (0.61\u0026ndash;3.46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e%FEV\u003csub\u003e1.0\u003c/sub\u003e (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e83.4 (31.1\u0026ndash;122)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e79.2 (28.0\u0026ndash;123)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFEV\u003csub\u003e1.0\u003c/sub\u003e/FVC (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e74.5 (31.9\u0026ndash;92.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e73.9 (29.4\u0026ndash;96.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.169\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDLCO (mL/min/mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11.9 (1.58\u0026ndash;28.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10.6 (1.97\u0026ndash;26.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e%DLCO (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e81.2 (16.0\u0026ndash;227)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e77.5 (20.2\u0026ndash;193)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eContinuous variables are expressed as median with range\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eCIRT, carbon-ion radiotherapy; VC, vital capacity; %VC, percent predicted VC; FVC, forced vital capacity; %FVC, percent predicted FVC; FEV\u003csub\u003e1.0\u003c/sub\u003e, forced expiratory volume in 1 second; %FEV\u003csub\u003e1.0\u003c/sub\u003e, percent predicted FEV\u003csub\u003e1.0\u003c/sub\u003e; DLCO, diffusing capacity of the lung for carbon monoxide; %DLCO, percent predicted DLCO\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Comparison between Patients with IP and without IP\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e shows a comparison of pretreatment pulmonary function between patients with and without IP. No significant differences were observed in VC, FVC, %FVC, FEV\u003csub\u003e1.0\u003c/sub\u003e, %FEV\u003csub\u003e1.0\u003c/sub\u003e, or FEV\u003csub\u003e1.0\u003c/sub\u003e/FVC ratio. However, %VC, DLCO, and %DLCO were significantly lower in patients with IP (n\u0026thinsp;=\u0026thinsp;15) than in those without IP (n\u0026thinsp;=\u0026thinsp;87). No significant differences were observed in DVH parameters between the groups (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of pre-CIRT pulmonary function between patients complicated with IP and those without IP.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCategory\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003enon-IP N\u0026thinsp;=\u0026thinsp;87\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIP N\u0026thinsp;=\u0026thinsp;15\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVC (L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.65 (1.32\u0026ndash;4.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.74 (1.45\u0026ndash;3.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.791\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e%VC (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e98.1 (49.7\u0026ndash;145)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e90.6 (65.0\u0026ndash;131)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.043\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFVC (L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.50 (1.09\u0026ndash;4.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.70 (1.40\u0026ndash;3.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.723\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e%FVC (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e85.5 (47.3\u0026ndash;133)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e81.8 (58.6 \u0026minus;\u0026thinsp;110)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.243\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFEV\u003csub\u003e1.0\u003c/sub\u003e (L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.78 (0.59\u0026ndash;3.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.92 (1.22\u0026ndash;2.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.372\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e%FEV\u003csub\u003e1.0\u003c/sub\u003e (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e84.0 (31.1\u0026ndash;122)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e79.5 (56.4\u0026ndash;108)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.828\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFEV\u003csub\u003e1.0\u003c/sub\u003e/FVC (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e74.2 (31.9\u0026ndash;92.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e77.4 (65.1\u0026ndash;90.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.199\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDLCO (mL/min/mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12.2 (1.58\u0026ndash;28.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8.47 (3.39\u0026ndash;16.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e%DLCO (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e85.0 (16.0\u0026ndash;227)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e53.4 (28.7\u0026ndash;95.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eContinuous variables are expressed as median with range\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eCIRT, carbon-ion radiotherapy; IP, interstitial pneumonia; VC, vital capacity; %VC, percent predicted VC; FVC, forced vital capacity; %FVC, percent predicted FVC; FEV\u003csub\u003e1.0\u003c/sub\u003e, forced expiratory volume in 1 second; %FEV\u003csub\u003e1.0\u003c/sub\u003e, percent predicted FEV\u003csub\u003e1.0\u003c/sub\u003e; DLCO, diffusing capacity of the lung for carbon monoxide; %DLCO, percent predicted DLCO\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of DVH parameters between patients complicated with IP and those without IP.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCategory\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003enon-IP N\u0026thinsp;=\u0026thinsp;87\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIP N\u0026thinsp;=\u0026thinsp;15\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGTV volume (cm\u003csup\u003e3\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.26 (0.13\u0026ndash;55.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6.12 (1.77\u0026ndash;49.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.688\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGTV maximum dose (Gy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e50.7 (49.9\u0026ndash;52.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e50.9 (50.0\u0026ndash;51.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.313\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGTV minimum dose (Gy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e49.1 (39.5\u0026ndash;49.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e48.9 (48.5\u0026ndash;49.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMLD (Gy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.59 (1.02\u0026ndash;5.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.01 (1.75\u0026ndash;5.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eV5 (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8.81 (3.84\u0026ndash;22.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9.97 (5.46\u0026ndash;18.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.698\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eV10 (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7.01 (1.93\u0026ndash;19.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8.55 (4.99\u0026ndash;14.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.549\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eV20 (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.82 (1.94\u0026ndash;12.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6.21 (3.48\u0026ndash;10.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.414\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eContinuous variables are expressed as median with range\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eDVH, dose volume histograms; IP, interstitial pneumonia; GTV, gross tumor volume; Gy, Gray; MLD, mean lung dose; V5, percentage of lung volume receiving\u0026thinsp;\u0026gt;\u0026thinsp;5 Gy; V10, percentage of lung volume receiving\u0026thinsp;\u0026gt;\u0026thinsp;10 Gy; V20, percentage of lung volume receiving\u0026thinsp;\u0026gt;\u0026thinsp;20 Gy\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e shows the pre- and post-CIRT pulmonary function for each group. In both groups, all parameters significantly decreased after treatment, except FEV\u003csub\u003e1.0\u003c/sub\u003e /FVC.\u003c/p\u003e\u003cp\u003eThe absolute change and rate of change in pulmonary function for patients with and without IP are summarized in Table 7. Patients with IP exhibited significantly greater declines than those without IP in terms of absolute changes in VC, %VC, FVC, FEV\u003csub\u003e1.0\u003c/sub\u003e, and %FEV\u003csub\u003e1.0\u003c/sub\u003e. Similarly, the rates of change in VC, %VC, FVC, %FVC, FEV\u003csub\u003e1.0\u003c/sub\u003e, and %FEV\u003csub\u003e1.0\u003c/sub\u003e were significantly lower in the IP group (Fig. 1). No significant differences were observed between the two groups in terms of changes in FEV\u003csub\u003e1.0\u003c/sub\u003e/FVC, DLCO, and %DLCO.\u003c/p\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003ch2\u003e3.5 Correlation between Pulmonary Function and DVH Parameters\u003c/h2\u003e\n\u003cp\u003eSpearman\u0026rsquo;s rank correlation analysis showed significant negative correlations between the rate of change in %DLCO and V20 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.012) and MLD (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.023; Fig. 2). In contrast, no statistically significant correlations were found between the rates of change in %VC, %FVC, or %FEV\u003csub\u003e1.0\u003c/sub\u003e and any DVH parameter.\u003c/p\u003e\n"},{"header":"4. Discussion","content":"\u003cp\u003eThis study investigated the effects of CIRT on pulmonary function. Significant declines were observed in major pulmonary function parameters after CIRT. The rate of change was approximately \u0026minus;\u0026thinsp;5% in patients without IP, whereas it was approximately \u0026minus;\u0026thinsp;10% in patients complicated with IP across all parameters, indicating a tendency toward a greater decline in pulmonary functions in patients complicated with IP. Significant negative correlations were observed between the rate of change in %DLCO and several DVH parameters, such as V20 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.012) and MLD.\u003c/p\u003e \u003cp\u003eStone et al. reported that in 127 patients treated with SBRT (48\u0026ndash;60 Gy in 4\u0026ndash;5 fractions), the percentage changes in pulmonary function at one year were \u0026minus;\u0026thinsp;4.1% for FEV\u003csub\u003e1.0\u003c/sub\u003e, \u0026minus;\u0026thinsp;5.7% for FVC, and \u0026minus;\u0026thinsp;5.2% for DLCO [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Furthermore, a systematic review by Niezink et al. on SBRT for lung cancer and chemoradiotherapy for lung or esophageal cancer demonstrated that the decline in DLCO after radiotherapy was more pronounced than that in FEV\u003csub\u003e1.0\u003c/sub\u003e [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In our study, the rate of change in %DLCO was the most substantial among patients complicated with IP, which is consistent with the previous findings. Regarding the comparison with surgery, Macke et al. reported that following segmentectomy for stage I NSCLC, the declines in %FEV\u003csub\u003e1.0\u003c/sub\u003e and %DLCO were \u0026minus;\u0026thinsp;4.3% and \u0026minus;\u0026thinsp;3.6%, respectively, for 1\u0026ndash;2 segment resections, and \u0026minus;\u0026thinsp;8.2% and \u0026minus;\u0026thinsp;5.9%, respectively, for 3\u0026ndash;5 segment resections [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The decline in pulmonary function observed after CIRT in our study is comparable to that reported for segmentectomy, particularly resembling the decline rates seen after 1\u0026ndash;2 segment resections. Additionally, in a study on wedge resection, VC recovered to near-preoperative levels 12 months postoperatively, but FEV\u003csub\u003e1.0\u003c/sub\u003e did not return to baseline [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Tane et al. reported that postoperative pulmonary function was significantly better preserved with segmentectomy than with lobectomy [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Conversely, Suzuki et al. reported no significant difference in pulmonary function between segmentectomy and lobectomy 6 months postoperatively, suggesting potential compensatory changes following lobectomy [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Fuzhi et al. demonstrated that the recovery of pulmonary function after lung cancer surgery varies depending on the surgical invasiveness and extent of resection. Although recovery occurs within 6\u0026ndash;12 months, it generally does not reach preoperative levels [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Based on these surgical outcome comparisons, the influence of CIRT on pulmonary function seems acceptable.\u003c/p\u003e \u003cp\u003ePatients complicated with IP are at high risk of AE across a wide range of treatment modalities, including surgery, chemotherapy, immunotherapy, and radiotherapy, which may lead to fatal outcomes [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Regarding SBRT, the incidence of Grade\u0026thinsp;\u0026ge;\u0026thinsp;2 radiation pneumonitis in patients complicated with IP ranges from 19% to 50% [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], with a high risk of Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 toxicity reported at 10%\u0026ndash;38.9% [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In contrast, a multi-institutional study by Okano et al. investigating CIRT for NSCLC patients complicated with IP reported a Grade\u0026thinsp;\u0026ge;\u0026thinsp;2 radiation pneumonitis incidence of 3.3%\u0026ndash;12% [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], representing a lower incidence compared with SBRT. Furthermore, lung V20 has been identified as a significant predictive factor for overall survival [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The more pronounced decline in pulmonary function observed in patients complicated with IP in the current study suggests that CIRT-induced lung tissue damage exacerbates pre-existing fibrosis and inflammation associated with IP, thereby imposing an additional burden on pulmonary function. Given that IP is a known risk factor for radiation pneumonitis, it has been suggested that its impact is similarly reflected in pulmonary function outcomes following CIRT.\u003c/p\u003e \u003cp\u003eIn this study, Spearman\u0026rsquo;s rank correlation analysis revealed significant negative correlations between DVH parameters (specifically V20 and MLD) and the rate of change in %DLCO. Previous reports on radiotherapy have suggested that radiation-induced lung injury, dependent on irradiation volume, contributes to a decline in DLCO [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Our findings were consistent with these observations. Yamamoto et al. reported that DLCO and DLCO/alveolar volume exhibit strong correlations with the low-dose region of the lungs, suggesting that DLCO may possess higher radiosensitivity than other pulmonary function parameters [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Similarly, a systematic review by Niezink et al. noted that the decline in DLCO was more pronounced than that in FEV\u003csub\u003e1.0\u003c/sub\u003e, which is consistent with the results of a previous review [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. This suggests that radiation-induced pulmonary microvascular damage may contribute to the reduction in DLCO. However, no clear correlations were observed between the parameters related to ventilatory function, such as VC and FEV\u003csub\u003e1.0\u003c/sub\u003e. This may be attributed to the fact that pulmonary function decline is influenced by multiple factors beyond dose distribution, including individual pulmonary reserves and the status of pre-existing lung diseases.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, this was a single-center study with a retrospective design; therefore, inherent biases may exist. Second, nearly half of the cases were diagnosed clinically rather than pathologically. Furthermore, the IP classification was based on clinical findings, which may have been insufficient. To address this issue, treatment indications and strategies were thoroughly discussed by our institutional cancer board before the initiation of therapy. Third, the relatively small sample size might have limited the statistical reliability of our results. Fourth, the median interval for posttreatment pulmonary function testing was approximately 7 months (212 days), which is insufficient to evaluate long-term longitudinal changes in pulmonary function. Previous studies on SBRT have reported continued declines in FEV\u003csub\u003e1.0\u003c/sub\u003e and FVC even at 24 months post-treatment [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Therefore, long-term follow-up is necessary for CIRT.\u003c/p\u003e \u003cp\u003eFuture research should aim to overcome these limitations through prospective cohort studies, long-term follow-ups of pulmonary function, and detailed multivariate analyses. Such efforts are warranted to identify the factors influencing pulmonary function after CIRT and to establish evidence for formulating optimized treatment plans tailored to individual patients.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNSCLC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003enon-small cell lung cancer\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSBRT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003estereotactic body radiotherapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCIRT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecarbon-ion radiotherapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRBE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003erelative biological effectiveness\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einterstitial pneumonia\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eacute exacerbation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePFTs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epulmonary function tests\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDVH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003edose-volume histogram\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGTV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003egross tumor volume\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMLD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emean lung dose\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eV5\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epercentage of lung volume receiving\u0026thinsp;\u0026gt;\u0026thinsp;5 Gy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eV10\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epercentage of lung volume receiving\u0026thinsp;\u0026gt;\u0026thinsp;10 Gy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eV20\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epercentage of lung volume receiving\u0026thinsp;\u0026gt;\u0026thinsp;20 Gy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePTV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eplanning target volume\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eVC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003evital capacity\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFVC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eforced vital capacity\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFEV\u003csub\u003e1.0\u003c/sub\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eforced expiratory volume in 1 s\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDLCO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ediffusing capacity of the lung for carbon monoxide\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e%VC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epercent predicted VC\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e%FVC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epercent predicted FVC\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e%FEV\u003csub\u003e1.0\u003c/sub\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epercent predicted FEV\u003csub\u003e1.0\u003c/sub\u003e\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e%DLCO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epercent predicted DLCO\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the principles of the Declaration of Helsinki and its amendments. This study was approved by the Institutional Review Board of our institution (Approval No. N23-023). The requirement for written informed consent from each patient was waived due to the retrospective design of the study.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAvailability of data and materials\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe dataset supporting the findings of this study are available from the QST Hospital, but restrictions apply to the availability of these data owing to patient privacy; therefore, they are not publicly available. However, the data are available from Ryo Karita ([email protected]) or Mio Nakajima ([email protected]) upon reasonable request and with permission from the QST Hospital.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNo funding sources to declare.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAuthors\u0026apos; contributions\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eConception, design, collection, and assembly of data: R Karita, M Nakajima. Supervision: H Ishikawa. Provision of study materials or patients: R Karita, Mio Nakajima, H Ishikawa. Data analysis and interpretation: R Karita. Manuscript writing: All authors. Final approval of manuscript: All authors.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSaji H, Okada M, Tsuboi M, Nakajima R, Suzuki K, Aokage K, et al. Segmentectomy versus lobectomy in small-sized peripheral non-small-cell lung cancer (JCOG0802/WJOG4607L): A multicentre, open-label, phase 3, randomised, controlled, non-inferiority trial. Lancet. 2022;399:1607\u0026ndash;17. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S0140-6736(21)02333-3\u003c/span\u003e\u003cspan address=\"10.1016/S0140-6736(21)02333-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTandberg DJ, Tong BC, Ackerson BG, Kelsey CR. 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PLoS ONE. 2022;17:e0278707. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1371/journal.pone.0278707\u003c/span\u003e\u003cspan address=\"10.1371/journal.pone.0278707\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Table 6 and 7","content":" \u003cp\u003eTable 6 and 7 are available in the Supplementary Files section.\u003c/p\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"radiation-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"raon","sideBox":"Learn more about [Radiation Oncology](http://ro-journal.biomedcentral.com/)","snPcode":"13014","submissionUrl":"https://submission.nature.com/new-submission/13014/3","title":"Radiation Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"lung cancer, carbon-ion therapy, pulmonary function","lastPublishedDoi":"10.21203/rs.3.rs-8791044/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8791044/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eWith the increasing incidence of lung cancer and the aging population in Japan, the demand for carbon-ion radiotherapy (CIRT) as a minimally invasive treatment for lung cancer has increased. Although there are reports on pulmonary function after surgery or stereotactic body radiotherapy, the effect of CIRT on pulmonary function remains unclear. We aimed to elucidate the impact of CIRT on pulmonary function and evaluate the safety of CIRT for interstitial pneumonia (IP) by comparing changes in pulmonary function between patients with and without IP.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe enrolled 102 patients who underwent single-fraction CIRT (50 Gy [relative biological effectiveness]) for untreated lung cancer (including clinically diagnosed cases) and pre- and post-CIRT pulmonary function tests between June 2011 and November 2017. Clinical factors including dosimetric parameters that affect pulmonary function after CIRT, such as the mean lung dose (MLD) and the percentage of lung volume receiving\u0026thinsp;\u0026gt;\u0026thinsp;5 Gy (V5) and \u0026gt;\u0026thinsp;20 Gy (V20), were also evaluated to determine the calculated dose-volume histogram.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003ePulmonary function decreased after CIRT. Comparison between the non-IP and IP groups shows that the respective median rates of change were \u0026minus;\u0026thinsp;4.91% vs -8.41% for percent predicted vital capacity (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007), -4.35% vs -9.90% for percent predicted force vital capacity (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.036), -6.31% vs -10.5% for percent predicted forced expiratory volume in 1 s (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.035), and \u0026minus;\u0026thinsp;4.51% vs -9.93% for percent predicted diffusing capacity of the lung for carbon monoxide (%DLCO) (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.083). Significant weak negative correlations were observed among the rates of change in %DLCO, V20 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.012), and MLD (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.023).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003ePulmonary function declined after CIRT. This decline was more pronounced in patients with IP than in those without IP.\u003c/p\u003e","manuscriptTitle":"Changes in Pulmonary Function Following Single-Fraction Carbon Ion Radiotherapy: A Retrospective Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-11 17:00:37","doi":"10.21203/rs.3.rs-8791044/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-30T10:00:48+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-23T23:06:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"70005082313758433412236843276023345192","date":"2026-02-25T09:33:56+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-19T17:50:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"283910484451875887687814845357368959691","date":"2026-02-10T06:14:32+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-09T11:44:38+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-05T09:37:30+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-05T09:31:49+00:00","index":"","fulltext":""},{"type":"submitted","content":"Radiation Oncology","date":"2026-02-05T01:19:37+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"radiation-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"raon","sideBox":"Learn more about [Radiation Oncology](http://ro-journal.biomedcentral.com/)","snPcode":"13014","submissionUrl":"https://submission.nature.com/new-submission/13014/3","title":"Radiation Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9aaab7fd-9264-4a96-936e-d64cbcaa2f2f","owner":[],"postedDate":"February 11th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-27T09:09:12+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-11 17:00:37","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8791044","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8791044","identity":"rs-8791044","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}