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Radiation Oncology Journal > Volume 42(3); 2024 > Article
Park, Lee, Chang, Son, Kwon, Choi, Shin, Yu, and Kim: Optimizing target and diaphragmatic configuration, and dosimetric benefits using continuous positive airway pressure in stereotactic ablative radiotherapy for lung tumors

Abstract

Purpose

This study aimed to evaluate the impact of facilitating target delineation of continuous positive airway pressure (CPAP) in patients undergoing stereotactic ablative radiation therapy (SABR) for lung tumors by lung expansion and respiratory motion management.

Materials and Methods

We performed a prospective single-institutional trial of patients who were diagnosed with either primary lung cancer or lung metastases and received SABR with a dose of 40 to 60 Gy in 4 fractions. Four-dimensional computed tomography simulations were conducted for each patient: once without CPAP and again with CPAP.

Results

Thirty-two patients with 39 tumors were analyzed, after the withdrawal of five patients due to discomfort. For 26 tumors separated from the diaphragm, CPAP significantly increased the superoinferior distance between the tumor and the diaphragm (5.96 cm vs. 8.06 cm; p < 0.001). For 13 tumors located adjacent to the diaphragm, CPAP decreased the overlap of planning target volume (PTV) with the diaphragm significantly (6.32 cm3 vs. 4.09 cm3; p = 0.002). PTV showed a significant reduction with CPAP (25.06 cm3 vs. 22.52 cm3, p = 0.017). In dosimetric analyses, CPAP expanded lung volume by 58.4% with a significant reduction in mean dose and V5 to V40. No more than grade 2 adverse events were reported.

Conclusion

This trial demonstrated significant improvement of CPAP in target delineation uncertainties for lung SABR, with dosimetric benefits, a favorable safety profile and tolerability. Further investigation is warranted to explore the role of CPAP as a novel strategy for respiratory motion management.

Introduction

Lung cancer is a significant global malignancy and a leading cause of cancer deaths, with approximately 238,000 new cases reported each year, 26.6% of which are diagnosed at an early stage [1]. Stereotactic ablative radiotherapy (SABR) is a highly effective treatment option for medically inoperable patients with early-stage non-small-cell lung cancer (NSCLC) and lung oligometastases, achieving in-field local control rates of over 90% [2,3]. With steep dose gradients to cover the target volume with a high dose while preserving adjacent normal organs, the need for accurate target delineation is emphasized to enhance the efficacy and safety of SABR.
Respiration-induced movement leads to inherent uncertainties for lesions within the lung [1-4]. Tumors located in the lower lobes show a greater magnitude and variability of motion, inevitably resulting in a larger planning target volume (PTV) [4]. Notably, precise contouring for tumors adjacent to the diaphragm presents challenges due to potential artifacts and the risk of overlap with the target [5].
Strategies to manage respiratory motion used in radiation oncology include real-time tumor tracking, gated radiotherapy (RT), active breathing control, and deep inspiratory breath hold (DIBH) [6]. However, certain techniques, such as gating and motion tracking, require prolonged treatment time and intricate apparatus, which poses implementation challenges. Active breathing control and DIBH also necessitate the cooperation of patients with eligible pulmonary function.
Continuous positive airway pressure (CPAP) is a ventilator that maintains a constantly positive pressure on the airway and eventually extends to the lung tissues. Originally proven as an effective and safe treatment for patients with sleep apnea [7], CPAP is considered an alternative strategy for respiratory motion management, replicating the favorable anatomy, stability and tumor immobilization achieved through lung inflation, similar to the DIBH technique.
Several studies have investigated the benefits of CPAP in the setting of RT. CPAP has demonstrated an organ-sparing effect on volumetric and dosimetric analyses in patients with lung tumors and left-sided breast cancer [8]. Additionally, CPAP decreases respiration-induced tumor motion and results in PTV reduction [9]. The pressure of the CPAP requires less force from the diaphragm, thereby supporting diaphragmatic stability and reproducibility [10].
In this study, we prospectively evaluated tumor excursion and dosimetric parameters in patients with lung tumors, comparing those with and without CPAP setting, and assessed related complications. Of significant interest was the impact of CPAP on facilitating target delineation by separating the diaphragm and immobilizing the tumor.

Materials and Methods

1. Patients

The Institutional Review Board of Seoul National University Hospital (IRB No. 2108-087-1245) approved a prospective study. Forty patients with stage I primary lung tumors or lung metastases referred for SABR were enrolled from November 2021 to July 2022 after providing written informed consent.
Patients meeting the following criteria were eligible for inclusion: aged 19 years or older, received SABR in 3‒5 fractions for primary lung cancer or lung metastases, had an Eastern Cooperative Oncology Group performance status score of 0 to 3, and had adequate pulmonary function. Exclusion criteria included a history of pneumothorax or head and neck surgery, recent cranial surgery or trauma, claustrophobia, severe bullous emphysema, medically uncontrolled hypotension, dehydration, current craniospinal fluid leakage, contraindications for contrast-enhanced computed tomography (CT), and any clinical conditions unsuitable for lung SABR. Pulmonary functional tests were performed before the simulation to assess baseline lung functions. A preliminary evaluation was conducted at the initiation of patient enrollment by an ear, nose, and throat specialist to assess the potential risk for anastomotic breakdown due to increased pressure.

2. Application of CPAP on CT simulation and treatment

All patients underwent subsequent four-dimensional (4D) CT scans using a helical mode with a scanning pitch of 0.09–0.15. The Bellows System (version 3.6.2.17012; Philips Medical Systems, Cleveland, OH, USA) served as an external surrogate for respiratory motion.
Patients were fitted with a facial mask and underwent training in the use of the CPAP machine (AirSense10; ResMed, San Diego, CA, USA) before simulation. All the patients were simulated in the supine position with their arm raised up and immobilized with a Vac-lok bag and wing board. CPAP pressure was initiated at 7.5 cm H2O and gradually raised based on patient comfort to a target pressure of 15 cm H2O. CT images were acquired by sorting corresponding to 10 respiratory phases (0%–90%) and reconstructed into 10-phase-based bins. Phase 0% corresponds to the maximum end-inspiration and 50% denotes the maximum end-expiration, respectively. CT scans were performed twice for each patient, first with free breathing (FB-arm) and then with CPAP (CPAP-arm). Images from both simulations were acquired with 2- or 3-mm slice thickness and transferred to the Eclipse treatment planning system (Eclipse 13.7; Varian Medical Systems, Palo Alto, CA, USA).
Adverse events were examined on the simulation day, the start date of the treatment, the end date of the treatment, and 2 months after the treatment, through patient interviews and physical examinations. CPAP-related adverse events encompassed cough, epistaxis, dry mouth, dyspnea, facial skin damage, hoarseness, hiccup, headache, visual disturbance, upper respiratory infection, facial pain, abdominal distension, and pneumothorax [11]. We also assessed RT-related adverse events, such as pneumonitis, dermatitis, pericarditis, liver damage, and nausea. Complications were graded according to the Common Terminology Criteria for Adverse Events version 5.0.

3. Contouring and image analyses

The gross target volume (GTV) was delineated for the lung tumor on lung windows across 10 phases of the 4D-CT scans. The internal target volume (ITV) was delineated using all GTVs in respiratory phases and a maximum-intensity projection image from the CT scans. The PTV was generated by adding a radial margin of 3‒7 mm and a craniocaudal margin of 5‒7 mm to the ITV. The prescribed dose and PTV margins were determined by the radiation oncologists based on clinical factors such as tumor histology, location, and baseline lung functions. The most common radial PTV margin ranged from 3 to 5 mm. A 7-mm margin was applied in selected cases, particularly for tumors exhibiting larger sizes, excessive movement, and blurred or masked margins due to interstitial fibrosis or diaphragmatic overlap. Normal organs, including the lungs, esophagus, heart, and liver were delineated using automatic segmentation of the treatment planning system and corrected manually by radiation oncologists.
To understand differences associated with target delineation, we measured factors, including the tumor’s proximity to the diaphragm, tumor excursion, and electron density of the lung. To assess the extent of tumor proximity to the diaphragm, we measured the PTV volumes that overlapped with the diaphragm (Fig. 1A). If the PTV was completely separated from the diaphragm, we evaluated the amplitude of the tumor from the diaphragm, by measuring the superoinferior (SI) distance between the caudal border of the tumor and the diaphragm across all available phases, including 0% and 50% phases in all patients, and then calculating the average value (Fig. 1B). Tumor motion excursion was determined as the maximum distance between GTV centroids, including 0% and 50% phases. Considering the nonlinear and rotational movement of the diaphragm during breathing [12], we calculated two parameters: the trajectory of the diaphragm’s dome and the point of the diaphragm directly beneath the tumor centroid, to investigate the impact of CPAP on diaphragmatic movement.

4. RT planning

The median prescribed radiation dose was 60 Gy (range, 48 to 60 Gy) in 4 fractions. The 95% isodose delivered to the PTV with 95% of the PTV being covered by 100% of the prescription dose. Maximum dose was limited to 110%. After cone-beam CT images were taken and matched with the original plan in each treatment session, volumetric-modulated arc therapy plans were generated using a 6-MV flattening filter-free beam using two coplanar 180° arcs from the Truebeam STx (Varian Medical Systems).
The dose constraints for the organs at risk (OARs) were defined based on the National Comprehensive Cancer Network Clinical Practice Guideline in oncology for NSCLC. Dosimetric parameters (V5, V10, V20, V30, and V40) of OARs (lung, heart, and liver) were calculated (Vx indicates the percentage of total normal volume receiving equal to or greater than x Gy of radiation).

5. Statistical analysis

Tumor proximity, excursion, lung tissue density, as well as volumetric and dosimetric values with and without CPAP were compared using a paired Student t-test and a Wilcoxon signed-rank test. Data are presented as mean ± standard deviation. All tests were two-tailed and a p-value lower than 0.05 was considered significant. Statistical analysis was performed using the Stata Statistical package (version IC 11.2; StataCorp, College Station, TX, USA).

Results

1. Patients characteristics

A total of 40 patients were initially enrolled in the study. However, five patients withdrew, and three patients were excluded due to not receiving SABR. The final cohort was 32 patients with a total of 39 lung tumors, all of whom underwent treatment using CPAP planning. Volumetric data for these patients were analyzed.
The patient and tumor characteristics are summarized in Table 1. The median age of the patients was 67.3 years, with 23 (71.9%) patients being non-smokers. All patients showed tolerable pulmonary function for SABR, with mean of forced expiratory volume in 1 second (FEV1)/forced vital capacity, FEV1, and diffusing capacity of the lung for carbon monoxide of 70.6%, 95.9%, and 83.5%, respectively. Seven (21.9%) patients had underlying lung diseases other than lung cancer, including five with chronic obstructive lung disease, three with idiopathic pulmonary fibrosis (IPF), and one with active tuberculosis. Four patients had underlying heart disease: one had aortic stenosis treated with transcatheter aortic valve implantation, another had atrial fibrillation managed with medication, the third complete atrioventricular block status post-pacemaker insertion, and the fourth had three-vessel disease with coronary artery bypass grafting.
SABR was administered to 11 primary lung tumors (28.2%) and 28 metastatic tumors (71.8%). Among the primary tumors, there were five adenocarcinomas, three squamous cell carcinomas, and three tumors with unknown pathology. The metastatic tumors included 13 from the rectum, six from the colon, four from the lung, four from the liver, and one from the vagina. Most tumors (76.9%) were located in either the left lower lobe (LLL) or the right lower lobe (RLL).
Five patients did not proceed with SABR using CPAP during the CT simulation due to discomfort and cough. A comparative analysis between the withdrawn patients and the remaining participants revealed significant associations with a higher prevalence of current smokers (60.0% and 9.4%; p = 0.013), a history of heart disease (80.0% and 3.1%; p < 0.001), and age over 80 years (80.0% and 21.9%; p = 0.034).

2. Tumor proximity to the diaphragm and excursion

For 26 tumors that were separated from the diaphragm in all respiratory phases, the SI distance between the tumor and the diaphragm significantly increased when using CPAP (5.96 ± 3.14 cm vs. 8.06 ± 4.45 cm in the FB-arm vs. CPAP-arm, respectively; p < 0.001). For 13 tumors located adjacent to the diaphragm, the PTV overlapped with the diaphragm significantly decreased with the use of CPAP (6.32 ± 5.85 cm3 vs. 4.09 ± 5.46 cm3; p = 0.002) (Fig. 2A). With CPAP, four out of 13 tumors (30.8%) achieved complete target separation from the diaphragm. Significant differences in SI motion amplitudes were observed both in the diaphragmatic dome (0.96 ± 0.6 cm vs. 0.59 ± 0.4 cm; p < 0.001) and the point of the diaphragm below the tumor (1.28 ± 0.68 cm vs. 1.08 ± 0.65 cm; p = 0.036) (Fig. 2B).
Table 2 showed that the use of CPAP decreased tumor excursion by a mean of 0.03 cm (95% confidence interval [CI] -0.01 – 0.06 cm; p = 0.223), 0.11 cm (95% CI 0.03–0.19; p = 0.020), and 0.43 cm (95% CI 0.26–0.60; p < 0.001) in the right-left, anterior-posterior, and SI planes, respectively. The absolute differences of GTV, ITV, and PTV volumes were a mean of -0.08 cm3 (95% CI -0.38–0.21; p = 0.871), 0.32 cm3 (95% CI -0.16–0.79; p = 0.105), and 2.55 cm3 (95% CI -0.50–5.60; p = 0.017), respectively.

3. Volumetric and dosimetric analysis

The mean volume of the bilateral lung was 2,975 cm3 (range, 2,697 to 3,252 cm3) in the FB-arm and elevated to 4,712 cm3 (range, 4,381 to 5,045 cm3) in the CPAP-arm, with a relative increase of 58% (95% CI 53–64; p < 0.001). As a result of lung inflation, there was a significant reduction in the average lung parenchyma density, from -668.92 Housefield Units (HU) in the FB-arm to -776.84 HU in the CPAP-arm (p = 0.026). With the use of CPAP, the density differences between the tumor and the lung parenchyma significantly increased (647.57 ± 173.27 HU vs. 745.92 ± 207.87 HU; p < 0.001). Table 3 provides dosimetric parameters for plans generated in the FB-arm versus CPAP-arm, with a statistically significant reduction in all metrics of the ipsilateral and bilateral lung.
Regarding the heart, there was a paradoxical increase in V10 with WC plans compared with FB plans, with a mean absolute difference of 0.81%, despite a significant decrease in heart volume in the CPAP-arm. Twenty-six patients (81.3%) showed a reduction in mean dose for the heart with CPAP, but the overall mean dose did not significantly differ compared with the FB-arm. Six patients showed higher mean heart dose with CPAP, mainly when tumors were located in the lower and posterior aspect of the lungs (3 in RLL, 2 in LLL, and 1 in RML). The dose to the liver was evaluated in 21 patients who underwent SABR in the right-sided lung. V5, V10, and the mean dose of the liver revealed a significant reduction in the CPAP-arm (all p < 0.05).

4. Adverse events and oncological outcomes

All patients who initiated treatment completed all fractions with CPAP. No grade 3 to 5 adverse events were reported throughout the study. Dry mouth was the most common CPAP-related adverse event, occurring in seven, seven, five, and eight patients on the simulation day, the start date of the treatment, the end date of the treatment, and 2 months after the treatment, respectively. Grade 1 cough and dyspnea were observed in nine and seven patients, respectively. Notably, there were no reported facial skin damage, headache, visual disturbance, abdominal distension, and pneumothorax events. For RT-related adverse events, four patients developed grade 1 pneumonitis with mild cough and sputum, which resolved without medical intervention. One patient with underlying IPF developed grade 2 pneumonitis and was treated with oral steroids. Two patients reported chest wall pain 2 months after the treatment, which was managed with analgesics.
After a median follow-up of 11.5 months among the 32 patients, in-field local recurrences were developed in two patients, at 11 and 14 months after the completion of SABR, respectively. Both patients received salvage chemotherapy and were alive with no evidence of disease at the most recent follow-up. One patient experienced regional recurrence in the mediastinum outside the irradiation field. Of the 12 patients who had metastatic progression, all but one patient had pre-existing systemic disease before undergoing lung SABR.

Discussion and Conclusion

In the modern era, SABR stands out as a standard treatment for patients with early-stage, inoperable NSCLC [3]. The SABR technique requires substantial contributions from medical physics and dosimetry, involving precise delineation of target structures with narrow margins. To spare critical organs in the thorax while delivering a high dose of radiation to the target, sophisticated imaging and mapping are essential [13].
Respiratory motion is becoming a significant challenge in the era of lung SABR [14,15], as one of the main sources of uncertainty in SABR for lung tumors [16]. Tumors located in the lower regions, in particular, exhibit increased movement, with the motion amplitude generally being largest in the SI direction [12,17]. This respiratory motion results in an increased PTV and radiation exposure to normal lung tissue, with the potential for radiation pneumonitis [18].
The diaphragm plays a crucial role in respiratory motion, significantly influencing tumor movement. As the diaphragm contracts and descends, it forces the abdomen inferiorly and anteriorly, expanding the SI dimension of the thorax [12]. Unfortunately, diaphragmatic motion induced a discrepancy between the 4D-CT acquisition and reconstruction, especially in lower lobes. This mismatch can affect the delineation of the target volume, the shape of beam aperture, subsequently leads to systematic errors. In a retrospective analysis of 4D-CT images of patients who received thoracic or abdominal RT, more than 90% of patients had at least one artifact with a mean magnitude of larger than 1 cm due to diaphragm motions [19]. Moreover, for the tumors adjacent to the diaphragm, diaphragmatic motion results in the blurring of maximum intensity projection images, which makes it difficult to visualize the boundaries of tumor and diaphragm which have similar tissue density with tumors, potentially increasing the target volume delineation uncertainty [5,20].
To address these uncertainties caused by respiratory motion in RT, various respiratory motion management strategies have been developed. Gating, a strategy that delivers radiation only during specific respiratory phases, and real-time tracking, which continuously adjusts the radiation beam to tumor position variations, are effective but technically complex and time-consuming to implement in clinics [21]. DIBH technique involves hyperinflating the lungs during inspiration, resulting in anatomical and physiological changes that reduce respiratory tumor motion and lung toxicity. However, procedures for setup and verification of DIBH increases CT simulation and treatment time, thereby presenting challenges in terms of costs such as staff time and equipment requirements in clinical settings. Furthermore, some patients are unable to implement DIBH due to poor compliance and unsuitability for deep inspiration. For example, in the INHALE trial [22], 28% of the patients were unable to perform DIBH throughout the treatment course. Similarly, Memorial Sloan-Kettering Cancer Center on the use of DIBH for inoperable NSCLC patients showed that approximately 60% of patients were unable to tolerate the DIBH maneuver [23]. Given that the patients recommended for SABR are often elderly and have comorbidities, there remains a need to minimize dependence on patient cooperation.
In recent years, researchers have investigated the introduction of CPAP as respiratory motion management. CPAP delivers a positive airway pressure and induces lung hyperinflation, similar to the anatomic and physiologic effects of DIBH. It offers advantages such as shorter treatment times and less need for patient cooperation. Another advantage of CPAP is its cost-effectiveness, requiring only basic equipment such as a CPAP machine and a mask. This is a substantially low cost compared to a real-time position management system for DIBH, which costs hundreds of thousands of dollars to equip [24]. Kil and his colleagues [25,26] utilized the CPAP for thoracic RT, exhibiting its easy implementation in RT practice. They reported that no need for additional procedures were required beyond routine steps, and there was no increase in treatment time or staff requirements. As such, it is expected to have a much lower barrier to implementing CPAP for respiratory motion management strategy in radiation oncology departments into practice.
In our study, we highlighted the beneficial impact of the CPAP on target delineation for lung tumors, as well as its effectiveness in managing tumor motion and sparing adjacent organs. We found a significant improvement in the separation between the diaphragm and tumors in the lower lung lobes, leading to an extended SI distance with a mean difference of 35.3% (95% CI 18.6–51.9). Tumors overlapped by the diaphragm showed a substantial reduction of 35.3% (95% CI 14.6–56.0) in overlapped volume, indicating improved segmentation of lesions adjacent to the diaphragm with the use of CPAP. This strongly supports the utilization of CPAP in lung SABR to optimize accurate target delineation and radiation delivery. The use of CPAP led to reductions in tumor excursion, as well as ITV and PTV volumes, because of suppressed target motion. We observed a slight increase in GTV, which could be attributed to clearer visualization of tumor borders due to lower lung density and higher contrast with the solid tumor when using CPAP. The reduction in lung density contributes to moving normal lung tissue out of the irradiated region [27], and dosimetric analyses also revealed a reduction in irradiation to the normal lungs. However, six out of 32 patients experienced a rise in the mean heart dose and V10, particularly among tumors located in the lower and posterior regions of the lungs. These discrepancies might be attributed to heart movement caudally and posteriorly when using CPAP [28].
Several attempts have been made to demonstrate the beneficial effects of CPAP for RT. In a pilot study by Goldstein et al. [4], the use of CPAP demonstrated a potential organ-sparing effect by displacing normal lung and heart out of the radiation field, reducing respiration-induced tumor movement, and decreasing PTV in most patients. In a sequential prospective study in the same institution involving 49 patients with lung tumors, left-sided breast cancer, or liver metastases, CPAP was found to reduce PTV by 19%, indicating a reduction in tumor trajectory. Tumor excursion significantly decreased with CPAP, particularly in tumors located in the lower third of the lung, resulting in a PTV reduction ranging from 7% to 42% for tumors located within 2 cm from the diaphragm. A significant increase in lung volume was observed in patients with both normal and restrictive lung function, and these volumetric and dosimetric changes correlated with a 22% reduction in lung dose and a 29% reduction in heart dose [9].
Di Perri et al. [29] analyzed the benefits of CPAP in 20 patients undergoing SABR for lung tumors. The study demonstrated lung inflation did not show significant differences in tumor motion amplitude or baseline shift, with a wide inter-patient variability. Rather, a paradoxical increase in tumor trajectory was observed in four patients with tumors adjacent to the diaphragm. It is noteworthy that this study used a nasal mask, which does not fully cover the patient’s nose and mouth, reducing the administered pressure of CPAP. Additionally, the study employed a lower pressure to facilitate significant lung inflation. A study by Park et al. [24] suggested that an optimal pressure for achieving dosimetric organ-sparing benefits with CPAP is at least 7 cmH2O, with 14 cmH2O being recommended.
In a prospective trial by Allen et al. [8], the volumetric and dosimetric changes in lung and heart were evaluated in 17 patients with left-sided breast cancer. CPAP significantly increased the lung volume and reduced heart volume and mean heart dose, with a caudal and rightward shift in heart position. The study also highlighted that CPAP improved the reproducibility of the treatment setting by providing more stable lung inflation compared with DIBH.
Several case reports also demonstrated the advantages of CPAP in RT for patients within the thorax, including pleural mesothelioma and Hodgkin lymphoma (mediastinal involved-site RT), and left-sided breast cancer. Patients who were unable to reproduce and maintain DIBH achieved similar physiological changes and dosimetric benefits using CPAP. CPAP inflated the lung and displaced the heart and liver away from RT fields in the thorax, saving adjacent organs from unnecessary irradiation [25,26,30].
This study has several limitations. Firstly, it is a single-institutional prospective study, and further investigations in diverse clinical settings might be necessary to validate our findings. Despite being conducted with a single institutional cohort, we implemented a crossover design, obtaining both plans with and without CPAP for each participant serving as their own control, so that we could minimize individual variations and biases. To address potential biases in measurement accuracy, we ensured consistent patient position for all CT scans and used the treatment planning system to co-register all CT studies, facilitating accurate comparison of the differences with and without CPAP. While multiple radiation oncologists participated in delineating target volumes and OARs, all radiation oncologists were highly experienced, ensuring high repeatability in contouring.
In our study, 12.5% of patients were unable to undergo simulation and treatment using CPAP due to chest discomfort. Among patients who were unable to tolerate CPAP, a strong association was observed with current smoking and comorbidities in the heart, consistent with previous studies [31]. Baseline lung function did not show significant differences between tolerant and intolerant patients, suggesting that chest discomfort could likely be attributed to acute airway irritation and congestion. However, above all, the primary reasons for the inability to implement CPAP are presumed to be a lack of familiarity with the equipment and individual patients' psychological anxiety. It is anticipated that improvements in coaching systems and humidification could substantially expand the pool of patients able to tolerate CPAP. Given the fragility and advanced age of potential candidates, establishing patient selection criteria and providing clear coaching instructions will be essential to enhance patients’ compliance and ensure treatment reproducibility, based on extensive clinical experiences. However, the novel use of CPAP in RT has not yet been approved by the Ministry of Food and Drug Safety in South Korea yet. Therefore, CPAP is currently only administered to patients under clinical trials, in a limited number of institutions.
In conclusion, this study was the first to prospectively evaluate a potential benefit of CPAP in target delineation by separating adjacent organs and managing respiratory motion. CPAP significantly saved normal organs and improved dosimetric parameters, with high tolerability and patient safety in lung SABR. To maximize the benefits of CPAP and integrate it into routine practice in radiation oncology centers, standardization of CPAP implements and financial reimbursement is essential. Our findings strongly support the continued enrollment in further extensive trials.

Statement of Ethics

This study protocol was reviewed and approved by the Institutional Review Board of Seoul National University Hospital (IRB No. 2108-087-1245). Written informed consent was obtained from all patients to participate in the study prior to study enrollment.

Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Funding

This study was supported by Grant No. 03-2022-2150 provided by the Seoul National University Hospital Research Fund and Grant No. 50602-2020 from the Dongnam Institute of Radiological & Medical Sciences, funded by the Korean government (Ministry of Science and ICT).

Author Contributions

Conceptualization, JHC, HJK; Investigation and methodology, JBP, JHL, JHC, JS, SK, SCH, HWS; Project administration, JHC, HJK; Resources, JHL, JS, HJK; Supervision, HJK; Writing of the original draft, JBP, SCH; Writing of the review and editing, JHC, HJK; Formal analysis, JBP, SK, SCH; Data curation, JBP, SK; Visualization, JBP, SK; Funding acquisition; HJK.

Data Availability Statement

Research data are stored in an institutional repository and will be shared upon request to the corresponding author.

Fig. 1.
Measurement of tumor proximity to the diaphragm. (A) Overlapped planning target volume (PTV) volumes with the diaphragm (red arrow). (B) Superoinferior distance between the caudal border of the tumor and the diaphragm (white line). The green line indicates a lung tumor; light blue line, PTV contour; blue line, diaphragmatic dome; and red line, overlapped volume.
roj-2024-00101f1.jpg
Fig. 2.
(A) Overlapped planning target volumes (PTV) with the diaphragm, (B) superoinferior (SI) distance between the tumor and the diaphragm, highlighting the increased extent of separation between the target and the diaphragm with continuous positive airway pressure (CPAP). FB, free breathing.
roj-2024-00101f2.jpg
Table 1.
Patient and tumor characteristics
Characteristic Value
Patient characteristic (n = 32)
 Age (year) 66 (37–90)
 Follow-up duration (month) 11.5 (1.0–22.4)
Sex
 Male 19 (59.4)
 Female 13 (40.6)
Smoking history
 Non-smoker 23 (71.9)
 Ex-smoker 6 (18.8)
 Current-smoker 3 (9.3)
Smoking history (pack-year) 10.9 ± 22.3
Pulmonary function test
 FEV1/FVC 70.6 ± 13.5
 FEV1 (L) 2.2 ± 0.6
 FEV1 (%) 95.9 ± 18.7
 DLCO (mL) 14.3 ± 4.7
 DLCO (%) 83.5 ± 19.6
Underlying lung disease
 Yes 7 (21.9)
 No 25 (78.1)
ECOG performance status
 1 31 (96.9)
 2 1 (3.1)
Tumor characteristic (n = 39)
 Primary site
  Rectum 13 (33.3)
  Lung (primary) 11 (28.2)
  Colon 6 (15.4)
  Lung (metastases) 4 (10.3)
  Liver 4 (10.3)
  Vagina 1 (2.5)
 Histology
  Adenocarcinoma 28 (71.8)
  Hepatocellular carcinoma 4 (10.3)
  Squamous cell carcinoma 3 (7.7)
  Clear cell carcinoma 1 (2.6)
  Unknown 3 (7.6)
 Tumor location
  LLL 14 (35.9)
  LUL 4 (10.3)
  RLL 16 (41.0)
  RML 3 (7.7)
  RUL 2 (5.1)
 Radiation dose (Gy)
  40 1 (2.5)
  48 6 (15.4)
  50 1 (2.6)
  60 31 (79.5)

Values are presented as median (range) or number (%) or mean ± standard deviation.

FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; DLCO, diffusing capacity of the lung for carbon monoxide; ECOG, Eastern Cooperative Oncology Group; LLL, left lower lobe; LUL, left upper lobe; RLL, right lower lobe; RML, right middle lobe; RUL, right upper lobe.

Table 2.
Tumor excursion and target volume differences between the FB-arm and CPAP-arm
Measurements FB CPAP Mean paired differences (95% CI) p-value
Tumor excursion (cm)
 X (RL) 0.14 ± 0.10 0.12 ± 0.08 0.03 (-0.01–0.06) 0.223
 Y (AP) 0.26 ± 0.24 0.15 ± 0.11 0.11 (0.03–0.19) 0.020
 Z (SI) 1.08 ± 0.74 0.65 ± 0.46 0.43 (0.26–0.60) < 0.001
 XYZ (R vector) 1.15 ± 0.74 0.70 ± 0.44 0.45 (0.27–0.63) < 0.001
Target volume (mL)
 GTV 3.31 ± 5.13 3.40 ± 5.09 -0.08 (-0.38–0.21) 0.871
 ITV 6.28 ± 8.01 5.96 ± 8.05 0.32 (-0.16–0.79) 0.105
 PTV 25.06 ± 23.20 22.52 ± 20.48 2.55 (-0.50–5.60) 0.017

Values are presented as mean ± standard deviation.

FB, free breathing; CPAP, continuous positive airway pressure; RL, right-left; AP, anterior-posterior; SI, superior-inferior; GTV, gross target volume; ITV, internal target volume; PTV, planning target volume; CI, confidence interval.

Table 3.
Volumetric and dosimetric parameters
Measurements FB CPAP Mean paired differences (95% CI) p-value
Lung (ipsilateral)
 V5 (%) 23.3 ± 11.7 19.4 ± 10.4 3.8 (2.2–5.5) <0.001
 V10 (%) 15.1 ± 9.0 11.8 ± 7.4 3.3 (1.8–4.8) <0.001
 V20 (%) 6.2 ± 4.1 4.7 ± 3.2 1.4 (0.7–2.2) <0.001
 V30 (%) 3.0 ± 2.8 2.3 ± 1.6 0.7 (0.3–1.0) <0.001
 V40 (%) 1.5 ± 1.1 1.2 ± 0.9 0.4 (0.2–0.5) <0.001
 Mean dose (cGy) 442.7 ± 224.8 362.1 ± 188.2 80.7 (46.8–114.5) <0.001
 Volume (mL) 1,498.2 ± 461.5 2,389.6 ± 547.5 -891.4 (-977.1–-805.8) <0.001
Lung (contralateral)
 V5 (%) 0.7 ± 1.7 1.6 ± 3.7 -0.9 (-1.9–0.3) 0.057
 V10 (%) 0.01 ± 0.06 0.4 ± 1.8 -0.4 (-1.0–0.2) 0.186
 Mean dose (cGy) 80.9 ± 59.8 77.8 ± 56.5 3.1 (-5.0–11.3) 0.442
 Volume (mL) 1,476.2 ± 455.2 2,323.3 ± 559.2 -847.0 (-938.7–-755.4) <0.001
Lung (bilateral)
 V5 (%) 12.2 ± 6.9 10.7 ± 6.1 1.5 (0.7–2.4) <0.001
 V10 (%) 7.7 ± 5.0 6.2 ± 3.9 1.5 (0.8–2.2) <0.001
 V20 (%) 3.1 ± 2.2 2.4 ± 1.7 0.7 (0.4–1.1) <0.001
 V30 (%) 1.5 ± 1.1 1.2 ± 0.8 0.3 (0.14–0.5) 0.001
 V40 (%) 0.8 ± 0.6 0.6 ± 0.4 0.2 (0.1–0.3) 0.001
 Mean dose (cGy) 262.1 ± 139.2 222.7 ± 115.2 39.4 (20.8–58.0) <0.001
 Volume (mL) 2,974.7 ± 832.7 4,712.9 ± 995.7 -1,738.2 (-1,906.2–-1,570.2) <0.001
Heart
 V5 (%) 14.9 ± 11.6 16.4 ± 14.6 -1.5 (-0.7–-3.7) 0.182
 V10 (%) 3.0 ± 4.1 3.8 ± 5.5 -0.8 (-1.6–-0.1) 0.040
 Mean dose (cGy) 234.8 ± 144.2 229.5 ± 167.1 5.2 (-15.7–26.2) 0.614
 Volume (mL) 709.0 ± 205.8 657.4 ± 180.6 51.6 (34.0–69.1) <0.001

Values are presented as mean ± standard deviation.

FB, free breathing; CPAP, continuous positive airway pressure; Vx, the percentage of total normal volume receiving equal to or greater than x Gy of radiation; CI, confidence interval.

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