Efficacy and safety of applying oxidized regenerated cellulose sheets to the parietal pleura of open chest wounds in thoracic surgery: a prospective randomized controlled trial protocol

Introduction

Background

The indication for segmentectomy in lung cancer is increasing following the publication of the results of a randomized trial comparing segmentectomy with lobectomy in small peripheral non-small cell lung cancer, which showed the superiority of segmentectomy despite a higher local recurrence rate of 5.4% versus 10.5% in the patients who underwent lobectomy and those who underwent segmentectomy, respectively (1). Surgical resection of ipsilateral metachronous non-small cell lung cancer, including second primary lung cancer and intrapulmonary recurrence, was required in 3.6% of patients (2), but there would be more opportunities for reoperation in the future, with an increase in recurrent patients due to the establishment of segmentectomy.

Rationale and knowledge gap

In ipsilateral thoracic reoperation, the presence of adhesions due to previous surgery is generally an issue. Because of the relatively low frequency of reoperation, favorable aspects of adhesions in pulmonary fistula control have been prioritized over the prevention of adhesions. Therefore, there is currently no standardized adhesion prevention strategy in the thoracic region. Oxidized regenerated cellulose (ORC) sheets have been shown to prevent postoperative adhesions in the abdominal region (3,4), and similar effects can be expected in the thoracic region. A retrospective study in Japan showed that ORC sheets can be used safely in the thorax and may contribute to the prevention of adhesions (5). However, there is a lack of data on the accurate efficacy and safety of ORC sheets in thoracic surgery.

Objective

The purpose of this study is to verify that the application of ORC sheets to the parietal pleura of open chest wounds could prevent postoperative adhesions in the thoracic region in a randomized controlled trial. The primary endpoint is the presence rate of pleural adhesion as determined by postoperative chest echography performed 4–20 weeks postoperatively. The postoperative complications and adverse events will also be evaluated. We present this article in accordance with the SPIRIT reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1296/rc).

Methods

Study design and objectives

This prospective randomized controlled trial includes patients with pulmonary diseases requiring surgery with incision of the parietal pleura. The following inclusion and exclusion criteria are established, considering that surgery can be performed safely and that the enrollment of patients with preoperative adhesions in the thoracic cavity could remain but should be minimized.

Inclusion criteria

• Adults 18 years of age or older at the time of providing consent to participate in the study;
• Eastern Cooperative Oncology Group performance status of 0–2;
• Preserved main organ function;
• Patients undergoing initial surgery to the affected side of thoracic cavity;
• Patients who have been fully informed of the study and have given their informed and voluntary written consent to participate in the study.

Exclusion criteria

• Patients with a history of thoracic drainage on the affected side;
• Patients with a history of inflammatory disease including pneumonia on the affected side;
• Patients scheduled to undergo a total lung resection or a combined chest wall resection during surgery;
• Patients with dementia or other conditions that require surrogate consent;
• Patients who are pregnant, possibly pregnant, or within 28 days postpartum, or lactating;
• Other patients who are judged by the principal investigator or investigators to be inappropriate for the safe conduct of this study.

In total, 240 patients will be recruited at Chiba University Hospital between September 2023 and December 2025. Patients will be assigned to ORC sheets applied group or non-applied group. In the applied group, the sheets will be applied to the parietal pleura of open chest wounds at the end of surgery, while in the non-applied group, chest closure will be performed as usual. Based on a previous study on abdominal adhesions with ORC sheets (4), assuming that the probability of adhesion prevention would be 57.6% in the applied group and 37.9% in the non-applied group, α=0.05 (both sides) and β=0.2, the number of patients required in each group is estimated to be 100. Assuming that 20% of the patients would drop out or have incomplete data, the target number of patients was set at 120 per group, for a total of 240 patients.

There is no reliable evaluation tool for the presence of adhesions other than intrathoracic inspection by thoracoscopic or open surgery; however, chest echography has recently been developed as an alternative. Chest echography is considered an adequate substitute, based on the findings of a report discussing the usefulness of thoracic echography for evaluating adhesions, in which sensitivity and specificity were 63.6% and 79.4% respectively in the upper intercostal region, and the lower intercostal region showed even higher sensitivity (81.5%) and specificity (81.0%) (6). The visceral pleura is depicted in white on echography. Without adhesions, it moves independently of the chest wall with respiration, but with adhesions, it is fixed to the chest wall or moves in conjunction with the chest wall. Board-certified laboratory technicians in Chiba University Hospital will perform echography exclusively on the largest of the multiple wounds. If there are multiple wounds of the largest size, observation will be performed on the most caudal wound, since the caudal chest wall is more accurate for chest echography. Wounds in which drains are inserted will be excluded. Two echography technologists, who will not be aware of the group the examined patient has been assigned to, will perform the procedure to evaluate intrapleural adhesions, to maintain blindness in the trial. Echographic findings will be stored on video, and in cases where judgment is difficult, the evaluators and researchers will discuss the findings and make a joint judgment based on the recording. The timing of the examination is set so that it can be performed after the complete absorption period of ORC sheets, which is approximately 4 weeks. Since the outpatient follow-up interval may vary depending on the case, the examination timing is set broadly within a range of 4–20 weeks.

The study will be conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study has received an ethical approval by Chiba University Certified Clinical Research Review Board (CRB0074-23) and has been registered on the Japan Registry of Clinical Trials (No. jRCT1032230271). Investigators will explain the concept of the trial to the patients and obtain written informed consent from all participating patients. The informed consent form contains a specific description of this study, such as its background, objectives, methods, duration, and the number of participants. It also outlines the expected benefits and potential risks associated with participation. Furthermore, the form explains the procedures for using medical devices, the schedule for study visits, and the treatment options available after the study. Participants are informed of their right to withdraw from the study at any time without penalty. The confidentiality of personal data is ensured, and details on data storage, handling, and disposal are provided. Additionally, information on how to contact the study team for inquiries or in case of adverse events is included. The initial version of the protocol was approved on July 20^th, 2023, and patient recruitment began in September 2023. The latest version 1.4, was approved on June 17^th, 2024.

Endpoints

The primary endpoint is the presence rate of pleural adhesions on chest echography performed 4–20 weeks postoperatively.

The secondary endpoints are set as follows:

• Postoperative wound infection;
• Postoperative pulmonary fistula;
• Prolonged pulmonary fistula: is defined as a pulmonary fistula that persists for 7 days or more after surgery or is expected to persist for that period;
• Delayed pulmonary fistula: is defined as a pulmonary fistula that requires chest drainage again after the chest tube has been removed;
• Postoperative bleeding: is defined as intrapleural bleeding that requires blood transfusion or reoperation after surgery;
• Duration of chest drain placement (days).

These endpoints were chosen due to the potential risks associated with the use of ORC sheets, including infection from foreign materials, pulmonary fistula formation due to adhesion prevention, hemorrhage, and increased pleural effusion. Other postoperative adverse outcomes, including pleural empyema will be confirmed as safety endpoint. Exploratory endpoints are set as follows to confirm the impact on other perioperative outcomes and to prepare for situations where intrathoracic observation could be performed after complete absorption of ORC sheets: (I) operative time (minute); (II) procedure for prolonged or delayed pulmonary fistula and the date of its implementation; (III) postoperative hospital day (day); (IV) presence, degree, nature, and location of adhesions in ipsilateral reoperation performed 4 weeks after initial surgery.

Data collection and management

The study schema is described in Figure 1. Once the patients perform the usual preoperative tests and are considered eligible for enrollment, a screening test will be performed after obtaining consent to participate in the study. If eligible to participate, the patients will be enrolled before the day of surgery and will be anonymized by assignment of clinical trial subject numbers in the hospital. The detailed schedule of the measurements is summarized in Table 1. After enrollment, patients will be randomly assigned to either the sheets applied group or the non-applied group according to age, sex, and the planned surgical approach: these factors are selected, because wound healing could be delayed with aging, factors confounding gender, such as smoking history and general frailty, can influence postoperative adhesion formation, and the accuracy of adhesion assessment with chest echography can vary depending on the size of the open wound. Random allocation will be performed at a 1:1 ratio with central registration at an independent data center to minimize bias. In the applied group, ORC sheets will be applied to the parietal pleura of all open chest wounds at the end of surgery: include small incisions in a complete thoracoscopic surgery, but exclude wounds where drains are placed. However, the sheet should be applied to the wound where the drain is placed only when the surgical procedure is completed in a single wound: note that single port surgery is rarely performed at Chiba University Hospital. If direct application of ORC sheets to the parietal pleura is difficult due to the size of the wounds and/or the angle of manipulation, the sheets are applied to the visceral pleura while checking that the sheets are in contact with the open chest wounds by inflating the lungs. When applying the sheet to a large wound, the sheet is cut into several pieces as needed. In addition to conventional follow-up in the outpatient clinic after discharge, chest echography will be performed at 4–20 weeks after surgery to evaluate the presence of adhesions directly on the given wound. If participation in the study is terminated for any reason, the test results will be retained to the greatest extent possible.

Figure 1 Study design of the clinical trial. ORC, oxidized regenerated cellulose; PS, performance status.

Statistical analysis

The full analysis set (FAS), the per-protocol set (PPS), and the safety population (SP) will be analyzed. The FAS will be the main analysis population, and all three target populations will be analyzed.

In the analysis of the primary endpoint of this study, the evaluation of pleural adhesions on postoperative chest echography, the incidence of pleural adhesion findings and 95% confidence intervals will be calculated for each group. A Chi-squared test will be used to examine the null hypothesis that the incidence of adhesions in the two groups in the main analysis is equal. The significance level for the null hypothesis test is 5% two-sided. For continuous variables in the secondary endpoints, summary statistics will be calculated for each group, and an unpaired t-test will be used to examine the null hypothesis that the means of the two groups are equal. For categorical variables, the proportions will be calculated for each group, and a Chi-squared test will be used to examine the null hypothesis that the proportions are equal in both groups. The safety endpoint is the frequency of adverse events. The incidence rate of all adverse events and two-sided 95% confidence interval by the presence or absence and degree of association will be calculated for each group and compared between groups. The Chi-squared test or Fisher’s exact test will be used for comparisons between groups, depending on the incidence rate. In addition, a subgroup analysis of the following ten items will be performed: (I) sex (male/female); (II) age (≥75/<75 years); (III) presence of respiratory dysfunction (obstructive and restrictive ventilatory defects); (IV) nutritional status (blood hemoglobin and albumin); (V) presence of diabetes mellitus; (VI) with or without systemic steroid administration; (VII) surgical approach (complete video-assisted thoracoscopic surgery/hybrid video-assisted thoracoscopic surgery and open chest surgery); (VIII) pathological diagnosis and stage [according to Tumor Node Metastasis (TNM) Classification of Malignant Tumours, 8^th edition]; (IX) presence, degree (mild/moderate/severe), nature (fibrinous/fibrous), and location (presence of adhesions in the lateral chest, where echography would be performed) of adhesions in observation of thoracic cavity at the time of chest opening; (X) with or without postoperative pleurodesis therapy: these items are set as factors that influence the occurrence of postoperative adhesions. After the follow-up period, the analysis will be performed after the data are obtained and the cases are fixed. The statistical analyst will compile an “Analysis Report” and submit it to the principal investigator. The results of the study will be reported regardless of the outcome.

Quality control

The monitoring manager is responsible for ensuring that the human rights of the subjects are protected, the study is conducted in accordance with the protocol, and the data are accurately collected. Central monitoring will be conducted on a regular basis based on data from case report forms obtained at the data center. The monitoring manager shall prepare a report that includes a summary of important findings such as diseases, nonconformities, or other facts, and shall report the results of such monitoring to the principal investigator. The independent data monitoring committee, which consists of at least three expert members independent of the study, conducts safety monitoring, including comparison of the incidence of adverse events between the study treatment and control group, and detailed examination of serious adverse events, as necessary, for the purpose of ensuring patient safety. The principal investigator will make a decision to discontinue the study as a whole if it is considered difficult to continue the study due to unforeseen adverse events, illness, or other factors.

Discussion

The aim of this study is to verify the efficacy and safety of ORC sheets in preventing adhesions in the thoracic region. In addition to local recurrence after limited surgeries for lung cancer, patients who require repeated lung surgeries for metastatic lung tumors may also benefit from the anti-adhesion effect of ORC sheets.

A previous report evaluated adhesions in the abdominal region during repeated abdominal surgeries (3,4). Considering the high invasiveness of the procedure, an alternative method of examining the presence or absence of adhesions by echography will be used in this study. It is unclear whether this alternative method truly reflect the actual occurrence of adhesions, but this method has high sensitivity and specificity. In actual patients that may require ipsilateral reoperation for conditions such as recurrence or delayed pulmonary fistula in the future, the details of the adhesions could be accurately confirmed by intrathoracic observation. Nonetheless, this evaluation method is judged to be unfeasible as a primary endpoint due to the need for long-term follow-up and the difficulty in predicting how many of the patients enrolled in the study would require ipsilateral reoperation: thus, this evaluation method is set as an exploratory endpoint. Since echography can be performed unrelated to ipsilateral recurrence or reoperation, it is assumed that an earlier evaluation period of primary endpoint would not be an issue.

Adhesions around the pulmonary hilum and blood vessels due to previous surgery are at risk for fatal complications than those below the open chest wound, but they were not evaluated in this study due to the design of the study. If this study would demonstrate the efficacy and safety of the ORC sheet application to the open chest wounds, its effectiveness in preventing adhesions around the pulmonary hilum and blood vessels would be evaluated in the future.

In conclusion, this study will help validate the effect of adhesion prevention with ORC sheets, which could lead to postoperative adhesion prevention with the sheets becoming a new treatment strategy, to prepare for the predicted increase in ipsilateral reoperations that will accompany the increase in limited surgeries.

Acknowledgments

The authors would like to thank the Translational Research and Development Center at Chiba University Hospital for their support in protocol creation and Editage (www.editage.com) for English language editing.

Funding: This work is a self-funded trial under the supported by Clinical Research Initiation-Fund of Chiba University Hospital.

Footnote

Reporting Checklist: The authors have completed the SPIRIT reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1296/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1296/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1296/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study will be conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study has received an ethical approval by Chiba University Certified Clinical Research Review Board (No. CRB0074-23) and has been registered on the Japan Registry of Clinical Trials (No. jRCT1032230271). Investigators will explain the concept of the trial to the patients and obtain written informed consent from all participating patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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