DOI: https://doi.org/10.21203/rs.2.10216/v2
Background: Pleural lavage is regularly performed before closing chest wall in pulmonary surgery to prevent pleural implantation of tumor cells and postoperative infection. However, no proper regimen of pleural lavage isdefinednow. To establish areliable volume of pleural lavage, weherein designed this randomized controlled trial.
Methods: A total of 400 participants with non-small cell lung cancer (NSCLC) undergoing video-assisted thoracoscopic surgery (VATS) lobectomy and systematic mediastinallymph node dissection (MLND) will be randomly assigned into 2 groups: Group A (500ml pleural lavage fluid) and Group B (3000ml pleural lavage fluid). The primary outcomes include the levels of leukocytes, neutrophils, inflammatory factors on the first postoperative day. The secondary outcomes mainly include: (i) the levels of leukocytes, neutrophils, inflammatory factors on the second and third postoperative day; (ii) the incidence of postoperative fever on the first, second and third postoperative day; (iii) the volumes of chest drainage on 1 to 3 days after operation, the duration of drainage, and postoperative hospitalization; (iv) the incidence of postoperative complications (incision infection, pain, atelectasis, hemorrhage, etc.) and the incidence of pleural effusion requiring thoracic puncture or drainage within 30 days after surgery.The main content of the analysis includes effectiveness and safety analysis. We will perform subgroup analysis to identify potential influence factors.
Discussion: This first randomized controlled trial isexpected to compare the clinical outcomes between different volume of pleural lavage fluid following VATS and MLND, and provide us evidence to develop a standardized procedure of pleural lavage before closing chest wall in lung cancer operation.
Pleural lavage is regularly performed before closing chest wall in pulmonary surgery, by which some potentially residual tumor cells and tissues can be washed away, to prevent pleural implantation of tumor and postoperative infection [1]. It was early reported that even if there were no obvious malignant pleural effusion or pleural implants, the positive rate of tumor exfoliated cells in postoperative pleural lavage was as high as 33% in 1958[2]. Various studies found that intraoperative pleural lavage is an independent prognostic factor of patients who underwent pulmonary surgery [3–5]. The positive results of pleural lavage cytology before closure not only have higher prognostic value than pleural lavage cytology before thoracotomy, but also could guide adjuvant chemotherapy for lung cancer patients and improve recurrence-free survival.
Currently, no proper regimen of pleural lavage is available [6]. The most common liquid used for irrigating the thoracic cavity was 0.9% sodium chloride injection varying from 20 to 2000 ml[2, 7–9] nearly to the temperature of human body at 38~40 ℃ [10]. However, there are no determinant criteria on volume of pleural lavage fluid. If the volume of pleural lavage is too less, the residual tumor cells and tissue cannot be washed away, which may result in increased absorption of inflammatory mediators, fever, and even severe inflammatory reactions [11]. And it will affect prognosis and prolong hospitalization [12]. Furthermore, the residual tumor cells may increase the risk of recurrence [13] and metastasis [14–16]. And if the volume of pleural lavage is too more, it will cause waste of resources and prolongation of operation time and Kaneda M et al. [9] found that the doses of over 500ml could cause false negative results of PLC. In our study, We chose 500ml pleural fluid and 3000ml pleural fluid to wash thoracic cavity before closure based on clinical practice and literatures[7, 8].
To find a reliable procedure of pleural lavage, we will prospectively enroll non-small cell lung cancer (NSCLC) patients undergoing video-assisted thoracoscopic surgery (VATS) for lobectomy and systematic mediastinal lymph node dissection (MLND). And we will randomly divide them into 2 groups: Group A (500ml pleural lavage fluid) and Group B (3000ml pleural lavage fluid). Blood samples will be collected to test for leukocytes, neutrophils and inflammatory factors. Postoperative complications, the volume of pleural drainage and length of hospital stay will be also recorded. We aim to compare the clinical benefits for NSCLC patients between different volume of pleural lavage fluid following VATS lobectomy and MLND.
This is a double-blind, single-center clinical, randomized controlled trial (Fig. 1). This study protocol is conceived based on the Recommendation for Interventional Trials (SPIRIT). The SPIRIT figure (Fig. 2) summaries the items of enrollment, intervention and follow-up. The detailed SPIRIT checklist is also provided (see Additional file 1).
We aim to identify the effects of different volume of pleural lavage fluid on perioperative outcomes of NSCLC patients following VATS lobectomy and MLND.
This study will be conducted in NSCLC patients undergoing VATS lobectomy and MLND in the Department of Thoracic Surgery, West China Hospital, Sichuan University.
Patients eligible for this trial must comply with all the inclusion criteria and do not meet any exclusion criterion before enrollment. To achieve adequate participant enrolment, all physicians in the thoracic department of the hospital are informed of the trial, and to contact the trial coordinator if they encounter potential eligible patients. All the included patients will sign an informed consent form. The consent form at least contains: (i) the detailed explanation of the study design, including backgrounds and aims of this trial; (ii) the benefits and risk of participating; (iii) the strategy and compensation for the participants who experienced any harms as a result of trial participation.
Patients who, at the start of the treatment, meet all the following criteria, are eligible for the study: (i) patients aged between 18 and 75 years; (ii) patients undergoing planned VATS lobectomy and MLND; (iii) ASA risk class of I-II; (iv) essential materials were complete such as clinical staging of lung cancer and medication; (v) confirmed with NSCLC through pathological examination after surgery; (vi) willing to participant after reading and signing an informed consent form.
Patients who, at the start of treatment, meet any of the following criteria are not eligible for the study: (i) last smoked <2 weeks prior to surgery for current smokers; (ii) preoperative hydrothorax of patients was predominant; (iii) patients were pregnant or breastfeeding women (females aged 18 to 55 should receive pregnancy test); (iv) patients with preoperative severe mental illness; (v) patients with preoperative gastrointestinal or blood system disease; (vi) patients underwent cardiac ischemia; (vii) patients received preoperative radiotherapy or neoadjuvant chemotherapy; (viii) intraoperative accidents happened to the patients, such as hemorrhage (>500ml), conversion to open surgery, and cardiac arrest; (ix) patients with severe postoperative bleeding or persistent air leakage, which require reoperations.
We will perform the randomization to assign candidates into 2 groups based on computer-generated random numbers shortly prior to the surgery. The random numbers will be printed and placed in consecutively numbered and separate sealed opaque envelopes, which will be only opened once a patient is deemed eligible. When receiving a patient who meets the inclusion criteria, the principal doctors will assign the newly participant to a group and inform the treatment group. The research assistant should receive the notification timely and assign patients to their study group strictly as required. The study will be double blind. The participants and investigators will be blinded to the allocation of the participants, while the project manager will be unblinded. If unexpected emergency circumstances happen, the allocation will be disclosed to the investigators. If unblinding happens, the participant will withdraw from this study and a detailed explanation will be recorded.
This is the first study focusing on the effect of different volume of pleural lavage on the clinical outcomes following VATS lobectomy and MLND, and no reference could be available to estimate sample size. With respect to our experience, a total of 400 candidates will be recruited in this study, with each group consists of 200 candidates. The numbers of participants will allow a 5% chance of type I error. The effect size is estimated as 0.5 based on clinical experience. According to the current sample size, we calculate the power of this trial is 99.96%.
A total of 400 NSCLC patients aged 18–75 years, who will undergo VATS lobectomy and MLND, will be recruited in our study according to inclusion and exclusion criteria. All the patients will be divided into 2 groups:
Group A (experimental group): 500 ml pleural lavage fluid
Before closing the chest wall, we will perform careful hemostasis and then flush the thoracic cavity with 500 ml 0.9% sodium chloride injection at 38–40 ℃. A 28F catheter will be indwelled to drainage.
Group B (experimental group): 3000 ml pleural lavage fluid
We will use 3000ml 0.9% sodium chloride injection at 38–40 ℃ to flush the thoracic cavity in this group. Other procedures are the same with group A.
All the recruited participants have the right to quit this study at any time for any reason based on the ethical consideration, without any negative effect on their further therapy. Meanwhile, all the researchers have the right to terminate the enrollment of any patients at any time with reasonable circumstance. All the changes and reasons will be recorded immediately in the Case reported form (CRF). If dropout rate is higher than 10%, we will apply multiple imputation to avoid pitfalls involved with listwise deletion of cases. Intention-to-treatment (ITT) principle will be applied to analyze the data.
All the data recorded in CRF will be checked twice by two independent researchers. A data management safety committee (DMSC) will be needed, which will be comprised of 3 independent investigators. They will supervise the study protocol adherence, participant recruitment, and confirm that the CRF is correctly completed and consistent with the original data. All the data can only be acquired by the study investigators who have signed the confidential disclosure agreement and only identical data will be published. We do not plan to collect personal information about potential and enrolled participants beyond what is collected during normal hospitalization. After the trial, personally identifiable information will be omitted and placed in a separate database before any data analysis will be performed. All the participants’ data collected in this trial will not be used for other ancillary studies. The adherence to the study protocol, data collection, statistical analysis and publication issue as well as related safe issues will be strictly monitored by the Institutional Ethic Committee of West China Hospital, Sichuan University.
The main content of the analysis is effectiveness analysis and safety analysis. The analysis of all continuous variable will be presented as mean, standard deviation (SD), median, quartile spacing, maximum and minimum values. The analysis of all dichotomous variable will be presented as rate, constituent ratio and hazard ratio. We will use the t-test and χ2 test, analysis of variance, univariate and multivariate logistic regression analysis to describe our data. The factors (p<0.15) in univariate analysis will be analyzed in multivariate analysis. All the data will be checked twice by two independent statisticians. The two independent statisticians will also be blinded to treatment assignment. We will perform post-hoc subgroup analysis to identify potential significant factors based on age, sex, tumor location, clinical stage of tumor, resection scope, surgery time, the volume of intraoperative bleeding, and pathological stage of tumor. Demographics and clinical characteristic of the subjects are summarized as mean ± SD for continuous variables and number (%) for categorical variables. The difference between groups will be considered statistically significant if P<0.05. All data will be analyzed using SPSS (software version 25.0, Chicago, IL).
Collecting blood sample of patients to check leukocytes, neutrophils and inflammatory factors. Sample collection will be performed by trained nurses. Samples will be sent to the Department of Laboratory Medicine immediately after collection. The laboratory evaluation would be conducted by technicians, blinded to treatment groups. Laboratory results will be placed in the electronic chart. Specimens will be destroyed and not stored for ancillary studies. Preoperative data will be collected within 3 days after recruitment. Surgery data will be collected within 2 days after the operation. Postoperative data will be collected within 3 days after discharge. For patients discharged home, we will conduct follow-up information by phone calls, and these data will be recorded within 3 days. If there are any errors or omissions, the investigator will correct them immediately. The raw data will be marked clearly when revising, and signed by the investigator with date when the modifications are made.
All the data can only be obtained by the study researchers who have signed the confidential disclosure agreement. We do not plan to collect personal information about potential and enrolled participants beyond what is collected during normal hospitalization. The adherence to the study protocol, data collection, statistical analysis as well as related safe issues will be strictly monitored by the Institutional Ethic Committee of West China Hospital, Sichuan University.
Some postoperative complications, such as bleeding, incision site pain, postoperative air leak, prolonged air leak, atelectasis, will be treated according to clinical guidelines. During every ward round, which is conducted at least twice a day, the doctors in charge will ask for the patients’ feelings and perform specific physical examination to monitor adverse events. All the adverse events will be recorded timely in CRF. Postoperative follow-up will be conducted for all the participants. participants with any serious harms experienced as a result of trial participation will be treated timely and receive adequate compensation.
All the outcomes will be defined according to two previous studies[17, 18].
Primary outcomes:
The levels of leukocytes, neutrophils, inflammatory factors [interleukin–1β (IL–1β), IL–6, IL–8, IL–2, tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), prostaglandin E2 (PGE2), and 5-hydroxytryptamine (5-HT)] on the first postoperative day. On the first postoperative morning, a trained nurse will collect blood samples and then send samples to test. The mean difference of the levels of leukocytes, neutrophils, and inflammatory factors will be compared between the 2 groups.
Secondary outcomes:
(i) the levels of leukocytes, neutrophils, inflammatory factors (IL–1β, IL–6, IL–8, IL–2, TNF-α, CRP, PGE2, and 5-HT) on the second and third postoperative day; (ii) the incidence of postoperative fever on the first, second and third postoperative day; (iii) the volumes of chest drainage on 1 to 3 days after operation, the duration of drainage, and postoperative hospitalization; (iv) the incidence of postoperative complications (incision infection, pain, atelectasis, hemorrhage, etc.) and the incidence of pleural effusion requiring thoracic puncture or drainage within 30 days after surgery.
The current protocol is version 1.0 (25 September 2018). Any amendments in the protocol during the trial which will affect the process of study, the benefit and risk of participants will require a formal amendments agreement of Ethic Committee.
It is essential to flush the thoracic cavity before closing the chest wall, however, few studies were found focusing on the volume of pleural lavage. The most frequently used method is to flush the thoracic cavity with 0.9% sodium chloride injection heated nearly to the temperature of the human body at 38~40℃. No determinant criteria on volume of pleural lavage fluid has been set. If the volume of pleural lavage is too less, the residual tumor cells and tissue cannot be washed away, which may result in increased absorption of inflammatory mediators, fever, and even severe inflammatory reactions. And it will affect prognosis and prolong hospitalization. Furthermore, the residual tumor cells may increase the risk of recurrence and metastasis. If the volume of pleural lavage is too high, it will cause waste of resources and prolongation of operation time.
The study will enroll 400 NSCLC patients undergoing VATS lobectomy and MLND, and divide them into 2 groups. We will change the volume of 0.9% sodium chloride injection to find out whether different volumes of pleural lavage fluid have different effects on prognosis of NSCLC patients measuring by some important clinic indices such as the plasma levels of leukocytes, neutrophils, inflammatory factors, and the incidence of fever after operation were observed 1 to 3 days after operation.
However, the study has some limitations. First, it is a single-center trial which will restrict its generalizability, so a multiple-center large-sample clinical trial is warranted in the future. Second, the anesthesiologist and surgeons in charge of the intraoperative part of the study cannot be blinded to the study group regarding the safety. Third, the hospitalization time may be different across participants, which may bring effects on the prognosis of NSCLC patients. Fourth, patients of different somatotype may need different volume of pleural lavage.
In conclusion, this study is the first randomized controlled trial aiming at comparison of the clinical benefits for non-small cell lung cancer (NSCLC) patients between different volume of pleural lavage fluid following video-assisted thoracoscopic lobectomy and systematic lymph node dissection. This study may help to develop a standardized procedure of pleural lavage before closing thoracic cavity in lung cancer operation.
This study is not yet open for recruitment. This trial is scheduled to begin in July 2019 and to end in July 2021.
NSCLC:non-small cell lung cancer; VATS: video-assisted thoracoscopic surgery; MLND: mediastinal lymph node dissection; SPIRIT: the Standard Protocol Items: Recommendation for Interventional Trials; CRF: Case reported form; ITT: intention-to-treatment; SD: standard deviations.
Ethic approval has been obtained from the Institutional Ethic Committee for Clinical Research of West China Hospital, Sichuan University (NO. 2018–417). This study has been registered with the Chinese Clinical Trial Registry (ChiCTR 1900021950) on 17 March 2019. The URL of the trial registry record is http://www.chictr.org.cn/listbycreater.aspx. Only participants who read and write inform consent will be recruited.
Not applicable.
The results of this trial will be published in an international peer-reviewed journal and presented at international scientific meetings. No later than 3 years after the publication of the results of this trial, we will deliver a completely deidentified data set to an appropriate data archive for sharing purposes. Any requests for acquiring data will be sent to the corresponding author and be considered carefully.
The authors declare that they have no competing interests.
This work was supported by Key Science and Technology Program of Sichuan Province, China (2016FZ0118) (to Dr. Lunxu Liu).The study funders played no role in the study design, writing of the protocol or the decision to submit the report for publication. The study funders will play no role and have no authority over the collection, management, analysis or interpretation of data.
LL, JZ and CL conceived of the study, finished its design and coordination. JZ, CL, SM and ML developed the protocol and collected data. JZ, CL, HL, and LL are responsible for the operations. NC and YC participated in statistics analysis. JZ and CL drafted the manuscript. LL financially supported this study. All authors read and approved the final manuscript.
Not applicable.
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