Aims of the study
This trial aims to assess the long-term effects of the Pringle maneuver on the rate of tumor recurrence after curative resection of HCC. The effects on disease-free survival, overall survival, operative morbidity and mortality, duration of operation, blood loss, transfusion requirements, hospital stay, intensive care unit stay, and blood test results with prognostic relevance, will be examined. The trial will test whether hepatic resection without the Pringle maneuver reduces recurrence rate and improves disease-free survival rate.
Our study group includes researchers in five leading hospitals in China (Southwest Hospital, Chinese PLA General Hospital, Zhongshan Hospital, Nanjing Drum Tower Hospital, and the First Affiliated Hospital of SunYet-Sen University) located in the southwestern, northern, eastern, middle, and southern parts of China, respectively. All eligible patients from these five participating hospitals with a clinical diagnosis of HCC with infection will be enrolled. The study will include patients’ aged 18
years or older undergoing potentially curative (R0) resection, if preoperative imaging indicates that R0 resection can be undertaken both with and without the Pringle maneuver. Patients with extrahepatic disease, severe liver cirrhosis, or tumor-positive lymph nodes in the abdomen or hepatoduodenal ligament will be excluded. We anticipate that 50 eligible cases per month will be enrolled in the trial. A detailed list of all eligibility criteria follows.
1. Aged from 18 to 65
years, no gender restriction.
2. Clinical diagnosis of resectable HCC.
3. Liver function tests showing Child-Pugh grade A and clearance of indocyanine green at 15 minutes (ICG-R15) less than 15%.
4. Tumor nodes in the liver which can be radically excised.
5. No preoperative anti-cancer therapy.
6. Written informed consent from the patient or legal guardian prior to enrollment in the study.
2. Extrahepatic tumor or lymph node metastasis.
3. 3.Tumor invasion or thrombosis in the portal vein, hepatic vein, or inferior vena cava.
4. Surgical marginal positive.
This study is funded by the National Major Science and Technology Project of China on the prevention and treatment of infectious diseases, for human immunodeficiency virus and HBV [2008ZX10002-026]. This clinical trial is a registered [NCT00725335], prospective, intraoperatively randomized multicenter trial of patients undergoing curative resection for HCC. The patients will be stratified by center and allocated to groups by a permuted-blocks randomization protocol. The primary objective of this study is to compare the disease free-survival rates at 1, 2, and 3
years postoperatively between the two groups. We hypothesize that the long-term prognosis of patients who have undergone curative resection will be worse in the control group (Pringle maneuver) than in the experimental group (non-Pringle maneuver).
The detailed study design is shown in Figure.
Figure 1 Detailed flow chart of the clinical trial. Eligible patients from five centers will be enrolled, and randomly divided into an experimental group and a control group by permuted-blocks randomization. Each patient will be followed up for 3years (more ...)
All surgical interventions in this trial are described in the study protocol.
Incision lines and decision-making
Specific teams of surgeons have been designated in each center participating in this trial, and have completed the operative and postoperative management training for following the protocol. The abdominal incision can be decided according to the surgeon’s preference. A complete exploration of the abdomen and an intraoperative ultrasound evaluation of the whole liver will be performed to decide whether curative resection is feasible. If necessary, frozen section biopsies will be taken to evaluate suspicious lesions or lymph nodes. If both intervention procedures seem possible to the surgeon, randomization will be performed at this time point.
Experimental group (group a, non-Pringle group)
The liver will be mobilized from the retroperitoneum and the peripheral ligament. Anatomical liver resection is preferable. If anatomical resection is not possible, a surgical margin of more than 2
cm should be achieved, except if the location of tumor nodes makes this impossible (e.g., close to the inferior vena cava or portal vein).The resection method and surgical margin will be recorded for analysis. The liver parenchyma can be resected according to the surgeon’s preference and local standards (CUSA, Tissue-link.). The Pringle maneuver will not be used, and hepatic inflow and outflow will be maintained. For safety, the surgeon may use the Pringle maneuver if major bleeding occurs.
Control group (group B, Pringle maneuver group)
After mobilization, the Pringle maneuver will be performed. The same approach will be used for hepatic parenchymal transection as in the experimental group. If necessary, the outflow of the hepatic vein can be controlled, and this factor will be analyzed. For safety, the surgeon may change the surgical technique at any time during the operation.
The portal triad clamping is set to 15
min hepatic inflow occlusion followed by 5
min of reperfusion, repeated as needed. The last occlusion should be 15
min even if the transection has been completed. The total ischemia and reperfusion times and the number of occlusion cycles will be recorded for analysis. Any deviation in the standard operating procedures will be regarded as a protocol violation.
The surgical teams consist of senior surgeons who all have standard qualifications and have independently performed standard anatomical hepatectomy in more than 100 patients. The results of randomization will be made known to the operating surgeon only after the disease has been deemed suitable for curative resection. All surgical procedures and anesthesia will be performed by the specifically trained teams of experienced hepatobiliary surgeons and anesthesiologists, ensuring standardized execution of the study protocol. Patients will be randomly assigned to eligible surgeons to minimize the effects of variations between surgeons on operative outcomes.
Preoperative examination of patients will include blood biochemistry, alpha-fetoprotein assay, chest x-ray, percutaneous ultrasonography, computed tomography (CT) scan, and hepatic angiography in selected patients. Liver function will be assessed by Child-Pugh grading and the indocyanine green clearance test.
Acquisition of samples
Blood samples: Two blood samples will be obtained from each patient after induction of general anesthesia through a central venous catheter, which is routinely placed just before surgery. EDTA (not heparin) will be used as an anticoagulant for blood samples. Follow-up blood samples will be collected every 6
Tissue samples: Paracarcinomatous tissue and cancer tissue will be harvested from the resected liver specimen at the time of resection. Paracarcinomatous tissue should be harvested 1
cm from the tumor margin. All tumors will be pathologically confirmed to be HCC.
Each tissue sample will be divided into two parts, one of which will be placed in liquid nitrogen and the other in 10% formalin. Serial 4-μm sections from each specimen will be stained with hematoxylin and eosin to determine clinicopathological features such as venous invasion, capsule formation, Edmondson’s grade, and cirrhotic nodules.
Sample size calculation and data analysis plan
The sample size of this trial was calculated using data from our previous experience and from the published literature. There are currently no data from randomized controlled trials showing the recurrence rate of HCC after hepatectomy without the Pringle maneuver. Most studies used the Pringle maneuver. This trial plans to have equal numbers of control and experimental subjects, and a 36-month follow-up period. The median survival time after the treatment that the control group will receive has been reported to be 26
]. We anticipate a10-month difference in the median recurrence-free survival time between the experimental and control groups. If median survival times in the control and experimental groups are 26
months and 36
months, respectively, we will need to include 249 experimental subjects and 249 control subjects to be able to reject the null hypothesis that the experimental and control survival curves are equal with a probability (power) of 0.800. The Type I error probability associated with this test of the null hypothesis is 0.05.
Data for primary and secondary outcome measures will be analyzed using the SPSS statistical software package (SPSS UK Ltd., Woking, U.K.). Analysis will include standard descriptive statistics, Student’s
t tests, correlation and regression, and two-way (group x time) repeated measures ANOVA to examine differences between the groups over time. Survival analysis will be performed. Statistical significance will be set at p
0.05and all tests will be two-tailed. Subgroup stratified analysis will be performed according to tumor size, tumor encapsulation, Edmondson’s grade, HBV load, ischemic time, blood loss, and transfusion. The intention-to-treat analysis will be used for the patients whose portal triad clamping was changed due to safety reasons.
Randomization, stratification, and blinding
This is a randomized multicenter study. After giving informed consent and being enrolled in the study, patients will be randomized into different groups in the operating room after surgical exploration. The permuted-blocks randomization protocol will comprise five separate randomization lists, one for each participating hospital, and will be centrally managed by the Clinical Trial Center of the lead hospital, the Third Military Medical University. When an eligible case is enrolled, the Clinical Trial Center will be called and a randomization number will be assigned according to the designated list. Because there are two groups in this trial, the block sizes will be 4, 6, and 8 and will be randomly assigned. Patients will be stratified by site and randomized in a ratio of 1:1 into the two groups. Patients and outcome assessors will be blinded to achieve a minimum bias.
The primary trial endpoint will be tumor recurrence diagnosed by enhanced CT scan or serum alpha-fetoprotein level. Secondary objectives are to examine overall survival, blood loss, duration of operation, requirement for blood transfusion, length of hospital stay, and morbidity rate. The formal end of the study will be at the end of the 3-year follow-up period of the last patient to be enrolled. All these parameters will be recorded prospectively as part of the study protocol. Final evaluation of the primary and secondary endpoints of the study will be performed 1
year after enrollment of the last patient.
The clinical evaluation of patients will consist of three stages: preoperative, intraoperative, and postoperative. During the preoperative stage, the surgeon will evaluate whether curative resection of the tumor can be performed with and without the Pringle maneuver. For safety reasons, the operating surgeon can change the portal triad clamping status at any time during the operation. If the portal triad clamping is changed, the patient will still be included in the intention-to-treat analysis. If a pathological diagnosis of non-primary HCC is made postoperatively by two different professionals who were blinded to the treatment, the patient will be excluded.
Safety aspects and adverse advents
Both arms of this trial follow well-established procedures, which are widely used in many surgical centers allover the world. No specific side effects are expected other than the known complications of hepatectomy. The operating surgeon can change the portal triad clamping protocol at any time during the operation if necessary to ensure safety. All adverse events during the hospital stay and follow-up will be recorded for correlation analysis.
Ethics and informed consent
The final version of the study protocol was approved by the ethics committee of Southwest Hospital, Third Military Medical University. This protocol follows all requirements of the recent German version of the Declaration of Helsinki (Somerset West Version, 1996) and is in accordance with the principles of Good Clinical Practice guidelines. The trial has been initiated and will be carried out following all local legal and regulatory requirements. The medical secrecy act will also be followed. Prior to enrollment in the study, written informed consent will be obtained from each patient in oral and written form. Any measures specifically required only for the clinical trial will not be undertaken until valid consent has been obtained. Extensive information about the intent of the study, the interventions in each group, the potential associated risks, and potential alternative therapies will be fully discussed with each patient. Patients will be also informed that participation is voluntary and can be withdrawn at any time without prejudicing their subsequent care. Patients will be informed of the strict confidentiality of their personal data collected for this trial, and that their medical records may be reviewed for trial purposes by authorized individuals.
Patients who have completed the interventions will be included in the standard follow-up program. Follow-up visits will be at 1, 3, 6, 9, and 12
months and then every 6
months until 3
years after their operation. Each visit will include physical examination, tumor marker tests, liver function tests, chest x-ray, and ultrasound examination. In addition, enhanced CT scans of thorax and abdomen will be performed at 3, 6, 12, 18, 24, 32, and36 months postoperatively. Additional investigations including 18
F-fluorodexyglucose positron emission tomography scan, magnetic resonance imaging, or digital subtraction angiography will be scheduled as required to investigate possible tumor recurrence. At each visit, a follow-up evaluation form will be completed. If tumor recurs, the patient will be hospitalized and treated according to the clinical situation.
Data management and monitoring
The Institute of Hepatobiliary Surgery of Southwest Hospital is responsible for the coordination of this trial. The clinical and laboratory data of all patients will be centrally collected and entered in a password-protected database at the Clinical Trial Center of Southwest Hospital, Third Military Medical University. All samples and clinical data will be tracked using a unique research tracking number. The link between research tracking numbers and patient identifiers will be kept in a limited-access database on a computer. Trial data quality reports will be generated routinely to evaluate missing data and inconsistencies. Accrual rates and follow-up will be monitored periodically throughout the study period. If a potential problem is identified, it will be brought to the attention of the investigator for discussion and treatment. All operation records will be reviewed to ensure that the study protocol was followed.
Monitoring of data and patient safety will be performed according to good clinical practice GCP guidelines by an independent Data and Safety Monitoring Board (DSMB) established by the Chinese PLA General Hospital. The DSMB will meet approximately twice a year to monitor safety and to advise the centers about study progress. In addition, the Clinical Trial Center will provide data to the DSMB Chair at regular intervals, and at his or her request, to ensure early identification of any major adverse outcomes of treatment. The DSMB will monitor adverse effects and respond to variations in the data, and is responsible for recommending whether the study should continue, whether the protocol should be modified, or whether there should be early termination.
Duration of the trial, and current trial status
The trial is planned to last a total of 5
years, consisting of: protocol development (6
months), training (3
months), main recruitment (9
months), follow-up (36
months), and analysis (6
months). All the team members have completed their training. The expected end date of this trial will be July, 2013.