Hepatic resection versus TILA-TACE in the treatment of Resectable Hepatocellular Carcinoma: study protocol for a randomized controlled trial

Hepatic resection versus TILA-TACE in the treatment of Resectable Hepatocellular Carcinoma: study protocol for a randomized controlled trial | 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 Study protocol Hepatic resection versus TILA-TACE in the treatment of Resectable Hepatocellular Carcinoma: study protocol for a randomized controlled trial Yangyang Feng, Yun Jin, Kai Jin, Yuanquan Yu, Donger Zhou, Jianjun Wu, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.2.12620/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract Background: Hepatic resection and transcatheter arterial chemoembolization (TACE) are common treatments for hepatocellular carcinoma (HCC). Targeting intratumoral lactic acidosis TACE (TILA-TACE) is a new therapeutic approach developed by our team that has superior response rate and effective rate than conventional TACE (cTACE). In this randomized-controlled trial, we will compare the efficacy of hepatic resection and TILA-TACE in patients clinically diagnosed with HCC to provide reliable clinical data for the subsequent effective treatment of HCC patients. Methods: A total of 230 resectable HCC patients will be given hepatic resection or TILA-TACE using a parallel-controlled approach, and the efficacy of the treatments Page 4 of 24 will be compared. The primary endpoint is the post-treatment progression-free survival (PFS) of the patients, and the secondary endpoints are the post-treatment overall survival (OS), 1-year, 3-year and 5-year survival, and the quality of life of the patients at each corresponding stage. Discussion: The aim of this study is to compare the efficacy of hepatic resection and TILA-TACE in the treatment of resectable HCC. Trial registration: ClinicalTrials.gov,NCT03314532.Registered on 19 October 2017. Keywords: Hepatocellular carcinoma, Hepatic resection, TACE, TILA-TACE, Randomized-controlled study. Internal Medicine Integrative & Complementary Medicine Translational Medicine Hepatocellular carcinoma Hepatic resection TACE TILA-TACE Randomized-controlled study Figures Figure 1 Figure 2 Background Hepatocellular carcinoma (HCC) is one of the most common cancers in the world with major occurrences in eastern Asian countries such as China [1-6] .And its morbidity is still rising [7,8] ,more than 740,000 new cases are reported worldwide each year [9] . HCC is the third leading cause of cancer-related deaths in the world [10,11] . There are multiple treatment options for liver cancer including surgery, transcatheter arterial chemoembolization (TACE), liver transplantation, absolute ethanol injection, radiation therapy, and biological therapy [12] . Surgery is the primary radical treatment measure for HCC [13,14] , but its indication is narrow and is only suitable for certain group of patients. Another common treatment for liver cancer, TACE, can not only block tumor blood supply, control tumor growth, or even cause necrosis and result in tumor shrinkage, it can also deliver target chemotherapy drugs to the tumor tissue. The Barcelona Clinic Liver Cancer staging system (BCLC) is one of the more recognized staging criteria and has been recommended by the European Association for the Study of Liver and the American Association for the Study of Liver Diseases [15] . BCLC staging is based on patients’ general condition, tumor condition, and liver function to identify the best treatment option and predict prognosis using evidence-based medicine. Surgical excision is recommended for BCLC stage 0, liver transplantation or radiofrequency ablation is recommended for BCLC stage A, and TACE treatment is recommended for BCLC stage B [12] . However, there are still some controversies on the efficacy of TACE treatment. In recent years, development of technologies has led to improved methods including targeting-intratumoral-lactic-acidosis TACE (TILA-TACE). Early clinical practice has confirmed that compared with TACE, TILA-TACE has a relatively high response rate and efficiency [16] . After conventional TACE treatment, the residual glucose in the tumor will increase the accumulation of lactic acid, making the tumor less prone to necrosis. However, after TILA-TACE treatment, the local injection of sodium bicarbonate neutralized lactic acid in the tumor and depleted the residual glucose in the tumor. Without lactic acid accumulation, the tumor will quickly died of necrosis.. Most studies believe that hepatic resection is more effective than TACE for resectable hepatocellular carcinoma. A RCT study from China showed that 1-year, 2-year and 3-year OS rates in the hepatectomy group were 76.1%, 63.5% and 51.5%, respectively, while those in the TACE group were 51.8%, 34.8% and 18.1%, respectively [20] .According to our preliminary results, TILA-TACE can improve the therapeutic effect by 81.1% compared with cTACE [16] . Therefore in this study, we will conduct a randomized comparison study of the efficacy of surgical resection and TILA-TACE treatment. Methods Experimental design A randomized controlled experimental design method will be adopted. Grouping and sample size calculation A parallel comparison design will be used. According to preliminary data, the disease progression-free periods were 67 weeks and 98 weeks after surgical resection and TILA-TACE treatment, respectively. An α value of 0.05 will be used to correspond to the statistical significance level. According to the 1:1 design, the degree of assurance will be set at 80%, the experimental inclusion time will be two years, and the follow-up missing rate will be controlled at 10%. Each group will require 115 cases for a total of 230 cases. Cases will be randomized by computer into the following groups: (1) Surgery group: HCC resection. (2) TILA-TACE group: TILA-TACE treatment. Randomization A total of 230 HCC patients who qualify the inclusion criteria will be randomized 1:1 into the hepatic resection group and TILA-TACE group (Fig. 1). Treatment will be assigned by the research coordinator based on the randomization table. Aside from the research coordinator, all other research personnel will be concealed from the treatments that the patients are receiving. Case selection Diagnostic criteria [17] Evidence of cirrhosis and HBV/HCV infection Classical imaging features of HCC: MRI/CT/CEUS/EOB-MRI shows arterial hypervascularity and venous or delayed phase washout of the hepatic space-occupying lesion (HSOL). If the diameter of the HSOL is ≥2cm, one of the imaging tests must show the above classical features. If the diameter of the HSOL is <2cm, at least two of the imaging tests must show the above classical features. Serum AFP≥400ug/L for 1 month or ≥200ug/L for 2 months and other causes of AFP elevation including pregnancy, germline/embryonal cancer, active liver disease and secondary liver cancer are excluded. Liver biopsy indicates HCC. Patients are clinically diagnosed with HCC if (1) + (2)a or (1) + (2)b + (3) are met, or pathologically diagnosed with HCC if (4) is met. Definition of resectable HCC: Lesion can be completely resected with no residual tumor at the margin of resection. Residual liver volume is sufficient to compensate for postoperative liver functions. If HCC is complicated by portal vein tumor thrombus, the tumor thrombus should be grade I or grade II based on the Liver Cancer Study Group of Japan criteria [18] . Inclusion criteria Ages 18–75 with no gender, ethnicity, religion, or geographical restrictions. Diagnosed HCC patient. The following criteria will be used for the evaluation of tumor resectability and adequate remaining liver volume: ≥ 30% remaining liver volume/total liver volume for non-hepatitis patients; ≥ 40% remaining liver volume/total liver volume for hepatitis patients. Imaging examination with no cancer embolus above the secondary branch of the portal vein. New lesions found five years after liver cancer treatment. Child-Pugh A or B grade liver function. No concurrent malignancies in other systems. Informed subjects who fully understand and willingly cooperate with the test program with signed relevant documents. Exclusion criteria Patients with one or more of the following conditions will be excluded from the study: Suffer from other malignancies. Received radiofrequency ablation, traditional TACE, immunotherapy, chemotherapy and other treatments before enrollment. Pathological diagnosis as non-HCC. Experience large blood vessel invasion, distant metastases, or unresectable liver cancer. One or more organ failures. Child-Pugh C grade liver function. Incomplete removal of the tumor by resection or TILA-TACE. Case elimination criteria Other drugs, surgery, or other treatment programs have been used without permission after inclusion in this study. Accidental death other than death caused by HCC, such as car crash, earthquake, or other unforeseeable disasters. The data of the eliminated cases will be archived, labeled, and used for statistical analysis of relapse and survival rates in other studies. Treatment plan Control: HCC resection Patients who are randomized to this group will receive hepatic resection. Principles of surgery: 1. Complete tumor resection by eye; 2. Absence of residual tumor at the margin of resection; 3. Regular/irregular hepatic segmentectomy, partial hepatic resection or extensive hepatic resection of liver tissues that are burdened by the tumor. After hepatic resection, >30% of residual liver volume should be spared in normal patients, and >40% of residual liver volume should be spared in cirrhosis patients [19] . Intervention:TILA-TACE treatment After successful femoral artery catheterization, 5-Fr angiography catheters will be used for complete radiography of the celiac artery, the hepatic artery proper, left and right hepatic arteries and their branches, and 2.8-Fr micro-catheters will be used for complete radiography of the tumor's nutrient arteries and the extrahepatic blood supply such as the inferior phrenic arteries. After micro-catheter superselective catheterization, lipiodol-epirubicin emulsions and 5% sodium bicarbonate injection solutions will be used for perfusion of chemotherapy drugs. Different sizes of embolic microspheres will be used alternatively for chemoembolization. For nutrient arteries of relatively large tumors, different sizes of spring coils will be used to block the blood flow to eventually achieve total occlusion of the tumor's nutrient artery. Conversion from HCC resection to TILA-TACE treatment When the tumor cannot be completely removed by resection, patients in the HCC resection group will be converted to the TILA-TACE treatment group. Patients allocated to hepatic resection conversion to TILA-TACE treatment will still be analyzed in the hepatic resection group according to intention-to-treat principles. Reasons for conversion will be registered by our researchers. Patients blindng Patients will be blinded in this study, they will not know the treatment plan until the surgery is completed. Clinical experimental procedures For included cases, patient’s disease history, symptoms, signs, and other situations will be examined and patients will sign the informed consent. The patient's age, height, weight, medical history, symptoms, signs, pathological test results, and TNM stages will be recorded. Patients will be grouped randomly using the digital method. According to test requirements, the study intends to be limited to five years. Day 0 will be set as the day when liver resection or the first TILA-TACE treatment is performed. Re-examinations will be conducted one-month post-treatment and every three months thereafter. The content of the re-examination will include symptoms and signs and adverse events. Routine blood tests, liver and renal functions, hepatobiliary-pancreatic-splenic B-ultrasonography, chest low dose high resolution CT, and liver MRI will be performed and the results will be recorded. Bone ECT will be checked every six months. Disease-progression-free time will be used as the primary endpoint. The disease progression standards for surgical patients will be new intrahepatic or extrahepatic lesion images found during the re-examination. The progress of TILA-TACE patients will be evaluated using EASL guidelines mRECIST criteria on the treated lesions[28]. CR: disappearance of any intratumoral arterial enhancement in all target lesions. PR: at least a 30% decrease in the sum of the diameters of viable (enhancement in the arterial phase) target lesions, taking as reference the baseline sum of the diameters of targets. SD: any cases that do not qualify for either PR or PD. PD: an increase of at least 20% in the sum of the diameters of viable (enhancing) target lesions, taking as reference the smallest sum of the diameters of viable (enhancing) target lesions recorded since treatment started. For subsequent records until the secondary endpoint, all results will be recorded in the Case Report Form ( CRF) for assessing the clinical efficacy and safety with any adverse events observed and recorded. If the patient is unable to come to the hospital for re-examination, the re-examination would be conducted by follow-up methods such as telephone or mail. Efficacy and safety evaluation Observation index Index for diagnosis: The diagnostic indexes included cancer index, hepatobiliary-pancreatic-splenic B-ultrasonography, liver enhanced MRI, chest low dose high resolution CT, and bone ECT. Index for therapeutic efficacy: Index for primary efficacy: The primary efficacy index will be the disease-progression-free survival time of patients in the two groups post-treatment. Index for secondary efficacy: The secondary efficacy index will be the overall survival period post-treatment, the 1-year, 3-year, and 5-year survival rates, and the assessment of quality-of-life of patients in the two groups at each stage. Safety index: Adverse events occurring during study period, such as anaphylaxis, embolization syndrome, or other related adverse reactions after TILA-TACE treatment or surgery-related complications will be closely monitored. General physical examinations will include (temperature, resting heart rate, respiration, blood pressure), routine blood tests, liver functions (TBill, AST, ALT, Alb), cancer markers, chest high resolution CT plain scan, liver enhanced MRI, hepatobiliary-pancreatic-splenic B-ultrasonography, and bone ECT. The adverse event rate will be the main index for safety evaluation. Effectiveness evaluation standard Primary endpoint: The disease-progression-free period of patients after treatment. This will be the time period from the beginning of treatment to the time that disease progression has been observed. Secondary endpoint: The overall survival period recorded from the beginning of the treatment, the follow-up, until the death of the patient or the end of the study period, as well as the 1-year, 3-year, and 5-year survival rates. In the meantime, the patient's quality-of-life will be recorded. Safety assessment: Changes in the physical examination and laboratory tests before and after treatments will be compared between the two groups. Additionally, the rates of the adverse events and adverse reactions occurring during the study will be compared between the two groups. Statistical analysis will be carried out after all data are collected and p < 0.05 will be considered statistically significant. Adverse events recording and reporting Information of non-serious and serious adverse events occurring during treatment will be recorded on the CRF and Adverse event registration form (Appendix file 2.4). In this study, adverse reactions and complications including severe hepatic renal failure, possible chemotherapy drug allergy reaction, or embolization syndrome may occur in a very small portion of patients after TILA-TACE treatment. In light of this, we will fully evaluate liver and kidney functions before operation. Intensive management with care and caution will be used during the perioperative period. Scientific and rational operation procedures will be adopted to reduce complications. Close connections will be strengthened with relevant departments so that adverse events can be reported to the head of the department and the hospital supervisor at once and to the hospital adverse event ethics committee within the time limit. Data management and statistical analysis Data recording and auditing: Observation data will be recorded in the CRF by the attending doctor in black or blue-black pen to ensure the data will be recorded completely, accurately and truthfully in a timely manner. Any modifications made by relevant personnel will be signed and dated and amendments will not cover the originals. If possible, relevant laboratory testing sheets will be copied and pasted on the attached page at the end of the CRF. Data entry: A data entry program and database have been established for statistical analysis,data collection and entry was performed by two or more researchers. Statistical analysis: Primary and secondary endpoint data in the database will be collected and processed using the SPSS 17.0 statistical software. Patient survival (1-year, 3-year, 5-year OS and PFS) in the two groups will be calculated using the Kaplan-Meier method. A linear mixed model will be constructed to compare the quality of life between the two patient groups at each corresponding stage. P<0.05 is considered statistically significant. Informed consent Specific content related to the study should be known by the subject and written informed consent must be obtained from the subject before implementing the study procedures. The details are described in the consent form (Appendix file 5). The specific process to obtain informed consent is as follows: the doctor will inform the patient about his/her disease characteristics, treatment options, and related risks in detail and then the informed consent form is signed by the patient him/herself or by a legal guardian with capacity for civil conduct. Discussion This is a single-center randomized-controlled study aimed to compare the clinical efficacy of hepatic resection versus TILA-TACE in resectable HCC patients. Although both hepatic resection and TACE can be used as the clinical treatment for resectable HCC, the efficacy of these approaches is still debated. A randomized-controlled study by Lei Yin [20] found that patients who received hepatic resection and cTACE had a 3-year survival of 51.5% and 18.1% and a median survival time of 41 months and 18 months, respectively. Therefore, the authors concluded that the efficacy of hepatic resection is superior than cTACE. This finding was also supported by a retrospective non-randomized-controlled trial by Biao Yang et al [21-24] . who showed that hepatic resection provides significantly higher survival benefits to resectable HCC patients than TACE. In contrast, Lei Jianyong believe that hepatic resection should be used for patients with 1-3 intrahepatic nodules, whereas TACE is recommended for patients with >3 intrahepatic nodules [25] . In our previous study, we found that the geometric mean of residual live tumor was 6.4 times lower after TILA-TACE than after cTACE. Complete or partial response rate were significantly higher in the TILA-TACE group than in the cTACE group, and the objective response rate of the two groups were 100% and 44.4%, respectively. This indicates that TILA-TACE has superior treatment response rate and effective rate than cTACE. In addition, the 1-year, 2-year, and 3-year survival rates and median survival time were higher in the TILA-TACE group (82.8%, 67.7% , 61.8% and 41 months, respectively) than the cTACE group (66.7%, 40.7%, 25.9% and 14 months, respectively), demonstrating that TILA-TACE provides superior post-treatment survival than cTACE [ 16 ] . There is currently a lack of solid evidence on the efficacy of TILA-TACE versus hepatic resection in the treatment of resectable HCC, and we did not find any literature that compares the efficacy of the two treatment approaches. Further clinical studies, especially randomized-controlled studies, will be needed to provide insights to treatments that are more suitable for HCC patients. In summary, we will conduct a prospective randomized-controlled study to compare the efficacy of hepatic resection and TILA-TACE in the treatment of resectable HCC in the hopes of providing reliable evidence for the clinical treatment of resectable HCC. Trial status The first patient was recruited at 2 May 2018, and we will complete the recruitment of all patients by 31 Dec 2021. Protocol version 2 dated 23 August 2017 has been approved by the Ethics Committee of the Second Affiliated Hospital of Zhejiang University School of Medicine. Abbreviations HCC：hepatocellular carcinoma TACE：transcatheter arterial chemoembolization TILA-TACE:Targeting-intratumoral-lactic-acidosis transcatheter arterial chemoembolization BCLC：Barcelona Clinic Liver Cancer TNM： Tumor, Node, Metastases OS：overall survival PFS：progression-free survival CT： Computed tomography MRI：Magnetic Resonance Imaging CEUS：Contrast-enhanced ultrasound ECT：Emission Computed Tomography ALT：alanine aminotransferase AST：aspartate transaminase CRF：Case Report Form AFP：alpha fetoprotein TBill： total bilirubin Alb： albumin HBV：hepatitis B virus HCV：hepatitis C virus EASL：European Association for the Study of the Liver CR：complete response PR：partial response SD：stable disease PD：progressive disease Declarations Ethics approval and consent to participate The study will be conducted according to the principles of the Declaration of Helsinki. This study was approved by the Ethics Committee of the second affiliated hospital of Zhejiang university.The trial is registered in the US Trial Register (http://clinicaltrials.com.gov/) with identification number NCT03314532. Patients can only participate if written informed consent has been provided. Consent for publication Not applicable. Availability of data and material Not applicable. Competing interests The authors declare that they have no competing interests. Funding Our study was supported by National Natural Science Foundation of China (81570559 and 81770614) and the health high-level personnel training project of Zhejiang province. Authors' contributions Yangyang Feng and Yun Jin drafted the manuscript. Jiangtao Li and Ming Chao are the main coordinators of the trial.Yangyang Feng, Yun Jin, Kai Jin, Yuanquan Yu, Donger Zhou, Jianjun Wu, Bin Li, Guangqiang Zhang, Xiaogang Qi, Hao Geng, Yinghao Guo, Shuyou Peng, Jiangtao Li and Ming Chao participated in the design of the trial. Shuyou Peng and Ming Chao provided advice, support and assistance. All authors critically revised the manuscript and have approved the final version. Acknowledgements Not applicable. Authors' information 1. Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; 2. Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; 3. Department of Radiology and interventiona, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; 4. Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; 5. Department of Surgery, Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,China; 6. Department of Radiology and interventional, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; 7. Department of Radiology and interventional, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; 8. Department of Radiology and interventional, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; 9.Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; 10. Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; 11. Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; 12. Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; 13.Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; 14. Department of Radiology and interventional, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. References 1. Bosch FX, Ribes J, Borras J. Epidemiology of primary liver cancer [J]. Semin Liver Dis. 1999;19(3):271-285. Llovet JM, Zucman-Rossi J, Pikarsky E, Sangro B, Schwartz M, Sherman M, et al. Hepatocellular carcinoma [J]. Nat Rev Dis Primers. 2016;2:16018. White JA, Gray SH, Li P, Simpson HN, McGuire BM, Eckhoff DE, et al. Current guidelines for chemoembolization for hepatocellular carcinoma: Room for improvement? [J]. Hepatol Commun. 2017;1(4):338-346. Zamora-Valdes D, Taner T, Nagorney DM. Surgical Treatment of Hepatocellular Carcinoma [J]. Cancer Control. 2017;24(3):1073274817729258. 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Barcelona clinic liver cancer stage B hepatocellular carcinoma: transarterial chemoembolization or hepatic resection? [J]. Medicine (Baltimore). 2014;93(26):e180. Supplementary Files Appendixfile1SPIRITChecklist.pdf Appendixfile3SF36QUESTIONNAIRE.pdf Appendixfile2Casereportform.pdf Appendixfile4ADVERSEEVENTSLogform.pdf Appendixfile5Informedconsent.pdf Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions 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. We do this by developing innovative software and high quality services for the global research community. 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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-3364","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":260773,"identity":"17d0e93b-db0c-4937-80f2-42e1d4dff9f0","order_by":1,"name":"Yangyang Feng","email":"","orcid":"https://orcid.org/0000-0003-0598-8727","institution":"Zhejiang University School of Medicine Second Affiliated Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yangyang","middleName":"","lastName":"Feng","suffix":""},{"id":260774,"identity":"110ab348-dd75-40f1-b870-95015ea1b768","order_by":2,"name":"Yun 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Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiaogang","middleName":"","lastName":"Qi","suffix":""},{"id":260783,"identity":"f48cabd9-272f-4681-aef4-6fadfb55a6c6","order_by":11,"name":"Hao Geng","email":"","orcid":"","institution":"Zhejiang University School of Medicine Second Affiliated Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hao","middleName":"","lastName":"Geng","suffix":""},{"id":260784,"identity":"2e48ae81-31b0-48ba-9c62-181f2482c4af","order_by":12,"name":"Yinghao Guo","email":"","orcid":"","institution":"Zhejiang University School of Medicine Second Affiliated Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yinghao","middleName":"","lastName":"Guo","suffix":""},{"id":260785,"identity":"75cf937a-068f-4132-a30e-95ba1b387a7e","order_by":13,"name":"Ming Chao","email":"","orcid":"","institution":"Zhejiang University School of Medicine Second Affiliated Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ming","middleName":"","lastName":"Chao","suffix":""},{"id":260786,"identity":"681ee814-021d-4d5b-9df7-a99c3297cff2","order_by":14,"name":"Jiangtao Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvklEQVRIiWNgGAWjYFAC5gYDhgoGZhBTgkgtjA0GB86QqoXhYBuESZwW+dkHG4o/zqtjNzjAfPA2D4NdHmE7+hIbDA5uY2M2OMCWbM3DkFxMUAszDyNICw9QC4+ZNA/DgcQGQlrYwFrmSAC18H8jTgsPWEuDAcgWNuK0SIC0nDmWwCx5mM3Yco5BMmEt8j3MxwwqauqS+Y43P7zxpsKOsBaQdwyARDIkMg2IUA8EzA+AhB1xakfBKBgFo2BEAgA1GTQ/vVxGUgAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-7538-2910","institution":"","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Jiangtao","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2019-08-05 12:26:20","currentVersionCode":2,"declarations":"","doi":"10.21203/rs.2.12620/v2","doiUrl":"https://doi.org/10.21203/rs.2.12620/v2","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":287910,"identity":"07bcb961-2f56-4573-9b87-4ef82b87ba8e","added_by":"auto","created_at":"2019-12-20 14:59:17","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":48786,"visible":true,"origin":"","legend":"Trial flow diagram for randomized comparison study of the therapeutic effectiveness of hepatic resection or TILA-TACE in patients with resectable hepatocellular carcinoma.","description":"","filename":"FIgure1.png","url":"https://assets-eu.researchsquare.com/files/45e3194a-2a1f-4d00-86c3-009845c0dde9/v2/FIgure 1.png"},{"id":287913,"identity":"7450792a-fc06-445a-be42-e14b4fbeb173","added_by":"auto","created_at":"2019-12-20 14:59:17","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":31299,"visible":true,"origin":"","legend":"Schedule of enrolment, interventions, and assessments according to standard protocol items: recommendations for interventional trials (SPIRIT).","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/45e3194a-2a1f-4d00-86c3-009845c0dde9/v2/Figure 2.png"},{"id":13482993,"identity":"f52d7928-de07-4138-8a76-ebaec88fad47","added_by":"auto","created_at":"2021-09-16 21:51:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":508984,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3364/v2/04020b50-aeca-4877-9d3c-0e1b8e3662fa.pdf"},{"id":287916,"identity":"fdfb7951-9381-4432-8ed1-315f8281150a","added_by":"auto","created_at":"2019-12-20 14:59:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":114258,"visible":true,"origin":"","legend":"","description":"","filename":"Appendixfile1SPIRITChecklist.pdf","url":"https://assets-eu.researchsquare.com/files/45e3194a-2a1f-4d00-86c3-009845c0dde9/v2/Appendix file 1 SPIRIT Checklist.pdf"},{"id":287915,"identity":"b75fdc9a-6ad9-4390-88a8-05327a1faff8","added_by":"auto","created_at":"2019-12-20 14:59:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":62108,"visible":true,"origin":"","legend":"","description":"","filename":"Appendixfile3SF36QUESTIONNAIRE.pdf","url":"https://assets-eu.researchsquare.com/files/45e3194a-2a1f-4d00-86c3-009845c0dde9/v2/Appendix file 3 SF-36 QUESTIONNAIRE.pdf"},{"id":287914,"identity":"0c35e979-c628-442e-9270-c45df5deed41","added_by":"auto","created_at":"2019-12-20 14:59:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":309299,"visible":true,"origin":"","legend":"","description":"","filename":"Appendixfile2Casereportform.pdf","url":"https://assets-eu.researchsquare.com/files/45e3194a-2a1f-4d00-86c3-009845c0dde9/v2/Appendix file 2 Case report form.pdf"},{"id":287912,"identity":"7cde6320-9e96-4a95-a842-32e01ff57186","added_by":"auto","created_at":"2019-12-20 14:59:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":151549,"visible":true,"origin":"","legend":"","description":"","filename":"Appendixfile4ADVERSEEVENTSLogform.pdf","url":"https://assets-eu.researchsquare.com/files/45e3194a-2a1f-4d00-86c3-009845c0dde9/v2/Appendix file 4 ADVERSE EVENTS(Log form).pdf"},{"id":287911,"identity":"f7a36719-0f6e-4733-8451-21dd320f37b3","added_by":"auto","created_at":"2019-12-20 14:59:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":97865,"visible":true,"origin":"","legend":"","description":"","filename":"Appendixfile5Informedconsent.pdf","url":"https://assets-eu.researchsquare.com/files/45e3194a-2a1f-4d00-86c3-009845c0dde9/v2/Appendix file 5 Informed consent.pdf"}],"financialInterests":"","formattedTitle":"Hepatic resection versus TILA-TACE in the treatment of Resectable Hepatocellular Carcinoma: study protocol for a randomized controlled trial","fulltext":[{"header":"Background","content":"\u003cp\u003eHepatocellular carcinoma (HCC) is one of the most common cancers in the world with major occurrences in eastern Asian countries such as China\u003csup\u003e[1-6]\u003c/sup\u003e.And its morbidity is still rising\u003csup\u003e[7,8]\u003c/sup\u003e,more than 740,000 new cases are reported worldwide each year\u003csup\u003e[9]\u003c/sup\u003e. HCC is the third leading cause of cancer-related deaths in the world\u003csup\u003e[10,11]\u003c/sup\u003e. There are multiple treatment options for liver cancer including surgery, transcatheter arterial chemoembolization (TACE), liver transplantation, absolute ethanol injection, radiation therapy, and biological therapy\u003csup\u003e[12]\u003c/sup\u003e. Surgery is the primary radical treatment measure for HCC\u003csup\u003e[13,14]\u003c/sup\u003e, but its indication is narrow and is only suitable for certain group of patients. Another common treatment for liver cancer, TACE, can not only block tumor blood supply, control tumor growth, or even cause necrosis and result in tumor shrinkage, it can also deliver target chemotherapy drugs to the tumor tissue.\u003c/p\u003e\n\u003cp\u003eThe Barcelona Clinic Liver Cancer staging system (BCLC) is one of the more recognized staging criteria and has been recommended by the European Association for the Study of Liver and the American Association for the Study of Liver Diseases\u003csup\u003e[15]\u003c/sup\u003e. BCLC staging is based on patients\u0026rsquo; general condition, tumor condition, and liver function to identify the best treatment option and predict prognosis using evidence-based medicine. Surgical excision is recommended for BCLC stage 0, liver transplantation or radiofrequency ablation is recommended for BCLC stage A, and TACE treatment is recommended for BCLC stage B\u003csup\u003e[12]\u003c/sup\u003e. However, there are still some controversies on the efficacy of TACE treatment. \u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn recent years, development of technologies has led to improved methods including targeting-intratumoral-lactic-acidosis TACE (TILA-TACE). Early clinical practice has confirmed that compared with TACE, TILA-TACE has a relatively high response rate and efficiency\u003csup\u003e[16]\u003c/sup\u003e. After conventional TACE treatment, the residual glucose in the tumor will increase the accumulation of lactic acid, making the tumor less prone to necrosis. However, after TILA-TACE treatment, the local injection of sodium bicarbonate neutralized lactic acid in the tumor and depleted the residual glucose in the tumor. Without lactic acid accumulation, the tumor will quickly died of necrosis..\u003c/p\u003e\n\u003cp\u003eMost studies believe that hepatic resection is more effective than TACE for resectable hepatocellular carcinoma. A RCT study from China showed that 1-year, 2-year and 3-year OS rates in the hepatectomy group were 76.1%, 63.5% and 51.5%, respectively, while those in the TACE group were 51.8%, 34.8% and 18.1%, respectively\u003csup\u003e[20]\u003c/sup\u003e.According to our preliminary results, TILA-TACE can improve the therapeutic effect by 81.1% compared with cTACE\u003csup\u003e[16]\u003c/sup\u003e. Therefore in this study, we will conduct a randomized comparison study of the efficacy of surgical resection and TILA-TACE treatment.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eExperimental design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA randomized controlled experimental design method will be adopted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGrouping and sample size calculation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA parallel comparison design will be used. According to preliminary data, the disease progression-free periods were 67 weeks and 98 weeks after surgical resection and TILA-TACE treatment, respectively. An \u0026alpha; value of 0.05 will be used to correspond to the statistical significance level. According to the 1:1 design, the degree of assurance will be set at 80%, the experimental inclusion time will be two years, and the follow-up missing rate will be controlled at 10%. Each group will require 115 cases for a total of 230 cases. Cases will be randomized by computer into the following groups:\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(1) Surgery group: HCC resection.\u003c/p\u003e\n\u003cp\u003e(2) TILA-TACE group: TILA-TACE treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRandomization\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 230 HCC patients who qualify the inclusion criteria will be randomized 1:1 into the hepatic resection group and TILA-TACE group (Fig. 1). Treatment will be assigned by the research coordinator based on the randomization table. Aside from the research coordinator, all other research personnel will be concealed from the treatments that the patients are receiving.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase selection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiagnostic criteria\u003c/strong\u003e\u003csup\u003e[17]\u003c/sup\u003e\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003eEvidence of cirrhosis and HBV/HCV infection\u003c/li\u003e\n\u003cli\u003eClassical imaging features of HCC: MRI/CT/CEUS/EOB-MRI shows arterial hypervascularity and venous or delayed phase washout of the hepatic space-occupying lesion (HSOL).\u003c/li\u003e\n\u003cli\u003eIf the diameter of the HSOL is \u0026ge;2cm, one of the imaging tests must show the above classical features.\u003c/li\u003e\n\u003cli\u003eIf the diameter of the HSOL is \u0026lt;2cm, at least two of the imaging tests must show the above classical features.\u003c/li\u003e\n\u003cli\u003eSerum AFP\u0026ge;400ug/L for 1 month or \u0026ge;200ug/L for 2 months and other causes of AFP elevation including pregnancy, germline/embryonal cancer, active liver disease and secondary liver cancer are excluded.\u003c/li\u003e\n\u003cli\u003eLiver biopsy indicates HCC.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003ePatients are clinically diagnosed with HCC if (1) + (2)a or (1) + (2)b + (3) are met, or pathologically diagnosed with HCC if (4) is met.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDefinition of resectable HCC:\u003c/strong\u003e\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003eLesion can be completely resected with no residual tumor at the margin of resection.\u003c/li\u003e\n\u003cli\u003eResidual liver volume is sufficient to compensate for postoperative liver functions.\u003c/li\u003e\n\u003cli\u003eIf HCC is complicated by portal vein tumor thrombus, the tumor thrombus should be grade I or grade II based on the Liver Cancer Study Group of Japan criteria\u003csup\u003e[18]\u003c/sup\u003e.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003eAges 18\u0026ndash;75 with no gender, ethnicity, religion, or geographical restrictions.\u003c/li\u003e\n\u003cli\u003eDiagnosed HCC patient.\u003c/li\u003e\n\u003cli\u003eThe following criteria will be used for the evaluation of tumor resectability and adequate remaining liver volume: \u0026ge; 30% remaining liver volume/total liver volume for non-hepatitis patients; \u0026ge; 40% remaining liver volume/total liver volume for hepatitis patients.\u003c/li\u003e\n\u003cli\u003eImaging examination with no cancer embolus above the secondary branch of the portal vein.\u003c/li\u003e\n\u003cli\u003eNew lesions found five years after liver cancer treatment.\u003c/li\u003e\n\u003cli\u003eChild-Pugh A or B grade liver function.\u003c/li\u003e\n\u003cli\u003eNo concurrent malignancies in other systems.\u003c/li\u003e\n\u003cli\u003eInformed subjects who fully understand and willingly cooperate with the test program with signed relevant documents.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion criteria \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients with one or more of the following conditions will be excluded from the study:\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003eSuffer from other malignancies.\u003c/li\u003e\n\u003cli\u003eReceived radiofrequency ablation, traditional TACE, immunotherapy, chemotherapy and other treatments before enrollment.\u003c/li\u003e\n\u003cli\u003ePathological diagnosis as non-HCC.\u003c/li\u003e\n\u003cli\u003eExperience large blood vessel invasion, distant metastases, or unresectable liver cancer.\u003c/li\u003e\n\u003cli\u003eOne or more organ failures.\u003c/li\u003e\n\u003cli\u003eChild-Pugh C grade liver function.\u003c/li\u003e\n\u003cli\u003eIncomplete removal of the tumor by resection or TILA-TACE.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eCase elimination criteria \u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003eOther drugs, surgery, or other treatment programs have been used without permission after inclusion in this study.\u003c/li\u003e\n\u003cli\u003eAccidental death other than death caused by HCC, such as car crash, earthquake, or other unforeseeable disasters.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eThe data of the eliminated cases will be archived, labeled, and used for statistical analysis of relapse and survival rates in other studies.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment plan\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eControl: HCC resection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients who are randomized to this group will receive hepatic resection. Principles of surgery: 1. Complete tumor resection by eye; 2. Absence of residual tumor at the margin of resection; 3. Regular/irregular hepatic segmentectomy, partial hepatic resection or extensive hepatic resection of liver tissues that are burdened by the tumor. After hepatic resection, \u0026gt;30% of residual liver volume should be spared in normal patients, and \u0026gt;40% of residual liver volume should be spared in cirrhosis patients\u003csup\u003e[19]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntervention:TILA-TACE treatment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter successful femoral artery catheterization, 5-Fr angiography catheters will be used for complete radiography of the celiac artery, the hepatic artery proper, left and right hepatic arteries and their branches, and 2.8-Fr micro-catheters will be used for complete radiography of the tumor's nutrient arteries and the extrahepatic blood supply such as the inferior phrenic arteries. After micro-catheter superselective catheterization, lipiodol-epirubicin emulsions and 5% sodium bicarbonate injection solutions will be used for perfusion of chemotherapy drugs. Different sizes of embolic microspheres will be used alternatively for chemoembolization. For nutrient arteries of relatively large tumors, different sizes of spring coils will be used to block the blood flow to eventually achieve total occlusion of the tumor's nutrient artery.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConversion from HCC resection to TILA-TACE treatment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWhen the tumor cannot be completely removed by resection, patients in the HCC resection group will be converted to the TILA-TACE treatment group. Patients allocated to hepatic resection conversion to TILA-TACE treatment will still be analyzed in the hepatic resection group according to intention-to-treat principles. Reasons for conversion will be registered by our researchers.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatients blindng\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients will be blinded in this study, they will not know the treatment plan until \u0026nbsp;\u0026nbsp;the surgery is completed.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical experimental procedures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor included cases, patient\u0026rsquo;s disease history, symptoms, signs, and other situations will be examined and patients will sign the informed consent. The patient's age, height, weight, medical history, symptoms, signs, pathological test results, and TNM stages will be recorded. Patients will be grouped randomly using the digital method. \u003ca name=\"_Toc106418675\"\u003e\u003c/a\u003e\u003ca name=\"_Toc241576167\"\u003e\u003c/a\u003e\u003ca name=\"_Toc106418497\"\u003e\u003c/a\u003e\u003ca name=\"_Toc174349024\"\u003e\u003c/a\u003eAccording to test requirements, the study intends to be limited to five years. Day 0 will be set as the day when liver resection or the first TILA-TACE treatment is performed. Re-examinations will be conducted one-month post-treatment and every three months thereafter. The content of the re-examination will include symptoms and signs and adverse events. Routine blood tests, liver and renal functions, \u0026nbsp;hepatobiliary-pancreatic-splenic B-ultrasonography, chest low dose high resolution CT, and liver MRI will be performed and the results will be recorded. Bone ECT will be checked every six months.\u003c/p\u003e\n\u003cp\u003eDisease-progression-free time will be used as the primary endpoint. The disease progression standards for surgical patients will be new intrahepatic or extrahepatic lesion images found during the re-examination. The progress of TILA-TACE patients will be evaluated using EASL guidelines mRECIST criteria on the treated lesions[28]. CR: disappearance of any intratumoral arterial enhancement in all target lesions. PR: at least a 30% decrease in the sum of the diameters of viable (enhancement in the arterial phase) target lesions, taking as reference the baseline sum of the diameters of targets. SD: any cases that do not qualify for either PR or PD. PD: an increase of at least 20% in the sum of the diameters of viable (enhancing) target lesions, taking as reference the smallest sum of the diameters of viable (enhancing) target lesions recorded since treatment started.\u003c/p\u003e\n\u003cp\u003eFor subsequent records until the secondary endpoint, all results will be recorded in the Case Report Form (\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; CRF) for assessing the clinical efficacy and safety with any adverse events observed and recorded. If the patient is unable to come to the hospital for re-examination, the re-examination would be conducted by follow-up methods such as telephone or mail.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEfficacy and safety evaluation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObservation index\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIndex for diagnosis: \u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003eThe diagnostic indexes included cancer index, hepatobiliary-pancreatic-splenic B-ultrasonography, liver enhanced MRI, chest low dose high resolution CT, and bone ECT.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eIndex for therapeutic efficacy: \u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003eIndex for primary efficacy: The primary efficacy index will be the disease-progression-free survival time of patients in the two groups post-treatment.\u003c/li\u003e\n\u003cli\u003eIndex for secondary efficacy: The secondary efficacy index will be the overall survival period post-treatment, the 1-year, 3-year, and 5-year survival rates, and the assessment of quality-of-life of patients in the two groups at each stage.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eSafety index:\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n\u003cli\u003eAdverse events occurring during study period, such as anaphylaxis, embolization syndrome, or other related adverse reactions after TILA-TACE treatment or surgery-related complications will be closely monitored.\u003c/li\u003e\n\u003cli\u003eGeneral physical examinations will include (temperature, resting heart rate, respiration, blood pressure), routine blood tests, liver functions (TBill, AST, ALT, Alb), cancer markers, chest high resolution CT plain scan, liver enhanced MRI, hepatobiliary-pancreatic-splenic B-ultrasonography, and bone ECT.\u003c/li\u003e\n\u003cli\u003eThe adverse event rate will be the main index for safety evaluation.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eEffectiveness evaluation standard\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary endpoint:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe disease-progression-free period of patients after treatment. This will be the time period from the beginning of treatment to the time that disease progression has been observed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary endpoint:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe overall survival period recorded from the beginning of the treatment, the follow-up, until the death of the patient or the end of the study period, as well as the 1-year, 3-year, and 5-year survival rates. In the meantime, the patient's quality-of-life will be recorded.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety assessment:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eChanges in the physical examination and laboratory tests before and after treatments will be compared between the two groups. Additionally, the rates of the adverse events and adverse reactions occurring during the study will be compared between the two groups. Statistical analysis will be carried out after all data are collected and p \u0026lt; 0.05 will be considered statistically significant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdverse events\u003c/strong\u003e \u003cstrong\u003erecording and reporting \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformation of non-serious and serious adverse events occurring during treatment will be recorded on the CRF and Adverse event registration form (Appendix file 2.4). In this study, adverse reactions and complications including severe hepatic renal failure, possible chemotherapy drug allergy reaction, or embolization syndrome may occur in a very small portion of patients after TILA-TACE treatment. In light of this, we will fully evaluate liver and kidney functions before operation. Intensive management with care and caution will be used during the perioperative period. Scientific and rational operation procedures will be adopted to reduce complications. Close connections will be strengthened with relevant departments so that adverse events can be reported to the head of the department and the hospital supervisor at once and to the hospital adverse event ethics committee within the time limit. \u003ca name=\"_Toc241576187\"\u003e\u003c/a\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData management and statistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData recording and auditing:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eObservation data will be recorded in the CRF by the attending doctor in black or blue-black pen to ensure the data will be recorded completely, accurately and truthfully in a timely manner. Any modifications made by relevant personnel will be signed and dated and amendments will not cover the originals. If possible, relevant laboratory testing sheets will be copied and pasted on the attached page at the end of the CRF.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData entry:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA data entry program and database have been established for statistical analysis,data collection and entry was performed by two or more researchers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrimary and secondary endpoint data in the database will be collected and processed using the SPSS 17.0 statistical software. Patient survival (1-year, 3-year, 5-year OS and PFS) in the two groups will be calculated using the Kaplan-Meier method. A linear mixed model will be constructed to compare the quality of life between the two patient groups at each corresponding stage. P\u0026lt;0.05 is considered statistically significant.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSpecific content related to the study should be known by the subject and written informed consent must be obtained from the subject before implementing the study procedures. The details are described in the consent form (Appendix file 5). The specific process to obtain informed consent is as follows: the doctor will inform the patient about his/her disease characteristics, treatment options, and related risks in detail and then the informed consent form is signed by the patient him/herself or by a legal guardian with capacity for civil conduct.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis is a single-center randomized-controlled study aimed to compare the clinical efficacy of hepatic resection versus TILA-TACE in resectable HCC patients. Although both hepatic resection and TACE can be used as the clinical treatment for resectable HCC, the efficacy of these approaches is still debated. A randomized-controlled study by Lei Yin\u003csup\u003e[20]\u003c/sup\u003e found that patients who received hepatic resection and cTACE had a 3-year survival of 51.5% and 18.1% and a median survival time of 41 months and 18 months, respectively. Therefore, the authors concluded that the efficacy of hepatic resection is superior than cTACE. This finding was also supported by a retrospective non-randomized-controlled trial by Biao Yang et al\u003csup\u003e[21-24]\u003c/sup\u003e. who showed that hepatic resection provides significantly higher survival benefits to resectable HCC patients than TACE. In contrast, Lei Jianyong believe that hepatic resection should be used for patients with 1-3 intrahepatic nodules, whereas TACE is recommended for patients with \u0026gt;3 intrahepatic nodules\u003csup\u003e[25]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIn our previous study, we found that the geometric mean of residual live tumor was 6.4 times lower after TILA-TACE than after cTACE. Complete or partial response rate were significantly higher in the TILA-TACE group than in the cTACE group, and the objective response rate of the two groups were 100% and 44.4%, respectively. This indicates that TILA-TACE has superior treatment response rate and effective rate than cTACE. In addition, the 1-year, 2-year, and 3-year survival rates and median survival time were higher in the TILA-TACE group (82.8%, 67.7% , 61.8% and 41 months, respectively) than the cTACE group (66.7%, 40.7%, 25.9% and 14 months, respectively), demonstrating that TILA-TACE provides superior post-treatment survival than cTACE\u003csup\u003e[\u003ca href=\"https://docs.google.com/document/d/1tlv9NtaoA2JOFhLMobi62X3JFFh84Muojor0gPK9d4Q/edit#heading=h.2s8eyo1\"\u003e16\u003c/a\u003e]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThere is currently a lack of solid evidence on the efficacy of TILA-TACE versus hepatic resection in the treatment of resectable HCC, and we did not find any literature that compares the efficacy of the two treatment approaches. Further clinical studies, especially randomized-controlled studies, will be needed to provide insights to treatments that are more suitable for HCC patients.\u003c/p\u003e\n\u003cp\u003eIn summary, we will conduct a prospective randomized-controlled study to compare the efficacy of hepatic resection and TILA-TACE in the treatment of resectable HCC in the hopes of providing reliable evidence for the clinical treatment of resectable HCC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe first patient was recruited at 2 May 2018, and we will complete the recruitment of all patients by 31 Dec 2021. Protocol version 2 dated 23 August 2017 has been approved by the Ethics Committee of the Second Affiliated Hospital of Zhejiang University School of Medicine.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eHCC：hepatocellular carcinoma\u003c/p\u003e\n\u003cp\u003eTACE：transcatheter arterial chemoembolization\u003c/p\u003e\n\u003cp\u003eTILA-TACE:Targeting-intratumoral-lactic-acidosis transcatheter arterial chemoembolization\u003c/p\u003e\n\u003cp\u003eBCLC：Barcelona Clinic Liver Cancer\u0026nbsp;\u0026nbsp; TNM：\u003ca href=\"http://shortof.com/suolueci/Tumor_2C-Node_2C-Metastases-TNM\"\u003eTumor, Node, Metastases\u003c/a\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; OS：overall survival\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; PFS：progression-free survival\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; CT：\u0026nbsp;Computed tomography\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; MRI：Magnetic Resonance Imaging\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; CEUS：Contrast-enhanced ultrasound\u0026nbsp;\u0026nbsp;\u0026nbsp; ECT：Emission Computed Tomography\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; ALT：alanine aminotransferase\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; AST：aspartate transaminase\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; CRF：Case Report Form\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; AFP：alpha fetoprotein\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; TBill：\u003ca href=\"http://dict.youdao.com/w/TBil(total%20bilirubin)/#keyfrom=E2Ctranslation\"\u003etotal bilirubin\u003c/a\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Alb：\u003ca href=\"http://dict.youdao.com/w/albumin/#keyfrom=E2Ctranslation\"\u003ealbumin\u003c/a\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; HBV：hepatitis B virus\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; HCV：hepatitis C virus\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; EASL：European Association for the Study of the Liver\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; CR：complete response\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; PR：partial response\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; SD：stable disease\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; PD：progressive disease\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study will be conducted according to the principles of the Declaration of Helsinki. This study was approved by the Ethics Committee of the second affiliated hospital of Zhejiang university.The trial is registered in the US Trial Register (http://clinicaltrials.com.gov/) with identification number NCT03314532. Patients can only participate if written informed consent has been provided.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur study was supported by National Natural Science Foundation of China (81570559 and 81770614) and the health high-level personnel training project of Zhejiang province.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYangyang Feng and Yun Jin drafted the manuscript. Jiangtao Li and Ming Chao are the main coordinators of the trial.Yangyang Feng, Yun Jin, Kai Jin, Yuanquan Yu, Donger Zhou, Jianjun Wu, Bin Li, Guangqiang Zhang, Xiaogang Qi, Hao Geng, Yinghao Guo, Shuyou Peng, Jiangtao Li and Ming Chao participated in the design of the trial. Shuyou Peng and Ming Chao provided advice, support and assistance. All authors critically revised the manuscript and have approved the final version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1. Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; 2. Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; 3. Department of Radiology and interventiona, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; 4. Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; 5. Department of Surgery, Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,China; 6. Department of Radiology and interventional, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; 7. Department of Radiology and interventional, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; 8. Department of Radiology and interventional, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; 9.Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; 10. Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; 11. Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; 12. Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; 13.Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; 14. Department of Radiology and interventional, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003e1. Bosch FX, Ribes J, Borras J. Epidemiology of primary liver cancer [J]. Semin Liver Dis. 1999;19(3):271-285.\u003c/li\u003e\n\u003cli\u003eLlovet JM, Zucman-Rossi J, Pikarsky E, Sangro B, Schwartz M, Sherman M, et al. Hepatocellular carcinoma [J]. Nat Rev Dis Primers. 2016;2:16018.\u003c/li\u003e\n\u003cli\u003eWhite JA, Gray SH, Li P, Simpson HN, McGuire BM, Eckhoff DE, et al. 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Am Soc Clin Oncol Educ Book. 2018(38):262-279.\u003c/li\u003e\n\u003cli\u003eVogel A, Cervantes A, Chau I, Daniele B, Llovet J, Meyer T, et al. Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up [J]. Ann Oncol. 2018;29(Supplement_4):iv238-iv255.\u003c/li\u003e\n\u003cli\u003eArmengol C, Sarrias MR, Sala M. Hepatocellular carcinoma: Present and future [J]. Med Clin (Barc). 2018;150(10):390-397.\u003c/li\u003e\n\u003cli\u003eLlovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma [J]. Lancet. 2003;362(9399):1907-1917.\u003c/li\u003e\n\u003cli\u003eAyuso C, Rimola J, Vilana R, Burrel M, Darnell A, Garcia-Criado A, et al. Diagnosis and staging of hepatocellular carcinoma (HCC): current guidelines [J]. Eur J Radiol. 2018;101:72-81.\u003c/li\u003e\n\u003cli\u003eChawla A, Ferrone C. Hepatocellular carcinoma surgical therapy: perspectives on the current limits to resection [J]. Chin Clin Oncol. 2018;7(5):48.\u003c/li\u003e\n\u003cli\u003eEASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma [J]. J Hepatol. 2012;56(4):908-943.\u003c/li\u003e\n\u003cli\u003eYang Y, Si T. Yttrium-90 transarterial radioembolization versus conventional transarterial chemoembolization for patients with hepatocellular carcinoma: a systematic review and meta-analysis [J]. Cancer Biol Med. 2018;15(3):299-310.\u003c/li\u003e\n\u003cli\u003eXu D, Liu X, Wang L, Xing B. Hepatectomy plus adjuvant transcatheter arterial chemoembolization improves the survival rate of patients with multicentric occurrence of hepatocellular carcinoma [J]. Oncol Lett. 2018;16(5):5882-5890.\u003c/li\u003e\n\u003cli\u003eChao M, Wu H, Jin K, Li B, Wu J, Zhang G, et al. A nonrandomized cohort and a randomized study of local control of large hepatocarcinoma by targeting intratumorallactic acidosis [J]. Elife. 2016;5.\u003c/li\u003e\n\u003cli\u003eZhou J, Sun HC, Wang Z, Cong WM, Wang JH, Zeng MS, et al.. Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China (2017 Edition) [J]. Liver Cancer. 2018;7(3):235-260.\u003c/li\u003e\n\u003cli\u003eKatagiri S, Yamamoto M. Multidisciplinary treatments for hepatocellular carcinoma with major portal vein tumor thrombus [J]. Surg Today. 2014;44(2):219-226.\u003c/li\u003e\n\u003cli\u003eAoki T, Imamura H, Hasegawa K, Matsukura A, Sano K, Sugawara Y, et al. Sequential preoperative arterial and portal venous embolizations in patients with hepatocellular carcinoma [J]. Arch Surg. 2004;139(7):766-774.\u003c/li\u003e\n\u003cli\u003eYin L, Li H, Li AJ, Lau WY, Pan ZY, Lai EC, et al. Partial hepatectomy vs. transcatheter arterial chemoembolization for resectable multiple hepatocellular carcinoma beyond Milan Criteria: a RCT [J]. J Hepatol. 2014;61(1):82-88.\u003c/li\u003e\n\u003cli\u003eYang B, Zheng B, Yang M, Zeng Z, Yang F, Pu J, et al. Liver resection versus transarterial chemoembolization for the initial treatment of Barcelona Clinic Liver Cancer stage B hepatocellular carcinoma [J]. Hepatol Int. 2018;12(5):417-428.\u003c/li\u003e\n\u003cli\u003eLin CT, Hsu KF, Chen TW, Yu JC, Chan DC, Yu CY, et al.Comparing hepatic resection and transarterial chemoembolization for Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma: change for treatment of choice? [J]. World J Surg. 2010;34(9):2155-2161.\u003c/li\u003e\n\u003cli\u003eZhong JH, Xiang BD, Gong WF, Ke Y, Mo QG, Ma L, et al. Comparison of long-term survival of patients with BCLC stage B hepatocellular carcinoma after liver resection or transarterial chemoembolization [J]. PLoS One. 2013;8(7):e68193.\u003c/li\u003e\n\u003cli\u003eLiu W, Wang K, Bao Q, Sun Y, Xing BC. Hepatic resection provided long-term survival for patients with intermediate and advanced-stage resectable hepatocellular carcinoma [J]. World J Surg Oncol. 2016;14:62.\u003c/li\u003e\n\u003cli\u003eJianyong L, Lunan Y, Wentao W, Yong Z, Bo L, Tianfu W, et al. Barcelona clinic liver cancer stage B hepatocellular carcinoma: transarterial chemoembolization or hepatic resection? [J]. Medicine (Baltimore). 2014;93(26):e180.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Hepatocellular carcinoma, Hepatic resection, TACE, TILA-TACE, Randomized-controlled study","lastPublishedDoi":"10.21203/rs.2.12620/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.2.12620/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Hepatic resection and transcatheter arterial chemoembolization (TACE) are common treatments for hepatocellular carcinoma (HCC). Targeting intratumoral lactic acidosis TACE (TILA-TACE) is a new therapeutic approach developed by our team that has superior response rate and effective rate than conventional TACE (cTACE). In this randomized-controlled trial, we will compare the efficacy of hepatic resection and TILA-TACE in patients clinically diagnosed with HCC to provide reliable clinical data for the subsequent effective treatment of HCC patients. Methods: A total of 230 resectable HCC patients will be given hepatic resection or TILA-TACE using a parallel-controlled approach, and the efficacy of the treatments Page 4 of 24 will be compared. The primary endpoint is the post-treatment progression-free survival (PFS) of the patients, and the secondary endpoints are the post-treatment overall survival (OS), 1-year, 3-year and 5-year survival, and the quality of life of the patients at each corresponding stage. Discussion: The aim of this study is to compare the efficacy of hepatic resection and TILA-TACE in the treatment of resectable HCC. Trial registration: ClinicalTrials.gov,NCT03314532.Registered on 19 October 2017. Keywords: Hepatocellular carcinoma, Hepatic resection, TACE, TILA-TACE, Randomized-controlled study.\u003c/p\u003e","manuscriptTitle":"Hepatic resection versus TILA-TACE in the treatment of Resectable Hepatocellular Carcinoma: study protocol for a randomized controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2019-12-20 14:59:16","doi":"10.21203/rs.2.12620/v2","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2019-08-12 03:03:05","doi":"10.21203/rs.2.12620/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0b75b2b7-62b7-4695-a882-d955c65dc78d","owner":[],"postedDate":"December 20th, 2019","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":20594,"name":"Internal Medicine"},{"id":20595,"name":"Integrative \u0026 Complementary Medicine"},{"id":20596,"name":"Translational Medicine"}],"tags":[],"updatedAt":"","versionOfRecord":[],"versionCreatedAt":"2019-12-20 14:59:16","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v2","identity":"rs-3364","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"identity":"rs-3364","version":["v2"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}