Assessment of the Efficacy of Lenvatinib Versus Sorafenib in the Management of Advanced Hepatocellular Carcinoma

1. Introduction: Hepatocellular carcinoma is one of the most common type of liver cancer, which is the 3rd leading cause of cancer deaths worldwide. The incidence is expected to increase as a consequence of chronic liver disease with its multiple risk factors, including chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, excessive alcohol consumption, nonalcoholic fatty liver disease, hemochromatosis, drugs and aflatoxin B1. It is estimated that 70%-90% of patients with HCC have chronic liver disease and cirrhosis, which limits the feasibility of surgical procedures in advanced cases. There are limited treatment options for HCC patients who are ineligible for surgical resection. Locoregional therapies, such as radiofrequency ablation (RFA), transarterial chemoembolization (TACE), transarterial embolization (TAE), or hepatic arterial infusion chemotherapy (HAIC), are primarily recommended, and if one of those fail, then systemic therapy is considered. The 2013 Japan Society of Hepatology HCC Guidelines outlined that the factors influencing treatment decisions should be based on the degree of liver damage (Child-Pugh), presence or absence of extrahepatic spread and macrovascular invasion, the number of tumors, and tumor diameter. Sorafenib has been the standard of care since 2007, when the SHARP trial demonstrated that sorafenib improved median overall survival (OS) compared to placebo in patients who had not received prior systemic therapy (10.7 vs 7.9 months, HR =0.69, P<0.001). In patients from the Asia-Pacific region taking sorafenib, the median improvement in overall survival compared with placebo was 2.3 months (6.5 months vs 4.2 months; HR 0.68; p=0.014). Drug development for hepatocellular carcinoma in the past 10 years has been marked by four failed global phase 3 trials (of sunitinib, brivanib, linifanib, and erlotinib plus sorafenib) that did not show non inferiority. Sorafenib, an oral multikinase inhibitor, has been the only systemic therapy demonstrated to extend overall survibility as a firstline treatment, showing a median improvement of 2.8 months compared with placebo (10.7 months vs. 7.9 months; hazard ratio [HR] 0.69; p\0.001). Inpatients from the Asia-Pacific region taking sorafenib, the median OS (mOS) improvement compared with placebo was 2.3 months (HR 0.68; p = 0.014). The use of other molecularly targeted agents has not demonstrated efficacy via non-inferiority or superiority to sorafenib; thus, until the appearance of lenvatinib, sorafenib has also been widely used as the first-line treatment for HCC patients in Japan. Recently, regorafenib and Nivolumab were approved as a second-line systemic treatment for patients who do not respond to the first-line treatments. Otherwise, best supportive care or participation in clinical trials is recommended in the second-line setting by treatment guidelines. Chemotherapy in combination with sorafenib (doxorubicin), and radioembolization with SIR Spheres Y-90 resin microspheres failed to demonstrate a survival benefit or showed a worse safety profile compared to sorafenib in the first-line setting. Eventually, the PhaseIII non-inferiority REFLECT trial showed that lenvatinib was non-inferior compared to sorafenib.
2. Objectives 2.1 General objectives: To assess and compare the efficacy of Lenvatinib versus Sorafenib in the management of Hepatitis B virus related Hepatocellular Carcinoma. 2.2 Specific objectives:
3. To assess and compare the overall survibility of hepatocellular carcinoma patients between the groups of Lenvatinib and Sorafenib. b. To assess and compare the progression free survival outcome between the groups of Lenvatinib and Sorafenib. c. To assess and compare the improvement of liver function tests between the groups of Lenvatinib and Sorafenib. d. To assess and compare the improvement of AFP levels between the groups of Lenvatinib and Sorafenib. e. To assess and compare the improvement of ECOG performance status of the HCC patients between the groups of Lenvatinib and Sorafenib. f. To assess and compare the improvement of Chil-Pugh scores among the HCC patients between the groups of Lenvatinib and Sorafenib. g. To assess and compare the size and number of target lesions by mRECIST criteria among the HCC patients between the groups of Lenvatinib and Sorafenib.
4. Methodology:

The study will be conducted considering the following methodological aspects.

3.1 Study design: An open label randomized clinical control trial study.

3.2 Study duration: From the date of randomization to next 3 months or till death whichever one will be earlier

3.3 Study place: Department of Hepatology, Sir Salimullah Medical College Mitford Hospital

3.4 Study population: Patients diagnosed as advanced Hepatocellular Carcinoma by imaging, cytology or histology with no option of resectibility will be selected for the study.

3.5 Sample size calculation:

"n=" "P1" ("1-P1" )"+P2" ("1-P2" )/("P1" -"P2" )^2 ×〖(Zα+Zβ)〗^2

P1= Proportion of patients developed objective response in one arm (Lenvatinib group) P2= Proportion of patients developed objective response in another arm (Sorafenib group) Zα= Z-value (two tail) at a definite level of significance e.g. 1.96 at 5% level of significance Zβ= Z-value (one tail) at a definite power e.g. 0.84

Here, P1= 40.6% objective response with Lenvatinib (0.406), P2= 12.4% objective response with Sorafenib (0.124), Zα=1.96 and Zβ= 0.8419

n=(0.406(1-0.406)+ 0.124(1-0.124))/〖(0.406-0.124)〗^2 ×〖(1.96+0.84)〗^2 = 34.3 in each group = 35 in each group Total sample number 70 (35 in Lenvatinib group and 35 in Sorafenib group)

3.6 Sampling technique and recruitment of study subjects:

Participants of the study will be recruited via 1:1 randomization from patients admitted in the department of Hepatology, Sir Salimullah Medical College Mitford Hospital and diagnosed as a case of advanced Hepatocellular Carcinoma with no option of resectibility.

3.7 Eligibility criteria:

3.7.1 Inclusion criteria:

1. Patients with Hepatocellular Carcinoma (Diagnosed histologically or cytologically or by imaging criteria with CT or MRI) with no option of resectibility (BCLC stage B or C)
2. Age ≥ 18 years

3.7.2 Exclusion criteria:

1. Patients with very early stage Hepatocellular Carcinoma (BCLC stage 0)
2. Patients with early stage Hepatocellular Carcinoma (BCLC stage A)
3. Patients with terminal stage Hepatocellular Carcinoma (BCLC stage D)
4. Patients with Hepatocellular Carcinoma with obvious invasion to bile duct.
5. Patients who received previous systemic therapy for Hepatocellular Carcinoma.
6. Patients with jaundice (serum bilirubin ≥ 3 mg/dl) 8. Patients with aminotransferases ≥ 5ULN 8. Patients with other co-morbid conditions (COPD, CKD, Heart failure, IHD, pregnancy)

3.7.3 Primary outcome measure:

1. To measure overall survival of the patients from the date of randomization up to 6 months or till death whichever one will be earlier.

3.7.4 Secondary outcome measure:

1. Progression free survival
2. Time to progress
3. Objective response rate
4. Quality of life
5. Assessment of safety

3.8 Outcome measure:

1. Primary endpoint
2. Overall survibility (From the date of Randomization to next 3 months or till death)
3. Secondary endpoint
4. Progression free survival
5. Time to progress
6. Quality of life measurement (By ECOG performance status)
7. Liver function tests (By S.Bilirubin, ALT, AST, ALP, Prothrombin time, INR, Serum albumin)
8. AFP level
9. Child-turcotte-Pugh score
10. Tumor assessment by mRECIST criteria. 3.9 Research instrument For collection of primary data about patient a semi-structured questionnaire will be developed based on research objective. Pre-testing of the questionnaire will be done on other patients admitted at the same facility. After the pretesting, amendment of the items and question will be done based on study finding. In the final questionnaire both structured and open questions will be kept. A check list will be prepared to compile the data from hospital records, treatment records, outcome of treatment and laboratory investigation reports. 3.10 Data collection procedure: All data will be collected by face-to-face interview of the patients attendant by the researcher at health facility upon their consent and convenience. Socio demographic and personal information will be recorded from patient through interview, with a semi structured pre-tested questionnaire. Information regarding risk factors and risk behavior will be inquired taking effort to minimize the recall bias. 3.11 Data processing Data processing will include data cleaning and quality control check, editing of data, coding of data and data entry into computer. The edited data will be entered on to the template of SPSS® 23. 3.12 Data analysis The edited data will then be entered on to the template of SPSS® 23. For Back ground variables and socio-demographic data descriptive statistics and relative frequency (percentage) will be generated. All data will be presented as mean ± SD. Qualitative data will be analyzed by Chi-square test and quantitative data will be analyzed by student's t-test. Through univariate analysis the base line characteristics and treatment outcome will be compared. The effect of treatment will be identified through Multivariate analysis after adjusting for possible confounders. Relative risk with 95% CI will be generated through binary logistic regression adjusting for all possible confounders. A statistically significant result will be considered when p value < 0.05. 3.13 Data Presentation Data will be presented in the form of table and graphs. Descriptive statistics will be presented with frequency table. Association will be illustrated with cross tables and test statistics will be added in the foot note of the table. Bar and pie charts will be generated to illustrate descriptive statistics.
11. Ethical considerations Approval from the ethical review committee of Sir Salimullah Medical College and Mitford Hospital will be taken prior to commencement of the study. Informed written consent will be taken from the participants after explaining about the details of the study. The participants will be assured that the information acquired will be used for academic purpose. They will be assured of confidentiality, and for the purpose of data analysis no individual data were reported rather de identified data will be preceded for analysis.
12. Facilities (Resources, Equipments, Chemicals, Subjects etc. required for the study)

• Principal investigator has full-fledged Department of Hepatology at "Sir Salimullah Medical College Mitford Hospital, Dhaka."
• "Sir Salimullah Medical College Mitford Hospital, Dhaka" has adequate facilities to carry out all the investigations required for this study. "Sir Salimullah Medical College Mitford Hospital, Dhaka" has adequate facility to deal with the adverse effect of the drug under trial as well as management of the subjects of the current study.

1. Material \& methods: The study will be conducted in the department of Hepatology, Sir Salimullah Medical College Mitford Hospital. It will be an open label randomized clinical control trial study. Patients admitted in the department of Hepatology, diagnosed as a case of Hepatocellular Carcinoma by imaging or cytopathology or histopathology will be primarily targeted for the study. Initial assessment of each patient will be done by Chil-pugh score, ECOG performance status, Tumor assessment by mRECIST criteria and BCLC staging. According to initial assessment the patients who will fulfill the inclusion criteria (BCLC stage C) will be informed about the study procedure. Patients who will give informed written consent will be randomly assigned 1:1 ratio to receive either Lenvatinib or Sorafenib. Macroscopic portal vein invasion, extrahepatic spread, or both (yes or no), Eastern Cooperative Oncology Group performance status (0 or 1) will be considered as stratification factors. As the study will be open labeled, the treatment will not be masked to the patients or investigators. After randomization there will be two groups; Lenvatinib group (Group A) and Sorafenib group (Group B). Group A patients will receive Cap. Lenvatinib 8 mg/day in two divided doses and group B patients will receive tab. Sorafenib 400 mg/day in two divided doses. Tumor evaluation will be done in each treatment arm in accordance with mRECIST criteria. Liver will be examined with CT or MRI by using a triphasic scanning technique. Patient follow-up and tumor assessment will be done in every 6 weeks interval by liver function tests (S. Bilirubin, ALT, AST, ALP, Prothrombin time, S. Albumin), AFP and imaging (triphasic CT or MRI). Quality of life will be assessed by ECOG performance status on follow-up. Patients will followed up for next 3 months or till death whichever one will be earlier. After 3 months of treatment the two groups (Group A and Group B) will be compared of overall survibility, improvement of patient's clinical and biochemical status, reduction of tumor size as well as the tumor marker.
2. Statistical Analysis: The result of the study will be collected in a separate questionnaire sheet. After collection of data it will be compiled and analyzed using SPSS software version 23. References:
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