From April 2018 to February 2019, 68 patients received systemic anticancer treatment using lenvatinib for unresectable HCC at the Department of Hepatology, Toranomon Hospital, Tokyo, Japan. In this study, the following inclusion criteria were used: 1) triple-phase dynamic CT study performed prior to initiation of lenvatinib, 2) tumor with hyperenhancement in the arterial phase of dynamic CT, 3) performance of triple-dynamic CT to evaluate treatment response 8–12 weeks after initiation of lenvatinib, 4) Child-Pugh class A liver function at the time of lenvatinib initiation, 5) BCLC stage A to C tumor(s), 6) unresectable HCC and patient does not want to undergo local ablation or chemoembolization therapy for various reasons (i.e., tumor size, number and location, extrahepatic metastasis, TACE refractoriness, and various complications), 7) no treatment history of lenvatinib, 8) at least one measurable target nodule in the liver, 9) treatment interval of >28 days since previous tyrosine kinase inhibitor (TKI; sorafenib or regorafenib) therapy, and 10) an observation period of ³8 weeks. Finally, 37 patients met these inclusion criteria. All procedures followed were in accordance with the ethical standards of the responsible committees on human experimentation (institutional and national) and with the Helsinki Declaration of 1975. And, the study was approved by the Institutional Review Board of our hospital (protocol number; 1438-H/B).
Contrast infusion and CT protocol
All patients underwent triple-phase dynamic CT. CT was performed with a 64-multidetector CT (MDCT) scanner (Aquilion 64, Canon Medical Systems, Tochigi, Japan) with the following scanning parameters: rotation time, 0.5 seconds; beam collimation, 64 x 0.5 mm; section thickness and interval, 5 mm; beam pitch, 0.83; tube voltage, 120 kV; and tube current, 150 mAs. All helical scans were started at the top of the liver and proceeded in a cephalocaudal direction. Unenhanced and three-phase contrast-enhanced helical scans of the whole liver were acquired. Patients were instructed to hold their breath with exhalation during scanning. An automatic bolus-tracking program (Sure Start, Canon Medical Systems) was used to time the start of acquisition in each phase after contrast injection (nonionic contrast material with an iodine concentration of 350 mg I/mL iomeprol [Iomeron 350, Eisai, Tokyo] at a dose of 100-120 mL/body). Attenuation at the axis of the celiac artery level was monitored by one radiology technician; the region-of-interest (ROI) cursor (1 cm2) was placed in the abdominal aorta. Real-time low-dose (120 kV, 25 mAs) serial monitoring studies were begun 5 seconds after the start of contrast injection. The trigger threshold level was set at 100 Hounsfield units (HUs). Double arterial phase acquisition was started 15 and 20 seconds after triggering, and portal phase and delayed phase acquisition were started 70 and 180 seconds after the start of the contrast injection, respectively.
Diagnosis of HCC
The diagnosis of HCC was based predominantly on image analysis using dynamic CT. When a liver nodule showed hyperattenuation in the arterial phase of the dynamic study and washout in the portal or delayed phase, the nodule was diagnosed as HCC.
Imaging analysis of HCC and definitions of dynamic CT enhancement patterns
Before treatment, the dynamic study enhancement pattern on the arterial and portal phases was classified into one of four types defined in our previous report. The Type-1 pattern represented a homogeneous enhancement pattern with no increase in arterial blood flow, and the entire image was uniform during the arterial and portal phases. The Type-2 pattern represented a homogeneous enhancement pattern with increased arterial blood flow, and the entire image was uniform during the arterial and portal phases. The Type-3 pattern represented a heterogeneous enhancement pattern with septations, with heterogeneous enhancement and septations in the arterial phase, while the septations resembled a near-uniform tumor tissue periphery in the portal phase. The Type-4 pattern represented a heterogeneous enhancement pattern with irregular ring-like structures; the arterial phase was marked by the presence of irregularly shaped ring areas of enhancement and areas of little blood flow relative to the periphery of the tumor tissue, and the portal phase was characterized by areas of reduced blood flow (Figure 1).
The enhancement pattern on the arterial and portal phases of dynamic CT was determined by three expert hepatologists. Generally, macroscopic classification of the nodular type of SNEG and CMN types strongly relates to the Type-3 enhancement pattern, and histologically, the Type-1 enhancement pattern represents well-differentiated HCC, while the Type-2 and -3 patterns represent moderately-differentiated HCC; the Type-4 enhancement pattern is a significantly specific feature for predicting poorly-differentiated HCC.
In this study, all target HCC nodules appeared to be hypervascular; therefore, we classified all nodules into three enhancement patterns (Type-2 to -4). The enhancement pattern that accounts for 70% of the nodule is defined as the predominant enhancement pattern.
In addition, to analyze mean HU (HU-mean) of intrahepatic target tumors, a circular ROI was drawn on the axial plane to include the largest surface of the target lesion, and the HU-mean in each tumor was calculated. The hepatic HU-mean was measured in as many of the four segments (lateral, medial, anterior, and posterior) as possible at the level of the main portal vein, with an ROI of approximately 200 mm2. Finally, we calculated the median tumor-to-liver ratio (TLR) for each target tumor.
Imaging analysis of HCC using FDG-PET/CT
Within 1 month before initiation of lenvatinib, fluorine-18-fluorodeoxyglucose (FDG)-positron emission tomography (PET) /CT was performed with a dedicated whole-body PET scanner (Biograph mCT Flow40, Siemens Healthcare, Germany). Using a software for semi-quantitative analysis (SYNAPSE VINCENT ver.4, FUJIFILM MEDICAL SYSTEMS, Japan), the volume of interest (VOI) was drawn along the outline of the tumor and the maximum SUV (SUV-max) and mean SUV (SUV-mean) in each intrahepatic target tumor were calculated. After that, to measure normal liver activity, three non-overlapping spherical 1 cm3-sized VOIs were drawn in the liver (two in the right lobe and one in the left lobe) on the axial PET images, avoiding the areas of the HCC seen on
dynamic CT. The TLR was calculated using the following equation: TLR = SUV-max of the tumor/SUV-mean of the normal liver.
In 37 patients enrolled in this study, 17 patients underwent PET/CT before initiation of lenvatinib. We selected TLR ≥2 to indicate high malignant potential based on previous reports.[23-25]
Lenvatinib treatment and adverse event assessment
Lenvatinib (Eisai, Tokyo, Japan) was given orally to the majority of patients at either 8 mg/day for patients <60 kg or 12 mg/day for patients ≥60 kg; treatment was discontinued when any unacceptable or serious adverse events (AEs) or significantly clinical tumor progression were observed. According to the guidelines for administration of lenvatinib, the drug dose should be reduced or the treatment interrupted when a patient develops grade ≥3 severe AEs or any unacceptable grade 2 drug-related AEs occur. AEs were assessed using the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. If a drug-related AE occurred, dose reduction or temporary interruption was maintained until the symptom was resolved to Grade 1 or 2, according to the guidelines provided by the manufacturer.
Treatment response evaluation
Treatment response was evaluated in accordance with mRECIST. The liver was examined by dynamic CT. Tumor assessments were generally performed every 4–8 weeks.
Definition of TACE failure/refractoriness
TACE failure was defined as an insufficient response after ≥2 consecutive TACE procedures as evident on response evaluation CT or magnetic resonance imaging (MRI) after 1–3 months, even after the chemotherapeutic agent was changed and/or the feeding artery was reanalyzed. In addition, the appearance of a higher number of lesions in the liver than that recorded at the previous TACE procedure (other than the nodule being treated) was added to the definition of TACE failure/refractoriness.
Physicians examined patients every 1–2 weeks after initiation of lenvatinib, and biochemical laboratory and urine tests were also performed. After initiation of lenvatinib, patients underwent dynamic CT to evaluate early treatment response at 8–12 weeks. After the first evaluation of treatment response, dynamic CT was performed every 2–3 months.
Data are expressed as the median and range. Differences in background features between each parameter were analyzed by the chi-squared test, Fisher’s exact test, Mann-Whitney U test, and Kuraskal-Wallis test. Significance of trends in treatment response evaluated using mRECIST (OR vs. non-OR) and dynamic CT enhancement patterns was determined with the Cochran-Armitage trend test. Independent factors associated with treatment response were studied using multivariate logistic regression analysis. Potential prognostic factors for OR after initiation of lenvatinib included the following 17 variables: gender, age, body mass index, etiology of background liver disease, platelet count, serum albumin, bilirubin, prothrombin activity, aspartate aminotransferase (AST), alpha-fetoprotein (AFP), des-g-carboxy prothrombin (DCP), tumor diameter, number, macrovascular invasion, extrahepatic metastasis, dynamic study enhancement pattern (for a few cases, Type-3 and -4 are collectively referred to as a heterogeneous enhancement pattern), and initial dose of lenvatinib. In this multivariate analysis, to detect true factors, the integrated score was excluded.
Several variables were transformed into categorical data consisting of two simple ordinal numbers for univariate and multivariate analyses. All factors that were at least marginally associated with OR (P<0.15) in univariate analysis were entered into a multivariate logistic regression analysis. Significant variables were selected by a stepwise method. A two-tailed P-value less than 0.05 was considered to be statistically significant. Data analysis was performed with the Statistical Package for Social Sciences (SPSS) version 16.0 (SPSS Inc, Chicago, IL).