Background: The aims of this study were to evaluate the efficacy of additional treatment, especially lenvatinib-transarterial chemoembolization (TACE) sequential therapy, for unresectable hepatocellular carcinoma (HCC). Methods: Consecutive 56 patients who underwent lenvatinib treatment were reviewed. Oncological aggressiveness of tumor was estimated using a dynamic CT enhancement pattern classification, and clinical impact of subsequent treatment was investigated through analysis of progression-free survival (PFS), post-progression survival (PPS), and multivariate analysis of potential confounders for survival after progression during lenvatinib therapy. Results: Heterogeneous enhancement patterns (Type-3 and -4), which are reportedly associated with higher oncological aggressiveness of HCC, were associated with better objective response to lenvatinib compared to homogeneous enhancement pattern (Type-2) (86 and 85% vs. 53% in modified Response Evaluation Criteria in Solid Tumors), resulting in similar PFS (p = 0.313). Because of significantly worse PPS, overall survival of Type-4 tumor was poor compared to Type-2 or -3 tumors (p = 0.009). However, subgroup of patients who achieved subsequent treatment showed significantly better PPS, regardless of CT enhancement pattern. Multivariate analysis confirmed that use of lenvatinib-TACE sequential treatment after progression during lenvatinib therapy was associated with better PPS (hazard ratio [HR], 0.08; 95% CI, 0.01–0.71; p = 0.023), while Type-4 enhancement pattern was correlated with worse PPS (HR, 2.92; 95% CI, 1.06–8.05; p = 0.039). Conclusion: Oncological aggressiveness of HCC estimated by CT enhancement pattern was predictive of PPS after progression during lenvatinib. Successful subsequent treatment with lenvatinib-TACE sequential therapy may offer survival benefit regardless of CT enhancement pattern of HCC.

Introduction: For prognostication of hepatocellular carcinoma (HCC), the optimal size cutoff value and the significance of microvascular invasion (mvi) remain inconclusive. Objective: This study sought to revisit the inconclusive components of current American Joint Committee on Cancer (AJCC) staging system and to develop a new practical prognostication model for patients with HCC based on 2 large cohorts. Method: In 1,175 patients who underwent resection for HCC (training cohort), prognostic significance of mvi, and optimal size cutoff value were revisited and a new staging model was established. Then, its performance was validated using 5,249 patients derived from a population-based database (validation cohort). Results: The optimal size cutoff value was 2 cm in multiple HCC, similar to that for solitary HCC. Multivariate analyses confirmed that mvi, a size >2 cm, and multiple lesions were independent predictors with similar weights for disease-specific survival. Based on these results, earlier stages of HCC were reclassified according to the number of the following factors: multiple tumors, >2 cm in diameter, and presence of mvi. Also, given the similar prognosis of Stages IIIB and IVA according to the AJCC 8th edition, these groups were reclassified into the same stage. This new staging model had a better performance than the AJCC 8th edition in both training cohort (c-statistics, 0.648 vs. 0.629) and the validation cohort (c-statistics, 0.646 vs. 0.645) regardless of the presence of cirrhosis. Conclusions: Inclusion of a size cutoff value of 2 cm and mvi could reclassify the current version of the AJCC staging system and offer an alternative prognostication model using a single size-cutoff value of HCC.

Objective: The aim of this study was to evaluate the performance of pretreatment computed tomography (CT) enhancement of hepatocellular carcinoma (HCC) as a potential predictor of response to lenvatinib and its relevance to survival outcomes. Methods: We evaluated 51 consecutive patients who received lenvatinib treatment for unresectable HCC. On imaging analysis, pretreatment arterial/portal phase dynamic CT images were classified as follows: type 2, homogeneous enhancement pattern with increased arterial blood flow; type 3, heterogeneous enhancement pattern with a septum-like structure; and type 4, heterogeneous enhancement pattern with irregularly shaped ring structures. Treatment response was evaluated using modified Response Evaluation Criteria in Solid Tumors at 2–12 weeks after initiation of lenvatinib, and the correlations between the CT enhancement patterns and response to lenvatinib or survival outcomes were investigated. Results: Of the 51 patients, 38 (75%) experienced an objective response (OR). ORs were significantly more common in heterogeneously enhanced HCC (types 3 and 4) than in homogeneous HCC (type 2) (83 vs. 53%, respectively; p = 0.037). Multivariate analysis revealed that pretreatment heterogeneous enhancement pattern is an independent predictor for response to lenvatinib (odds ratio, 4.75; p = 0.042). Presence of OR was associated with longer progression-free survival (PFS) (hazard ratio, 0.36; p = 0.017), and patients with oncologically aggressive type 3 and 4 tumors showed similar PFS to those harboring type 2 tumors (p = 0.455), reflecting that OR was more common in type 3 or 4 tumors compared with type 2 tumors. Although postprogression survival was extremely poor in patients with type 4 tumors (p = 0.064), overall survival after introduction of lenvatinib was not statistically different among the three groups of patients (p = 0.053). Conclusion: The CT enhancement pattern of HCC may predict response to lenvatinib. OR seems to occur more frequently in HCC with oncologically aggressive features and may contribute to prolonged survival through a prolonged progression-free interval, even in an oncologically poor-risk group of patients.

Background and Aims: This study aimed to identify the utility of ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG-PET/CT) as a predictor of the response of hepatocellular carcinoma (HCC) to lenvatinib. Methods: We evaluated 28 consecutive patients with HCC diagnosed by dynamic CT or magnetic resonance imaging combined with ¹⁸F-FDG-PET/CT. The tumor-to-normal liver standardized uptake value ratio (TLR) of the target tumor was measured before treatment using ¹⁸F-FDG-PET/CT, with a TLR ≥2 classified as a high potential for malignant HCC. The treatment response was evaluated 2 weeks after the initiation of lenvatinib using modified Response Evaluation Criteria in Solid Tumors. Results: Of the 28 patients, 12 (43%) presented with a TLR ≥2. Evaluation of the treatment response at 2 weeks in these 12 patients revealed that 2 (17%) exhibited a complete response, 8 (67%) a partial response, 2 (17%) stable disease, and none with progressive disease. Therefore, 10 of the 12 patients (83%) experienced an objective response to lenvatinib. On the other hand, 7 of the 16 patients with a TLR <2 (44%) experienced an objective response. Thus, the objective response rate was higher in patients with a TLR ≥2 than in those with a TLR <2. Multivariate logistic regression analysis revealed that a TLR ≥2 (odds ratio 10.53; p = 0.028) is a useful predictor of an early objective response at 2 weeks. Conclusion: Patients with unresectable HCC showed a good early treatment response to lenvatinib. High TLR (≥2) may be a useful predictor of an extremely rapid treatment response.

Objective: To assess the clinical impact of a no-drain policy after hepatic resection. Summary of Background Data: Previous randomized controlled trials addressing no-drain policy after hepatic resection seem inconclusive because they did not adopt appropriate study design to validate its true clinical impact. Methods: This unblinded, randomized controlled trial was done at 7 Japanese institutions. Patients undergoing hepatic resection without biliary reconstruction were randomized to either D group or ND group. When the risk of postoperative bile leakage or hemorrhage were considered high, the patients were excluded during the operation. Primary endpoint was the postoperative complication of C-D grade 3 or higher within 90 postoperative days. A noninferiority of ND group to D group was assessed, and if it was confirmed, a superiority was assessed. Results: Between May 2015 and July 2017, a total of 400 patients were finally included in the per-protocol set analysis: 199 patients in D group and 201 patients in ND group. Intraoperatively, 37 patients were excluded from the final enrollment because of high risk of bile leakage or hemorrhage. Postoperative complication rate of C-D grade 3 or higher was 8.0% (16/199) in the D group and 2.5% (5/201) in the ND group. The risk difference was −5.5% (95% confidence interval: −9.9% to −1.2%) and fulfilled the prescribed noninferiority margin of 4%. No postoperative mortality was experienced in both groups. Bile leakage was diagnosed in 8.0% (16/199) of the D group and none in the ND group (P < 0.001). In none of the subgroups classified based on 8 potentially relevant factors, drain placement was favored in terms of C-D grade 3 or higher complication. Conclusions: Drains should not be placed after uncomplicated hepatic resections.