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Donafenib Versus Sorafenib in First-Line Treatment of Unresectable or Metastatic Hepatocellular Carcinoma: A Randomized, Open-Label, Parallel-Controlled Phase II-III Trial.
Qin, S, Bi, F, Gu, S, Bai, Y, Chen, Z, Wang, Z, Ying, J, Lu, Y, Meng, Z, Pan, H, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2021;(27):3002-3011
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PURPOSE Donafenib, a novel multikinase inhibitor and a deuterated sorafenib derivative, has shown efficacy in phase Ia and Ib hepatocellular carcinoma (HCC) studies. This study compared the efficacy and safety of donafenib versus sorafenib as first-line therapy for advanced HCC. PATIENTS AND METHODS This open-label, randomized, parallel-controlled, multicenter phase II-III trial enrolled patients with unresectable or metastatic HCC, a Child-Pugh score ≤ 7, and no prior systemic therapy from 37 sites across China. Patients were randomly assigned (1:1) to receive oral donafenib (0.2 g) or sorafenib (0.4 g) twice daily until intolerable toxicity or disease progression. The primary end point was overall survival (OS), tested for noninferiority and superiority. Efficacy was primarily assessed in the full analysis set (FAS), and safety was assessed in all treated patients. RESULTS Between March 21, 2016, and April 16, 2018, 668 patients (intention-to-treat) were randomly assigned to donafenib and sorafenib treatment arms; the FAS included 328 and 331 patients, respectively. Median OS was significantly longer with donafenib than sorafenib treatment (FAS; 12.1 v 10.3 months; hazard ratio, 0.831; 95% CI, 0.699 to 0.988; P = .0245); donafenib also exhibited superior OS outcomes versus sorafenib in the intention-to-treat population. The median progression-free survival was 3.7 v 3.6 months (P = .0570). The objective response rate was 4.6% v 2.7% (P = .2448), and the disease control rate was 30.8% v 28.7% (FAS; P = .5532). Drug-related grade ≥ 3 adverse events occurred in significantly fewer patients receiving donafenib than sorafenib (125 [38%] v 165 [50%]; P = .0018). CONCLUSION Donafenib showed superiority over sorafenib in improving OS and has favorable safety and tolerability in Chinese patients with advanced HCC, showing promise as a potential first-line monotherapy for these patients.
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Ramucirumab after prior sorafenib in patients with advanced hepatocellular carcinoma and elevated alpha-fetoprotein: Japanese subgroup analysis of the REACH-2 trial.
Kudo, M, Okusaka, T, Motomura, K, Ohno, I, Morimoto, M, Seo, S, Wada, Y, Sato, S, Yamashita, T, Furukawa, M, et al
Journal of gastroenterology. 2020;(6):627-639
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BACKGROUND The global, randomized, phase 3 REACH-2 study (ClinicalTrials.gov identifier: NCT02435433) found significantly longer overall survival (OS) for second-line ramucirumab versus placebo (hazard ratio [HR]: 0.710, 95% confidence interval [CI] 0.531-0.949, P = 0.0199) in patients with advanced hepatocellular carcinoma (HCC) and alpha-fetoprotein (AFP) ≥ 400 ng/mL. This prespecified subgroup analysis evaluated the efficacy and safety of ramucirumab in the Japanese patients enrolled in the study. METHODS Patients with advanced HCC and AFP ≥ 400 ng/mL after first-line sorafenib were randomized 2:1 to ramucirumab (8 mg/kg intravenously) or placebo every 2 weeks. Hazard ratios for progression-free survival (PFS) and OS (primary endpoint of the overall study) were estimated using the stratified Cox regression model. We also pooled individual patient data from REACH-2 with data from REACH (NCT01140347) for patients with AFP ≥ 400 ng/mL. RESULTS In the Japanese REACH-2 subpopulation, there were improvements for ramucirumab (n = 41) versus placebo (n = 18) in PFS (HR 0.282, 95% CI 0.144-0.553) and OS was numerically prolonged (HR 0.599, 95% CI 0.303-1.187), consistent with the significant benefit seen in the overall REACH-2 study population. In the ramucirumab and placebo arms, respectively, the objective response rate was 7.3% and 0%, and the disease control rate was 70.7% and 33.3%. The most frequently reported grade ≥ 3 treatment-emergent adverse event was hypertension (ramucirumab: 15%; placebo: 11%). CONCLUSIONS Ramucirumab after prior sorafenib improved PFS and OS compared with placebo, with a manageable safety profile, in the Japanese REACH-2 subpopulation, consistent with the overall REACH-2 study results. Ramucirumab is the first agent to demonstrate clinical benefit for Japanese patients with HCC in the second-line setting.
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Covariate-adjusted analysis of the Phase 3 REFLECT study of lenvatinib versus sorafenib in the treatment of unresectable hepatocellular carcinoma.
Briggs, A, Daniele, B, Dick, K, Evans, TRJ, Galle, PR, Hubner, RA, Lopez, C, Siebert, U, Tremblay, G
British journal of cancer. 2020;(12):1754-1759
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BACKGROUND In the Phase 3 REFLECT trial in patients with unresectable hepatocellular carcinoma (uHCC), the multitargeted tyrosine kinase inhibitor, lenvatinib, was noninferior to sorafenib in the primary outcome of overall survival. Post-hoc review revealed imbalances in prognostic variables between treatment arms. Here, we re-analyse overall survival data from REFLECT to adjust for the imbalance in covariates. METHODS Univariable and multivariable adjustments were undertaken for a candidate set of covariate values that a physician panel indicated could be prognostically associated with overall survival in uHCC. The values included baseline variables observed pre- and post-randomisation. Univariable analyses were based on a stratified Cox model. The multivariable analysis used a "forwards stepwise" Cox model. RESULTS Univariable analysis identified alpha-fetoprotein (AFP) as the most influential variable. The chosen multivariable Cox model analysis resulted in an estimated adjusted hazard ratio for lenvatinib of 0.814 (95% CI: 0.699-0.948) when only baseline variables were included. Adjusting for post-randomisation treatment variables further increased the estimated superiority of lenvatinib. CONCLUSIONS Covariate adjustment of REFLECT suggests that the original noninferiority trial likely underestimated the true effect of lenvatinib on overall survival due to an imbalance in baseline prognostic covariates and the greater use of post-treatment therapies in the sorafenib arm. TRIAL REGISTRATION Trial number: NCT01761266 (Submitted January 2, 2013).
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Individual Optimization of Contrast Media Injection Protocol at Hepatic Dynamic Computed Tomography Using Patient-Specific Contrast Enhancement Optimizer.
Matsumoto, Y, Higaki, T, Arataki, K, Masuda, T, Sato, T, Fukumoto, W, Nakamura, Y, Tatsugami, F, Awai, K
Journal of computer assisted tomography. 2020;(2):230-235
Abstract
OBJECTIVE We developed a patient-specific contrast enhancement optimizer (p-COP) that can exploratorily calculate the contrast injection protocol required to obtain optimal enhancement at target organs using a computer simulator. Appropriate contrast media dose calculated by the p-COP may minimize interpatient enhancement variability. Our study sought to investigate the clinical utility of p-COP in hepatic dynamic computed tomography (CT). METHODS One hundred thirty patients (74 men, 56 women; median age, 65 years) undergoing hepatic dynamic CT were randomly assigned to 1 of 2 contrast media injection protocols using a random number table. Group A (n = 65) was injected with a p-COP-determined iodine dose (developed by Higaki and Awai, Hiroshima University, Japan). In group B (n = 65), a standard protocol was used. The variability of measured CT number (SD) between the 2 groups of aortic and hepatic enhancement was compared using the F test. In the equivalence test, the equivalence margins for aortic and hepatic enhancement were set at 50 and 10 Hounsfield units (HU), respectively. The rate of patients with an acceptable aortic enhancement (250-350 HU) for the diagnosis of hypervascular liver tumors was compared using the χ test. RESULTS The mean ± SD values of aortic and hepatic enhancement were 311.0 ± 39.9 versus 318.7 ± 56.5 and 59.0 ± 11.5 versus 58.6 ± 11.8 HU in groups A and B, respectively. Although the SD for aortic enhancement was significantly lower in group A (P = 0.006), the SD for hepatic enhancement was not significantly different (P = 0.871). The 95% confidence interval for the difference in aortic and hepatic enhancement between the 2 groups was within the range of the equivalence margins. The number of patients with acceptable aortic enhancement was significantly greater in group A than in group B (P < 0.01). CONCLUSIONS The p-COP software reduced interpatient variability in aortic enhancement and obtained acceptable aortic enhancement at a significantly higher rate compared with the standard injection protocol for hepatic dynamic CT.
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Iodine dose optimization in portal venous phase virtual monochromatic images of the abdomen: Prospective study on rapid kVp switching dual energy CT.
Noda, Y, Goshima, S, Nakashima, Y, Miyoshi, T, Kawai, N, Kambadakone, A, Matsuo, M
European journal of radiology. 2020;:108746
Abstract
PURPOSE To investigate iodine dose concentration required for adequate hepatic parenchymal enhancement on fast-kilovoltage-switching dual-energy computed tomography (DECT) of the abdomen based on patient body weight. MATERIALS AND METHODS The protocol of this prospective study was approved by the local Institutional Review Board and written informed consent for study participation was obtained from all patients. The study cohort of 204 consecutive patients who underwent whole body single-source DECT to screen for tumor metastases and/or recurrence after surgical resection of malignant tumors were randomly assigned to one of three protocols according to the iodine dose (400, 500, and 600 mgI/kg). For each case, two radiologists quantitatively and qualitatively reviewed three energy levels (65, 70, and 75 kilo electron volt [keV]) of the portal venous phase virtual monochromatic images (VMIs). CT numbers of the liver and the qualitative hepatic parenchymal enhancement were compared among the VMIs with the three protocols and three energy levels. RESULTS Hepatic enhancement (ΔHU > 50HU) was achieved at 65 keV with 400, 500, and 600 mgI/kg, at 70 keV with 500 and 600 mgI/kg, and at 75 keV with 600 mgI/kg. The hepatic parenchymal enhancement was graded as sufficient hepatic enhancement in 97%, 100%, and 99% at 65 keV with 400, 500, and 600 mgI/kg, 88% and 97% at 70 keV with 500 and 600 mgI/kg, and 84% at 75 keV with 600 mgI/kg, respectively. CONCLUSION The iodine dose can be reduced to 400 mgI/kg at 65 keV or 500 mgI/kg at 70 keV in DECT without compromising hepatic parenchymal enhancement.
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Randomised, multicentre prospective trial of transarterial chemoembolisation (TACE) plus sorafenib as compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial.
Kudo, M, Ueshima, K, Ikeda, M, Torimura, T, Tanabe, N, Aikata, H, Izumi, N, Yamasaki, T, Nojiri, S, Hino, K, et al
Gut. 2020;(8):1492-1501
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OBJECTIVE This trial compared the efficacy and safety of transarterial chemoembolisation (TACE) plus sorafenib with TACE alone using a newly established TACE-specific endpoint and pre-treatment of sorafenib before initial TACE. DESIGN Patients with unresectable hepatocellular carcinoma (HCC) were randomised to TACE plus sorafenib (n=80) or TACE alone (n=76). Patients in the combination group received sorafenib 400 mg once daily for 2-3 weeks before TACE, followed by 800 mg once daily during on-demand conventional TACE sessions until time to untreatable (unTACEable) progression (TTUP), defined as untreatable tumour progression, transient deterioration to Child-Pugh C or appearance of vascular invasion/extrahepatic spread. Co-primary endpoints were progression-free survival (PFS), which is not a conventional one but defined as TTUP, or time to any cause of death plus overall survival (OS). Multiplicity was adjusted by gatekeeping hierarchical testing. RESULTS Median PFS was significantly longer in the TACE plus sorafenib than in the TACE alone group (25.2 vs 13.5 months; p=0.006). OS was not analysed because only 73.6% of OS events were reached. Median TTUP (26.7 vs 20.6 months; p=0.02) was also significantly longer in the TACE plus sorafenib group. OS at 1 year and 2 years in TACE plus sorafenib group and TACE alone group were 96.2% and 82.7% and 77.2% and 64.6%, respectively. There were no unexpected toxicities. CONCLUSION TACE plus sorafenib significantly improved PFS over TACE alone in patients with unresectable HCC. Adverse events were consistent with those of previous TACE combination trials. TRIAL REGISTRATION NUMBER NCT01217034.
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Contrast Material Injection Protocol With the Dose Determined According to Lean Body Weight at Hepatic Dynamic Computed Tomography: Comparison Among Patients With Different Body Mass Indices.
Matsumoto, Y, Masuda, T, Sato, T, Arataki, K, Nakamura, Y, Tatsugami, F, Awai, K
Journal of computer assisted tomography. 2019;(5):736-740
Abstract
OBJECTIVE The objective of this study was to compare enhancement of the aorta and liver on hepatic dynamic computed tomography scans acquired with contrast material doses based on the lean body weight (LBW) or the total body weight (TBW). METHODS We randomly divided 529 patients (279 men, 250 women; median age, 66 years) scheduled for hepatic dynamic computed tomography into 2 groups. The LBW patients (n = 278) were injected with 679 mg iodine/kg (men) or 762 mg iodine/kg (women). The TBW group (n = 251) was injected with 600 mg iodine/kg TBW. Each group was subdivided into the 3 classes based on the body mass index (BMI; low, normal, high). Aortic enhancement during the hepatic arterial phase and hepatic enhancement during the portal venous phase was compared. The aortic and hepatic equivalence margins were 100 and 20 Hounsfield units, respectively. RESULTS Comparison of the median iodine dose in patients with a normal or high BMI showed that it was significantly lower under the LBW protocol than the TBW protocol (558.2 and 507.0 mg iodine/kg, P < 0.001, respectively). However, in patients with a low BMI, the LBW protocol delivered a significantly higher dose than the TBW protocol (620.7 vs 600.0 mg iodine/kg, P < 0.001). The 95% confidence interval for the difference in aortic and hepatic enhancement between the 2 protocols was within the range of the predetermined equivalence margins in all BMI subgroups. CONCLUSIONS Contrast enhancement was equivalent under both protocols. The LBW protocol can avoid iodine overdosing, especially in patients with a high BMI.
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Cabozantinib exposure-response analyses of efficacy and safety in patients with advanced hepatocellular carcinoma.
Nguyen, L, Chapel, S, Tran, BD, Lacy, S
Journal of pharmacokinetics and pharmacodynamics. 2019;(6):577-589
Abstract
Cabozantinib, a multi-kinase inhibitor, is approved in the United States and European Union for treatment of patients with hepatocellular carcinoma following prior sorafenib treatment. In the Phase III CELESTIAL trial, hepatocellular carcinoma patients receiving cabozantinib showed longer overall survival (OS) and progression-free survival (PFS) than those receiving placebo. The approved cabozantinib (Cabometyx®) dose is 60 mg once daily with allowable dose modifications to manage adverse events (AE). Time-to-event Cox proportional hazard exposure-response (ER) models were developed to characterize the relationship between predicted cabozantinib exposure and the likelihood of various efficacy and safety endpoints. The ER models were used to predict hazard ratios (HR) for efficacy and safety endpoints for starting doses of 60, 40, or 20 mg daily. Statistically significant relationships between cabozantinib exposure and efficacy and safety endpoints were observed. For efficacy endpoints, predicted HR were lower for OS and PFS at 40 and 60 mg relative to the 20 mg dose: HR for death (OS) are 0.84 (40 mg) and 0.70 (60 mg); HR for disease progression/death (PFS) are 0.73 (40 mg) and 0.62 (60 mg). For safety endpoints, predicted HR were lower for palmar-plantar erythrodysaesthesia (PPE), diarrhea, and hypertension at 20 or 40 mg relative to the 60 mg dose: HR for PPE are 0.31 (20 mg) and 0.66 (40 mg); HR for diarrhea are 0.61 (20 mg) and 0.86 (40 mg); HR for hypertension are 0.46 (20 mg) and 0.76 (40 mg). The rate of dose modifications was predicted to increase in patients with lower cabozantinib apparent clearance. OS and PFS showed the greatest benefit at the 60 mg dose. However, higher cabozantinib exposure was predicted to increase the likelihood of AE and subsequent dose reductions appeared to decrease these risks.
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Sorafenib with or without concurrent transarterial chemoembolization in patients with advanced hepatocellular carcinoma: The phase III STAH trial.
Park, JW, Kim, YJ, Kim, DY, Bae, SH, Paik, SW, Lee, YJ, Kim, HY, Lee, HC, Han, SY, Cheong, JY, et al
Journal of hepatology. 2019;(4):684-691
Abstract
BACKGROUND & AIMS Sorafenib is first-line standard of care for patients with advanced hepatocellular carcinoma (HCC), yet it confers limited survival benefit. Therefore, we aimed to compare clinical outcomes of sorafenib combined with concurrent conventional transarterial chemoembolization (cTACE) vs. sorafenib alone in patients with advanced HCC. METHODS In this investigator-initiated, multicenter, phase III trial, patients were randomized to receive sorafenib alone (Arm S, n = 169) or in combination with cTACE on demand (Arm C, n = 170). Sorafenib was started within 3 days and cTACE within 7-21 days of randomization. The primary endpoint was overall survival (OS). RESULTS For Arms C and S, the median OS was 12.8 vs. 10.8 months (hazard ratio [HR] 0.91; 90% CI 0.69-1.21; p = 0.290); median time to progression, 5.3 vs. 3.5 months (HR 0.67; 90% CI 0.53-0.85; p = 0.003); median progression-free survival, 5.2 vs. 3.6 months (HR 0.73; 90% CI 0.59-0.91; p = 0.01); and tumor response rate, 60.6% vs. 47.3% (p = 0.005). For Arms C and S, serious (grade ≥3) adverse events occurred in 33.3% vs. 19.8% (p = 0.006) of patients and included increased alanine aminotransferase levels (20.3% vs. 3.6%), hyperbilirubinemia (11.8% vs. 3.0%), ascites (11.8% vs. 4.2%), thrombocytopenia (7.2% vs. 1.2%), anorexia (7.2% vs. 1.2%), and hand-foot skin reaction (10.5% vs. 11.4%). A post hoc subgroup analysis compared OS in Arm C patients (46.4%) receiving ≥2 cTACE sessions to Arm S patients (18.6 vs. 10.8 months; HR 0.58; 95% CI 0.40-0.82; p = 0.006). CONCLUSION Compared with sorafenib alone, sorafenib combined with cTACE did not improve OS in patients with advanced HCC. However, sorafenib combined with cTACE significantly improved time to progression, progression-free survival, and tumor response rate. Sorafenib alone remains the first-line standard of care for patients with advanced HCC. LAY SUMMARY For patients with advanced hepatocellular carcinoma requiring sorafenib therapy, co-administration with conventional transarterial chemoembolization did not improve overall survival compared to sorafenib alone. Therefore, sorafenib alone remains the first-line standard of care for patients with advanced hepatocellular carcinoma. Clinical Trial Number: NCT01829035.
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Antimicrobial prophylaxis for 1 day versus 3 days in liver cancer surgery: a randomized controlled non-inferiority trial.
Takayama, T, Aramaki, O, Shibata, T, Oka, M, Itamoto, T, Shimada, M, Isaji, S, Kanematsu, T, Kubo, S, Kusunoki, M, et al
Surgery today. 2019;(10):859-869
Abstract
PURPOSES This study compared the effectiveness of 1-day vs 3-days antibiotic regimen to prevent surgical site infection (SSI) in open liver resection. METHOD We performed a randomized controlled non-inferiority trial in 480 patients at 39 hospitals across Japan (registered as UMIN000002852). Patients with hepatocellular carcinoma scheduled to undergo resection were randomly assigned to receive either a 1-day regimen for antimicrobial prophylaxis, or a 3-day regimen. The primary endpoint was the incidence of SSI. RESULTS Among 480 randomized patients, 232 assigned to the 1-day regimen and 235 to the 3-day regimen were included in the full analysis set. Baseline characteristics of the two groups were well balanced. SSI was diagnosed in 22 patients (9.5%) in the 1-day group vs 23 patients (9.8%) in the 3-day group (difference, - 0.30; 90% CI - 4.80 to 4.19% [95% CI - 5.66% to 5.05%]; one-sided P = 0.001 for non-inferiority), meeting the non-inferiority hypothesis. In both groups, remote site infection (16 [6.9%] vs 22 [9.4%], P ˂ 0.001 for non-inferiority) and drain-related infection (5 [2.2%] vs 4 [1.7%], P ˂ 0.001 for non-inferiority) were comparable. CONCLUSION To prevent SSI in liver cancer surgery, a 1-day regimen of flomoxef sodium is recommended for antimicrobial prophylaxis because of confirming the non-inferiority to longer usage.