Article

Sunitinib Versus Sorafenib in Advanced Hepatocellular Cancer: Results of a Randomized Phase III Trial

Deng-Yn Lin, Chang Gung Memorial Hospital, Chang Gung University, Guishan Township, Taiwan, Republic of China
Journal of Clinical Oncology (Impact Factor: 18.43). 09/2013; 31(32). DOI: 10.1200/JCO.2012.45.8372
Source: PubMed

ABSTRACT

Open-label, phase III trial evaluating whether sunitinib was superior or equivalent to sorafenib in hepatocellular cancer.
Patients were stratified and randomly assigned to receive sunitinib 37.5 mg once per day or sorafenib 400 mg twice per day. Primary end point was overall survival (OS).
Early trial termination occurred for futility and safety reasons. A total of 1,074 patients were randomly assigned to the study (sunitinib arm, n = 530; sorafenib arm, n = 544). For sunitinib and sorafenib, respectively, median OS was 7.9 versus 10.2 months (hazard ratio [HR], 1.30; one-sided P = .9990; two-sided P = .0014); median progression-free survival (PFS; 3.6 v 3.0 months; HR, 1.13; one-sided P = .8785; two-sided P = .2286) and time to progression (TTP; 4.1 v 3.8 months; HR, 1.13; one-sided P = .8312; two-sided P = .3082) were comparable. Median OS was similar among Asian (7.7 v 8.8 months; HR, 1.21; one-sided P = .9829) and hepatitis B-infected patients (7.6 v 8.0 months; HR, 1.10; one-sided P = .8286), but was shorter with sunitinib in hepatitis C-infected patients (9.2 v 17.6 months; HR, 1.52; one-sided P = .9835). Sunitinib was associated with more frequent and severe adverse events (AEs) than sorafenib. Common grade 3/4 AEs were thrombocytopenia (29.7%) and neutropenia (25.7%) for sunitinib; hand-foot syndrome (21.2%) for sorafenib. Discontinuations owing to AEs were similar (sunitinib, 13.3%; sorafenib, 12.7%).
OS with sunitinib was not superior or equivalent but was significantly inferior to sorafenib. OS was comparable in Asian and hepatitis B-infected patients. OS was superior in hepatitis C-infected patients who received sorafenib. Sunitinib-treated patients reported more frequent and severe toxicity.

Download full-text

Full-text

Available from: Eric Raymond, Sep 08, 2015
  • Source
    • "However, the effects are modest with a median improvement in overall survival of 2 to 3 months with no clinical or molecular biomarkers to identify patients most likely to benefit. A number of randomised trials of other VEGF-targeted drugs (including sunitinib, brivanib) have failed to demonstrate any further survival benefit in either the first or second line setting and most patients die within one year of diagnosis, largely due to further metastases [115]. Therapy-induced tumour hypoxia has been observed in response to diverse treatments, including radiotherapy [116] [117], chemotherapy [118] [119], anti-angiogenic and vascular disrupting agents [120]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hypoxia inducible transcription factors (HIFs) activate diverse pathways that regulate cellular metabolism, angiogenesis, proliferation and migration, enabling a cell to respond to a low oxygen or hypoxic environment. HIFs are regulated by oxygen-dependent and independent signals including: mitochondrial dysfunction, reactive oxygen species, endoplasmic reticular stress and viral infection. HIFs have been reported to play a role in the pathogenesis of liver disease of diverse aetiologies. This review explores the impact of HIFs on hepatocellular biology and inflammatory responses, highlighting the therapeutic potential of targeting HIFs for an array of liver pathologies.
    Full-text · Article · Dec 2014 · Journal of Hepatology
  • Source
    • "Two randomized studies have shown that SOR offers benefits for overall survival (OS) [2] [3]. In previous years, different molecules, such as sunitinib [4], brivanib [5], linifanib [6], and erlotinib [7], have been used for first-line treatment in advanced HCC, but they did not show superiority to SOR. Different molecules for second-line treatment have been tested. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: The standard therapy in advanced hepatocellular carcinoma (HCC) is sorafenib (SOR), which has the inconvenience of toxicity and discontinuation. Patient selection and the use of early markers are critical for optimizing the potential benefit of SOR. Alpha-fetoprotein (AFP) has an established role in HCC prognosis. The objective was to evaluate whether AFP variation during SOR treatment reflects the lack of progression to SOR and can be used as a prognostic factor. Methods: AFP levels were prospectively analyzed in 114 patients to determine whether the time to progression of AFP (TPA) at 3 months had a prognostic value for survival. Results: Between July 2007 and October 2012, 114 patients were included (mean age 64 years, 97 male, 96 with cirrhosis). Etiology was alcohol 47 (41%) and hepatitis C virus (HCV) 31 (27%). According to the Barcelona Clinic Liver Cancer (BCLC) staging system: A (one case), B (24 cases) and C (89 cases). The Child-Pugh was Class A in 89 cases. The general condition of the patient according to ECOG-PS was 0 in 73 cases. The median duration of treatment was 5 months (3.47 - 6.53, 95% CI). The median overall survival (OS) was 9.23 months. The standard dose was maintained in 26 patients (22.8%). Sixty-seven percent of patients experienced at least one adverse event grade 3-4. The time to progression of AFP lower or higher than 3 months was an independent prognostic factor of OS (univariate and multivariate analysis): 8.10 vs. 18.85 months, P < 0.001. Conclusion: HCC treated with SOR with TPA > 3 months had longer OS, and TPA was an independent prognostic factor.
    Full-text · Article · Nov 2014 · Journal of Cancer Therapy
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hintergrund: Das hepatozelluläre Karzinom (HCC) ist eine der häufigsten Tumorerkrankungen weltweit. Mit dem Multikinase-Inhibitor Sorafenib konnte erstmals ein signifikanter Überlebensvorteil bei Patienten mit fortgeschrittenem HCC gezeigt werden. Bis heute ist Sorafenib die einzige zugelassene systemisch wirksame Substanz für Patienten mit fortgeschrittenem HCC. Die weiteren Behandlungsoptionen für Patienten mit einem fortgeschrittenen HCC sind jedoch beschränkt. Es fehlen insbesondere Second-line-Therapien für Patienten, die Sorafenib nicht tolerieren und/oder hierunter progredient werden. Methode: Neue molekulare Therapien befinden sich in klinischer Entwicklung, bislang allerdings mit zumeist ernüchternden Ergebnissen. Ergebnisse: Untersuchungen der alternativen Angiogenese-Inhibitoren Sunitinib und Brivanib, der EGFR(epidermaler Wachstumsfaktor-Rezeptor)-Inhibitoren Erlotinib, Gefitinib, Lapatinib und Cetuximab sowie des MEK(Mitogen-aktivierte Proteinkinase)-Inhibitors Selumetinib waren bislang nicht zielführend. Erfolg versprechend erscheint die Inhibition von c-MET mit Tivantinib, die bei c-MET-überexprimierenden Patienten eine signifikante Verlängerung des Überlebens und der Zeit zur Progression erbrachte. Untersuchungen von anderen Zielgruppen wie unter anderem Inhibitoren von mTOR, PI3K/ Akt und IGFR befinden sich in teils noch früher klinischer Entwicklung und bleiben abzuwarten. Schlussfolgerungen: Die Entwicklung der systemischen Behandlung des HCC bleibt anspruchsvoll. Zunehmend zeichnet sich ab, dass bei HCC-Patienten eine schwierige Balance zwischen Toxizität der Behandlung und antitumoraler Wirkung besteht, die eine signifikante Verbesserung des Überlebens der Patienten ermöglicht. Eine Lösung dieses Dilemmas könnte in der Identifikation von prognostischen und prädiktiven Faktoren wie c-MET bestehen, die eine personalisierte und effektive Therapie in Subgruppen der HCC-Patienten ermöglichen sollte.
    Full-text · Article · Apr 2013 · Viszeralmedizin / Visceral Medicine
Show more