BackgroundCabozantinib, an orally bioavailable inhibitor of tyrosine kinases including MET, AXL, and VEGF receptors, was assessed in patients with hepatocellular carcinoma (HCC) as part of a phase 2 randomized discontinuation trial with nine tumor-type cohorts.Patients and methodsEligible patients had Child-Pugh A liver function and ≤1 prior systemic anticancer regimen, completed ≥4 weeks before study entry. The cabozantinib starting dose was 100 mg daily. After an initial 12-week cabozantinib treatment period, patients with stable disease (SD) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 were randomized to cabozantinib or placebo. The primary endpoint of the lead-in stage was objective response rate (ORR) at week 12, and the primary endpoint of the randomized stage was progression-free survival (PFS).ResultsAmong the 41 HCC patients enrolled, the week 12 ORR was 5%, with 2 patients achieving a confirmed partial response (PR). The week 12 disease control rate (PR or SD) was 66% (Asian subgroup: 73%). Of patients with ≥1 post-baseline scan, 78% had tumor regression, with no apparent relationship to prior sorafenib therapy. Alpha-fetoprotein (AFP) response (>50% reduction from baseline) occurred in 9 of the 26 (35%) patients with elevated baseline AFP and ≥1 post-baseline measurement. Twenty-two patients with SD at week 12 were randomized. Median PFS after randomization was 2.5 months with cabozantinib and 1.4 months with placebo, although this difference was not statistically significant. Median PFS and overall survival from Day 1 in all patients were 5.2 and 11.5 months, respectively. The most common grade 3/4 adverse events, regardless of attribution, were diarrhea (20%), hand-foot syndrome (15%), and thrombocytopenia (15%). Dose reductions were utilized in 59% of patients.ConclusionsCabozantinib has clinical activity in HCC patients, including objective tumor responses, disease stabilization, and reductions in AFP. Adverse events were managed with dose reductions.Trial registration numberNCT00940225.

Background:Molecularly targeted agents with anti-angiogenic activity, including bevacizumab, have demonstrated clinical activity in patients with advanced/metastatic hepatocellular carcinoma (HCC). This multicentre phase II study involving patients from several Asian countries sought to evaluate the safety and efficacy of bevacizumab plus capecitabine in this population.Methods:Histologically proven/clinically diagnosed advanced HCC patients received bevacizumab 7.5 mg kg–1 on day 1 and capecitabine 800 mg m–2 twice daily on days 1–14 every 3 weeks as first-line therapy.Results:A total of 45 patients were enrolled; 44 (96%) had extrahepatic metastasis and/or major vessel invasion and 30 (67%) had hepatitis B. No grade 3/4 haematological toxicity occurred. Treatment-related grade 3/4 non-haematological toxicities included diarrhoea (n=2, 4%), nausea/vomiting (n=1, 2%), gastrointestinal bleeding (n=4, 9%) and hand–foot syndrome (n=4, 9%). The overall response rate (RECIST) was 9% and the disease control rate was 52%. Overall, median progression-free survival (PFS) and overall survival (OS) were 2.7 and 5.9 months, respectively. Median PFS and OS were 3.6 and 8.2 months, respectively, for Cancer of the Liver Italian Programme (CLIP) score ⩽3 patients, and 1.4 and 3.3 months, respectively, for CLIP score 4 patients.Conclusion:The bevacizumab–capecitabine combination shows good tolerability and modest anti-tumour activity in patients with advanced HCC.

Gemcitabine plus doxorubicin produces modest activity and moderate toxicity in this cohort of Chinese patients with advanced HCC.

In order to examine the physical characteristics that may determine racial differences in lung volumes, we studied healthy, nonsmoking Caucasian, Chinese and Indian males of similar ages (range 18-51 yrs). We measured spirometric function, flow volume curves, lung volumes, inspiratory and expiratory muscle pressures, alveolar distensibility and diffusing capacity, together with height, weight and fat free mass. Chest shape was measured using radiographs. The mean total lung capacity and vital capacity in the Caucasian group, expressed as percentage predicted, were 5 and 10% higher than in the Chinese group and 17 and 20% higher than in the Indian group. Chinese values for these measurements were 12 and 10% greater than Indian. We found that Caucasians had higher fat free masses, higher inspiratory and expiratory muscle pressures and wider chests than the other races. The Caucasians and Chinese had longer chests than the Indians. There was no difference in alveolar distensibility or in the diffusion coefficient between the groups. These findings suggest that Caucasians have larger lung volumes than Chinese and Indians because they have increased numbers of alveoli and physically larger chest cavities, and not because of greater alveolar distensibility. Chest dimensions, together with height and race explained 90% of the variation in forced vital capacity and 86% of the variation in total lung capacity. Height multiplied by fat free mass, a "physique factor", previously suggested as the best predictive factor for forced vital capacity in Caucasians, did not account for much of the variation in forced vital capacity between Caucasians and Indians, presumably because it takes no account of differences in chest dimensions.