Randomized Phase II Study of Gemcitabine Monotherapy vs. Gemcitabine with an EPA-Enriched Oral Supplement in Advanced Pancreatic Cancer.

BACKGROUND: Pancreatic cancer is often associated with cachexia. It had been reported that eicosapentaenoic acid (EPA) improve cachexia. This study aimed to evaluate the efficacy and safety of gemcitabine with an EPA-enriched oral supplement in patients with advanced pancreatic cancer. METHODS: This open-label phase II study consisted of patients (pts) who were randomly categorized into the EPA group (1,000 mg/m2 gemcitabine was administered on day 1, 8, and 15, every 4 weeks while an EPA-enriched oral supplement (prosure®, EPA 1.056 mg per pack) was taken daily at the maximum of two packs or the gemcitabine monotherapy group with an allocation ratio of 2:1. The primary endpoint was the evaluation of the 1-year survival estimating 10% addition. RESULTS: Randomized 68 pts were examined (EPA: 45, gemcitabine: 23). The 1-year survival probability of the EPA group was 35% while the gemcitabine group was 19%. The median survival times were 8.2 and 9.7 mo, respectively. The hazard ratio for EPA group was 0.79 [95% CI 0.46-1.37]; (P = 0.40). The toxicities were mild and insignificant in both groups. More beneficial effects of EPA in survival were observed in men, pancreatic body-tail and low C-reactive protein patients. CONCLUSION: An EPA-enriched oral supplement may be effective in advanced pancreatic cancer.

Repeated Lusutrombopag Treatment for Thrombocytopenia in Patients with Chronic Liver Disease.

BACKGROUND/AIMS: Lusutrombopag, a small-molecule thrombopoietin receptor agonist, is used to treat thrombocytopenia based on the results of a phase 3 trial, including data for single-use administration in patients with chronic liver disease (CLD) undergoing invasive procedures. We aimed to evaluate the efficacy and safety of repeated lusutrombopag use. METHODS: Lusutrombopag was administered repeatedly in patients undergoing multi-cycle invasive procedures at intervals >1 month. RESULTS: Data from 8 patients (median platelet count at baseline, 44.0 [range, 35-49] × 109/L) and 25 cycles of invasive procedures, including 2 cycles in 3 patients, 3 cycles in 4 patients, and 7 cycles in 1 patient, were retrospectively evaluated. The procedures included 18 transarterial chemoembolizations, 5 radiofrequency ablations, and 2 liver needle biopsies. Platelet counts increased significantly compared with baseline, and median changes in platelet counts were 46.0 × 109/L (p = 0.012) in cycle 1, 44.0 × 109/L (p = 0.012) in cycle 2, and 42.0 × 109/L (p = 0.008) in cycles 3-7. No severe adverse events, including portal vein thrombus or bleeding, were observed. CONCLUSIONS: Repeated use of lusutrombopag might be safe and effective against thrombocytopenia in patients with CLD undergoing multi-cycle invasive procedures, although long-term data from more patients are required.

A Phase II Trial of Everolimus in Patients with Advanced Pancreatic Neuroendocrine Carcinoma Refractory or Intolerant to Platinum-Containing Chemotherapy (NECTOR Trial).

BACKGROUND: Platinum-containing regimens are widely used as first-line chemotherapy for unresectable pancreatic neuroendocrine carcinoma (NEC), but second-line chemotherapies have yet to be established. OBJECTIVES: We evaluated the safety and efficacy of everolimus in patients with pancreatic NEC refractory or intolerant to platinum-containing chemotherapy. METHODS: This study was a prospective, multicenter, phase II trial in patients with pancreatic NEC after platinum-containing chemotherapy. Everolimus treatment was continued until disease progression or intolerable toxicity was observed. The primary endpoint was progression-free survival (PFS). RESULTS: Participants comprised 25 patients. Median age was 63 years, median PFS was 1.2 months (95% confidence interval [CI] 0.9-3.1 months), median overall survival was 7.5 months (95% CI 3.1-13.5 months), overall response rate was 0%, and disease control rate was 39.1%. Common grade 3/4 adverse events were hyperglycemia (20%), thrombocytopenia (16%), and anemia (16%). CONCLUSION: The efficacy of everolimus was limited in patients with unresectable pancreatic NEC.

Randomized, phase II trial of sequential hepatic arterial infusion chemotherapy and sorafenib versus sorafenib alone as initial therapy for advanced hepatocellular carcinoma: SCOOP-2 trial.

BACKGROUND: The efficacy of hepatic arterial infusion chemotherapy (HAIC) for advanced hepatocellular carcinoma (HCC) remains unclear. We conducted a multi-center randomized phase II study comparing a sequential HAIC-sorafenib regimen versus sorafenib alone as an initial therapy for HCC. METHODS: Patients were randomly assigned (ratio, 1:1) to receive sequential HAIC with cisplatin followed by sorafenib (HAIC group, n = 35) or sorafenib alone (sorafenib group, n = 33) as an initial therapy. The primary endpoint was the one-year survival rate. Secondary endpoint included overall survival (OS), the 2-year survival rate, the time-to-progression (TTP), the objective response rate (ORR), the disease control rate (DCR), and safety. RESULTS: For the primary endpoint, the one-year survival rates were 46% in the HAIC group and 58% in the sorafenib group. The median OS period was 10.0 months (95% CI, 7.0-18.8) in the HAIC group and 15.2 months (95% CI, 8.2-19.7) in the sorafenib group (hazard ratio [HR], 1.08; 95% CI, 0.63 to 1.86, P = 0.78). The median TTP, ORR and DCR in the HAIC group were 2.8 months (95% CI, 1.7-5.5), 14.3, and 45.7%, respectively, while those in the sorafenib group were 3.9 months (95% CI, 2.3-6.8), 9.1, and 45.5%, respectively. No unexpected adverse events related to HAIC or sorafenib were observed in either group. CONCLUSIONS: Sequential HAIC with cisplatin and sorafenib does not improve the survival benefit, compared with sorafenib alone, when used as an initial therapy for advanced HCC. However, this study was underpowered in regard to its primary and secondary endpoints, so the results should be interpreted with caution. TRIAL REGISTRATION: UMIN ID 000006147 , registration data: August 11, 2011.

Randomized phase III trial of post-operative chemotherapy for patients with stage I/II/III small bowel adenocarcinoma (JCOG1502C, J-BALLAD).

A randomized phase III trial was initiated in May 2017 to confirm the superiority of post-operative therapy with capecitabine and oxaliplatin over observation in terms of relapse-free survival in patients with curatively resected small bowel adenocarcinoma. Total 150 patients will be enrolled from 20 Japanese institutions over a period of 6.5 years. Relapse-free survival is the primary endpoint, while the secondary endpoints are overall survival, disease-free survival as defined by the Japan Clinical Oncology Group (JCOG), disease-free survival as defined by the International Rare Cancer Initiative (IRCI), and adverse events. Global phase III trial of IRCI to confirm the superiority of post-operative chemotherapy for small bowel adenocarcinoma was started in the UK in August 2015 (ClinicalTrials.gov Identifier: NCT02502370). An integrated analysis of the IRCI trial and our study are planned. Our trial has been registered in the UMIN Clinical Trials Registry as UMIN000027280 (http://www.umin.ac.jp/ctr/index.htm).

Alpha-fetoprotein kinetics in patients with hepatocellular carcinoma receiving ramucirumab or placebo: an analysis of the phase 3 REACH study.

BACKGROUND: Post-hoc analyses of AFP response and progression and their relationship with objective measures of response and survival were performed in patients from REACH. METHODS: Serum AFP was measured at baseline and every 3 cycles (2 weeks/cycle). Associations between AFP and radiographic progression and efficacy end points were analysed. RESULTS: Median percent AFP increase from baseline was smaller in the ramucirumab than in the placebo arm throughout treatment. Time to AFP progression (HR 0.621; P < 0.0001) and to radiographic progression (HR 0.613; P < 0.0001) favoured ramucirumab. Association between AFP and radiographic progression was shown at 6 (OR 6.44, 95% CI 4.03, 10.29; P < 0.0001) and 12 weeks (OR 2.28, 95% CI 1.47, 3.53; P = 0.0002). AFP response was higher with ramucirumab compared with placebo (P < 0.0001). More patients in the ramucirumab arm experienced tumour shrinkage and AFP response compared with placebo. Survival was longer in patients with AFP response (13.6 months) than in patients without (6.2 months), irrespective of treatment (HR 0.457, P < 0.0001). CONCLUSIONS: Treatment with ramucirumab prolonged time to AFP progression, slowed AFP increase and was more likely to induce AFP response. Similar benefits in radiographic progression and response correlated with AFP changes.

Switch to miriplatin for multinodular hepatocellular carcinoma unresponsive to transarterial chemoembolization with epirubicin: a prospective study.

OBJECTIVE: The aim of this prospective study was to evaluate the efficacy of transarterial chemoembolization using miriplatin, a platinum-based anticancer drug, as a retreatment regimen for hepatocellular carcinoma (HCC) unresponsive to chemoembolization using epirubicin. METHODS: Between April 2013 and December 2014, we enrolled 57 consecutive chamoembolization-naïve patients with unresectable HCC, and performed chemoembolization with epirubicin. Treatment effect, necrotizing rate of the target nodules, was evaluated at 1-3 months after treatment using contrast-enhanced CT or MRI. We subsequently included retreatment chemoembolization with miriplatin for patients whose treatment effect was <50% after chemoembolization with epirubicin. The treatment effect after chemoembolization with miriplatin and the liver function before and after chemoembolization were evaluated. RESULTS: Eighteen patients of the 57 showed a treatment effect <50% after chemoembolization with epirubicin, and were switched to chemoembolization with miriplatin. The treatment effect after chemoembolization with miriplatin was ≥50% in four (22%) patients. Four of the remaining 14 (78%) patients who had <50% necrosis exhibited deterioration of the liver function after chemoembolization with miriplatin. Univariate analysis indicated that an alpha-fetprotein-L3 level <10% and a serum albumin level ≥3.6 g/dl were predictive factors of therapeutic response after chemoembolization with miriplatin (P < 0.05). However, there was no predictive factor regarding the deterioration of liver function after chemoembolization with miriplatin. CONCLUSIONS: In unresectable HCC patients who were unresponsive to chemoembolization with epirubicin, switching the chemotherapeutic regimen to a platinum-based anticancer drug in retreatment chemoembolization should be considered as a treatment option. Trial registration: UMIN 000015887.

Unexpected Side Effects of a High S-1 Dose: Subanalysis of a Phase III Trial Comparing Gemcitabine, S-1 and Combinatorial Treatments for Advanced Pancreatic Cancer.

OBJECTIVE: In this subanalysis of a phase III trial using three categorized doses of S-1, the influence of the actual doses on safety and efficacy was evaluated. METHODS: We compared the efficacy and safety of the S-1 or gemcitabine plus S-1 combination (GS) arm between the top 10% group and the bottom 10% group according to the initial doses of S-1: ≥77.6 versus ≤65.9 mg/m2/day (n = 28 vs. 28) in the S-1 arm, and ≥65.1 versus ≤53.8 mg/m2/day (n = 27 vs. 28) in the GS arm. RESULTS: Overall and progression-free survival were not significantly different between these two groups: hazard ratios of 0.818 and 0.761 with p values of 0.498 and 0.330 in the S-1 arm, and hazard ratios of 0.836 and 0.759 with p values of 0.557 and 0.323 in the GS arm, respectively. Incidences of grade 3-4 hematological toxicities were significantly higher in the top 10% group than in the bottom 10% group: 42.9 versus 14.3 and 85.2 versus 57.1%, with p values of 0.037 and 0.037 in the S-1 and the GS combination arm, respectively. CONCLUSIONS: Higher actual doses of S-1 were associated with a higher incidence of hematological toxicity even in the same dose setting.

Duodenal stenting followed by systemic chemotherapy for patients with pancreatic cancer and gastric outlet obstruction.

OBJECTIVES: Endoscopic duodenal stenting has recently been proposed as a substitute for surgical gastrojejunostomy for the treatment of gastric outlet obstruction. We aimed to evaluate the efficacy and safety of duodenal stenting followed by systemic chemotherapy for patients with advanced pancreatic cancer with gastric outlet obstruction. METHODS: This was a single-center, retrospective cohort study, conducted at an academic medical center, of 71 patients with advanced pancreatic cancer and gastric outlet obstruction (mean age: 67.6 years; range: 31-92 years) who underwent duodenal stenting with or without subsequent chemotherapy. Overall survival, duration of oral intake of foods, the rate of introduction of chemotherapy, progression-free survival, and adverse events were evaluated. RESULTS: Stent placement was technically successful in 69 (97%) patients. Thirty-six (51%) patients were treated with chemotherapy: 17 with gemcitabine alone, 15 with S-1 alone, 3 with FOLFIRINOX, and 1 with paclitaxel. Median progression-free survival and overall survival after chemotherapy were 2.6 months (95% confidence interval: 1.3-3.9 months) and 4.7 months (95% confidence interval: 2.6-6.8 months), respectively. Cases of grade 3 anemia were frequently observed during chemotherapies following duodenal stenting (32%). Tumor stage, performance status, neutrophil-to-lymphocyte ratio, and introduction of chemotherapy were independent prognostic factors for survival (hazard ratios of 3.73, 2.21, 2.69, and 1.85 with p-values of <0.001, 0.010, <0.001, and 0.045, respectively). CONCLUSIONS: The findings of this study suggest that endoscopic duodenal stenting is an advantageous treatment in advanced pancreatic cancer patients with gastric outlet obstruction regarding its safety and smooth conduction of subsequent chemotherapies.

Associations between polymorphisms in folate-metabolizing genes and pancreatic cancer risk in Japanese subjects.

BACKGROUND: Evidence supporting the associations between folate metabolizing gene polymorphisms and pancreatic cancer has been inconclusive. We examined their associations in a case-control study of Japanese subjects. METHODS: Our case-control study involved 360 newly diagnosed pancreatic cancer cases and 400 frequency-matched, non-cancer control subjects. We genotyped four folate metabolizing gene polymorphisms, including two polymorphisms (rs1801133 and rs1801131) in the methylenetetrahydrofolate (MTHFR) gene, one polymorphism (rs1801394) in the 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) gene and one polymorphism (rs1805087) in the 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) gene. Genotyping was performed using Fluidigm SNPtype assays. Unconditional logistic regression methods were used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) for the associations between folate metabolizing gene variants and pancreatic cancer risk. RESULTS: Overall we did not observe a significant association between these four genotypes and pancreatic cancer risk. For rs1801133, compared with individuals with the CC genotype of MTHFR C677T, the OR for those with the CT genotype and TT genotype was 0.87 (0.62-1.22) and 0.99 (0.65-1.51), respectively. For rs1801131, individuals with the CC genotype had approximately 1.2-fold increased risk compared with those with the AA genotype, but the association was not statistically significant. In analyses stratified by smoking and drinking status, no significant associations were noted for C677T genotypes. No significant interactions were observed with smoking and drinking with respect to pancreatic cancer risk. CONCLUSIONS: Our data did not support the hypothesis that MTHFR polymorphisms or other polymorphisms in the folate metabolizing pathway are associated with pancreatic cancer risk.

Randomized phase II/III clinical trial of elpamotide for patients with advanced pancreatic cancer: PEGASUS-PC Study.

Gemcitabine is a key drug for the treatment of pancreatic cancer; however, with its limitation in clinical benefits, the development of another potent therapeutic is necessary. Vascular endothelial growth factor receptor 2 is an essential target for tumor angiogenesis, and we have conducted a phase I clinical trial using gemcitabine and vascular endothelial growth factor receptor 2 peptide (elpamotide). Based on the promising results of this phase I trial, a multicenter, randomized, placebo-controlled, double-blind phase II/III clinical trial has been carried out for pancreatic cancer. The eligibility criteria included locally advanced or metastatic pancreatic cancer. Patients were assigned to either the Active group (elpamotide + gemcitabine) or Placebo group (placebo + gemcitabine) in a 2:1 ratio by the dynamic allocation method. The primary endpoint was overall survival. The Harrington-Fleming test was applied to the statistical analysis in this study to evaluate the time-lagged effect of immunotherapy appropriately. A total of 153 patients (Active group, n = 100; Placebo group, n = 53) were included in the analysis. No statistically significant differences were found between the two groups in the prolongation of overall survival (Harrington-Fleming P-value, 0.918; log-rank P-value, 0.897; hazard ratio, 0.87, 95% confidence interval [CI], 0.486-1.557). Median survival time was 8.36 months (95% CI, 7.46-10.18) for the Active group and 8.54 months (95% CI, 7.33-10.84) for the Placebo group. The toxicity observed in both groups was manageable. Combination therapy of elpamotide with gemcitabine was well tolerated. Despite the lack of benefit in overall survival, subgroup analysis suggested that the patients who experienced severe injection site reaction, such as ulceration and erosion, might have better survival.

Potential prognostic significance of a new proteomic profile in patients with advanced pancreatic adenocarcinoma.

OBJECTIVES: Seven-signal proteomic approach has recently been developed as a new proteomic profile measured by matrix-assisted laser desorption/ionization mass spectrometry. The aim of this study was to evaluate prognostic significance of this proteomic value in patients with pancreatic adenocarcinoma. METHODS: Blood samples from the patients with pancreatic adenocarcinoma were prospectively collected before treatments including surgical resection and systemic chemotherapies. The seven-signal proteomic profiles of the samples were measured, and the prognostic significance of the proteomic value was evaluated through comparison with other existing prognostic markers. RESULTS: Cut-off value of the proteomic profiles at 52 stratified overall prognosis of the patients (6.5 months vs. 10.9 months with the values ≥52 vs. <52, p = 0.020). In subgroup analyses of inoperable cases with carcinoembryonic antigen level of <5 ng/ml or performance status of 0-1, the proteomic value at 52 stratified their prognosis (p = 0.002 and p = 0.006, respectively). CONCLUSIONS: The new seven-signal proteomics showed useful prognostic significance for patients with pancreatic adenocarcinoma. Further studies with a large sample size would be required to evaluate whether this proteomic approach possibly complements the existing parameters, such as carcinoembryonic antigen and performance status.

Field practice study of half-dose sorafenib treatment on safety and efficacy for hepatocellular carcinoma: A propensity score analysis.

AIM: Patients with hepatocellular carcinoma (HCC) who receive an initial full dose of sorafenib (800 mg/day) often require a decreased dose (400 mg/day) or discontinuation of therapy because of severe adverse events. We conducted a retrospective analysis of patients with HCC to compare the safety and efficacy of full- to half-dose sorafenib. METHODS: We reviewed the medical records of 218 consecutive patients with intermediate or advanced stage HCC who received half (n = 73) or full-dose sorafenib (n = 145) between 2009 and 2012 at four institutions. A propensity score-matching analysis was used to adjust for potential bias. RESULTS: Multivariate logistic regression analysis showed that increased age was an independent factor for the selection of initial half-dose sorafenib (odds ratio, 1.10; 95% confidence interval, 1.05-1.15; P < 0.001). Fifty-eight patients each in the half-dose and full-dose groups were selected for propensity score matching. The incidence of grade 3-4 severe adverse effects was lower in the half-dose group (47.4% vs 66.7%, P = 0.037). In contrast, the median progression-free survival (PFS) and overall survival (OS) rates were not significantly different (half-dose group, 3.8 and 10.2 months; full-dose group, 2.5 and 8.8 months; P = 0.143 and 0.911, respectively). CONCLUSION: Propensity score-matched analyses indicate that initial half-dose sorafenib treatment led to fewer severe adverse effects and a comparable survival benefit compared with a full dose in select patients with HCC, particularly for those of advanced age.

Efficacy and safety of axitinib in combination with gemcitabine in advanced pancreatic cancer: subgroup analyses by region, including Japan, from the global randomized Phase III trial.

OBJECTIVE: Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1-3. This analysis compared efficacy and safety of axitinib plus gemcitabine in patients with advanced pancreatic cancer from Japan, North America and the European Union, enrolled in a randomized Phase III study. METHODS: Patients (n = 632), stratified by disease extent, were randomly assigned (1:1) to receive axitinib/gemcitabine or placebo/gemcitabine. Axitinib was administered at a starting dose of 5 mg orally twice daily and gemcitabine at 1000 mg/m(2) once weekly for 3 weeks in 4 week cycles. Primary endpoint was overall survival. RESULTS: Among Japanese patients, median overall survival was not estimable (95% confidence interval, 7.4 months-not estimable) with axitinib/gemcitabine (n = 58) and 9.9 months (95% confidence interval, 7.4-10.5) with placebo/gemcitabine (n = 56) (hazard ratio 1.093 [95% confidence interval, 0.525-2.274]). Median survival follow-up (range) was 5.1 months (0.02-12.3) with axitinib/gemcitabine vs. 5.4 months (1.8-10.5) with placebo/gemcitabine. Similarly, no difference was detected in overall survival between axitinib/gemcitabine and placebo/gemcitabine in patients from North America or the European Union. Common adverse events with axitinib/gemcitabine in Japanese patients were fatigue, anorexia, dysphonia, nausea and decreased platelet count. Axitinib safety profile was generally similar in patients from the three regions, although there were differences in incidence of some adverse events. An exploratory analysis did not show any correlation between axitinib/gemcitabine-related hypertension and overall survival. CONCLUSIONS: Axitinib/gemcitabine, while tolerated, did not provide survival benefit over gemcitabine alone in patients with advanced pancreatic cancer from Japan or other regions.

Enhancement of radiofrequency ablation of the liver combined with transarterial embolization using various embolic agents.

PURPOSE: Reducing blood flow in the liver during radiofrequency ablation causes enlargement of the ablation area. In this animal study, we evaluated the extended effects of radiofrequency ablation combined with transarterial embolization using various embolic agents. METHODS: We treated 38 radiofrequency ablation lesions after embolization in 13 pigs using the following embolic agents: gelatin sponge (Group A); iodized oil followed by gelatin sponge (Group B); 700-900 µm calibrated microspheres (Group C); and 100-300 µm calibrated microspheres (Group D). Lesion size and pathological evaluations of these ablation lesions were compared with those receiving radiofrequency ablation alone (control). RESULTS: Both the long- and short-axis diameters of the ablation lesions for Groups A, B, C, and D were significantly longer than those of controls (long axis/short axis for Groups A, B, C, D, and controls were 27.2/23.2, 30.2/26.0, 28.2/22.2, 32.0/24.4, and 23.2 mm/18.5 mm, respectively) (P < 0.05). The long-axis of the ablation lesion for Group D was significantly longer than those for both Groups A and C (P < 0.05). At pathological examination, the central ablation lesions showed coagulative necrosis with a surrounding hemorrhagic rim, and the microspheres were fitted to occlude the small arteries in peripheral liver parenchyma in Groups C and D. CONCLUSIONS: The extended effects of embolization with small microspheres may be stronger than those with large microspheres and were equal to those with iodized oil followed by gelatin sponge.

Phase II study of FOLFIRINOX for chemotherapy-naïve Japanese patients with metastatic pancreatic cancer.

The FOLFIRINOX combination of chemotherapy drugs had not been fully evaluated for Japanese pancreatic cancer patients. Therefore, we carried out a phase II study to examine the efficacy and safety of FOLFIRINOX in chemotherapy-naïve Japanese patients with metastatic pancreatic cancer. FOLFIRINOX (i.v. infusion of 85 mg/m(2) oxaliplatin, 180 mg/m(2) irinotecan, and 200 mg/m(2) l-leucovorin, followed by a bolus of 400 mg/m(2) fluorouracil and a 46-h continuous infusion of 2400 mg/m(2) fluorouracil) was given every 2 weeks. The primary endpoint was the response rate. The 36 enrolled patients received a median of eight (range, 1-25) treatment cycles. The response rate was 38.9% (95% confidence interval [CI], 23.1-56.5); median overall survival, 10.7 months (95% CI, 6.9-13.2); and median progression-free survival, 5.6 months (95% CI, 3.0-7.8). Major grade 3 or 4 toxicities included neutropenia (77.8%), febrile neutropenia (22.2%), thrombocytopenia (11.1%), anemia (11.1%), anorexia (11.1%), diarrhea (8.3%), nausea (8.3%), elevated alanine aminotransferase levels (8.3%), and peripheral sensory neuropathy (5.6%). Febrile neutropenia occurred only during the first cycle. There were no treatment-related deaths. FOLFIRINOX can be a standard regimen showing favorable efficacy and acceptable toxicity profile in chemotherapy-naïve Japanese patients with metastatic pancreatic cancer.

Japanese phase I study of GC33, a humanized antibody against glypican-3 for advanced hepatocellular carcinoma.

GC33 is a humanized mAb against human glypican-3 (GPC3). In the first-in-human study carried out in the USA, GC33 was well tolerated and showed preliminary antitumor activity in patients with advanced hepatocellular carcinoma. This study aimed to assess the safety, tolerability, and pharmacokinetic characteristics of GC33 in Japanese patients with advanced hepatocellular carcinoma. The study design was a conventional 3 + 3 dose-escalation design to determine the maximum tolerated dose of GC33 given i.v. at 5, 10, or 20 mg/kg weekly. Immunohistochemistry was carried out on tumor biopsies to evaluate GPC3 expression. Thirteen patients were enrolled across the three dose levels, and no patients observed any dose-limiting toxicity up to the highest planned dose of 20 mg/kg. The most common adverse events were decreased lymphocyte count, decreased natural killer cell count, increased C-reactive protein, and pyrexia. Grade 3 adverse events (increased blood pressure, decreased lymphocyte count, and decreased platelet count) were observed in two or more patients. The AUCinf showed a dose-proportional increase from the 5 mg/kg dose group to the 20 mg/kg dose group. The trough concentrations of GC33 appeared to reach a steady state after the fourth to the sixth dose. Seven of the 13 patients showed stable disease, the other six showed progressive disease. Furthermore, three patients showed long-term stable disease of more than 5 months. In conclusion, GC33 given at up to 20 mg/kg weekly was well tolerated in Japanese patients with advanced hepatocellular carcinoma.

Renal toxicity associated with weekly cisplatin and gemcitabine combination therapy for treatment of advanced biliary tract cancer.

OBJECTIVE: A combination of weekly cisplatin plus gemcitabine is a new standard regimen for patients with advanced biliary tract cancer (BTC). This regimen does not require prolonged hydration schedules; however, the long-time safety profile has not been evaluated so far. In particular, the aim of this study was to evaluate the renal function during this regimen. METHODS: We reviewed 79 consecutive patients with BTC who received the weekly cisplatin plus gemcitabine regimen. The incidence of adverse events was evaluated by CTCAE v4.0. RESULTS: A total of 402 courses were administered. The median cumulative dose of cisplatin was 250 mg (range: 25-825). The renal function was exacerbated gradually throughout the treatment course. The incidence of a decreased glomerular filtration rate (GFR) at <50 ml/min was significantly related to a pretreatment GFR at <80 ml/min and a total dose of cisplatin>400 mg [p=0.011, odds ratio (OR) 58.2, 95% confidence interval (CI): 2.5-1334.0 and p=0.021, OR 18.3, 95% CI: 1.6-215.5]. CONCLUSIONS: The combination of weekly cisplatin and gemcitabine for advanced BTC gradually affected the renal function, and it was highly recommended to focus on both the change of GFR and total dose of cisplatin during this regimen.

Therapeutic Outcome of Multidisciplinary Treatment in Unresectable Biliary Tract Cancer: A Multicenter Retrospective Analysis.

Background: There is little established evidence regarding treatment strategies for unresectable biliary tract cancer (BTC). This study aimed to clarify the situation of multidisciplinary treatment for unresectable BTC in the 2000s when there was no international standard first-line therapy. Methods: We retrospectively reviewed 315 consecutive patients with unresectable BTC who had been treated at seven tertiary institutions in Kanagawa Prefecture, Japan between 1999 and 2008. Results: The unresectable factors were as follows: locally advanced, 101 cases (32.1%); hematogenous metastases, 80 cases (25.4%); and peritoneal dissemination, 30 cases (9.5%). Chemotherapy or radiation therapy was administered to 218 patients (69.2%). The best supportive care was provided in 97 cases (30.8%). The most common regimen was gemcitabine monotherapy, followed by gemcitabine combination therapy and S-1 monotherapy. The 1- and 2-year survival rates of all patients were 34.6% and 12.2%, respectively. The median survival time (MST) was 8 months in all patients. The 1-year survival rate was 65%, and the MST was 12 months among the locally advanced patients, whereas patients with peritoneal dissemination had the worst outcome; the 1-year survival rate was 7%, and the MST was 5 months. Among treated 90 cases of perihilar cholangiocarcinoma, patients who received chemoradiotherapy (n = 24) had a significantly better outcome than those who received chemotherapy alone (MST: 20 vs. 11 months, P < 0.001). Conclusions: Unresectable BTC has heterogeneous treatment outcomes depending on the mode of tumor extension and location. Multidisciplinary treatment seems useful for patients with locally advanced BTC, whereas patients with metastatic disease still have a poor prognosis.

Inflammation in background cirrhosis evokes malignant progression in HCC development from HCV-associated liver cirrhosis.

OBJECTIVE: It is accepted that inflammation promotes malignant progression in the development of cancers. Whether, this is true for hepatocellular carcinoma (HCC) remains as an open question. We examined the relationship between the inflammatory histology activity index (HAI) in the background liver cirrhosis (LC) and the histological grading of the HCC in the hepatectomized HCC patients with HCV-associated LC. MATERIAL AND METHODS: Out of 264 HCC patients who underwent curative hepatic resection, 197 had HCV-associated LC. Among them, 52 patients with a small solitary HCC nodule (< 5 cm in diameter) were studied. Inflammation in the background LC was evaluated by modified Knodell's HAI. To evaluate the inflammation, piece meal necrosis, intra lobular cellular degeneration and focal necrosis, portal cellular inflammation (0-4, each) were estimated. The average HAI was calculated. The grade of malignancy of HCC was determined by WHO classification. RESULTS: The average HAI in the 15 patients with moderately differentiated HCC (4.3 ± 0.8, mean ± SD) was significantly larger than that in 11 patients with well differentiated HCC (3.5 ± 0.6, p = 0.036). The HAI in the 24 patients whose HCC nodules contained poorly differentiated HCC (5.2 ± 1.1) was significantly larger than that in patients with moderately differentiated HCC (p = 0.025). Thus, the HAI order was well differentiated group < moderately differentiated group < poorly differentiated group. CONCLUSIONS: Inflammation in the background non-cancerous cirrhotic portion would evoke malignant progression in HCC development from HCV-associated LC.