Multicenter Phase II Trial of Axitinib Monotherapy for Gemcitabine-Based Chemotherapy Refractory Advanced Biliary Tract Cancer (AX-BC Study).

LESSONS LEARNED: Axitinib exhibited marginal activity against gemcitabine-refractory unselected biliary tract cancer. Pretreated soluble vascular endothelial growth factor receptor-2 may be a useful biomarker for axitinib treatment outcome. Ascites should be carefully monitored in patients receiving anti-vascular endothelial growth factor receptor therapy including axitinib in advanced biliary tract cancer. BACKGROUND: There are no clear options for second-line treatment in patients with gemcitabine (GEM)-refractory biliary tract cancer (BTC). We conducted a multicenter, single-arm, phase II trial to confirm the efficacy and safety of axitinib, a potent selective inhibitor of vascular endothelial growth factor receptor (VEGFR)-1/2/3, in patients with GEM-refractory BTC. METHODS: Patients refractory or intolerant to GEM-based chemotherapy were enrolled. Axitinib was administered orally at an initial dose of 5 mg twice daily. The primary endpoint was progression-free survival (PFS), and the threshold and expected values were set at 2 and 3 months, respectively. The target sample size was 32 patients. RESULTS: Nineteen patients were enrolled. The trial was interrupted for a total of 13 months for the evaluation of adverse events. Thirteen patients were previously treated with ≥2 regimens. The median PFS was 2.8 months (95% confidence interval [CI]: 2.1-4.1). The median overall survival was 5.8 months (95% CI: 3.3-9.7). The response rate was 5.3% (95% CI: 0.0-15.3). Grade 3 ascites occurred in two patients. Baseline soluble VEGFR-2 levels were significantly associated with PFS. CONCLUSION: Axitinib exhibited marginal activity against GEM-refractory BTC. Ascites should be carefully monitored in axitinib-treated patients with advanced BTC.

A phase II study of FOLFIRINOX with primary prophylactic pegfilgrastim for chemotherapy-naïve Japanese patients with metastatic pancreatic cancer.

BACKGROUND: Although FOLFIRINOX is currently one of the standard therapies for chemotherapy-naïve patients with metastatic pancreatic cancer (MPC), the high rate of febrile neutropenia (FN) presents a clinical problem. This study aimed to evaluate the safety and efficacy of primary prophylactic pegfilgrastim with FOLFIRINOX in Japanese MPC patients. METHODS: FOLFIRINOX (intravenous oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, levofolinate 200 mg/m2, 5-fluorouracil (5-FU) bolus 400 mg/m2 and 5-FU 46 h infusion 2400 mg/m2) and pegfilgrastim 3.6 mg on day 4 or 5, every 2 weeks was administered to previously untreated MPC patients. The primary endpoint was the incidence of FN during the first 3 cycles. The planned sample size was 35 patients, but the trial was predefined to discontinue enrollment for safety if 4 patients developed FN. RESULTS: At the enrollment of 22 patients, 4 patients developed FN in the first cycle, resulting in an incidence of FN of 18% {95% confidence interval [CI], 0.5-40.3%}, and enrollment was discontinued early. The incidence of grade 3 or higher neutropenia was 36.4%. Median relative dose intensities during the initial 3 cycles of oxaliplatin, irinotecan, bolus 5-FU, infusional 5-FU, and levofolinate maintained high (100%, 89.0%, 100%, 66.0%, and 100%, respectively). Response rate and median overall survival were 54.5% (95% CI 32.7-74.9) and 15.7 months (95% CI 7.9-18.8), respectively. CONCLUSIONS: This phase II study could not demonstrate any reduction in the incidence of FN, nevertheless some patients experience benefits for efficacy by maintaining dose intensity using prophylactic pegfilgrastim. TRIAL REGISTRATION: http://www.umin.ac.jp/ctr/index-j.htm , UMIN000017538. Date of registration: May/13/2015.

Quality evaluation of investigator-initiated trials using post-approval cancer drugs in Japan.

Investigator-initiated trials (IIT) are important aspects of medical research and have contributed substantially to modern oncology. IIT using post-approval drugs have been conducted by domestic institutions in Japan. Data from the present study were obtained by all IIT registered clinical trials for five cancers (lung, colorectal cancer, gastric cancer, liver cancer, and breast cancer) using drugs approved from 1999 to 2009 in Japan. Kaplan-Meier method, analysis of variance (anova), and Kruskal-Wallis test were used to estimate time to enrolment completion (TTEC) and time to enrolment per patient (TTEP). Of 1222 trials eligible for analysis, 465 trials (38%) completed enrolment to the studies, and 203 trials (17%) published results. In the distribution according to trial phase, 98 (8%) were phase I, 1058 (87%) were phase I/II + II, and 66 (5%) were phase II/III + III. Accrual achievement and publication rates were higher in late-phase than in early-phase trials. Median TTEC was 1387 days (95% confidence interval [CI], 1302-1472). Median TTEP was 38.5 days (95% CI, 34.5-42.5). The median TTEC and TTEP were significantly different in each trial phase (P < 0.01), funding source (P < 0.01), and publication status (median TTEC published trials versus unpublished trial; 720 days vs 1672 days, median TTEP; 16 days vs 55.8 days; P < 0.001). Many IIT using approved cancer drugs have been conducted; however, the quality of the clinical trials was low in terms of accrual achievement, publication rate, and time to publication of trial results.

Transarterial infusion chemotherapy with cisplatin plus S-1 for hepatocellular carcinoma treatment: a phase I trial.

BACKGROUND: In Japan, transarterial infusion chemotherapy using cisplatin (CDDP-TAI) is frequently used for advanced hepatocellular carcinoma (HCC). Moreover, oral chemotherapy with S-1, an oral fluoropyrimidine derivative, has also elicited promising responses in HCC patients. We determined the recommended dosage for CDDP-TAI plus S-1 combination therapy for advanced HCC. METHODS: Twelve Child-Pugh class A or B patients with advanced HCC who met the eligibility criteria were enrolled in this phase I trial. Patients received CDDP-TAI (infusion, day 1) plus S-1 (oral administration, days 1-21) every 5 weeks until disease progression. RESULTS: Cisplatin (65 mg/m(2)) was administered with S-1 at 50 mg · m(-2) day-1 (level 1, 3 patients), 60 mg · m(-2) day-1 (level 2, 3 patients), or 80 mg · m(-2) day-1 (level 3, 6 patients). The total number of treatment courses was 25 (median, 2 courses/patient; range, 1-6 courses). Dose-limiting toxicity was not observed in any patient at any level; therefore, the recommended dosage for cisplatin and S-1 in combination was level 3. Grade 3 adverse events were elevated alanine aminotransferase levels (2 patients), elevated aspartate aminotransferase levels (2 patients), anemia (1 patient), and decreased platelet counts (1 patient). Median progression-free survival and overall survival were 73 days and 328 days, respectively. The disease control rate was 58% (7/12); 17% (2/12) of patients achieved partial response and 42% (5/12) achieved stable disease. CDDP-TAI plus S-1 is safe for the treatment of HCC. CONCLUSION: The recommended dosage for further evaluation of this combination therapy in phase II studies is 65 mg/m(2) CDDP and 80 mg/m(2) S-1. TRIAL REGISTRATION: UMIN; number: UMIN000003113.

Usefulness of procalcitonin for severity assessment in patients with acute cholangitis.

BACKGROUND: The aim of the present study was to examine the usability of procalcitonin (PCT) for severity assessment in patients with acute cholangitis (AC). METHODS: Serum PCT concentrations were measured on admission in patients with AC. Patients were classified with mild, moderate, or severe AC based on severity assessment guidelines. RESULTS: We included 159 treatment-naïve patients with AC (95 males, 64 females) in this study. The median PCT concentrations were 0.08 ng/mL (interquartile range (IQR) 0.04 - 0.18 ng/mL), 0.37 ng/mL (IQR 0.15 - 1.85 ng/mL), and 5.56 ng/mL (IQR 3.59 - 25.89 ng/mL) in patients with mild, moderate and severe AC, respectively. PCT concentrations were significantly higher in patients with severe AC than in patients with moderate AC (p < 0.0001), and in patients with moderate AC than in patients with mild AC (p < 0.0001). The areas under the receiver operating characteristic curves for PCT to discriminate patients with moderate and severe AC were 0.84 (95% CI 0.77 to 0.92, p < 0.001) and 0.86 (95% CI 0.78 to 0.92, p < 0.001), respectively. CONCLUSIONS: Serum PCT concentrations were elevated in patients with AC and may be a useful parameter for the severity assessment of AC.

Germline mutations in cancer-predisposition genes in patients with biliary tract cancer.

The prevalence of germline mutations in patients with biliary tract carcinoma (BTC) remains unclear. Here, we investigated the prevalence and types of germline mutations in patients with BTC. We reviewed 269 patients with pathologically proven BTC and collected clinical characteristics, including medical and family histories. Additionally, we evaluated germline variants in 21 genes associated with hereditary predisposition for cancer by targeted sequencing in patients meeting ≥1 of the following criteria: 1) hereditary breast and/or ovarian cancer (HBOC) testing criteria modified for BTC, 2) Revised Bethesda Guidelines (RBGs) modified for BTC (modified RBG), 3) familial BTC criteria, or 4) young BTC criteria. Among the 269 patients, 80 met at least one criterion. Three pathogenic mutations in three patients were identified: two in BRCA2 and one in BRCA1. Among the 16 patients meeting modified HBOC testing criteria, 2 harbored germline BRCA2 mutations, and 1 harbored a germline BRCA1 mutation. However, no mutation in mismatch-repair genes were detected, despite 63 patients meeting modified RBG screening criteria and 18 qualifying as young BTC patients. We detected high prevalence of pathogenic germline mutations in BRCA1/2 and none in mismatch-repair genes in BTC patients following enrichment according to family or medical history in this study.

Lipid profiling of pre-treatment plasma reveals biomarker candidates associated with response rates and hand-foot skin reactions in sorafenib-treated patients.

Sorafenib is a multi-kinase inhibitor for treatment of advanced hepatocellular carcinoma (HCC). Beyond its clinical benefit against advanced HCC, the efficacy and safety of sorafenib chemotherapy are critical concerns. In this study, we addressed the lipid profiles associated with the efficacy and safety of sorafenib chemotherapy. Plasma samples from HCC patients before sorafenib chemotherapy (N = 44) were collected and subjected to lipidomic analysis. We measured the levels of 176 lipids belonging to 8 classes of phosphoglycerolipids, 2 classes of sphingolipids, 3 classes of neutral lipids, and 4 other classes of lipids. To characterize lipids associated with efficacy, we compared the responder group (N = 21; partial response and stable disease) with non-responder group (N = 22; progressive disease). To characterize lipids associated with hand-foot skin reaction (HFSR), we compared the susceptible group (N = 12; grade 2 and 3) with non-susceptible group (N = 32; grade 0 and 1). The levels of 8 lipids, including phosphatidylcholine (PC)[34:2], PC[34:3]a, PC[35:2], PC[36:4]a, PC[34:3e], acylcarnitine (Car)[18:0], cholesterol ester[20:2], and diacylglycerol (DG)[34:2], were significantly lower in the responder group, and 6 out of 8 these lipids contained FA(18:2). In addition, the levels of 7 lipids (Car[12:0], Car[18:0], Car[18:1], Car[20:1] and fatty acid amides (FAA[16:0], FAA[18:0], and FAA[18:1]b)) were significantly lower in the group susceptible to HFSR. Our comprehensive lipidomics study using samples from sorafenib-treated patients with HCC revealed that significant differences in the lipid profiles of pre-treatment plasma were associated with sorafenib efficacy and sorafenib-induced HFSR. Validation using another set of patient plasma samples and elucidating the molecular basis of these changes will lead to better treatment with sorafenib chemotherapy.

Incidence and risk factors for venous thromboembolism in patients with pretreated advanced pancreatic carcinoma.

Patients with pancreatic carcinoma are at an increased risk of venous thromboembolism (VTE), which is a major cause of morbidity and mortality in various types of cancer. The aim of this study was to determine the incidence and clinical significance of VTE in patients with pancreatic carcinoma, and to identify biomarkers for the detection of VTE in these patients. The eligibility criteria were chemo-naïve patients with primary pancreatic carcinoma, an Eastern Cooperative Oncology Group performance status of 0-2, and adequate organ function. All patients were screened for VTE using compression ultrasonography and dynamic computed tomography. The primary endpoint was the incidence of VTE, which we hypothesized would be between 10.0-20.0% for symptomatic and asymptomatic patients combined. Associations between clinical presentation and VTE were evaluated. VTE-associated markers were also investigated for their role in predicting prognosis. In total, 103 patients met the eligibility criteria. The overall cumulative incidence rate of VTE in patients with previously untreated pancreatic carcinoma was 16.5%. VTE occurrence was strongly associated with elevated serum D-dimer, fibrin degradation product, thrombin/antithrombin III complex, and prothrombin fragment 1 + 2 levels. The median overall survival time of VTE-positive and VTE-negative patients was 427 and 515 days, respectively. Approximately one-sixth of patients with advanced pancreatic carcinoma experienced VTE, although most were asymptomatic. Measurement of serum D-dimer, fibrin degradation product, thrombin/antithrombin III complex, and prothrombin fragment 1 + 2 levels may be useful for the early detection of VTE in patients with advanced pancreatic carcinoma.

Germline variants in pancreatic cancer patients with a personal or family history of cancer fulfilling the revised Bethesda guidelines.

BACKGROUND: Pancreatic cancer (PC) is categorized as a neoplasm associated with Lynch syndrome; however, the precise proportion of PC patients harboring DNA mismatch repair genes (MMR genes) remains unclear, especially in the Asian population. METHODS: Among 304 Japanese patients with pathologically proven pancreatic ductal adenocarcinoma, we selected 20 (6.6%) patients with a personal or family history involving first- or second-degree relatives fulfilling the revised Bethesda guidelines (RBG), defined as RBG-compatible cases. We analyzed germline variants in 21 genes related to a hereditary predisposition for cancer as well as clinical features in all 20 cases. RESULTS: The RBG-compatible cases did not show any unique clinicopathological features. Targeted sequencing data revealed three patients carrying deleterious or likely deleterious variants. Specifically, these three patients harbored a nonsense variant in ATM, a frameshift variant in ATM, and a concurrent nonsense variant in PMS2 and missense variant in CHEK2 (double-mutation carrier), respectively. Although an MMR gene mutation was identified in only one of the 20 patients, up to 15% of the RBG-compatible PC cases were associated with germline deleterious or likely deleterious variants. CONCLUSIONS: These findings showed that these guidelines could be useful for identifying PC patients with DNA damage repair genes as well as MMR genes.

Familial pancreatic cancer: Concept, management and issues.

Familial pancreatic cancer (FPC) is broadly defined as two first-degree-relatives with pancreatic cancer (PC) and accounts for 4%-10% of PC. Several genetic syndromes, including Peutz-Jeghers syndrome, hereditary pancreatitis, hereditary breast-ovarian cancer syndrome (HBOC), Lynch syndrome, and familial adenomatous polyposis (FAP), also have increased risks of PC, but the narrowest definition of FPC excludes these known syndromes. When compared with other familial tumors, proven genetic alterations are limited to a small proportion (< 20%) and the familial aggregation is usually modest. However, an ethnic deviation (Ashkenazi Jewish > Caucasian) and a younger onset are common also in FPC. In European countries, "anticipation" is reported in FPC families, as with other hereditary syndromes; a trend toward younger age and worse prognosis is recognized in the late years. The resected pancreases of FPC kindred often show multiple pancreatic intraepithelial neoplasia (PanIN) foci, with various K-ras mutations, similar to colorectal polyposis seen in the FAP patients. As with HBOC patients, a patient who is a BRCA mutation carrier with unresectable pancreatic cancer (accounting for 0%-19% of FPC patients) demonstrated better outcome following platinum and Poly (ADP-ribose) polymerase inhibitor treatment. Western countries have established FPC registries since the 1990s and several surveillance projects for high-risk individuals are now ongoing to detect early PCs. Improvement in lifestyle habits, including non-smoking, is recommended for individuals at risk. In Japan, the FPC study group was initiated in 2013 and the Japanese FPC registry was established in 2014 by the Japan Pancreas Society.

A retrospective analysis of factors associated with selection of end-of-life care and actual place of death for patients with cancer.

OBJECTIVES: The factors associated with end-of-life (EOL) care that patients with cancer selected and actual place of death (POD) is less elucidated. We analysed how specific EOL care, especially anticancer therapies, selected by patients with pancreatic carcinoma affected their POD in Japan. SETTING: A retrospective cohort study using clinical records of a single institute. PARTICIPANTS: This study included 433 advanced or recurrent patients with pancreatic carcinoma who had completed standard chemotherapies and were receiving hospice care in the National Cancer Center Hospital between April 2008 and April 2011. OUTCOME MEASURES: We analysed statistical association factors, demographic information, geographical differences, medical environment, EOL care selection, along with actual POD using logistic regression analysis. RESULTS: Of the 433 patients, 147 selected palliative care units (PCUs) as the POD; 229, hospital; and 57, home with hospice care. POD selection was associated with several factors. Notably, EOL care selection, especially the use of complementary and alternative medicine (CAM), is associated with POD selection (death in PCU; OR=0.23, p=0.02). CONCLUSIONS: This study is, to the best of our knowledge, the first to unveil that EOL care selection is associated with POD in Japan. Certain factors such as gender, medical environment and EOL care selection might influence the POD. Patients who pursue aggressive anticancer therapies, such as CAM use, were possibly deprived of a chance of early reference to a PCU.

Cine magnetic resonance imaging evaluation of peristalsis of small bowel with longitudinal ulcer in Crohn disease: preliminary results.

OBJECTIVE: To evaluate peristalsis of the small bowel with a longitudinal ulcer in Crohn disease using cine magnetic resonance imaging (MRI). METHODS: Fifteen patients with suspected or diagnosed Crohn disease were examined by cine MRI using a multislice and multiphase method. Inclusion criteria were pathological evidence of Crohn disease and confirmation of longitudinal ulceration in the small bowel by ileocolonoscopy, single- or double-contrast radiography of the small bowel, or surgery. Six of these patients were included in this study. Cine MRI findings of the small bowels were retrospectively reviewed by 2 radiologists. RESULTS: Asymmetric involvement or mesenteric rigidity with antimesenteric flexibility was seen in all patients by cine MRI. This finding was not seen in normal small bowel segments. A combination of ileocolonoscopy and contrast radiography detected longitudinal ulcers in 5 of the 6 patients, and surgery revealed ulceration in the remaining patient. CONCLUSIONS: Cine MRI was a feasible approach for detecting a longitudinal ulcer in small-bowel Crohn disease.