The purpose of this study is to compare the efficacy of a single administration of dexamethasone (DEX) on day 1 against DEX administration on days 1–3 in combination with palonosetron (PALO), a ...second‐generation 5‐HT3 receptor antagonist, for chemotherapy‐induced nausea and vomiting (CINV) in non‐anthracycline and cyclophosphamide (AC) moderately‐emetogenic chemotherapy (MEC). This phase III trial was conducted with a multi‐center, randomized, open‐label, non‐inferiority design. Patients who received non‐AC MEC as an initial chemotherapy were randomly assigned to either a group administered PALO (0.75 mg, i.v.) and DEX (9.9 mg, i.v.) prior to chemotherapy (study treatment group), or a group administered additional DEX (8 mg, i.v. or p.o.) on days 2–3 (control group). The primary endpoint was complete response (CR) rate. The CR rate difference was estimated by logistic regression with allocation factors as covariates. The non‐inferiority margin was set at −15% (study treatment group − control group). From April 2011 to March 2013, 305 patients who received non‐AC MEC were randomly allocated to one of two study groups. Overall, the CR rate was 66.2% in the study treatment group (N = 151) and 63.6% in the control group (N = 154). PALO plus DEX day 1 was non‐inferior to PALO plus DEX days 1–3 (difference, 2.5%; 95% confidence interval CI: −7.8%–12.8%; P‐value for non‐inferiority test = 0.0004). There were no differences between the two groups in terms of complete control rate (64.9 vs 61.7%) and total control rate (49.7% vs 47.4%). Anti‐emetic DEX administration on days 2–3 may be eliminated when used in combination with PALO in patients receiving non‐AC MEC.
In this study, we evaluated the efficacy of a single administration of dexamethasone (DEX) on day 1 against DEX administration on days 1–3 with palonosetron (PALO), for chemotherapy‐induced nausea and vomiting (CINV) in non‐AC (anthracycline and cyclophosphamide) moderately‐emetogenic chemotherapy (MEC) in the phase III study. Our randomized phase III study successfully demonstrated non‐inferiority of DEX administration only on day 1 compared to days 1–3 when used in combination with PALO during non‐AC MEC.
Gain-of-function mutation of the K-ras gene is one of the most common genetic changes in human tumors. In tumors carrying K-ras mutation, the presence of oncogenic K-Ras is necessary for maintenance ...of the transformed phenotype. ESXR1 is a human paired-like homeodomain-containing protein expressed primarily in the testis. In cells, the 65-kDa full-length ESXR1 protein is proteolytically processed into an N-terminal 45-kDa fragment containing the homeodomain, which localizes exclusively within the nucleus, and a C-terminal 20-kDa fragment consisting of a proline-rich repeat region, which is located in the cytoplasm. In this work, we demonstrated that the N-terminal ESXR1 fragment specifically recognizes the TAATNNNATTA P3 consensus sequence for the paired-like homeodomain and functions as a sequence-specific transcriptional repressor. We also showed that the N-terminal ESXR1 fragment binds to the TAATGTTATTA sequence present within the first intron of the human K-ras gene and inhibits its expression at both mRNA and protein levels. Ectopic expression of the N-terminal ESXR1 fragment in human carcinoma cells that carry mutated K-ras reduces the level of K-Ras and thereby inhibits the tumor cell proliferation. Identification of ESXR1 as a transcriptional repressor of K-ras has an important implication for the development of cancer therapy that inhibits oncogenic K-Ras expression.
Capecitabine plus cisplatin (XP) is a standard global regimen, while S-1 plus cisplatin (SP) is a Japanese standard for first-line treatment of advanced gastric cancer (AGC). We conducted a phase II ...trial comparing XP with SP for patients with AGC to confirm whether these regimens can be used as controls in a phase III study and to explore whether histological subtypes favour XP or SP.
Eligible patients were randomised to receive either S-1 40 mg/m2 for 21 days plus cisplatin 60 mg/m2 (q5w) or capecitabine 1000 mg/m2 for 14 days plus cisplatin 80 mg/m2 (q3w). The primary end-point was progression-free survival (PFS). The secondary end-points were overall survival (OS), overall response rate (ORR) and safety.
In 110 eligible patients, 24-week PFS was higher in both groups (SP 50.9%, XP 43.5%) than the protocol-specified threshold of 40%. The median PFS for SP versus XP was 5.6 and 5.1 months (hazard ratio HR, 1.126; p = 0.5626); OS was 13.5 and 12.6 months (HR, 0.942; p = 0.7769) and the ORR was 42.4% and 69.4% (p = 0.0237), respectively. The most common grade ≥3 adverse events with SP/XP were anaemia (16%/20%), neutropenia (9%/18%) and anorexia (18%/13%). Subgroup analysis by histological classification showed no statistical difference between treatments.
XP and SP are comparable and can be recommended as control arms in a phase III study for AGC. Histological subtypes were not sensitive markers for the selection of XP or SP.
NCT00140624.
•Capecitabine plus cisplatin (XP) and S-1 plus cisplatin (SP) showed promising progression-free survival (PFS; 5.1 and 5.6 months).•PFS of 24 weeks was higher in both groups than the protocol-specified threshold of 40%.•XP and SP for first-line treatment of AGC was well tolerated and showed appropriate overall survival and overall response rate.•Histological subtyping showed no survival difference between XP and SP.•Histological subtypes were not sensitive markers for fluorouracil selection.
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Background: The J003 trial and RECOURSE trial revealed the safety and efficacy of TAS-102 for patients with metastatic colorectal cancer (mCRC). In March 2014, TAS-102 was approved ...in Japan. However, in these pivotal trials, there were few cases in which regorafenib was administered as prior treatments, and also there were few reports on the effectiveness and safety of TAS-102 after administration of regorafenib. Methods: We retrospectively analyzed the clinical data of 126 patients who received TAS-102 after administration of regorafenib in the multi-institutional retrospective study (HGCSG1503). This study was analyzed by CTCAE v4.0 for adverse events (AEs), RECIST v1.1 for response rate (RR)/disease control rate (DCR), and Kaplan-Meier method for progression free survival (PFS) and overall survival (OS). Results: Patients characteristics were as follows; male/female 75/51, median age 66.5 (range 38-84), ECOG PS (0/1/2/3) 48/64/12/2, KRAS Exon2 wild/mutant 64/60 (2 patients; KRAS Exon2 was not tested). The initial starting dose was 70 mg/m2 (n = 100, 79.4%) and reduced dose (n = 26, 20.6%). Dose reductions were required in 30 patients (30.9%). The common ≥grade 3 AEs were neutrophil count decreased (45.1%), white blood cell decreased (34.9%), and anemia (28.6%). RR and DCR were 0% and 36.5%, respectively. Median PFS and OS were 2.1 and 5.7 months. In the analysis on the relationship between ECOG PS 0-1 and PS 2-3, median PFS was 2.2 vs. 1.4 months (HR 2.187, p = 0.008), and MST was 6.5 vs. 2.7 months (HR 2.424, p = 0.002). Conclusions: In this analysis, TAS-102 after administration of regorafenib in the real-world clinical practice showed similar efficacy and safety to the pivotal clinical trials, except for patients with PS 2-3. Clinical trial information: 000020551.
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Background: Capecitabine plus cisplatin (XP) is a standard global regimen for first-line treatment of advanced gastric cancer, however its efficacy compared to S-1 plus cisplatin ...(SP), a standard treatment in Japan has not been reported. To evaluate the efficacy of XP treatment, we conducted a multicenter randomized phase II trial comparing XP with SP for patients with advanced gastric cancer (ClinicalTrials.gov Identifier NCT0140624). Methods: Patients with unresectable metastatic or recurrent gastric cancer, 20–74 years of age and HER2-negative, were assigned to receive either S-1 40 mg/m2 bid for 21 days plus cisplatin 60 mg/m2 (day 8) every 5-week cycle or capecitabine 1000 mg/m2 bid for 14 days plus cisplatin 80 mg/m2 (day 1) every 3-week cycle. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), time to treatment failure, overall response rate (ORR) and safety. Planned sample size was 100 (50 in each arm) according to PFS at 24-weeks. Immunohistochemical evaluation of biomarkers was also implemented. Results: From November 2011 to June 2013, 116 patients were randomized: median age, 65 years; 79 (68%) male; 63 intestinal and 53 diffuse cancer subtypes. In 109 eligible patients, 24-week %PFS was higher in both groups than the protocol-specified threshold of 40%. Median PFS for SP vs. XP was 25 weeks vs. 23 weeks (HR, 0.76; 95%CI, 0.5-1.16; p=0.203); OS was 58 weeks vs. 56 weeks (HR, 0.90; 95%CI, 0.52-1.57; p=0.712); and ORR was 27.5% vs. 32.7% (p=0.562), respectively. Sub-group analysis by histological classification showed that SP gave better PFS than XP in the diffuse type (HR, 0.42; 95%CI, 0.20-0.86; p=0.015) with no other statistical difference. Most common grade ≥3 adverse events with SP and XP were anemia (16%/ 19%), neutropenia (9%/17%), anorexia (18%/13%), diarrhea (11%/0%), nausea or vomiting (11%/15%), fatigue (5%/6%) and hyponatremia (7%/13%), respectively. Conclusions: XP and SP are comparable and can be recommended as 1
st
line treatments for advanced gastric cancer. Further analysis for biomarkers related to histology is warranted. Clinical trial information: NCT0140624.
The efficacy of sorafenib in hepatocellular carcinoma (HCC) has been demonstrated in two pivotal clinical trials: the European SHARP trial and a second trial that recruited patients in the ...Asia-Pacific region. Sorafenib was approved for the treatment of advanced HCC in Japan based on the results of these studies. This article presents experiences with sorafenib in patients with HCC at three institutions in Japan, representing the viewpoints of a liver surgeon and a hepatologist at university hospitals, and a hepatologist at a community hospital. The three physicians discuss representative cases and current clinical practice at their institutions, and their recommendations for the use of sorafenib in the wider clinical setting. Overall, the experiences at these institutions show that sorafenib is most effective when administered for a long time, and the management of adverse events (AEs) including dose-reduction and modification is critical to achieving high levels of adherence to treatment. A team-focussed treatment strategy that includes patient counselling and follow-up can contribute to managing AEs to ensure successful continuation of sorafenib therapy. In addition, a proposed definition of unresponsiveness to transarterial chemoembolization and the implications of treatment lag on the outcomes of sorafenib therapy, as well as measures for the prevention and treatment of hand-foot skin reaction are discussed. PUBLICATION ABSTRACT
The efficacy of sorafenib in hepatocellular carcinoma (HCC) has been demonstrated in two pivotal clinical trials: the European SHARP trial and a second trial that recruited patients in the ...Asia-Pacific region. Sorafenib was approved for the treatment of advanced HCC in Japan based on the results of these studies.
This article presents experiences with sorafenib in patients with HCC at three institutions in Japan, representing the viewpoints of a liver surgeon and a hepatologist at university hospitals, and a hepatologist at a community hospital. The three physicians discuss representative cases and current clinical practice at their institutions, and their recommendations for the use of sorafenib in the wider clinical setting.
Overall, the experiences at these institutions show that sorafenib is most effective when administered for a long time, and the management of adverse events (AEs) including dose-reduction and modification is critical to achieving high levels of adherence to treatment. A team-focussed treatment strategy that includes patient counselling and follow-up can contribute to managing AEs to ensure successful continuation of sorafenib therapy. In addition, a proposed definition of unresponsiveness to transarterial chemoembolization and the implications of treatment lag on the outcomes of sorafenib therapy, as well as measures for the prevention and treatment of hand-foot skin reaction are discussed.
A 63-year-old woman with Behçet disease presented with epigastric pain due to refractory gastric ulcers. Examinations indicated that these ulcers were caused by gastrointestinal Behçet disease. ...Steroid therapy proved ineffective, so we gave 5mg/kg of infliximab. However, since the patient responded poorly to the treatment the infliximab was discontinued and a total gastrectomy was performed. After surgery, a marginal ulcer developed and infliximab was again administered. Although this brought about improvement in the conditions of the marginal ulcer, infusion-related hypersensitivities in the patient caused polyarthralgia. We therefore discontinued the infliximab treatment and began 40mg of adalimumab every other week. After 3 months of the new treatment, the patient's marginal ulcer completely healed and her epigastric pain disappeared. This case suggests that adalimumab may be as useful as infliximab for treating refractory gastrointestinal Behçet disease.
A 57-year-old man presented with jaundice. Abdominal computed tomography showed a 10-cm left hepatic lobe heterogeneous solid mass with low attenuated areas in the mass, multiple liver metastases and ...lung metastasis. Serology for hepatitis B and C were negative. Serum alpha-fetoprotein, CEA and CA19-9 were normal. The patient died a few weeks later of progressive liver failure and an autopsy was performed. Histologically, the tumor consisted of sarcomatoid mononuclear cells and osteoclast-like giant cells. The liver tissue surrounding the tumor showed no cirrhotic pattern. The osteoclast-like giant cells were uniformly and strongly immunoreactive with CD68. The mononuclear cells demonstrated expression of vimentin but were negative for CAM5.2. The MIB-1 index was 20% for the mononuclear cells. In conclusion, the histopathological diagnosis revealed an osteoclast-like giant cell tumor of the liver.
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