Satoru Iwasa

Cisplatin and Etoposide as First-line Chemotherapy for Poorly Differentiated Neuroendocrine Carcinoma of the Hepatobiliary Tract and Pancreas

OBJECTIVE The combination chemotherapy consisting of cisplatin and etoposide, one of the standard regimens for small cell lung cancer, has been widely used to treat extrapulmonary poorly differentiated neuroendocrine carcinomas. However, there were no prior reports limited to the hepatobiliary tract and pancreas as the primary sites. METHODS We reviewed the cases in our database from October 1995 to January 2009 and retrospectively examined the clinical data of patients, with unresectable or recurrent poorly differentiated neuroendocrine carcinoma arising from the hepatobiliary tract and pancreas, who received combination chemotherapy with cisplatin and etoposide as the first-line treatment. The chemotherapy regimen consisted of cisplatin 80 mg/m(2) given intravenously on day 1 and etoposide 100 mg/m(2) intravenously on days 1-3, repeated every 3-4 weeks. RESULTS Twenty-one patients were treated with the above regimen of cisplatin and etoposide combination chemotherapy. The primary tumor site was the liver in 2 patients, gallbladder in 8 patients, pancreas in 10 patients and ampulla of Vater in 1 patient. Although no complete responses were obtained, three patients had partial responses, resulting in an overall response rate of 14%. Median progression-free survival was 1.8 months, and median overall survival was 5.8 months. The major adverse events were myelosuppression and gastrointestinal toxicities, with Grade 3 or 4 neutropenia (90%), nausea (33%) and anorexia (24%). CONCLUSIONS Cisplatin and etoposide combination as the first-line chemotherapy for hepatobiliary or pancreatic poorly differentiated neuroendocrine carcinoma had only marginal antitumor activity and relatively severe toxicity compared with previous studies on extrapulmonary poorly differentiated neuroendocrine carcinoma treated with the same regimen.

Prognostic Factors in Japanese Patients with Advanced Pancreatic Cancer Treated with Single-agent Gemcitabine as First-line Therapy

OBJECTIVE The purpose of the retrospective analysis is to elucidate the treatment efficacy and toxicity as well as to identify prognostic factors in Japanese patients with advanced pancreatic cancer treated with gemcitabine. METHODS Two hundred and sixty-four patients with pathologically confirmed locally advanced or metastatic pancreatic cancer, who had received gemcitabine monotherapy as first-line chemotherapy for pancreatic cancer, were analyzed. A dose of 1000 mg/m(2) gemcitabine was administered intravenously for 30 min on Days 1, 8 and 15 of a 28-day cycle. RESULTS One patient achieved a complete response (0.3%) and 27 patients showed a partial response (10.2%), with an overall response rate of 10.6% (95% confidence interval: 6.9-14.3%). The main grade 3/4 toxicities were neutropenia in 94 patients (35.6%) and leukocytopenia in 52 patients (19.7%). The median survival time, 1-year survival proportion and median progression-free survival time were 6.8 months, 21.6% and 3.7 months, respectively. A multivariate analysis using the Cox proportional hazards model demonstrated that a Karnofsky performance status > or = 90 (P = 0.01), Stage III (P = 0.01), serum carbohydrate antigen 19-9 level <10,000 U/ml (P = 0.02), serum hemoglobin level > or = 10 g/dl (P = 0.01) and serum C-reactive protein level <5.0 mg/dl (P < 0.01) were the independent favorable prognostic factors. CONCLUSIONS The treatment efficacy, toxicity and prognostic factors of single-agent gemcitabine in Japanese patients with advanced pancreatic cancer are comparable to those that have been reported in Western patients. These results may be useful as reference data in determining treatments strategies and planning for further clinical trials in Japanese patients with advanced pancreatic cancer.

Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial

BACKGROUND Nivolumab is a human monoclonal IgG4 antibody that inhibits programmed cell death protein 1 (PD-1) expressed on activated T cells. We investigated the safety and activity of nivolumab in patients with treatment-refractory oesophageal cancer. METHODS We did an open-label, single-arm, multicentre phase 2 study. Eligible patients had advanced squamous-cell carcinoma, adenosquamous-cell carcinoma, or adenocarcinoma of the oesophagus refractory or intolerant to fluoropyrimidine-based, platinum-based, and taxane-based chemotherapy. Patients were treated with 3 mg/kg nivolumab given intravenously once every 2 weeks in 6-week cycles. The primary endpoint was centrally assessed objective response (the proportion of patients whose best response was complete or partial response), according to the Response Evaluation Criteria In Solid Tumors, version 1.1. Adverse events and treatment-related adverse events (defined as events for which a causal relation to nivolumab could not be ruled out) were monitored throughout the study. The safety analysis was done in patients who received at least one dose of nivolumab, and drug activity was assessed in patients who received at least one dose of nivolumab and had at least one central assessment of tumour response. This study is registered with clinicaltrials.jp, number ONO-4538-07/JapicCTI-No.142422. Follow-up of patients is ongoing. FINDINGS Between Feb 25 and Nov 14, 2014, 65 patients were enrolled, all with squamous-cell carcinoma. 64 patients were assessable for the primary endpoint as one patient was excluded due to having multiple primary cancers; all patients were assessable for safety. Median follow-up was 10·8 months (IQR 4·9-14·3). 11 (17%, 95% CI 10-28) of 64 patients had a centrally assessed objective response. Of the 65 patients assessed for adverse events, the most common grade 3 or 4 events were grade 4 dyspnoea and hyponatraemia (one [2%) patient each), grade 3 lung infection (five [8%] patients), grade 3 decreased appetite (two [3%] patients), grade 3 increased blood creatinine phosphokinase (two [3%] patients), and grade 3 dehydration (two [3%] patients). Serious adverse events that occurred during the study were lung infection (four [6%] patients), dehydration (two [3%]), interstitial lung disease (two [3%]), and hyponatraemia, dyspnoea, fatigue, abnormal hepatic function, diarrhoea, bile duct stenosis, gastroenteritis, pneumonia, oedema, and back pain (one [2%] patient each). There were no treatment-related deaths. INTERPRETATION Nivolumab showed promising activity with a manageable safety profile. This drug could offer a potential new treatment approach for patients with treatment-refractory advanced squamous-cell carcinoma. FUNDING Ono Pharmaceutical, Bristol-Myers Squibb.

Serum levels of hepatocyte growth factor and epiregulin are associated with the prognosis on anti-EGFR antibody treatment in KRAS wild-type metastatic colorectal cancer

Background:Ligands of transmembrane receptor tyrosine kinases have important roles in cell proliferation, survival, migration and differentiation in solid tumours. We conducted this study to evaluate the relationship between concentration of serum ligands and prognosis of patients with metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) antibodies.Methods:Between August 2008 and August 2011, serum samples were obtained from KRAS wild-type patients who met the inclusion criteria and received an anti-EGFR antibody treatment. Serum concentration of ligands was measured by an enzyme-linked immunosorbent assay, and somatic mutations of KRAS, BRAF, PIK3CA and BRAF were analysed by direct sequencing.Results:A total of 103 patients were enrolled in the present study. At the pretreatment serum levels, patients with high levels of hepatocyte growth factor (HGF) had shorter progression-free survival (PFS) and overall survival (OS) compared with those with low levels of HGF (median PFS: 6.4 months vs 4.4 months; P<0.001, median OS: 15.3 months vs 8.0 months; P<0.001, respectively). Patients with high levels of epiregulin (EREG) also had shorter PFS and OS compared with those with low levels of EREG (median PFS: 6.6 months vs 4.9 months; P=0.016, median OS: 13.8 months vs 7.4 months; P=0.048, respectively). In addition, patients whose serum levels of ligands were elevated at progressive disease had shorter PFS and OS compared with other patients.Conclusions:Our study indicated that high levels of HGF and EREG were associated with resistance to treatment with anti-EGFR antibodies in KRAS wild-type patients with mCRC. Our findings will contribute to the newly combination therapy on the treatment of anti-EGFR antibodies.

Transcatheter Arterial Infusion Chemotherapy with a Fine-powder Formulation of Cisplatin for Advanced Hepatocellular Carcinoma Refractory to Transcatheter Arterial Chemoembolization

OBJECTIVE The aim of this study was to assess the safety and efficacy of transcatheter arterial infusion chemotherapy using a fine-powder formulation of cisplatin for patients with advanced hepatocellular carcinoma refractory to transcatheter arterial chemoembolization. METHODS We retrospectively examined the data of 84 consecutive patients with transcatheter arterial chemoembolization-refractory hepatocellular carcinoma who underwent transcatheter arterial infusion chemotherapy with a fine-powder formulation of cisplatin. Cisplatin was administered at the dose of 65 mg/m(2) into the feeding artery of the hepatocellular carcinoma. The treatment was repeated every 4-6 weeks, until the appearance of evidence of tumor progression or of unacceptable toxicity. RESULTS Of the 84 patients, one patient (1.2%) showed complete response and two patients (2.4%) showed partial response, representing an overall response rate of 3.6% (95% confidence interval, 0.7-10.1). Of the remaining, 38 patients (45.2%) showed stable disease and 41 (48.8%) showed progressive disease. The median overall survival, 1-year survival rate and median progression-free survival in the entire subject population were 7.1 months, 27% and 1.7 months, respectively. Major Grade 3 or 4 adverse events included thrombocytopenia in 12 patients (14%) and elevation of the serum aspartate aminotransferase in 33 patients (39%). The gastrointestinal toxicities were mild and reversible. CONCLUSIONS Transcatheter arterial infusion chemotherapy using a fine-powder formulation of cisplatin appears to have only modest activity, although the toxicity was also only mild, in patients with transcatheter arterial chemoembolization-refractory hepatocellular carcinoma.

Hepatic Arterial Infusion Chemotherapy with Epirubicin in Patients with Advanced Hepatocellular Carcinoma and Portal Vein Tumor Thrombosis

Objective: The objective of this study was to evaluate the antitumor, survival, and adverse effects of hepatic arterial infusion chemotherapy using epirubicin in patients with advanced hepatocellular carcinoma and portal vein tumor thrombosis. Methods: The study population comprised 45 consecutive patients with advanced hepatocellular carcinoma associated with tumor thrombosis in the main and/or first portal vein. A dose of 50–60 mg/m2 epirubicin was administered from the proper, right, or left hepatic artery. Treatment was repeated every 4–12 weeks if there was no evidence of tumor progression or unacceptable toxicity. Results: Of the 45 treated patients, 4 (9%) achieved a partial response, 12 (27%) had no change, and 29 (64%) showed progressive disease. The median survival time, 1-year survival rate and median time to progression were 6.0 months, 20.0%, and 1.1 months for all patients, respectively. The main grade 3 and 4 toxicities were leukopenia (27%), neutropenia (47%), thrombocytopenia (9%), and elevation of aspartate (36%) and alanine aminotransferases (13%). Febrile neutropenia was observed in 2 patients (4%). Conclusion: Hepatic arterial infusion chemotherapy with epirubicin is well tolerated, but appears to have little activity as a single agent in patients with hepatocellular carcinoma and portal vein tumor thrombosis.

Serum level of hepatocyte growth factor is a novel marker of predicting the outcome and resistance to the treatment with trastuzumab in HER2-positive patients with metastatic gastric cancer

HER2-overexpression in tumor tissue is observed in 6 to 23% of advanced gastric cancer (GC) cases, and trastuzumab is an active molecular drug for these patients. There are no data available on whether serum levels of ligands are associated with the response and resistance to trastuzumab in HER2-positive patients with metastatic GC. HER2 screening of 502 patients with advanced gastric cancer was performed in our institution. Among these patients, 84 patients (16.8%) were diagnosed as HER2-positive, and those who were treated with trastuzumab and met the inclusion criteria were enrolled in the present study. Serum levels of ligands that affect the HER2 signal pathway were measured by an enzyme-linked immunosorbent assay. Forty-six HER2-positive patients were enrolled in this study, and 26 patients (56.5%) achieved a partial response to treatment with trastuzumab. Among several ligands, the serum level of hepatocyte growth factor (HGF) was significantly lower in responders compared with that in non-responders (p = 0.014). Multivariate analyses showed that a high level of serum HGF was a poor prognostic factor for overall survival (OS) compared with low levels of HGF (adjusted HR: 3.857, 95% CI: 1.309–11.361, p = 0.014). Among 25 patients without initial disease progression on the treatment with trastuzumab, the mean value of serum HGF at disease progression was significantly higher than that at pre-treatment (p = 0.041). As novel findings, our study indicated that serum level of HGF was associated with tumor shrinkage and time to progression of trastuzumab in HER2-positive patients with metastatic GC.

Predictive Factors of Outcome and Tumor Response to Systemic Chemotherapy in Patients with Metastatic Hepatocellular Carcinoma

OBJECTIVE Systemic chemotherapy is an important treatment modality for metastatic hepatocellular carcinoma (HCC); however, the predictive factors of outcome and tumor response have not been fully investigated. The aim of this study was to identify factors that could be used to predict outcome and tumor response to systemic chemotherapy in patients with metastatic HCC. METHODS We retrospectively examined 82 consecutive patients with metastatic HCC undergoing systemic chemotherapy to investigate factors associated with outcome and tumor response. The patients underwent 5-fluorouracil, mitoxantrone and cisplatin (FMP) therapy. RESULTS The overall objective response rate was 22% (95% confidence interval, 14-32), and the median survival time and 1-year survival for all patients were 11.2 months and 43.5%, respectively. Multivariate analysis demonstrated that the absence of radiologically active intrahepatic disease (P = 0.02) and ascites (P = 0.002) was independent favorable prognostic factors. Although multivariate analysis revealed no significant predictive factors of tumor response, the response rates in patients without radiologically active intrahepatic disease (response rate, 46%) tended to be higher than those in patients with active intrahepatic disease (response rate, 17%) (P = 0.05). CONCLUSION Patients with metastatic HCC, who had sufficient hepatic function and no radiologically active intrahepatic disease, might be good candidates for systemic chemotherapy.

Phase II study of the effectiveness and safety of trastuzumab and paclitaxel for taxane- and trastuzumab-naïve patients with HER2-positive, previously treated, advanced, or recurrent gastric cancer (JFMC45-1102).

Paclitaxel is a standard second‐line gastric cancer treatment in Japan. Trastuzumab could be active as second‐line chemotherapy for taxane/trastuzumab‐naïve patients with epidermal growth factor 2 (HER2)‐positive advanced gastric cancer. Patients aged ≥20 years with HER2‐positive, previously treated (except for trastuzumab and taxane), unresectable or recurrent gastric adenocarcinoma underwent combined trastuzumab (first and subsequent doses of 8 and 6 mg kg−1, respectively, every 3 weeks) and paclitaxel (days 1, 8, 15, every 4 weeks) treatment. Study endpoints were best overall response, progression‐free survival, overall survival, and safety. From September 2011 to March 2012, 47 Japanese patients were enrolled. Forty patients discontinued treatment after a median of 128.5 (range 4–486) days. Complete and partial responses were obtained in one and 16 patients (response rate of 37% [95% CI 23–52]), respectively. Median progression‐free survival and overall survival were 5.1 (95% CI 3.8–6.5) and 17.1 (95% CI 13.5–18.6) months, respectively. Grade 3/4 adverse events were neutropenia (32.6%), leukopenia (17.4%), anemia (15.2%) and hypoalbuminemia (8.7%). There was no clinically significant cardiotoxicity or cumulative toxicity. Three (disturbed consciousness, pulmonary fibrosis, and rapid disease progression) grade 5 events occurred. In conclusion, trastuzumab combined with paclitaxel was well tolerated and was a promising regimen for patients with HER2‐positive, previously treated, advanced or recurrent gastric cancer.

Comprehensive screening of target molecules by next-generation sequencing in patients with malignant solid tumors: guiding entry into phase I clinical trials

It is still controversial whether comprehensive genome screening of target molecules by next generation sequencing (NGS) is needed to increase clinical efficacy of investigational drugs or accelerate drug development, although several studies are being carried out. Therefore, we performed a prospective study to evaluate the feasibility of comprehensive gene screening in this setting. Our findings indicate that actionable alterations were identified in 45% of the analyzed patients, most frequently in those with breast cancer. Common actionable alterations were found in PIK3CA mutation, BRCA2 mutation, ERBB2 amplification, and CCND1 amplification. In total, 22% of the analyzed patients could be entered into phase I clinical trials, and 8% of them were treated with “matched” drugs. Among patients who received matched therapies, response and disease control rates were 33 and 78%, respectively. On the other hand, in the patients who received “non-matched” therapy, the objective response rate was 6%. We believe this data indicates that NGS-based molecular pre-screening is a potent platform for use before patient entry into phase I trials.