Akiyoshi Kasuga

Multicenter retrospective analysis of systemic chemotherapy for advanced neuroendocrine carcinoma of the digestive system

This study analyzed outcomes of systemic chemotherapy for advanced neuroendocrine carcinoma (NEC) of the digestive system. Clinical data from 258 patients with unresectable or recurrent NEC of the gastrointestinal tract (GI) or hepato‐biliary‐pancreatic system (HBP), who received chemotherapy, were collected from 23 Japanese institutions and analyzed retrospectively. Patients had primary sites in the esophagus (n = 85), stomach (n = 70), small bowel (n = 6), colorectum (n = 31), hepato‐biliary system (n = 31) and pancreas (n = 31). Median overall survival (OS) was 13.4 months the esophagus, 13.3 months for the stomach, 29.7 months for the small bowel, 7.6 months for the colorectum, 7.9 months for the hepato‐biliary system and 8.5 months for the pancreas. Irinotecan plus cisplatin (IP) and etoposide plus cisplatin (EP) were most commonly selected for GI‐NEC and HBP‐NEC. For patients treated with IP/EP (n = 160/46), the response rate was 50/28% and median OS was 13.0/7.3 months. Multivariate analysis among patients treated with IP or EP showed that the primary site (GI vs HBP; hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.35–0.97) and baseline serum lactate dehydrogenase levels (not elevated vs elevated; HR 0.65, 95% CI 0.46–0.94) were independent prognostic factors for OS, while the efficacy of IP was slightly better than for EP (HR 0.80, 95% CI 0.48–1.33; P = 0.389). IP and EP are the most common treatment regimens for NEC of the digestive system. HBP primary sites and elevated lactate dehydrogenase levels are unfavorable prognostic factors for survival. A randomized controlled trial is required to establish the appropriate chemotherapy regimen for advanced NEC of the digestive system. This study was registered at UMIN as trial number 000005176.

Role of chemotherapy in treatments for biliary tract cancer

The purpose of chemotherapy in patients with advanced solid cancers, including biliary tract cancer, is generally to improve the survival and quality of life of the patients. Also, adjuvant chemotherapy is expected to increase the curability of surgery in patients scheduled to undergo surgery. Most patients with unresectable biliary tract cancer develop obstructive jaundice, and biliary drainage is needed before any of the aforementioned treatments. Once jaundice is resolved by stenting of the bile duct or bilio-intestinal bypass, cholangitis often develops, leading to rapid deterioration of the patient’s general condition. Therefore, the beneficial effect of chemotherapy in such patients remains controversial. A few randomized controlled trials have demonstrated the survival benefit of chemotherapy as compared with supportive care. In one of these trials, improvement of the quality of life was also confirmed. Recently, since the survival benefit of combined gemcitabine plus cisplatin therapy over gemcitabine alone has been demonstrated in randomized controlled clinical trials, this combined regimen has been recognized as a standard therapy for unresectable biliary tract cancer. A second-line regimen is now expected to be established for patients with gemcitabine-refractory biliary tract cancer, although the significance of second-line therapy remains unclear. One of the next issues in relation to chemotherapy for biliary tract cancer is the development of molecular-targeted agents; however, few large clinical trials of such agents have been conducted for biliary tract cancer. Various issues in chemotherapy for biliary tract cancer remain to be investigated, and global cooperation is necessary to conduct large clinical trials.

Multicenter retrospective analysis of systemic chemotherapy in poorly differentiated neuroendocrine carcinoma of the digestive system.

274 Background: Poorly differentiated neuroendocrine carcinoma (PDNEC) is a rare and aggressive disease. No standard regimen has yet been established for advanced PDNEC, although regimens for small-cell lung carcinoma such as irinotecan + cisplatin (IP) or etoposide + cisplatin (EP), are usually adopted. The aim of this study was to investigate the outcomes according to the patients characteristics and treatment regimens for patients with PDNEC of the digestive system. METHODS Data was collected from the medical records of patients at 23 hospitals. The selection criteria were as follows: 1) histologically proven PDNEC, small cell carcinoma, mixed endocrine-exocrine carcinoma with a PDNEC component, or histologically proven neuroendocrine tumor with rapidly progressive clinical course; 2) primary tumor arising from the gastrointestinal tract (GI) or the hepato-biliary-pancreatic system (HBP); and 3) inoperable or recurrent disease treated with systemic chemotherapy between April 2000 and March 2011. RESULTS There were 258 patients (pts). The median age was 62.5 years (range, 26-81); male/female, 182/76 pts; the primary site was the esophagus/stomach/small bowel/colorectum/hepato-biliary system/pancreas in 85/70/6/31/31/35 pts. According to these primary sites, the median overall survival period (mOS) was 13.4/13.3/29.7/7.6/7.9/8.5 months, respectively. The most commonly used regimen was IP (160 pts, 62%), followed by EP (46 pts, 18%). For the patients treated with IP/EP, the response rates (RR) were 50%/27%, the progression free survival periods (mPFS) were 5.2/4.0 months, and mOS were 13.0/7.3 months. The subgroup outcome data for patients with HBP or GI cancers are shown in Table. A multivariate analysis demonstrated that a primary HBP cancer (HR=1.96, p=0.002), and a poor PS (HR=2.33, p=0.01) were independent unfavorable prognostic factors. CONCLUSIONS PDNEC of the HBP has a poorer prognosis than GI. IP was the most commonly selected treatment regimen, and seemed to have a favorable treatment outcome. [Table: see text].

Ultrasound-guided vs endoscopic ultrasound-guided fine-needle aspiration for pancreatic cancer diagnosis

AIM To clarify the effectiveness and safety of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) for the diagnosis of pancreatic cancer (PC). METHODS Patients who were diagnosed with unresectable, locally advanced or metastatic PC between February 2006 and September 2011 were selected for this retrospective study. FNA biopsy for pancreatic tumors had been performed percutaneously under extracorporeal ultrasound guidance until October 2009; then, beginning in November 2009, EUS-FNA has been performed. We reviewed the complete medical records of all patients who met the selection criteria for the following data: sex, age, location and size of the targeted tumor, histological and/or cytological findings, details of puncture procedures, time from day of puncture until day of definitive diagnosis, and details of severe adverse events. RESULTS Of the 121 patients who met the selection criteria, 46 had a percutaneous biopsy (Group A) and 75 had an EUS-FNA biopsy (Group B). Adequate cytological specimens were obtained in 42 Group A patients (91.3%) and all 75 Group B patients (P = 0.0192), and histological specimens were obtained in 41 Group A patients (89.1%) and 65 Group B patients (86.7%). Diagnosis of malignancy by cytology was positive in 33 Group A patients (78.6%) and 72 Group B patients (94.6%) (P = 0.0079). Malignancy by both cytology and pathology was found in 43 Group A (93.5%) and 73 Group B (97.3%) patients. The mean period from the puncture until the cytological diagnosis in Group B was 1.7 d, which was significantly shorter than that in Group A (4.1 d) (P < 0.0001). Severe adverse events were experienced in two Group A patients (4.3%) and in one Group B patient (1.3%). CONCLUSION EUS-FNA, as well as percutaneous needle aspiration, is an effective modality to obtain cytopathological confirmation in patients with advanced PC.

Clinical Outcome of Biliary Drainage for Obstructive Jaundice Caused by Colorectal and Gastric Cancers

OBJECTIVE To clarify the prognostic factors for patients with obstructive jaundice due to advanced colorectal and gastric cancers who had undergone percutaneous transhepatic biliary drainage. METHODS Baseline variables and clinical outcomes were evaluated for 92 consecutive patients treated with percutaneous transhepatic biliary drainage. RESULTS Of the 92 patients, 32 (35%) had colorectal cancer and the remaining 60 (65%) had gastric cancer. Percutaneous transhepatic biliary drainage was successfully achieved in 74 (80%) patients, and 39 of them could receive subsequent chemotherapy. The median survival after percutaneous transhepatic biliary drainage was 273 days in the 39 patients who had undergone successful percutaneous transhepatic biliary drainage and subsequent chemotherapy, 65 days in 35 patients who had undergone successful percutaneous transhepatic biliary drainage but who had not received subsequent chemotherapy and 34 days in the remaining 18 patients who had undergone unsuccessful percutaneous transhepatic biliary drainage (P < 0.001). Multiple liver metastases and hepatic hilar bile duct stricture were independently associated with unsuccessful percutaneous transhepatic biliary drainage. Poor performance status, multiple liver metastases, presence of ascites, multiple prior chemotherapy administrations, undifferentiated type histology and high serum CA19-9 level were independently associated with a poor prognosis. A prognostic index calculated based on the number of these six factors was used to classify the patients into a good-risk group (index ≤2) (n = 56) and a poor-risk group (index ≥3) (n = 36). The median survival time and 2-month survival rate for the two groups were 163 and 44 days, respectively, and 85.7 and 33.3%, respectively (P < 0.001). CONCLUSIONS As regards the introduction of percutaneous transhepatic biliary drainage in patients with obstructive jaundice due to colorectal and gastric cancers, careful patient selection might be necessary. A prognostic model seems to be useful for making decisions as to whether percutaneous transhepatic biliary drainage is indicated for particular patients.

A transcatheter arterial chemotherapy using a novel lipophilic platinum derivative (miriplatin) for patients with small and multiple hepatocellular carcinomas.

Background/purpose Miriplatin is a platinum complex developed to treat hepatocellular carcinoma (HCC) through administration into the hepatic artery as a sustained-release formulation suspended in lipiodol. A single-institute pilot study was conducted to investigate the antitumor efficacy of miriplatin infusion therapy for small and multiple HCCs. Materials and methods Small HCCs sized 2 cm or less, judged to be inadequate for curative treatment, were indicated for transcatheter arterial miriplatin infusion therapy. We prospectively investigated the course of patients treated with miriplatin between March 2010 and September 2010. Efficacy was evaluated by computed tomography at 4–8 weeks and the overall evaluation was carried out more than 3 months after treatment. Results The study included 14 patients, of whom 13 were evaluable for efficacy. Of the 13 patients, one (8%) showed a complete response and three (23%) showed a partial response, with an overall response rate of 31%. Grade 3/4 hematological toxicity including thrombocytopenia was not seen. Increases to grade 3/4 in aspartate aminotransferase and alanine aminotransferase were observed for nonhematological toxicity. Irreversible deleterious changes in hepatic function were not seen. Conclusion Miriplatin infusion therapy showed safe and moderate effects on small HCCs. However, transarterial chemoembolization as a standard therapy cannot be replaced. We await the results of an ongoing study of transarterial chemoembolization with miriplatin.

Efficacy and safety of trametinib in Japanese patients with advanced biliary tract cancers refractory to gemcitabine

Gemcitabine‐based therapy remains the mainstay of treatment for patients with biliary tract cancers (BTCs) with no second‐line treatment(s) established yet. Aberrant activation of the MAPK pathway in patients with BTC indicates its importance in BTC. Trametinib is a potent, highly selective, allosteric non‐competitive inhibitor of MEK1/MEK2. In this phase IIa open‐label, single‐arm study, we investigated the efficacy and safety of trametinib in Japanese patients with advanced BTC refractory to gemcitabine‐based therapy. All patients received oral trametinib 2 mg once daily until progressive disease (PD), death, or unacceptable toxicity. The primary objective was to determine the 12‐week non‐PD rate. Secondary assessments included safety, progression‐free survival (PFS), overall survival, and overall response rate. Targeted exome sequencing was used to identify biomarkers for sensitivity or resistance to trametinib monotherapy. Twenty patients (median age, 61.5 years) with carcinoma of gall bladder (40%), intrahepatic (25%) or extrahepatic (30%) bile duct, and ampulla of Vater (5%) were enrolled. The non‐PD rate at week 12 was 10% (95% confidence interval, 1.2‐31.7); it did not reach the threshold rate of 25%. Median PFS was 10.6 weeks (95% confidence interval, 4.6‐12.1) and 1‐year overall survival was 20.0%. Stable disease and PD were observed in 13 (65%) and seven (35%) patients, respectively. No new safety signals were reported. Although the primary end‐point was not met, prolonged PFS was observed in one patient having six somatic variants including synonymous NF1 exon 12 splice variant and a loss‐of‐function variant in ARID1A. Efforts to understand responsive mutations and sensitivity to targeted therapies are warranted. This trial was registered with ClinicalTrials.gov: NCT01943864.

714PFIXED DOSE RATE GEMCITABINE AND S-1 COMBINATION THERAPY (FGS) AS SALVAGE CHEMOTHERAPY FOR GEMCITABINE-REFRACTORY ADVANCED PANCREATIC CANCER

ABSTRACT Aim: No standard salvage chemotherapy regimens has been established for patients with advanced pancreatic cancer after failure of gemcitabine-based treatment. Although a phase I/II clinical trial of FGS was conducted, the number of patients enrolled was small and the efficacy and safety of FGS is still not well known. Methods: We retrospectively reviewed 67 patients who received FGS as salvage chemotherapy at our institution from March 2009 to Mach 2014. The selection criteria in this study was progressive disease under gemcitabine-based chemotherapy, ECOG performance status Results: Sixty-six patients were selected for the analysis. Twenty-two patients of them had received FGS as third line treatment. The overall responce rate was 12% and the disease control rate was 45%. The median progression-free survival time was 2.7 months and the median overall survival time was 6.0 months. The common grade 3/4 toxicities were leukopenia (11%), neutropenia (15%), diarrhea (3%), anorexia (2%) and fatigue (2%). Univariate analysis showed that performance status of >0, presence of ascites, serum carcinoembryonic antigen level of > 10 ng/ml, serum albumin level of 500 IU/L and serum C-reactive protein level of > 1.0 mg/dl were significantly associated with a poor prognosis. Multivariate analysis identified serum C-reactive protein level of > 1.0 mg/dl and serum albumin level of Conclusions: FGS as salvage chemotherapy for patients with gemcitabine-refractory advanced pancreatic cancer is marginally effective and well tolerated in a practical setting. These results suggest FGS is of value to be further investigated in a clinical trial in patients with gemcitabine-refractory pancreatic cancer. Disclosure: All authors have declared no conflicts of interest.