Akinori Sugaya

Panitumumab-Induced Interstitial Lung Disease in a Case of Metastatic Colorectal Cancer

Background: A Japanese postmarketing survey of panitumumab revealed that panitumumab-associated interstitial lung disease (ILD) occurred in approximately 1% (19/1767) of patients, causing death in 36.8% of these cases. Case Report: We report the case of a 60-year-old Japanese man who developed ILD associated with panitumumab therapy (third-line therapy) for metastatic sigmoid colon cancer involving the liver, lymph nodes, and lungs. 2 months after the initiation of panitumumab therapy, he developed a progressive nonproductive cough, dyspnea, and a fever, and was diagnosed with ILD. Intravenous pulse methylprednisolone treatment led to quick recovery. The patient had some risk factors for ILD associated with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors. Conclusion: Further studies are required to elucidate the association between anti-EGFR antibodies and ILD.

Collagenous sprue diagnosed by double balloon endoscopy

Double balloon endoscopy (DBE) is useful for diagnosing many intestinal diseases and for endoscopic procedures. We report a case of chronic diarrhea in a 58‐year‐old Japanese man. He was initially suspected to have malabsorption syndrome. DBE showed reduction of folds, scalloping, mucosal nodularity and granularity. Pathological examinations of biopsies from the jejunum showed severe villous atrophy with subepithelial collagen bands. These findings led to the final diagnosis of collagenous sprue (CS). With1 month of total parenteral nutrition followed by a low‐gluten diet, his symptoms gradually improved. CS has never been reported before in Japan. DBE is useful for making a diagnosis of CS, and may be considered for patients who are suffering from diarrhea of unknown cause.

Correlations of survival with progression-free survival, response rate, and disease control rate in advanced biliary tract cancer: a meta-analysis of randomised trials of first-line chemotherapy.

Background:The need to promote novel drug development for advanced biliary tract cancer (ABTC) has emphasised the importance of determining whether various efficacy end points can act as surrogates for overall survival (OS).Methods:We conducted a literature search of randomised trials of first-line chemotherapy for ABTC and investigated correlations between efficacy end points and OS using weighted linear regression analysis. The ratios of the median OS, median progression-free survival (PFS), response rate, and disease control rate in each trial were used to summarise treatment effects. The surrogate threshold effect (STE), which was the minimum treatment effect on PFS required to predict a non-zero treatment effect on OS, was calculated.Results:Seventeen randomised trials with 36 treatment arms were identified, and a sample size of 2148 patients with 19 paired arms was analysed. The strongest correlation between all evaluated efficacy end points was observed between median OS and median PFS ratios (r2=0.66). In trials with gemcitabine-containing therapies and targeted agents, the r2-values were 0.78. The STE was estimated at 0.83 for all trials and 0.81 for trials with gemcitabine-containing therapies, and was not calculated for trials with targeted agents.Conclusions:The median PFS ratio correlated well with the median OS ratio, and may be useful for planning a clinical trial for novel drug development.

Utility of epirubicin‐incorporating micelles tagged with anti‐tissue factor antibody clone with no anticoagulant effect

Tissue factor (TF), an initiator of the extrinsic blood coagulation cascade, is overexpressed in different types of cancer. Tissue factor overexpression is also known as a poor prognostic factor in pancreatic cancer. We recently developed anti‐TF antibody (clone1849)‐conjugated epirubicin‐incorporating micelles (NC‐6300), and reported that this anti‐TF1849‐NC‐6300 showed enhanced antitumor activity against TF‐high expressed human pancreatic cancer cells, when compared with NC‐6300 alone. However, clone 1849 antibody inhibited TF‐associated blood coagulation activity. We studied another anti‐TF antibody, clone 1859, which had no effect on blood coagulation and prepared anti‐TF1859‐NC‐6300. In addition, to determine the optimum size of the antibody fragment to conjugate with NC‐6300, three forms of the 1859 antibody (whole IgG, F[ab’]2, and Fab’) were conjugated to NC‐6300. The antitumor effect of each anti‐TF1859‐NC‐6300 was studied in vitro and in vivo, using two human pancreatic cancer cell lines, BxPC3 with high‐expressed TF, and SUIT2 with low levels of TF. In vitro, all forms of anti‐TF1859‐NC‐6300 showed higher cytocidal effects than NC‐6300 in BxPC3, whereas this enhanced effect was not observed in SUIT2. Likewise, all forms of anti‐TF1859‐NC‐6300 significantly suppressed tumor growth when compared to NC‐6300 in the BxPC3, but not in the SUIT2, xenograft model. Among the three forms of conjugates, anti‐TF1859‐IgG‐NC‐6300 had a higher antitumor tendency in TF‐high expressed cells. Thus, we have confirmed an enhanced antitumor effect of anti‐TF1859‐NC‐6300 in a TF‐high expressing tumor; anti‐TF1859‐IgG‐NC‐6300 could be used to simplify the manufacturing process of the antibody–micelle conjugation for future clinical studies.

Successful Treatment with Modified FOLFOX6 and Panitumumab in a Cecal Cancer Patient Undergoing Hemodialysis

Combination chemotherapy of mFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin) plus panitumumab, a fully human monoclonal antibody against epidermal growth factor receptor (EGFR), is one of the standard treatments for metastatic colorectal cancer (mCRC) without KRAS mutation. A few reports suggested no need of dose adjustment of cetuximab, a similar chimeric anti-EGFR antibody, in patients with renal impairment. However, panitumumab combined with cytotoxic drugs for hemodialysis patients has not been reported. We herein report a case of a hemodialysis mCRC patient successfully treated with mFOLFOX6 and panitumumab combination therapy.

Phase I study of gemcitabine, cisplatin, and S-1 combination therapy for patients with untreated advanced biliary tract cancer.

To develop a triplet regimen containing gemcitabine, cisplatin, and S‐1 (GPS), we assessed the recommended dose for patients with untreated advanced biliary tract cancer in this phase I study.

Correlation between overall survival and other efficacy endpoints in advanced biliary tract cancer: Literature-based analysis from 13 randomized trials of first-line chemotherapy.

352 Background: Chemotherapy for advanced biliary tract cancer (ABC) has progressed. Now gemcitabine plus cisplatin combination is considered the standard 1st-line treatment based on the results of many randomized studies. However, the impact of various efficacy parameters on overall survival (OS) remains unclear. Methods: We searched PubMed database with the key words of (“biliary tract neoplasms” or “bile duct neoplasms” or “gallbladder neoplasms” or “cholangiocarcinoma” [All fields]) AND (“chemotherapy”[All fields]) AND Clinical trial [ptyp] between Apr 1984 to Jun 2013 and abstracts presented at the meetings of ASCO/Gastrointestinal Cancers Symposium (2004–2013) and ESMO/WCGC (2002–2013). Then we identified randomized trials of 1st-line chemotherapy for ABC, and analyzed the relations between the results of OS and those of progression-free survival (PFS) or time to progression (TTP), response rate (RR), disease control rate (DCR), post-progression survival (PPS = median OS − median PFS/TTP), and the p...

Survival analysis of platinum-refractory patients with advanced esophageal cancer treated with docetaxel or best supportive care alone: a retrospective study

The survival benefit of second-line chemotherapy with docetaxel in platinum-refractory patients with advanced esophageal cancer (AEC) remains unclear. A retrospective analysis of AEC patients with Eastern Cooperative Oncology Group performance status (PS)≤2 was performed, and major organ functions were preserved, who determined to receive docetaxel or best supportive care (BSC) alone after failure of platinum-based chemotherapy. The post-progression survival (PPS), defined as survival time after disease progression following platinum-based chemotherapy, was analyzed by multivariate Cox regression analysis using factors identified as significant in univariate analysis of various 20 characteristics (age, sex, PS, primary tumor location, etc) including Glasgow prognostic score (GPS), which is a well-known prognostic factor in many malignant tumors. Sixty-six and 45 patients were determined to receive docetaxel and BSC between January 2007 and December 2011, respectively. The median PPS was 5.4 months (95% confidence interval [CI] 4.8-6.0) in the docetaxel group and 3.3 months (95% CI 2.5-4.0) in the BSC group (hazard ratio [HR] 0.56, 95% CI 0.38-0.84, P=0.005). Univariate analysis revealed six significant factors: treatment, PS, GPS, number of metastatic organs, liver metastasis, and bone metastasis. Multivariate analysis including these significant factors revealed three independent prognostic factors: docetaxel treatment (HR 0.62, 95% CI 0.39-0.99, P=0.043), better GPS (HR 0.61, 95% CI 0.46-0.81, P=0.001), and no bone metastasis (HR 0.31, 95% CI 0.15-0.68, P=0.003). There was a trend for PPS in favor of the docetaxel group compared with patients who refused docetaxel treatment in the BSC group (adjusted HR 0.61, 95% CI 0.29-1.29, P=0.20). Docetaxel treatment may have prolonged survival in platinum-refractory patients with AEC.

725PA PHASE I STUDY OF GEMCITABINE (GEM), CISPLATIN (CDDP), AND S-1 COMBINATION IN UNTREATED PATIENTS (PTS) WITH ADVANCED BILIARY TRACT CANCER (ABTC)

ABSTRACT Aim: GEM plus CDDP has been established as standard first-line chemotherapy based on the results of the phase III study (ABC-02) in ABTC. An oral FU derivative, S-1 showed a similar activity to GEM in a phase II study and is mainly used in GEM-refractory pts in Japan. To develop a triplet regimen, GEM + CDDP + S-1 (GPS), we assessed its safety in this phase I study. Methods: The main eligibility criteria were; histologically or cytologically confirmed ABTC, ECOG Performance Status (PS) 0-2, no prior chemotherapy, and written informed consent. Dose limiting toxicities (DLT) were evaluated in following 2 dose levels; GEM (1000 mg/m2 at level 1 and 1200 mg/m2 at level 2 on day 1) + CDDP (fixed dose of 30 mg/m2 on day 1) + S-1 (fixed dose of 40—60 mg/day bid for 7 days), repeated every 2 weeks until progression. The relative dose intensity of GEM and CDDP at level 2 corresponded to 90% of standard GEM plus CDDP regimen. In each level, 6-10 pts were enrolled and assessed. DLTs were evaluated during the first 2 cycles. Results: Between Oct 2011 and Oct 2013, 18 pts were enrolled and 16 pts were evaluated (median age: 71 years, ECOG PS 0/1: 10/6, intrahepatic/extrahepatic/gallbladder: 7/3/6). DLTs (grade 3 nausea to stop S-1 in cycle 1 and treatment delay due to grade 3 neutropenia in cycle 2) at level 1 were observed in 2 of the first 6 pts. Additional 4 pts enrolled at this dose level experienced no DLTs. A DLT (G3 anorexia) at level 2 was observed in 1 of 6 pts. Grade 3 or 4 treatment-related adverse events within the first 2 cycles were leukocytopenia (38%), neutropenia (50%), thrombocytopenia (0.6%), nausea (0.6%), and anorexia (0.6%). Of 14 pts with measurable lesions, 7 (50%) pts had partial response and 6 (43%) patients had stable disease. Median progression free survival was 9.2 months (95%CI 6.8-11.6, event in 63%) and overall survival did not reach the median value (event in 38%). Conclusions: GPS of dose level 2 (GEM 1200 mg/m2 and 30 mg/m2 on day 1 plus S-1 for 1-7 days, given bi-weekly) was well tolerated, and showed preliminary anti-tumor activity. Further study is warranted. Clinical trial information: UMIN000006123. Disclosure: T. Moriwaki: Research funding for other study and honoraria from Taiho Pharmaceutical; I. Hyodo: Research funding for other study from Taiho Pharmaceutical and Lilly. Honoraria from Taiho Pharmaceutical. All other authors have declared no conflicts of interest.