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Pancreatic adenosquamous carcinoma (PASC) is a rare variant of pancreatic ductal adenocarcinoma (PDAC). The usual treatment for metastatic or recurrent PASC is systemic chemotherapy in accordance with the PDAC treatment strategy. This study aimed to investigate the efficacy of chemotherapy, especially the benefit of recent combination therapies, in patients with metastatic or recurrent PASC.We conducted a multicenter retrospective analysis of 116 patients with metastatic or recurrent PASC treated with first-line chemotherapy between April 2001 and December 2017 at 24 Japanese institutions.Combination chemotherapies included gemcitabine + nab-paclitaxel (GnP, n = 28), fluorouracil/leucovorin + irinotecan + oxaliplatin (FFX, n = 10), gemcitabine + S-1 (GS, n = 10), and others (n = 9). Monotherapies included gemcitabine (n = 51) and S-1 (n = 8). The median overall survival (OS) was 6.5, 7.3, and 4.3 months for the whole cohort, the combination therapy group, and the monotherapy group, respectively. Multivariate analysis indicated that combination therapy showed a better trend in OS than monotherapy (hazard ratio = 0.68; 95% confidence interval, 0.38-1.20). GnP or FFX were selected in 58.7% of patients after FFX was approved in Japan, and revealed a median OS, median progression-free survival, and objective response rate of 7.3 months, 2.8 months, and 26.9% in GnP and 7.2 months, 2.3 months, and 20.0% in FFX respectively.This study suggests that combination therapy may be more effective than monotherapy. GnP and FFX showed similar and clinically meaningful efficacy for patients with metastatic or recurrent PASC.

Objective S-1 and modified FOLFIRINOX (mFFX) were often used as the second-line chemotherapies after failure of gemcitabine plus nab-paclitaxel (GnP) in unresectable pancreatic cancer (UPC) until nanoliposomal irinotecan plus 5-fluorouracil/leucovorin therapy was approved as an alternative in Japan in 2020. However, the clinical outcomes of S-1 and mFFX after GnP have scarcely been reported. Therefore, we retrospectively studied them. Methods We extracted the clinical data of 86 patients with UPC who received second-line chemotherapy after GnP between 2015 and 2020. Among the patients who had a good organ functions and no massive ascites, 41 patients treated with S-1 and 21 treated with mFFX were enrolled. Results Compared to S-1, mFFX tended to be used for younger patients with a good general condition (median age, 63 vs. 71 years, p0.01; and performance status 0, 67% vs. 37%, p0.05). The median progression-free and overall survival were similar between the S-1 (3.7 and 7.2 months, respectively) and mFFX (3.3 and 7.4 months, respectively) groups. The response rate in patients with measurable lesions was 4% (n=1/23) in the S-1 group and 17% (n=2/12) in the mFFX group. The incidence of grade 3 or 4 adverse events was 20% in the S-1 group and 57% (neutrophil count decreased in 43%) in the mFFX group (p0.01). Conclusion S-1 and mFFX were both acceptable second-line chemotherapies after GnP therapy for UPC, although attention should be paid to myelosuppression during mFFX treatment. Further studies involving nanoliposomal irinotecan plus 5-fluorouracil/leucovorin therapy are necessary to facilitate the selection of the optimal regimen for each patient.

Background Zinc deficiency during long-term courses of chemotherapy and its related symptoms, including skin rash, taste disorder, and oral mucositis, has not been sufficiently investigated. Methods This prospective observational study enrolled patients with gastric and colorectal cancer who underwent standard first-line chemotherapy. According to the Practice Guideline for Zinc Deficiency, zinc deficiency is defined as a serum level of < 60 μg/dL. Serum zinc levels were measured before and after (1, 3, and 6 months) chemotherapy, and symptoms were assessed using the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events version 1.0. Repeated measures were analyzed using a generalized linear mixed model. Results Of the 61 enrolled patients, we analyzed 48 patients who underwent standard first-line chemotherapy with fluoropyrimidine plus oxaliplatin. Zinc deficiency was observed in 18 patients (38 %) before chemotherapy. The least-square means of serum zinc levels significantly decreased at 3 and 6 months of chemotherapy in 30 patients without zinc deficiency at the start of chemotherapy (both p < 0.01) but not in 18 patients with zinc deficiency at the start. Changes in serum zinc levels during chemotherapy were negatively correlated with taste changes, rash, and itching (all p < 0.04) in patients without zinc deficiency before treatment initiation. Conclusions Serum zinc levels decreased during chemotherapy in zinc-non-deficient patients at the start of chemotherapy and were correlated with taste changes, skin rash, and itching. Therefore, it is necessary to investigate whether zinc supplementation can improve these symptoms.

Objectives The aim of this multicenter retrospective study was to identify the optimal chemotherapeutic regimen for advanced pancreatic acinar cell carcinoma (PACC). Methods Fifty-eight patients with histopathologically confirmed advanced PACC who had received chemotherapy between 1996 and 2013 were enrolled. The clinical characteristics of the patients and the treatment efficacy data were collected from the medical records at 16 Japanese institutions, using standardized data collection instrument. Results The most commonly selected treatment regimens were gemcitabine-, fluoropyrimidine-, platinum-, and irinotecan-containing regimens. The overall response rate in the patients who received first-line chemotherapy were 7% and 38%, respectively, and the median overall survival was 13.2 months. When the data for all the treatment lines were aggregated, the response rates to gemcitabine-, fluoropyrimidine-, platinum-, and irinotecan-containing regimens were 7%, 18%, 40%, and 29%, respectively. The overall survival tended to be better in patients who had received a platinum-containing regimen (hazard ratio, 0.50; 95% confidence interval, 0.23-1.11; P = 0.08) or irinotecan-containing regimen (hazard ratio, 0.42; 95% confidence interval, 0.15-1.19; P = 0.09) at least once in the treatment course as compared with those who had not. Conclusions Our findings suggested that platinum- and irinotecan-containing regimens exhibited some potential efficacy in patients with advanced PACC.

Background: Platinum-containing regimens are widely used as first-line chemotherapy for unresectable pancreatic neuroendocrine carcinoma (NEC), but second-line chemotherapies have yet to be established. Objectives: We evaluated the safety and efficacy of everolimus in patients with pancreatic NEC refractory or intolerant to platinum-containing chemotherapy. Methods: This study was a prospective, multicenter, phase II trial in patients with pancreatic NEC after platinum-containing chemotherapy. Everolimus treatment was continued until disease progression or intolerable toxicity was observed. The primary endpoint was progression-free survival (PFS). Results: Participants comprised 25 patients. Median age was 63 years, median PFS was 1.2 months (95% confidence interval [CI] 0.9–3.1 months), median overall survival was 7.5 months (95% CI 3.1–13.5 months), overall response rate was 0%, and disease control rate was 39.1%. Common grade 3/4 adverse events were hyperglycemia (20%), thrombocytopenia (16%), and anemia (16%). Conclusion: The efficacy of everolimus was limited in patients with unresectable pancreatic NEC.

We aimed to evaluate pancreatic cancer (PC) with positive peritoneal lavage cytology (CY1) outcomes following a change in adjuvant therapy.The clinicopathological data of patients with pancreatic adenocarcinoma with CY1 at 14 institutions, between 2007 and 2015, were collected and analyzed.Of the 124 eligible patients, 114 underwent macroscopically curative resection. Of the 114 patients, 80 (70%) did not have early recurrence and received postoperative chemotherapy that was S-1 in 43 (54%), gemcitabine in 31 (39%), and others in six (7%). The median overall survival was 21.0 months in S-1 and 19.2 in gemcitabine therapy (p=0.23), whereas the median relapse-free survival was 10.2 and 7.1 months (p=0.03), respectively.Following the change in adjuvant therapy, most PC patients with CY1 who underwent macroscopically curative resection received S-1; however, it was insufficient. Further development of postoperative chemotherapy is required.

Background Gemcitabine plus cisplatin (GC) is the standard treatment of advanced biliary tract cancer (BTC); however, it causes nausea, vomiting, and anorexia, and requires hydration. Gemcitabine plus S-1 (GS) reportedly has equal to, or better, efficacy and an acceptable toxicity profile. We aimed to confirm the non-inferiority of GS to GC for patients with advanced/recurrent BTC in terms of overall survival (OS). Patients and methods We undertook a phase III randomized trial in 33 institutions in Japan. Eligibility criteria included chemotherapy-naive patients with recurrent or unresectable BTC, an Eastern Cooperative Oncology Group Performance Status of 0−1, and adequate organ function. The calculated sample size was 350 with a one-sided α of 5%, a power of 80%, and non-inferiority margin hazard ratio (HR) of 1.155. The primary end point was OS, while the secondary end points included progression-free survival (PFS), response rate (RR), adverse events (AEs), and clinically significant AEs defined as grade ≥2 fatigue, anorexia, nausea, vomiting, oral mucositis, or diarrhea. Results Between May 2013 and March 2016, 354 patients were enrolled. GS was found to be non-inferior to GC [median OS: 13.4months with GC and 15.1months with GS, HR, 0.945; 90% confidence interval (CI), 0.78–1.15; P=0.046 for non-inferiority]. The median PFS was 5.8months with GC and 6.8months with GS (HR 0.86; 95% CI 0.70–1.07). The RR was 32.4% with GC and 29.8% with GS. Both treatments were generally well-tolerated. Clinically significant AEs were observed in 35.1% of patients in the GC arm and 29.9% in the GS arm. Conclusions GS, which does not require hydration, should be considered a new, convenient standard of care option for patients with advanced/recurrent BTC. Clinical Trial number This trial has been registered with the UMIN Clinical Trials Registry (http://www.umin.ac.jp/ctr/index.htm), number UMIN000010667.

Fibroblast growth factor receptor 2 (FGFR2) rearrangement is expected to be a novel therapeutic target in advanced/recurrent biliary tract cancer (BTC). However, efficient detection and the exact frequency of FGFR2 rearrangements among patients with advanced/recurrent BTC have not been determined, and the clinical characteristics of FGFR2 rearrangement-positive patients have not been fully elucidated. We aimed to determine the frequency of FGFR2 rearrangement-positive patients among those with advanced/recurrent BTC and elucidate their clinicopathological characteristics. Paraffin-embedded tumor samples from formalin-fixed surgical or biopsy specimens of patients with advanced/recurrent BTC were analyzed for positivity of FGFR2 rearrangement by fluorescent in situ hybridization (FISH). RNA sequencing was performed on samples from all FISH-positive and part of FISH-negative patients. A total of 445 patients were enrolled. FISH was performed on 423 patients (272 patients with intrahepatic cholangiocarcinoma (ICC), 83 patients with perihilar cholangiocarcinoma (PCC), and 68 patients with other BTC). Twenty-one patients with ICC and four patients with PCC were diagnosed as FGFR2-FISH positive. Twenty-three of the 25 FISH-positive patients (20 ICC and 3 PCC) were recognized as FGFR2 rearrangement positive by targeted RNA sequencing. Younger age (≤ 65 years; p = 0.018) and HCV Ab- and/or HBs Ag-positivity (p = 0.037) were significantly associated with the presence of FGFR2 rearrangement (logistic regression). FGFR2 rearrangement was identified in ICC and PCC patients, and was associated with younger age and history of hepatitis viral infection.

Definitive chemoradiotherapy(CRT)for esophageal cancer is the standard treatment and alternative to surgery. However, the tolerability of CRT in elderly patients is not well known. In this study, we retrospectively analyzed 60 patients with esophageal cancer who were treated with CRT(5-FU 700 mg/m2, cisplatin 70 mg/m2, radiation 60 Gy)at our hospital between January 2015 and September 2017. The patients were divided into 2 groups: an elderly group comprising 16 patients aged75 years and a non-elderly group comprising 44 patients aged74 years. The relative dose intensity of cisplatin in the elderly group was significantly lower than that in the non-elderly group. Radiotherapy was successfully executed in both groups. More patients in the elderly(25%)than the non-elderly group(7%)developed pneumonitis, and all patients who developed severe pneumonitis in the elderly group died. Application of definitive CRT and irradiation methods in elderly patients with a subpleural reticular shadow should be carefully considered before initiating therapy.

Skin toxicity induced by gemcitabine, a chemotherapeutic agent, is not rare, but is usually mild. However, the occurrence of moderate to severe skin rash has been reported in patients treated with combinations of gemcitabine and other anticancer drugs. The aim of this study was to assess the characteristics of rash caused by gemcitabine-based chemotherapy. We analyzed 12 patients who developed maculopapular rash over more than 10% of their body surface following gemcitabine-based chemotherapy. Maculopapular rash appeared at 6.3 ± 1.3 days after the first administration in eight patients and the second administration in four patients. In two patients, the rash was localized on the lateral aspect of the trunk. The other 10 patients showed various degrees of rash on the chest and abdomen, in addition to the lateral aspect of the trunk. However, rash was absent on the upper and middle back in almost all patients. After the rash disappeared, gemcitabine was re-administrated in eight patients. They continued the therapy with no or only mild rash relapse. In conclusion, maculopapular rash caused by gemcitabine-based chemotherapy shows biased distribution to frontal and lateral sites of the trunk, which may be informative for consecutive chemotherapy.

A family/personal history of breast, ovarian, or pancreatic cancer is a useful predictive marker for response to platinum-based chemotherapy in treating patients with pancreatic cancer. These cancers, and prostate cancer, are known as BRCA-related malignancies. We evaluated the efficacy of gemcitabine plus oxaliplatin (GEMOX) in patients with metastatic pancreatic cancer with a family/personal history of these cancers. Chemotherapy-naive patients with metastatic pancreatic cancer with a family history of pancreatic/breast/ovarian/prostate cancer or a personal history of breast/ovarian/prostate cancer were included. Patients received fixed dose-rate gemcitabine (1000 mg/m2) and oxaliplatin (100 mg/m2) every 2 weeks. The primary endpoint was 1-year survival, and the threshold and expected values were set at 30 and 50%, respectively. The target sample size was determined to be 43, with a one-sided alpha value of 5% and power of 80%. A total of 45 patients were enrolled. Among the first 43 enrolled patients, the 1-year survival rate was 27.9% [90% confidence interval (CI) 17.0–41.3], which did not meet the primary endpoint. Median overall survival, progression-free survival, and response rates were 7.6 months (95% CI 6.0–10.7), 4.0 months (95% CI 2.0–4.6), and 26.7% (95% CI 14.6–41.9), respectively, in all registered patients. The GEMOX regimen was generally tolerated; the most common grade three or higher adverse events were hematological toxicities. GEMOX did not show the expected efficacy in patients with metastatic pancreatic cancer with a family or personal history of pancreatic/breast/ovarian/prostate cancer. Selection of GEMOX based on family/personal history is not recommended. UMIN000017894.

Objective To evaluate prospectively the efficacy and safety of sorafenib, which has been the first-line treatment for advanced hepatocellular carcinoma (HCC), in Japanese HCC patients (pts) with not only Child-Pugh (C-P) A class but also C-P B class. Methods Sorafenib was administered orally at the dose of 400 mg twice daily for pts with HCC and liver function of C-P score of 5-8. Administration was continued until the detection of disease progression or appearance of unacceptable toxicity. The primary endpoint was time to progression (TTP), and toxicity and the secondary endpoints included objective response, overall survival (OS). Results Forty C-P A pts and 12 C-P B pts were enrolled. The median TTP in the C-P A pts and C-P B pts was 3.3 months and 3.2 months, respectively. Among the pts with C-P A, complete response, partial response, and stable disease were achieved for 2.5%, 7.5% and 47.5%. Among the pts with C-P B, there were no treatment responses, 66.7% of pts had stable disease. The median OS in the C-P A pts and C-P B pts was 13.4 months and 7.4 months, respectively. With regard to toxicities, fewer C-P A pts experienced Grade 3/4 toxicities than C-P B pts (77.5% vs. 91.6%). There were no treatment-related deaths in either group of patients. Conclusions This study shows sorafenib has similar effectiveness in the recent post-approval studies and is well-tolerated in Japanese pts with HCC and Child Pugh A class. Sorafenib should be used with great care for Child Pugh class B pts.

695 Background: Although macroscopically curative resection has been performed for pancreatic cancer with positive peritoneal lavage cytology (CY1), the prognosis is poor in most reports. In 2013, the JASPAC01 trial showed that S-1 was superior to Gemcitabine (GEM) as adjuvant chemotherapy for resected pancreatic cancer, and S-1 was also administered to the patients with CY1 who had undergone macroscopically curative resection. Methods: This is a multicenter retrospective observational study that collected data of the patients with pancreatic adenocarcinoma who were diagnosed with CY1 between 2007 and 2015 and had no other noncurable factors. Results: One hundred twenty-seven patients were enrolled from 14 institutions, and 3 were excluded due to liver metastasis or non-adenocarcinoma. The median age was 67 years old and almost patients had PS 0 or 1. Of the 124 patients, 114 underwent macroscopically curative resection and the median overall survival (OS) and recurrence free survival (RFS) were 16.7 and 7.2 months. Of the resected patients, 80 (70%) had no early recurrence and started postoperative adjuvant chemotherapy. Adjuvant chemotherapy regimens were S-1 in 43 patients (54%), GEM in 31 (39%) and others in 6 (7%). The median OS was 21.0 months with S-1 and 19.2 months with GEM (HR: 0.73, 95%CI: 0.44-1.22, P = 0.23), whereas the median RFS was 10.2 and 7.1 months (HR: 0.58, 95%CI: 0.36-0.95, P = 0.03), respectively. Conclusions: After the report of JASPAC01, most patients with pancreatic cancer with CY1 received macroscopically curative resection and treated with S-1 as adjuvant therapy, however the efficacy was insufficient. We should consider appropriate treatment strategies for patients with pancreatic cancer with CY1 intended for surgical resection.

647 Background: Pancreatic adenosquamous carcinoma (PASC) is a rare variant of pancreatic ductal adenocarcinoma (PDAC). Although unresectable or recurrent PASC is usually treated by systemic chemotherapy, there are few reports which show the efficacy of chemotherapy. The aim of this study was to evaluate the efficacy of chemotherapy for patients (pts) with unresectable or recurrent PASC. Methods: We collected data retrospectively from 24 Japanese institutions. The selection criteria were as follows: 1) histologically or cytologically proven PASC (non-surgical specimens were eligible if squamous cell carcinoma (SCC) was detected), 2) unresectable or recurrent disease treated with 1st line chemotherapy between April 2001 and December 2017. Results: This study included 138 pts with median age of 66 years (range: 36-85). About 60% of pts were diagnosed with biopsy and only SCC was detected in 13.0% of pts. Median overall survival (mOS) was 6.7 months (M), median progression free survival (mPFS) was 2.8 M, and the 1-year survival rate (1YSR) was 26.7%. For the 102 metastatic or distal recurrent pts with PS of 0-1, patient characteristics were as follows: ≥76 years old, 9 (8.8%); PS of 0, 39 (38.2%); number of metastatic sites ≥2, 25 (24.5%). The treatment efficacies (The objective response rates(%)/mPFS(M)/mOS(M)/1YSR(%)) of the 5 major regimens were Gemcitabine(GEM) (n=45, 4.4%/2.2M/4.8M/28.1%), GEM+nab-PTX (n=24, 29.2%/2.9M/7.6M/23.1%), GEM+S-1 (n=9, 11.1%/5.1M/9.9M/25.4%), FOLFIRINOX (n=7, 14.3%/2.5M/7.5M/14.3%), and S-1 (n=7; 28.6%/2.6M/5.0M/28.6%), respectively. One patient with liver metastasis underwent conversion surgery after GEM+nab-PTX and achieved long survival. CRP ≥3.0mg/dl, CA19-9 ≥1000 U/ml, residual primary site, and monotherapy had a significant correlation with poor survival in multivariate analysis. Conclusions: Although combination chemotherapy regimens such as FOLFIRINOX and GEM+nab-PTX are now available, the prognosis of metastatic PASC remains poor. Development of more effective treatment options is required.

Background Epithelioid hemangioendothelioma is an exceedingly rare sarcoma often occurring as an indolent angiocentric vascular tumor at various anatomic sites. Few reports have evaluated large case series of epithelioid hemangioendothelioma. Methods We conducted a retrospective analysis of the clinical data of 42 consecutive patients with epithelioid hemangioendothelioma who were pathologically diagnosed between 1990 and 2014 at 13 Japanese tertiary hospitals. We analyzed their clinical characteristics, tumor features and prognostic factors. Results The study included 22 men and 20 women, with a median age of 54 (range, 18–78) years. Pain was the most common symptom, occurring in 15 (68%) of the 22 symptomatic patients. The median maximum tumor diameter was 4.0 (range, 1.0–12.8) cm. The most commonly involved organs were the liver (81%), lungs (57%), and bones (12%). The overall survival rates were 79.5% at 1 year and 72.0% at 5 years. Substantially better survival was observed in asymptomatic patients than in symptomatic patients (P = 0.03), and better survival was also ovserved in patients with Ki-67 index ≤10% than in those with Ki-67 index > 10% (P = 0.04). By multivariate analysis, tumor size > 3.0 cm was associated with decreased survival (P = 0.049, hazard ratio 13.33). Conclusions This study showed the clinical characteristics of Japanese patients with epithelioid hemangioendothelioma. Tumor size > 3.0 cm is an independent indicator of a poor prognosis in epithelioid hemangioendothelioma. The presence of symptoms at the time of diagnosis and high Ki-67 index implied poor survival.

We conducted a multicenter retrospective analysis to evaluate the efficacy of systemic chemotherapy for unresectable combined hepatocellular and cholangiocarcinoma. We enrolled 36 patients with pathologically proven, unresectable combined hepatocellular and cholangiocarcinoma treated with systemic chemotherapy. The log-rank test determined the significance of each prognostic factor. Elevated alpha-fetoprotein, carcinoembryonic antigen and carbohydrate antigen 19-9 levels were observed in 58.3%, 16.7% and 38.9% of patients, respectively. First-line chemotherapy included platinum-containing regimens consisting of gemcitabine/cisplatin (n = 12) and fluorouracil/cisplatin (n = 11), sorafenib (n = 5) and others (n = 8). The median overall and progression-free survival times were 8.9 and 2.8 months, respectively, with an overall response rate of 5.6%. Prognostic factors associated with negative outcomes included poor performance status, no prior primary tumor resection, a Child-Pugh class of B, and elevated carcinoembryonic antigen levels with a hazard ratio of 2.25, 2.48, 3.25 and 2.84 by univariate analysis, respectively. The median overall survival times of the gemcitabine/cisplatin, fluorouracil/cisplatin, sorafenib and other groups were 11.9, 10.2, 3.5 and 8.1 months, respectively. Multivariate analysis revealed that the overall survival of patients within the sorafenib monotherapy group was poor compared with platinum-containing regimens (HR: 15.83 [95% CI: 2.25-111.43], P = .006). All 7 patients in the sorafenib group had progressive disease, including 2 patients with second-line therapy. In conclusion, the platinum-containing regimens such as gemcitabine/cisplatin were associated with more favorable outcomes than sorafenib monotherapy for unresectable combined hepatocellular and cholangiocarcinoma.

Background Patients with biliary tract carcinomas (BTC) have a dismal prognosis. The FGFR2-fusion gene has been recently implicated in 14-17% of intrahepatic cholangiocarcinomas (ICC) and is expected to be a promising novel druggable target. However, the exact frequency in patients of advanced BTC (including cancers other than ICC) and detailed clinicopathological background of the FGFR2-fusion have not been sufficiently elucidated. Methods Histologically confirmed advanced or recurrent BTC patients who planned to or received systemic chemotherapy were eligible. Because FGFR2-fusion gene was identified in only ICC and perihilar cholangiocarcinoma (PCC) among first 209 patients (March 2014 to February 2016), we limited the subjects to those with ICC/PCC and continued enrollments until November 2018. To determine FGFR2-fusion status, break-apart fluorescent in situ hybridization and target RNA sequencing were performed on formalin fixed, paraffin-embedded tumor samples obtained by resection or core biopsy. Results During the entire study period, 445 patients were registered and 423patients (272 ICC, 83 PCC, 20 distal cholangiocarcinoma, 43 carcinoma of gallbladder, and 5 ampullary carcinoma) were successfully tested for FGFR2-fusion status. Among those, 21 ICC and 4 PCC patients were identified as harboring the FGFR2-fusion. Characteristics of FGFR2-fusion positive patients were as follows: male/female = 19/6; median age (range) = 60 (41-76); stage (metastatic/locally advanced/recurrent) = 15/2/8. Macroscopic type was mass forming type in all 21 ICC patients. Age of 60g of ethanol/day (p = 0.023), and HCV Ab and/or HBs Ag positive (p = 0.012) were significantly related with FGFR2-fusion positive status (logistic regression). Conclusions In this study, frequency of FGFR2-fusion was 7.7% in advanced ICC patients, which was lesser than the previous reports. We found that 4.8% of the PCC patients also harbored the FGFR2-fusion. Younger age, alcohol abuse, and hepatitis B or C positive status were related to FGFR2-fusion positive status. The survival data of FGFR2-fusion positive patients will be presented at the meeting. Clinical trial identification UMIN000014767. Legal entity responsible for the study National Cancer Center. Funding National Cancer Center Research and Development Fund. Disclosure M. Ikeda: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer Yakuhin; Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Honoraria (self): Taiho Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly Japan; Research grant / Funding (institution): Yakult; Advisory / Consultancy: Otsuka Pharmaceutical; Advisory / Consultancy: Daiichi-Sankyo; Honoraria (self): Sumitomo Dainippon Pharma; Honoraria (self), Advisory / Consultancy: Teijin Pharma; Honoraria (self): EA Pharma; Honoraria (self): Kaken Pharmaceutical; Advisory / Consultancy: Shire; Honoraria (self): MSD; Advisory / Consultancy, Research grant / Funding (institution): ASLAN Pharmaceuticals; Advisory / Consultancy, Research grant / Funding (institution): Chugai Pharmaceutical; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Nano Carrier; Honoraria (institution): Gilead; Advisory / Consultancy: Astellas Pharma; Research grant / Funding (institution): Takeda Pharmaceutical; Research grant / Funding (institution): J-Pharma; Advisory / Consultancy: Micron. M. Ueno: Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Yakult Honsha; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self): Novartis; Honoraria (self): Lilly; Honoraria (self): Teijin Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Shire; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): MSD; Research grant / Funding (institution): NanoCarrier; Research grant / Funding (institution): Dainippon Sumitomo Pharma; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Aslan Pharmaceuticals. T. Ioka: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Taiho; Honoraria (self): Yakult Honsha; Honoraria (self): Chugai; Honoraria (self), Advisory / Consultancy: Daiichi-Sankyo; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Shire Japan; Honoraria (self), Advisory / Consultancy: Otsuka; Research grant / Funding (institution): Dainippon Sumitomo; Research grant / Funding (institution): Takara-bio; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Nihon Zouki. A. Naganuma: Speaker Bureau / Expert testimony: AbbVie; Speaker Bureau / Expert testimony: Eisai; Speaker Bureau / Expert testimony: Gilead; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Chugai; Speaker Bureau / Expert testimony: Taiho; Speaker Bureau / Expert testimony: Novartis. Y. Nakai: Honoraria (self), Research grant / Funding (self): Taiho Pharmaceutical; Honoraria (self): Daiichi Sankyo; Honoraria (self): AstraZeneca; Research grant / Funding (self): Eisai; Research grant / Funding (self): Yakult Honsha; Research grant / Funding (self): J-Pharma. M. Kanai: Licensing / Royalties: Therabiopharma Ltd; Licensing / Royalties: JMS Co., Ltd. S. Shimizu: Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Baxalta Japan; Research grant / Funding (institution): Taiho pharmaceutical; Research grant / Funding (institution): Sumitomo Dainippon Pharma; Research grant / Funding (institution): Yakult; Research grant / Funding (institution): IQVIA Survices Japan. T. Yamanaka: Honoraria (self): Pfizer. T. Shibata: Advisory / Consultancy: MSD. C. Morizane: Honoraria (self): Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self): Lilly; Honoraria (self), Research grant / Funding (institution): Nobelpharma; Honoraria (self): Fujifilm; Honoraria (self): Teijin Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Eisai; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Yakult Honsha; Honoraria (self): AbbVie; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): J-Pharma. T. Okusaka: Honoraria (self), Research grant / Funding (institution): Novartis Pharma KK; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Taiho; Honoraria (self), Research grant / Funding (institution): Eli Lilly; Honoraria (self), Research grant / Funding (institution): Bayer Yakuhin; Honoraria (self): Nobel Pharma; Honoraria (self), Research grant / Funding (institution): Yakult; Honoraria (self): FUJIFILM; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Ono; Honoraria (self): EA pharma; Honoraria (self), Research grant / Funding (institution): Eisai; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self): Teijin; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Honoraria (self): Shire; Honoraria (self): Takara Bio; Honoraria (self): AbbVie; Honoraria (self): Takeda; Advisory / Consultancy, Research grant / Funding (institution): Dainippon Sumitomo; Advisory / Consultancy: Zeria; Advisory / Consultancy, Research grant / Funding (institution): Bristol Myers; Research grant / Funding (institution): Kowa; Research grant / Funding (institution): Kyowa Hakko Kirin; Research grant / Funding (institution): Chugai. All other authors have declared no conflicts of interest.

Background A family and personal history of breast (B), ovarian(O), and pancreatic(P) cancer was reported to be a predictive marker in patients with pancreatic adenocarcinoma (PA) treated with platinum-based chemotherapy. We planned a prospective phase II trial to evaluate the efficacy and safety of platinum-based chemotherapy in this population. Method Eligible patients had chemotherapy-naive metastatic PA, had one or more of the followings: 1) at least one family history of P/B/O/prostate (PR) cancer in a first-degree relative, 2) at least two family members with history of P/B/O/PR cancer within third-degree relatives, and 3) at least one personal history of B/O/PR cancer.Patient suitable for FOLFIRINOX or gemcitabine plus nab-paclitaxel were ineligible unless patient refuse those regimens. Patients received gemcitabine 1000mg/m2and oxaliplatin 100 mg/m2 every two weeks (GEMOX). The primary endpoint was the one-year survival rate and 44% were desired. The sample size was calculated to be 43 pts, with a one-sided alpha of 5% and a power of 80%. Results A total of 45 pts were enrolled. First 43 pts were included in primary analysis. One-year survival rate was 27.9 [90%CI;17.0-41.3]% and didn’t met pre-planned boundary. Response rate was 27.9%. Tendency of prolonged survival was observed in patients with two or more family histories of P/B/O/PR cancer (HR 0.65, 95%CI [0.34-1.23]). Family history or personal history with B/O/PR cancer tended to be associate with better response and prolonged survival. In this study, patient with family history of pancreatic cancer seemed to be associate with poor response. The most common adverse events of grade 3 or higher were neutropenia (36%), leukopenia (27%), thrombocytopenia (23%) and elevated level of ALT (20%). Treatment related death was not observed. Conclusion GEMOX did not show expected efficacy in patients with metastatic PA with family history or personal history of P/B/O/PR cancer.

387 Background: This Phase 1 study (NCT01938612) evaluated D (anti-PD-L1 mAb) and T (anti-CTLA-4 mAb) in Asian pts, in whom optimal dosing of D and T is undetermined. No dose-limiting toxicities were observed, and durable responses were seen in a dose escalation phase evaluating various D doses and regimens in Japanese pts (Iguchi, ASCO 2015). The study was subsequently expanded to larger cohorts of Asian pts with advanced solid tumors including BTC. Methods: Two regimens were selected for the expansion phase: D monotherapy (10 mg/kg q2w) and D+T (D 20 mg/kg + T 1.0 mg/kg q4w). One cohort of pts with advanced BTC was enrolled to receive D monotherapy followed by a separate cohort that received D+T with additional pts enrolled if efficacy was observed. Safety, response, and survival endpoints were based on investigator assessment. Results: Pts were enrolled to D (N = 42) or D+T (N = 65). Median age was 64 years for the D cohort and 62 years for the D+T cohort, the majority were male, and ECOG PS was 0 or 1: 64% and 36% for pts in the D cohort and 49% and 51% for pts in the D+T cohort, respectively. Median number of prior chemotherapy regimens was 2 for both cohorts. Treatment-related adverse events (trAE) of any grade occurred in 64% and 82% of pts in the D and D+T cohorts. Grade ≥ 3 trAEs occurred in 19% and 23% of pts in the D and D+T cohorts. trAEs led to discontinuation in 2 pts in the D cohort and 5 pts in the D+T cohort. A death due to trAE (drug-induced liver injury) was reported in the D+T cohort, none in the D cohort. In the D cohort, 2 pts had a partial response (PR) and 7 pts had a PR in the D+T cohort; disease control rate at 12 weeks was 16.7% and 32.2%, respectively. Median duration of response for the D cohort was 9.7 months and 8.5 months for the D+T cohort. Median overall survival was 8.1 (95% CI, 5.6-10.1) months and 10.1 (95% CI, 6.2-11.4) months for the D and D+T cohorts, respectively. Conclusions: Both D monotherapy and D+T combination therapy were tolerable for Asian pts with BTC, and no unexpected toxicities were observed with either regimen. Promising clinical benefit was observed with both D and D+T therapy. This study provides valuable information regarding these therapeutic regimens for future studies in pts with BTC. Clinical trial information: NCT01938612.

Objectives: Fluorodeoxyglucose (FDG)-positron emission tomography/contrast-enhanced computed tomography (PET/CE-CT) involving whole-body scanning first by non-CE-CT and FDG-PET followed by CE-CT has been used for detailed examination of pancreatic lesions. We evaluated PET/CE-CT images with regard to differential diagnosis, staging, treatment response, and postoperative recurrence in pancreatic cancer. Methods: Positron emission tomography/CE-CT was conducted in 108 patients with pancreatic cancer and in 41 patients with other pancreatic tumor diseases. Results: The maximum standardized uptake value (SUVmax) overlapped in benign and malignant cases, suggesting that differential diagnosis of pancreatic tumors based on the SUVmax is difficult. In the evaluation of staging in 31 resectable pancreatic cancer by PET/CE-CT, the diagnostic accuracy rate was more than 80% for most factors concerning local invasion and 94% for distant metastasis but only 42% for lymph node metastasis. Significant positive correlations were found between the SUVmax and tumor size/markers, suggesting that SUVmax may be a useful indicator for the treatment response. Regarding the diagnosis of the postoperative recurrence, PET/CE-CT correctly detected local recurrence in all the 11 cases of recurrence, whereas abdominal CE-CT detected only 7 of 11 cases, suggesting that PET/CE-CT is superior in this context. Conclusions: Positron emission tomography/CE-CT is useful for the clinical management of pancreatic cancer.

66歳，男性．平成11年，膵癌にて膵体尾部切除を施行し，組織型は類破骨細胞型巨細胞癌であった．経過観察中の平成20年2月にCA19-9の上昇を認め，PET/CTにおいて残存膵頭部の腫瘤及び同部位へのFDG集積所見より膵癌再発を疑われ，当院紹介となった．術前の造影CTにおける進展度はT4（TS2，CH（-），DU（-），S（+），RP（+），PV（+），A（-），PL（-），OO（-））N2M0，Stage IVbであった．膵頭十二指腸切除に臨んだが，開腹時に腹腔動脈周囲神経叢への浸潤を認め，切除不能と判断し，試験開腹で終了した（組織診断：tubular adenocarcinoma）．その後はgemcitabineによる化学療法を施行している．本症例は膵破骨細胞型巨細胞癌の術後9年目にして管状腺癌（tubular adenocarcinoma）を発症した極めて稀な症例と考える．

症例は70歳の男性．腹痛を主訴に膵癌，切除可能と診断された．膵体尾部切除術およびD2郭清ののち，GEMによる術後補助化学療法を開始した．5コース目day1に血清クレアチニンが2.05mg/dl ，尿蛋白+になり，腹部CTで両側腎腫大あったためGEMを中止した．腎生検で薬剤性腎障害，溶血性尿毒症症候群と診断した．プレドニゾロンの投与で血清クレアチニンは低下し，プレドニゾロン開始から13カ月の現在，膵癌の再発はない．

A 42-year-old woman with hepatitis C virus-related cirrhosis underwent peginterferon alpha-2b therapy combined with ribavirin but could not achieve a sustained viral response. Following discontinuation of this combined therapy, the patient's serum transaminase levels suddenly became elevated. Therefore, the administration of very-low-dose peginterferon alpha-2a with ursodeoxycholic acid was introduced. Thereafter, the patient's serum transaminase levels gradually improved. Four years later, enhanced computed tomography showed shrinkage of the spleen and enlargement of the liver. Long-term combined therapy with very-low-dose peginterferon and ursodeoxycholic acid may be effective not only in preventing disease progression, but also in improving portal hypertension in patients hepatitis C virus-related cirrhosis.

e15626Background: Although relatively good therapeutic effects have been reported about 3D-CRT for the treatment of HCC with MVI, there is few comparative data between them and those of sorafenib t...

422 Background: FOLFIRINOX has been shown superior to GEM in terms of OS, PFS and/or RR for treatment of metastatic PC in Accord 11, and this regimen has become the standard of care for the first-line chemotherapy. However, the major disadvantage of FOLFIRINOX is significantly higher toxicity, and, in particular, quite higher incidence of neutropenia (78%) and febrile neutropenia (22%) was observed in the PII clinical trial of FOLFIRINOX performed in Japan (LOHP-PII-05, JSCO 2013). Thus, in clinical practice for the Japanese patients, it should be needed to make modification on this regimen in terms of dose reduction without compromising in its effectiveness. We evaluated the safety and efficacy of modified (m) FOLFIRINOX in Japanese patients with unresectable locally advanced PC (LAPC), metastatic PC (MPC), and/or postoperative recurrence. Methods: The modifications to FOLFIRINOX include discontinuation of the bolus 5-FU and dose-reduction (25%) of irinotecan. 36 patients with unresectable LAPC, MPC and postoperative recurrence were treated with mFOLFIRINOX, and toxicity and efficacy were evaluated. Results: Patient characteristics were as follows: LAPC/MPC/Postoperative recurrence 6/20/10; median age 65 years (range 39-75); male/female 27/9. Median number of cycles was 5 (range 1-28). Grade 3/4 toxicities included neutropenia (16.7%), leukopenia (13.9%), diarrhea (13.9%) and enteritis (11.1%) in order. Febrile neutropenia was only in 2 patients (5.6%). Both hematologic and non-hematologic toxicities were reduced, although diarrhea was observed in a bit higher incidence compared to those in LOHP-PII-05. The response rate and disease control rate evaluated in 28 patients were favorable, in LAPC, MPC and/or post operative recurrence, which were similar to those in LOHP-PII-05. In response of CA19-9 was evaluated in 26 patients. 20 patients (76.9%) showed a decline in CA19-9 levels from baseline, and a greater than 50% decline was noted in 15 patients (57.7%). Conclusions: mFOLFIRINOX has an improved safety profile with maintained efficacy in the selected population of MPC. mFOLFIRINOX has promising activity also in LAPC with respect to RR.

Pancreatic cancer shows the worst prognosis among the solid tumors, and survival for patients with high-grade liver metastasis is estimated at around a few months. We reported the effects of combination therapy with gemcitabine and S-1 (GS therapy) on pancreatic cancer patients with high-grade hepatic metastasis. Patients with severe metastatic pancreatic cancer received chemotherapy comprising S-1 (30mg/m² p.o. b.i.d., days 1-14) and gemcitabine (1000mg/m² on days 1 and 8), repeated every 3 weeks. Fourteen patients (7 men, 7 women) received treatment at a mean age of 56.5 years (range, 39-76 years), achieving complete response in 1 patient, partial response in 5 patients, and stable disease in 3 patients and progressive disease in 5 patients. The response rate was thus 43%. Median progression-free survival was 186 days (95% confidence interval, 40-247 days). Median overall survival was 261 days (95% confidence interval, 162-358 days). GS therapy appears to be well-tolerated and effective in patients with high-grade hepatic metastasis.

Early gastric cancer (EGC) has a favorable prognosis after surgical gastrectomy. For intramucosal EGC with little risk of lymph node metastasis, endoscopic mucosal resection (EMR) is an accepted treatment method. Herein we document a noteworthy case of small undifferentiated gastric cancer with nodal metastasis. A 60-year-old Japanese woman underwent gastrectomy with D2 lymph node dissection for the treatment of EGC in the lower gastric body. Histological examination revealed that signet-ring cell carcinoma was located in approximately one-third of the superficial portion of the mucosal layer, with a tumor size of 13 mm. No lymphatic invasion, venous invasion, or fibrosis was observed in the submucosal layer. This case had nodal metastasis and was finally diagnosed as stage IB (T1N1M0) according to the Japanese Classification of Gastric Carcinoma (JCGC). The patient is alive without recurrence 6 years after treatment.

A 75-year-old man was admitted to our hospital because of right hypochondralgia. Computed tomography (CT) revealed a large tumor in the right lobe of the liver. Ultrasonography (US) showed vessels in the tumor. Needle biopsy specimens showed malignant lymphoma (Diffuse large B cell lymphoma). Ga scintigraphy and FDG-PET did not demonstrate other lesions and the definitive diagnosis was primary malignant lymphoma of the liver. CHOP with Rituximab therapy (R-CHOP therapy) was performed. After 8 courses of therapy the FDG-PET results were negative and we considered complete remission. We describe a case of primary malignant lymphoma of the liver treated successfully by R-CHOP therapy.

A 70-year-old right-handed Japanese man who had undergone surgical resection for hepatocellular carcinoma (HCC) 2 years earlier was diagnosed with lung metastasis 3 months before consulting our hospital with a headache and visual field disturbance. Head computed tomography revealed a brain tumor with an intracerebral hemorrhage. Using (99m)Tc-PMT (pyridoxal-5-methly-triptophan) scintigraphy, we determined that the brain tumor was metastasis from the HCC and utilized the cyber-knife for treatment. The prognosis of patients with brain metastasis from HCC has been reported to be poor. Use of the cyber-knife was non-invasive, and proved to be effective for improving prognosis and quality of life.

480 Background: FOLFIRINOX has been shown superior to GEM in terms of OS, PFS and/or RR for treatment of metastatic PC in Accord 11, and this regimen has become the standard of care for the first-line chemotherapy. However, the major disadvantage of FOLFIRINOX is significantly higher toxicity, and, in particular, quite higher incidence of neutropenia(78%) and febrile neutropenia(22%) was observed in the PII clinical trial of FOLFIRINOX performed in Japan (LOHP-PII-05, JSCO 2013). Thus, in clinical practice for the Japanese patients, it should be needed to make modification on this regimen in terms of dose reduction without compromising in its effectiveness. We evaluated the safety and efficacy of modified(m) FOLFIRINOX in Japanese patients with unresectable locally advanced PC(LAPC) and/or metastatic PC(MPC). Methods: The modifications to FOLFIRINOX include discontinuation of the bolus 5-FU and dose-reduction(25%) of irinotecan. 20 patients with unresectable LAPC and/or MPC (PS 0-1) were treated with m FOLFIRINOX given every 2 weeks, and toxicity and efficacy were evaluated in these patients who received more than 3 courses. All patients did not receive prophylactic filgrastim. Results: Patient characteristics were as follows: LAPC/MPC 4/9; median age 65 yrs(range 39~75); male/female 15/5. Median number of cycles was 5.5 (range 1~17). Grade 3/4 toxicities included neutropenia(25%), nausea(30%), anorexia(35%) and diarrhea(20%). Grade 1/2 toxicities were sensory neuropathy(45%) and vomiting(40%). Febrile neutropenia was noted in 2 patients(10%). Toxic death was not observed, and 12 patients(60%) required dose reduction due to toxicity. Hematologic toxicities were decreased, however, those concerned with gastrointestinal toxicities were observed in a bit higher incidence compared to those in LOHP-PII-05. Response by CA19-9 was evaluable in 11 patients. 9 of 11 patients (82%) showed a decline in CA19-9 levels from baseline, and a greater than 50% decline was noted in 5 of 11 patients(45%). Conclusions: m FOLFIRINOX seems to have an improved safety profile even without prophylactic filgrastim and to maintain its efficacy.

Background The aim of this study was to evaluate the efficacy and safety of intra-arterial chemotherapy with a fine-powder formulation of cisplatin in patients with advanced intrahepatic cholangiocarcinoma. Methods Eligibility criteria were as follows: histologically proven intrahepatic cholangiocarcinoma, unresectable or recurrent disease, having a measurable lesion in the liver, no history of chemotherapy with platinum, and an ECOG performance status (PS) of 0-1. A fine-powder formulation of cisplatin was administered at a dose of 65 mg/m2 into the hepatic artery over 20 min. The treatment was repeated every 4–6 weeks until a maximum of six courses, unless unacceptable toxicity or disease progression occurred. The primary end point was the response rate according to RECIST ver.1.0. Results Thirty-five patients were enrolled between June 2007 and July 2010. There were 22 men and 13 women with a median age of 63 years (range 42–77). Thirty and five were in PS 0 and 1, respectively. Fifteen patients had received prior chemotherapy. One, 2, 17 and 15 patients were in UICC stage I, II, III and IV, respectively. Treatment courses ranged from 1 to 8 with a median of 3. The partial response was observed in six patients (17.1%, 95% confidential interval: 6.6–33.7%), stable disease in 15 and progressive disease in 14. Median time to progression, median overall survival and 1-year survival rate were 3.3 months, 11.0 months and 41.9%, respectively. The main grade 3/4 toxic effects were neutropenia (5.7%), thrombocytopenia (11.4%), elevation of the serum levels of aspartate aminotransferase (20%) and alanine aminotransferase (28.6%), anorexia (5.7%) and fatigue (8.6%). These toxic effects were transient and well tolerated. Conclusions Intra-arterial chemotherapy with a fine-powder formulation of cisplatin failed to demonstrate a favorable tumor response in patients with advanced intrahepatic cholangiocarcinoma.