Pancreatic Cancer In Japan Research Articles

Paradigm Shifting of Systemic Chemotherapy for Unresectable Pancreatic Cancer in Japan.

Systemic chemotherapy plays an important role in the treatment of pancreatic cancer, to improve the survival of patients with pancreatic cancer. Unresectable pancreatic cancer can be classified into three categories: metastatic, locally advanced, and hereditary pancreatic cancers. Furthermore, the second-line chemotherapy is required to prolong the survival. The combined regimens of oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX) and gemcitabine plus nab-paclitaxel (GEM plus nab-PTX) have been recognized as the standard of care for advanced pancreatic cancer. However, the consensus of selection of the first-line chemotherapy still remains. Randomized controlled trials (RCTs) between FOLFIRINOX and GEM plus nab-PTX are ongoing for locally advanced and metastatic disease in Japan, respectively. Hereditary pancreatic cancer, especially associated with BRCA mutations, is responsive to platinum-containing regimens and/or poly (ADP-ribose) polymerase (PARP) inhibitors. It is becoming more important to examine the presence/absence of BRCA mutations to select the appropriate treatment strategy for individual patients. Although some S-1-based regimens have been investigated in the second-line treatment after GEM-based chemotherapy in Japan, no regime demonstrated survival benefit. Nanoliposomal irinotecan (nal-IRI) plus FF has been established as the standard of care in the second-line treatment in a global phase III trial (NAPOLI-1). A randomized phase II trial comparing FF plus nal-IRI with FF alone was also conducted in Japan to examine the efficacy and safety of the FF plus nal-IRI in Japanese patients.

A randomised controlled trial of gemcitabine hydrochloride plus S-1 combination therapy versus gemcitabine hydrochloride therapy alone in pancreatic cancer patients aged ≥75 years: a study protocol for an open-label randomised feasibility study

IntroductionIn Japan, the age of patients with pancreatic cancer has increased. Combination chemotherapies such as 5-fluorouracil/leucovorin, oxaliplatin and irinotecan therapy and gemcitabine hydrochloride (GEM) +nab paclitaxel therapy have been developed...

Multicenter study of early pancreatic cancer in Japan

Background/ObjectivesThe diagnosis of early-stage pancreatic ductal adenocarcinoma (PDAC) is still challenging. We conducted a multicenter study to clarify the clinical features of early-stage PDAC in Japan. MethodsWe collected patients with stage 0 and stage I PDAC according to the sixth edition of the Japanese Classification of Pancreatic Carcinoma. We retrospectively analyzed the clinical profiles including opportunities for medical examination, imaging modalities and findings, methods of cytological diagnosis, and prognosis according to the stages at diagnosis. ResultsTwo hundred cases with Stage 0 and stage I PDAC were reported from 14 institutions, which accounted for approximately 0.7% and 3% of all PDAC cases, respectively. Overall, 20% of the early-stage PDAC cases were symptomatic. Indirect imaging findings such as dilatation of the main pancreatic duct were useful to detect early-stage PDAC. In particular, local fatty changes may be specific to early-stage PDAC. For preoperative pathologic diagnosis, cytology during endoscopic retrograde cholangiopancreatography was more commonly applied than endoscopic ultrasound fine-needle aspiration. Although the overall prognosis was favorable, new PDAC lesions developed in the remnant pancreas in 11.5% cases. ConclusionsThis multicenter study revealed several key points concerning the diagnosis and management of early-stage PDAC, including screening of asymptomatic cases, importance of indirect imaging findings, application of cytology during endoscopic retrograde cholangiopancreatography, and the risk of carcinogenesis in the remnant pancreas.

233P - Real-world experience with FOLFIRINOX and gemcitabine plus nab-paclitaxel in the treatment of pancreatic cancer in Japan

233P - Real-world experience with FOLFIRINOX and gemcitabine plus nab-paclitaxel in the treatment of pancreatic cancer in Japan

Clinical trials in progress of chemotherapy for unresectable pancreatic cancer in Japan

The aim of this study was to investigate the role of hypertriglyceridemia for acute kidney injury (AKI) in the course of acute pancreatitis.Patients with acute pancreatitis were retrospectively divided into four groups according to admission triglyceride: normal group, mild HTG group, moderate HTG group and severe HTG group. Clinical characteristics were compared among these groups. Wild type (WT) mice and Human ApoC III transgenic (ApoCIIItg) mice were used in the next animal experiments. Severe acute pancreatitis (SAP) model was established by retrograde injection of 0.5% sodium taurocholate (0.1 ml/100 g) from duodenum to pancreatic duct. Histological scores, serum amylase, creatinine, usea nitrogen were compared between WT mice and ApoCIIItg mice.Two hundred and sixty-two patients were classified into 4 groups: normal TG (104, 39.7%), mild HTG (72, 27.5%), moderate HTG (47, 17.9%), and severe HTG (39, 14.9%) groups. The proportions of AKI were 13.5% (14/104, normal), 13.9% (10/72, mild), 21.3% (10/47, moderate), and 38.5% (15/39, severe), respectively. After establishing SAP model, the levels of serum amylase (P < 0.05) and pancreatic histological score (P < 0.05) of ApoCIII-SAP-9h group were significantly higher than that of WT-SAP-9h group, respectively. ApoCIII-SAP-9h group had significantly higher levels of serum creatinine (P < 0.001), usea nitrogen (P < 0.001), and kidney histological score (P < 0.05) than that of WT-SAP-9h group, respectively.Mild HTG has little adverse impact on disease severity of acute pancreatitis; severe HTG can aggravate kidney injury in the course of acute pancreatitis. ApoCIII-SAP mice have more serious pancreatic damage and kidney injury than WT-SAP mice.

Genomic Signature of the Natural Oncolytic Herpes Simplex Virus HF10 and Its Therapeutic Role in Preclinical and Clinical Trials.

Oncolytic viruses (OVs) are opening new possibilities in cancer therapy with their unique mechanism of selective replication within tumor cells and triggering of antitumor immune responses. HF10 is an oncolytic herpes simplex virus-1 with a unique genomic structure that has non-engineered deletions and insertions accompanied by frame-shift mutations, in contrast to the majority of engineered OVs. At the genetic level, HF10 naturally lacks the expression of UL43, UL49.5, UL55, UL56, and latency-associated transcripts, and overexpresses UL53 and UL54. In preclinical studies, HF10 replicated efficiently within tumor cells with extensive cytolytic effects and induced increased numbers of activated CD4+ and CD8+ T cells and natural killer cells within the tumor, leading to a significant reduction in tumor growth and prolonged survival rates. Investigator-initiated clinical studies of HF10 have been completed in recurrent breast carcinoma, head and neck cancer, and unresectable pancreatic cancer in Japan. Phase I trials were subsequently completed in refractory superficial cancers and melanoma in the United States. HF10 has been demonstrated to have a high safety margin with low frequency of adverse effects in all treated patients. Interestingly, HF10 antigens were detected in pancreatic carcinoma over 300 days after treatment with infiltration of CD4+ and CD8+ T cells, which enhanced the immune response. To date, preliminary results from a Phase II trial have indicated that HF10 in combination with ipilimumab (anti-CTLA-4) is safe and well tolerated, with high antitumor efficacy. Improvement of the effect of ipilimumab was observed in patients with stage IIIb, IIIc, or IV unresectable or metastatic melanoma. This review provides a concise description of the genomic functional organization of HF10 compared with talimogene laherparepvec. Furthermore, this review focuses on HF10 in cancer treatment as monotherapy as well as in combination therapy through a concise description of all preclinical and clinical data. In addition, we will address approaches for future directions in HF10 studies as cancer therapy.

Postmarketing surveillance study of erlotinib plus gemcitabine for pancreatic cancer in Japan: POLARIS final analysis.

Erlotinib plus gemcitabine is approved in Japan for the treatment of metastatic pancreatic cancer. The POLARIS surveillance study investigated safety (focusing on interstitial lung disease [ILD]) and efficacy of erlotinib plus gemcitabine in Japanese pancreatic cancer patients. Patients receiving erlotinib plus gemcitabine for pancreatic cancer in Japan between July 2011 and August 2012 were enrolled. ILD-like events were independently confirmed by a review committee. Overall survival (OS) and progression-free survival (PFS) were assessed, and risk factors for ILD occurrence were analyzed by multivariate Cox regression analysis. Safety data were available for 843 patients and efficacy data for 841. Adverse drug reactions were reported in 83.5% of patients, no new safety signals were identified. ILD events were confirmed by the review committee in 52 patients (6.2%), with two fatal cases (0.2%). Median time from initial erlotinib treatment to ILD events was 70.5 days. Of the 52 patients with ILD events, 86.5% improved or fully recovered from ILD (median time 24 days). Multivariate analysis identified previous or concurrent lung disease (hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.0-4.5; P = 0.0365) and ≥3 organs with metastases (HR, 4.2; 95% CI, 2.2-8.2; P < 0.0001) as potential ILD risk factors. Accumulated OS rate at 28 weeks was 68.2%, and median PFS was 92 days (95% CI, 86-101). Erlotinib plus gemcitabine has an acceptable safety and efficacy profile in pancreatic cancer; however, patients should be assessed for previous/concurrent lung disease and metastatic burden, before and during treatment.

Expert consensus on surveillance methods for early detection of familial pancreatic cancer in Japan

Expert consensus on surveillance methods for early detection of familial pancreatic cancer in Japan

Dendritic cell-based vaccine for pancreatic cancer in Japan.

"Vaccell" is a dendritic cell (DC)-based cancer vaccine which has been established in Japan. The DCs play central roles in deciding the direction of host immune reactions as well as antigen presentation. We have demonstrated that DCs treated with a streptococcal immune adjuvant OK-432, produce interleukin-12, induce Th1-dominant state, and elicit anti-tumor effects, more powerful than those treated with the known DC-maturating factors. We therefore decided to mature DCs by the OK-432 for making an effective DC vaccine, Vaccell. The 255 patients with inoperable pancreatic cancer who received standard chemotherapy combined with DC vaccines, were analyzed retrospectively. Survival time of the patients with positive delayed type hypersensitivity (DTH) skin reaction was significantly prolonged as compared with that of the patients with negative DTH. The findings strongly suggest that there may be "Responders" for the DC vaccine in advanced pancreatic cancer patients. We next conducted a small-scale prospective clinical study. In this trial, we pulsed HLA class II-restricted WT1 peptide (WT1-II) in addition to HLA class I-restricted peptide (WT1-I) into the DCs. Survival of the patients received WT1-I and -II pulsed DC vaccine was significantly extended as compared to that of the patients received DCs pulsed with WT1-I or WT1-II alone. Furthermore, WT1-specific DTH positive patients showed significantly improved the overall survival as well as progression-free survival as compared to the DTH negative patients. The activation of antigen-specific immune responses by DC vaccine in combination with standard chemotherapy may be associated with a good clinical outcome in advanced pancreatic cancer. We are now planning a pivotal study of the Vaccell in appropriate protocols in Japan.

Current Treatment Options for Metastatic Pancreatic Adenocarcinoma.

Pancreatic adenocarcinoma is the fourth leading cause of cancer-related death and have extremely poor prognosis. Although, declining trends for some major cancers, death rates are rising in both sexes for pancreatic cancer. Surgical resection is the only curative treatment of pancreatic cancer, but only 10 to 20 percent of patients are candidates for curative surgery. Fifty to sixty percent of patients with pancreatic cancer diagnosed in metastatic stage and 5-year overall survival (OS) rate is less than 5% for metastatic pancreatic cancer. Gemcitabine was the first chemotherapeutic agent that superior to 5-Fluorouracil. In most of the phase II trials combination gemcitabine with cytotoxic chemotherapy or targeted therapy showed promising results, but phase III trials with gemcitabine in combination with cisplatin, oxaliplatin, capacitabine, pemetrexed, irinotecan, bevacizumab, aflibercept, axitinib and cetuximab failed to improve primary endpoint OS. Monotherapy with S-1 demonstrated noninferiority to gemcitabine in OS and S-1 approved for pancreatic cancer in Japan. In a randomized phase II/III ACCORD trial median progression free survival (PFS), response rate (RR), median OS and quality of life were significantly prolonged in FOLFIRINOX arm compared to gemcitabine alone arm. In phase III (MPACT) trial, like FOLFIRINOX regimen, median PFS, RR and OS significantly prolonged with the combination nab-paclitaxel and gemcitabine compared to gemcitabine arm alone. As a targeted agent erlotinib is the first and only agent that demostrate signifiacnt activity with gemcitabine combination in patients with metastatic pancreatic cancer. Gemcitabine plus erlotinib combination significantly prolonged PFS and OS compared to gemcitabine alone arm. Although some combination regimens showed significant OS benefit compared to single-agent gemcitabine, the median OS was less than 1 year. On these grounds, future directions are needed to integrate new targeted agents and combination protocols for metastatic pancreatic cancer.

SY11-2 - Adjuvant Chemotherapy for Resected Pancreatic Cancer: Focusing on the Jsap Study

Although approximately 20% of patients with pancreatic cancer (PC) undergo surgery, their prognosis is relatively poor, as most develop recurrences after resection. Adjuvant therapies have been used in attempts to improve the prognosis of these patients, but a consensus has not been established for many years. However, recently performed large-scale phase III studies, such as ESPAC-1 and CONKO-001, have revealed that adjuvant chemotherapy using 5-FU plus leucovorin or gemcitabine (GEM) improves the prognosis of PC patients after surgery. Furthermore, JASPAC-01, a phase III study conducted in Japan last year, has demonstrated that S-1 is superior to GEM for resected PC with respect to overall survival. Consequently, S-1 has become the standard adjuvant therapy for resected PC in Japan. In this presentation, we will review the latest information on clinical trials for adjuvant therapy and will report the results of studies conducted by our group (Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer: JSAP). We recently performed a phase I/II study (JSAP03) of GEM and S-1 combination (GS) therapy for resected PC and are presently conducting a phase III study (JSAP04) comparing GEM vs. GS therapy. Although GS therapy did not demonstrate a significant survival benefit in a phase III study for unresectable advanced PC (GEST), its application in an adjuvant setting may be more appropriate, as previous studies have demonstrated high response rates against PC.

704P - Final Safety Analysis of Erlotinib Plus Gemcitabine in a Post-Marketing Surveillance Study (Polaris) of >800 Japanese Pancreatic Cancer Patients

ABSTRACT Aim: Erlotinib is approved in Japan for the treatment of unresectable pancreatic cancer (PC) in combination with gemcitabine (GE). This surveillance study investigated the safety and efficacy of GE in Japanese patients (pts), focusing on the incidence of interstitial lung disease (ILD), an adverse drug reaction (ADR) of particular concern in these pts. Methods: All pts receiving GE for treatment of PC in Japan between Jul 2011 and Aug 2012 were enrolled; pts with current/former ILD were excluded. Observation period: 28 wks. ADRs: adverse events where GE could not be ruled out as the cause. All ILD-like events were assessed by an independent ILD review committee (IRC). ILD: all ILD-like events excluding those deemed non-ILD by the IRC. Risk factors for ILD occurrence were analysed by multivariate Cox regression analysis. Both PFS and OS were assessed by the investigator. Results: A total of 848 pts had case report forms by the data cut-off of Dec 2013 (safety data were available for 843 pts). Baseline characteristics included: male 58.1%; median age 65 yrs; any smoking history 44.1%; lung metastases 14.0%; ECOG PS 0 69.2%; prior treatment lines 0/1/2/ ≥ 3: 80.5%/11.3%/5.1%/3.1%. ADRs were reported in 83.5% of pts; the most common were skin disorders (69.9%), including rash (63.6%), and diarrhoea (17.6%). Most ADRs were grade ≤2. ILD events were confirmed by IRC in 52 pts (6.2%), of whom 2 pts had grade 5 ILD (0.2%). This is in contrast to the higher ILD mortality rate (1.5%) previously seen in NSCLC pts. The multivariate analysis identified age ≥75 yrs and existence of any lung disease as a potential risk factor for whether pts developed ILD. Median PFS was 104 days (95% CI 92–112) and accumulated OS rate at 8, 16 and 28 wks was 95.3%, 85.0% and 68.2%, respectively. Conclusions: The safety profile from this large surveillance study was similar to previous clinical studies of GE in PC. These final data from this study in Japanese PC pts provide further information, especially on risk factors for ILD occurrence, which will be reported in more detail. Improved awareness of these risk factors will help clinicians guide GE treatment in these pts. Note: Authors Furuse, Gemma, Hatori, Okusaka attended an Independent Advisory Board for Erlotinib. Disclosure: J. Furuse: I have served on an independent erlotinib advisory board for Chugai Pharmaceutical Co., Ltd.; A. Gemma: I have served on an independent erlotinib advisory board for Chugai Pharmaceutical Co., Ltd.; T. Hatori: I have served on an advisory board for Chugai Pharmaceutical Co., Ltd.; T. Okusaka: I have served on an advisory board for Chugai Pharmaceutical Co., Ltd.; A. Seki: I am an employee of Chugai Pharmaceutical Co., Ltd. and have some stock ownership at Kissei Pharmaceutical Co., Ltd.

Consumption of fruits, vegetables, and seaweeds (sea vegetables) and pancreatic cancer risk: The Ohsaki Cohort Study

Studies on the effects of consumption of fruits, vegetables, and seaweeds on the incidence of pancreatic cancer are not conclusive. We examined the association (if any) between the consumption of fruits, vegetables, and seaweeds and the risk of pancreatic cancer in Japan. Data from 32,859 participants registered in the Ohsaki National Health Insurance Cohort Study who were 40–79 years old and free of cancer at baseline were analyzed. Consumption of fruits, vegetables, and seaweeds was assessed at baseline using a self-administered food frequency questionnaire (containing 40 items). Incidences of pancreatic cancer were identified by computer linkage with the Miyagi Prefectural Cancer Registry. During 11 years of follow-up, 137 pancreatic cancers (67 men and 70 women) were identified. The hazard ratios (95% confidence interval) of pancreatic cancer risk for the highest versus the lowest tertile were 0.82 (0.40–1.68, trend P=0.57) in men and 0.64 (0.35–1.20, trend P=0.22) in women for total consumption of fruits, 0.89 (0.46–1.73, trend P=0.76) in men and 0.67 (0.33–1.35, trend P=0.23) in women for total consumption of vegetables, and 0.92 (0.46–1.84, trend P=0.81) in men for consumption of seaweeds (results for the consumption of seaweeds in women were not analyzed because of poor reliability), respectively. Total consumption of fruits, vegetables, and seaweeds was not associated with a reduced risk of pancreatic cancer.

S-1 in the treatment of pancreatic cancer.

S-1 is an oral 5-fluorouracil (5-FU) prodrug, which is designed to improve the antitumor activity of 5-FU by inhibiting dihydropyrimidine dehydrogenase, the key enzyme of 5-FU catabolism. Recently, two important studies on the clinical use of S-1 for pancreatic cancer have been reported from Japan. In the first study (GEST study), S-1 demonstrated non-inferiority to gemcitabine (GEM) in overall survival (OS) for metastatic or locally advanced pancreatic cancer, but combination chemotherapy with GEM and S-1 did not show superiority to GEM in OS. In the second study (JASPAC-01 study), S-1 showed superiority to adjuvant chemotherapy with GEM in OS in patients with resected pancreatic cancer. In addition to GEM, S-1 is now regarded as the key drug in the management of pancreatic cancer in Japan. To date, many studies have investigated the effectiveness of S-1 in various settings, such as first-line chemotherapy for metastatic or locally advanced pancreatic cancer, second-line chemotherapy after GEM failure, and chemoradiotherapy for locally advanced disease. In this review, we focus on recent clinical trials of S-1-based chemotherapy for advanced pancreatic cancer.

Phase II study of biweekly administration of CPT-11 and gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer in Japan.

e15150 Background: The current standard therapies for metastatic pancreatic adenocarcinoma in Japan are the single-agent Gemcitabine (Gem) or S-1 and Gem plus erlotinib. Irinotecan (CPT-11) is one of the promising drugs for Gem-refractory PC pts. Both Irinotecan and Gem have shown activity against these diseases with different mechanisms and are non-cross-resistant with each other. Japanese pts have the different metabolism with Irinotecan rather than pts in western countries. Methods: The aim of this phase II study was to evaluate the efficacy and safety of CPT-11 and Gem in Japanese pancreatic cancer pts. Patients with MPC and PS 0-2 were enrolled in this phase II trial. CPT-11, 100mg/m (2), was administered in 90 min. and Gem, 1000mg/m (2), was administered in 30 min. soon after CPT-11 on day1. Chemotherapy was repeated biweekly. Results: From May 2002 to May 2006 40 pts, with median age of 62 (40-74) years, were enrolled in this study. The overall response rate (RR) was 15% with disease control rate of 50%. The median progression-free survival (PFS) was 4.0 months (range: 1.0-15.0 months), and median overall survival (OS) was 7.5 months (range: 3.0-24.0 months). Grade 3/4 anemia, leucopenia occurred in 26.3, 5.2% of pts. The most common non-hematologic toxities were fatigue, diarrhea, nausea/vomiting and anorexia. Grade 3 diarrhea and nausea occurred in 10.5% of pts. Conclusions: The combination chemotherapy with Gem and CPT-11 showed favorable RR as expected and the treatment was manageable in Japanese pts with MPC. We plan to evaluate this combination chemotherapy for MPC pts after progression of FOLFIRINOX in near the future. Clinical trial information: UMIN000009963.

Randomized Phase III Study of Gemcitabine Plus S-1, S-1 Alone, or Gemcitabine Alone in Patients With Locally Advanced and Metastatic Pancreatic Cancer in Japan and Taiwan: GEST Study

The present phase III study was designed to investigate the noninferiority of S-1 alone and superiority of gemcitabine plus S-1 compared with gemcitabine alone with respect to overall survival. The participants were chemotherapy-naive patients with locally advanced or metastatic pancreatic cancer. Patients were randomly assigned to receive only gemcitabine (1,000 mg/m(2) on days 1, 8, and 15 of a 28-day cycle), only S-1 (80, 100, or 120 mg/d according to body-surface area on days 1 through 28 of a 42-day cycle), or gemcitabine plus S-1 (gemcitabine 1,000 mg/m(2) on days 1 and 8 plus S-1 60, 80, or 100 mg/d according to body-surface area on days 1 through 14 of a 21-day cycle). In the total of 834 enrolled patients, median overall survival was 8.8 months in the gemcitabine group, 9.7 months in the S-1 group, and 10.1 months in the gemcitabine plus S-1 group. The noninferiority of S-1 to gemcitabine was demonstrated (hazard ratio, 0.96; 97.5% CI, 0.78 to 1.18; P < .001 for noninferiority), whereas the superiority of gemcitabine plus S-1 was not (hazard ratio, 0.88; 97.5% CI, 0.71 to 1.08; P = .15). All treatments were generally well tolerated, although hematologic and GI toxicities were more severe in the gemcitabine plus S-1 group than in the gemcitabine group. Monotherapy with S-1 demonstrated noninferiority to gemcitabine in overall survival with good tolerability and presents a convenient oral alternative for locally advanced and metastatic pancreatic cancer.

Randomized phase II trial of S-1 versus S-1 plus irinotecan (IRIS) in patients with gemcitabine-refractory pancreatic cancer.

263 Background: Gemcitabine (Gem) monotherapy or Gem-based combination therapy is a standard first-line therapy for advanced pancreatic cancer (PC). There is no consensus on second-line therapy in patients (pts) with disease progression (PD) after Gem-based therapy. S-1, an oral fluoropyrimidine derivative, is commonly used for the second-line treatment of PC in Japan. Shitara et al previously reported that IRIS regimen showed that 44% of response rate (RR), 4.9 mo of median progression free survival (PFS), and 11.3 mo of median overall survival (OS), respectively. Therefore a randomized phase II trial was conducted to evaluate the efficacy and safety of IRIS compared with S-1 alone in the second-line setting. Methods: The inclusion criteria were as follows: (1) histologically or cytologically proven pancreatic adenocarcinoma or adenosquamous carcinoma; (2) confirmed PD after Gem treatment; (3) ECOG PS, 0-1; (4) measurable metastatic lesion based on RECIST criteria; (5) age ≥ 20 years; (6) total bilirubin &lt; 2.0 mg/dL. Patients were randomized to receive either IRIS (CPT-11 100 mg/m2, iv, d1,15 plus S-1 80/100/120 mg/day based on BSA, po, d1-14, q4w; Arm A) or S-1 (80/100/120 mg/day based on BSA, po, d1-28, q6w; Arm B). The primary endpoint was to compare PFS in Arm A and Arm B. Results: Of a total of 137 pts enrolled between Nov 2008 and Mar 2011, 127 were eligible (60 randomized to Arm A and 67 to B). Median PFS in Arm A and B was 107 and 58 days, respectively (HR= 0.767; 95% CI, 0.527-1.114; p=0.1750). Median OS in Arm A and B was 208 and 176 days, respectively (HR=0.749; 95% CI, 0.512-1.093; p=0.1338). RR was 18.3% in Arm A (11/60; 95% CI, 9.5-30.4) and 6.0% in Arm B (4/67; 95% CI, 1.7-14.6)(p=0.0311). The incidences of grade 3/4 toxicities were as follows: neutropenia (15.6% and 4.3%), anorexia (23.4% and 17.3%), nausea (6.3% and 2.9%), and diarrhea (3.1% and 2.9%) in Arm A and B, respectively. Both regimens were tolerable. Conclusions: Although IRIS showed no significant improvement in PFS or OS compared with S-1 alone in this study, it showed significant advantage in RR, and favorable HR in both of PFS and OS. IRIS might have potential power to treat second-line PC patients. Further study is warranted. Clinical trial information: JapicCTI-080657.

EL29 - Hepatobiliary Pancreatic Cancer: Cutting-Edge Drug Therapy

ABSTRACT Chemotherapy appears to prolong survival in patients with advanced pancreatic cancer (PC) or biliary tract cancer (BTC) and can take clinical benefits and improve quality of life since the clinical use of gemcitabine (Gem) in 1999 in Japan [1]. Many investigators have struggled to prove the superiority of Gem-contained combination therapy to Gem monotherapy for PC patients. Unfortunately, they all failed to prove the better survival benefit except Gem plus Erlotinib (GE) [2]. GE therapy demonstrate to be superior both in metastatic and locally advanced PC (HR 0.81). Many patients with GE therapy suffer from skin rush, and sometimes are afraid of a risk of Interstitial lung diseases (ILD). French investigators created a new standard chemotherapy which does not contain Gem: FOLFIRINOX. FORFIRINOX regimen can deliver a much better survival benefit rather than Gem monotherapy in metastatic PC, although it increased both hematological and non-hematological adverse effects (AE). Gem plus S1 (GS) showed both good survival benefits and anti-tumor effect in previous phase II studies [3,4]. We carried phase III study called GEST trial in Japan and Taiwan, which aimed to make sure the superiority of GS to Gem and non-inferiority of S1 to Gem. However, we can prove only non-inferiority of S1 to Gem in OS both in metastatic and locally advanced PC [5]. It is not clear whether radiotherapy should be useful or beneficial for locally advanced PC. Moreover, we do not have a good answer which drug we should administer when we plan the chemoradiotherapy for PC. Currently, there are some randomized phase II studies of chemoradiotherapy for PC in Japan, one is a study of chemoradiotherapy using GS combination compared with GS therapy, and the other is a study of Gem monotherapy followed by S1-chemoradiothrapy compared with S1-chemoradiotherapy. We need a well-designed phase II or phase III trial to prove a benefit of radiotherapy in PC near the future. But it is difficult to standardize a procedure of radiotherapy in many institutions even only in Japan. Gem plus cisplatin (CisGem) showed a better OS compared with Gem6) in BTC [6]. Kanai et al. study a phase I study of CisGem plus S1 in BTC (KHBO1002) [7]. We need to develop much more chemotherapy or chemoradiotherapy in PC or BTC, because we do not have enough agents to administer and there are many clinical questions still.

Surgery for chronic pancreatitis decreases the risk for pancreatic cancer: A multicenter retrospective analysis

Chronic pancreatitis is suggested to be one of the risk factors for the development of pancreatic cancer. The aim of this study was to confirm the high incidence of pancreatic cancer in patients with chronic pancreatitis in Japan and to determine the factors associated with the risk for pancreatic cancer in patients with chronic pancreatitis. The working group of the Research Committee of Intractable Disease supported by the Ministry of Health, Labour and Welfare of Japan carried out a nationwide survey to investigate the relationship between chronic pancreatitis and pancreatic cancer. This retrospective study included patients diagnosed with chronic pancreatitis who had had at least 2 years of follow-up. They were contacted through 22 Japanese referral centers experienced in the management of chronic pancreatitis. The standardized incidence ratio (95 CI) of pancreatic cancer was 11.8 (7.1-18.4). The incidence of pancreatic cancer was significantly lower in patients who had received surgery for chronic pancreatitis than in those who had not undergone surgery (hazard ratio estimated by Cox regression 0.11; 95% CI, 0.0014-0.80; P=.03). Patients who continued to drink alcohol after diagnosis of chronic pancreatitis showed a significantly higher incidence of pancreatic cancer than those who stopped drinking after diagnosis of chronic pancreatitis (hazard ratio, 5.07; 95% CI, 1.13-22.73; P=.03). This study confirmed that chronic pancreatitis is an important risk factor for the development of pancreatic cancer in Japan. Patients who underwent surgery for the treatment of chronic pancreatitis had significantly lower incidences of pancreatic cancer. Surgery for chronic pancreatitis may inhibit the development of pancreatic cancer in patients with chronic pancreatitis.

Updated results of the GEST study: Randomized phase III study of gemcitabine plus S-1 (GS) versus S-1 versus gemcitabine (GEM) in unresectable advanced pancreatic cancer in Japan and Taiwan.

4035 Background: The GEST study (Ioka et al. ASCO 2011, Abstract 4007) demonstrated the non-inferiority of S-1 to GEM with respect to the primary endpoint of overall survival (OS) in patients with pancreatic cancer (PC). We now report the updated results of this study. Methods: The GEST study was a randomized, 3-arm, phase III study. Chemotherapy-naive patients with unresectable advanced PC, an ECOG Performance status (PS) of 0-1, and adequate organ functions were randomly assigned to receive GEM (1000 mg/m2, iv, d1, 8 and 15, q4w), S-1 (80/100/120 mg/day based on BSA, po, d1-28, q6w), or GS (GEM 1000 mg/m2, iv, d1 and 8 plus S-1 60/80/100 mg/day based on BSA po, d1-14, q3w). The primary endpoint was OS, used to assess the non-inferiority of S-1 and the superiority of GS to GEM. Patient information was updated in July 2011. Results: At the time of this follow-up analysis, median follow-up was 29.8 months with 795 OS events, compared with 18.4 months with 710 OS events out of 832 patients at the previous analysis. Median OS was 8.8 months (95% CI: 8.0–9.7) in the GEM group and 9.7 months (95% CI: 7.6-10.8) in the S-1 group (HR=0.96, 97.5% CI: 0.79-1.17, p&lt;0.001 for non-inferiority), which is consistent with prior results (HR=0.96, 97.5% CI: 0.78-1.18, p&lt;0.001). In the GS group, median OS was 9.9 months (95% CI: 9.0-11.2). The HR was 0.91 (97.5%CI: 0.75-1.11, p=0.28 for superiority versus the GEM group). On subgroup analysis, GS was associated with a non-statistically significant trend toward better OS compared with GEM among patients with locally advanced disease and those with a PS of 1. Median OS was 12.7 months (95% CI: 9.7–14.9) in the GEM group and 15.9 months (95% CI: 13.0-19.7) in the GS group (HR=0.72, 95% CI: 0.51-1.03) among patients with locally advanced disease, and 6.2 months (95% CI: 4.9–8.3) in the GEM group and 9.6 months (95% CI: 8.0-10.9) in the GS group (HR=0.62, 95% CI: 0.46-0.83) among patients with a PS of 1. Conclusions: The non-inferiority of S-1 to Gem in terms of the primary endpoint of OS was reconfirmed. Monotherapy with S-1 can be used as one of the standard treatments for advanced PC. As for GS therapy, there is room for further investigation.