Feasibility of S-1 adjuvant chemotherapy after major hepatectomy for biliary tract cancers: An exploratory subset analysis of JCOG1202.

INTRODUCTION: Major hepatectomy (MH) may produce the impaired liver function and affect the feasibility of adjuvant chemotherapy in terms of early period after the surgery, but there have not been detailed investigations. JCOG1202 (UMIN000011688) is a randomized phase III trial demonstrating the superiority of adjuvant S-1 chemotherapy for biliary tract cancer (BTC). The aim of this study is to examine the influence of MH for BTC on adjuvant S-1. MATERIALS AND METHODS: Of the total 424 patients, 207 received S-1 (S-1 arm) while the remaining 217 were not. We compared MH with non-major hepatectomy (NMH) for BTC. RESULTS: In the S-1 arm, 42 had undergone MH, and 165 had undergone NMH. MH had similar pretreatment features to NMH, including the proportion of biliary reconstruction, to NMH, except for a lower platelet count (17.7 vs. 23.4 × 104/mm3, p < 0.0001) and lower serum albumin level (3.5 vs. 3.8 g/dL, p < 0.0001). The treatment completion proportion tended to be lower for MH than for NMH (59.5 % vs. 75.8 %; risk ratio, 0.786 [95 % confidence interval, 0.603-1.023], p = 0.0733), and the median dose intensity was lower as well (88.7 % vs. 99.6 %, p = 0.0358). The major reasons for discontinuation were biliary tract infections and gastrointestinal disorders after MH. The frequency of grade 3-4 biliary tract infection was 19.0 % in MH vs. 4.2 % in NMH. CONCLUSION: The treatment completion proportion and dose intensity were lower in MH than in NMH. Caution should be exercised against biliary tract infections and gastrointestinal disorders during adjuvant S-1 after MH for BTC.

Prevalence of psychological distress and associated factors among patients undergoing comprehensive genomic profiling testing: protocol for a multicentre, prospective, observational study.

INTRODUCTION: Since May 2019, comprehensive genomic profiling (CGP) has been covered by Japan's health insurance system for patients with solid tumours that have progressed on standard chemotherapy, rare tumours or tumours of unknown primary origin. Although CGP has the potential to identify actionable mutations that can guide the selection of genomically matched therapies for patients with advanced cancer and limited treatment options, less than 10% of patients benefit from CGP testing, which may have a negative impact on patients' mental status. The aim of this study is to investigate the prevalence of psychological distress and associated factors among patients with advanced cancer who are undergoing CGP testing across Japan. METHODS AND ANALYSIS: This multicentre, prospective cohort study will enrol a total of 700 patients with advanced cancer undergoing CGP testing. Participants will be asked to complete questionnaires at three timepoints: at the time of consenting to CGP testing (T1), at the time of receiving the CGP results (T2; 2-3 months after T1) and 4-5 months after T2 (T3). Primary outcome is the prevalence of depression as measured by the Patient Health Questionnaire-9 at the three timepoints. Secondary outcomes are the prevalence of anxiety and Quality of Life Score. Associated factors with psychological distress will also be examined, including knowledge about CGP, attitudes, values and preferences towards CGP, satisfaction with oncologists' communication and patient characteristics as well as medical information including CGP test results and genomically matched therapies if provided. The prevalence of depression and anxiety will be estimated using the unadjusted raw rates observed in the total sample. Longitudinal changes in measures will be explored by calculating differences between the timepoints. Multivariate associations between variables will be examined using multiple or logistic regression analysis depending on the outcomes to adjust for confounders and to identify outcome predictors. ETHICS AND DISSEMINATION: This study was approved by the Institutional Review Board of the National Cancer Center Japan on 5 January 2023 (ID: 2022-228). Study findings will be disseminated through peer-reviewed journals and conference presentations. TRIAL STATUS: The study is currently recruiting participants and the enrolment period will end on 31 March 2025, with an expected follow-up date of 31 March 2026. TRIAL REGISTRATION NUMBER: UMIN000049964.

Adjuvant and neoadjuvant chemotherapy for biliary tract cancer: a review of randomized controlled trials.

The first randomized controlled trial of adjuvant chemotherapy for biliary tract cancer was reported in 2002. Since then, studies have continued, with efficacy reported for capecitabine in 2018 and S-1 in 2023. Oral fluoropyrimidines have become established as the standard of care. This article reviews the evidence from the randomized controlled trials reported to date and those that are ongoing or from which results have not yet been reported.

A Multicenter Survey on Eligibility for a Randomized Phase III Trial of Adjuvant Chemotherapy for Resected Biliary Tract Cancer (JCOG1202, ASCOT).

BACKGROUND: The Adjuvant S-1 for Cholangiocarcinoma Trial (JCOG1202, [ASCOT]) was a multicenter, randomized controlled trial aimed at investigating the efficacy and safety of adjuvant chemotherapy (AC) with S-1 for resected biliary tract cancer (BTC). This trial reported that overall survival was prolonged with AC compared with observation. METHODS: With the aim of increasing enrollment, the present survey biannually recorded the number of patients eligible for enrollment into ASCOT and reasons for ineligibility among patients who had undergone surgery for BTC from April 2015 to September 2017 at 36 institutions participating in ASCOT. RESULTS: Of 2039 patients who underwent surgery for BTC, 211 (10.3%) were already enrolled, 166 (8.1%) were eligible but had not been enrolled, and 1662 (81.5%) were ineligible. Among ineligible patients, the predominant reasons for ineligibility were patient refusal (n = 332, 20.0%), pathologic stage (pT1N0; n = 248, 14.9%), age (≥ 81 years; n = 196, 11.8%), and prolonged postoperative complications (n = 176, 10.6%). CONCLUSIONS: Patients undergoing surgery for BTC are a heterogeneous cohort comprising patients with earlier pathologic stage, advanced age, and prolonged postoperative complications. These factors should be considered during the design of future clinical trials of perioperative treatments for resectable BTC.

Adjuvant S-1 compared with observation in resected biliary tract cancer (JCOG1202, ASCOT): a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: S-1 has shown promising efficacy with a mild toxicity profile in patients with advanced biliary tract cancer. The aim of this study was to evaluate whether adjuvant S-1 improved overall survival compared with observation for resected biliary tract cancer. METHODS: This open-label, multicentre, randomised phase 3 trial was conducted in 38 Japanese hospitals. Patients aged 20-80 years who had histologically confirmed extrahepatic cholangiocarcinoma, gallbladder carcinoma, ampullary carcinoma, or intrahepatic cholangiocarcinoma in a resected specimen and had undergone no local residual tumour resection or microscopic residual tumour resection were randomly assigned (1:1) to undergo observation or to receive S-1 (ie, 40 mg, 50 mg, or 60 mg according to body surface area, orally administered twice daily for 4 weeks, followed by 2 weeks of rest for four cycles). Randomisation was performed by the minimisation method, using institution, primary tumour site, and lymph node metastasis as adjustment factors. The primary endpoint was overall survival and was assessed for all randomly assigned patients on an intention-to-treat basis. Safety was assessed in all eligible patients. For the S-1 group, all patients who began the protocol treatment were eligible for a safety assessment. This trial is registered with the University hospital Medical Information Network Clinical Trials Registry (UMIN000011688). FINDINGS: Between Sept 9, 2013, and June 22, 2018, 440 patients were enrolled (observation group n=222 and S-1 group n=218). The data cutoff date was June 23, 2021. Median duration of follow-up was 45·4 months. In the primary analysis, the 3-year overall survival was 67·6% (95% CI 61·0-73·3%) in the observation group compared with 77·1% (70·9-82·1%) in the S-1 group (adjusted hazard ratio [HR] 0·69, 95% CI 0·51-0·94; one-sided p=0·0080). The 3-year relapse-free survival was 50·9% (95% CI 44·1-57·2%) in the observation group compared with 62·4% (55·6-68·4%) in the S-1 group (HR 0·80, 95% CI 0·61-1·04; two-sided p=0·088). The main grade 3-4 adverse events in the S-1 group were decreased neutrophil count (29 [14%]) and biliary tract infection (15 [7%]). INTERPRETATION: Although long-term clinical benefit would be needed for a definitive conclusion, a significant improvement in survival suggested adjuvant S-1 could be considered a standard of care for resected biliary tract cancer in Asian patients. FUNDING: The National Cancer Center Research and the Ministry of Health, Labour, and Welfare of Japan.

A randomised phase II study of modified FOLFIRINOX versus gemcitabine plus nab-paclitaxel for locally advanced pancreatic cancer (JCOG1407).

AIM: We compared the efficacy of modified 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) with that of gemcitabine plus nab-paclitaxel (GnP) for locally advanced pancreatic cancer (LAPC). METHODS: Patients with untreated LAPC were randomly assigned (1:1) to receive mFOLFIRINOX or GnP. One-year overall survival (OS) was the primary endpoint. The major secondary end-points included progression-free survival (PFS), response rate (RR), carbohydrate antigen 19-9 (CA19-9) response, and adverse events. The sample size was 124 patients to select a more effective regimen with a minimum probability of 0.85 and to examine the null hypothesis of the 1-year OS <53%. RESULTS: Of the 126 patients enrolled from 29 institutions, 125 were deemed eligible. The 1-year OS was 77.4% (95% CI, 64.9-86.0) and 82.5% (95% CI, 70.7-89.9) in the mFOLFIRINOX and GnP arms, respectively. The median PFS was 11.2 (95% CI, 9.9-15.9) and 9.4 months (95% CI, 7.4-12.8) in the mFOLFIRINOX and GnP arms, respectively. The RR and CA19-9 response rate were 30.9% (95% CI, 19.1-44.8) and 57.1% (95% CI, 41.0-72.3) and 42.1% (95% CI 29.1-55.9) and 85.0% (95% CI, 70.2-94.3) in the mFOLFIRINOX and GnP arms, respectively. Grade 3-4 diarrhoea and anorexia were predominant in the mFOLFIRINOX arm. CONCLUSION: GnP was considered the candidate for a subsequent phase III trial because of its better RR, CA19-9 response, and mild gastrointestinal toxicities. Both regimens displayed higher efficacy in the 1-year survival than in the historical data of gemcitabine monotherapy.

Association of the Low-density Lipoprotein Cholesterol/High-density Lipoprotein Cholesterol Ratio with Glecaprevir-pibrentasvir Treatment.

Objective The change in serum lipid levels by direct-acting antiviral (DAA) treatment for chronic hepatitis C varies depending on the type of DAA. How the lipid level changes induced by glecaprevir-pibrentasvir (G/P) treatment contribute to the clinical outcome remains unclear. We conducted a prospective observational study to evaluate the effectiveness of G/P treatment and the lipid level changes. Methods The primary endpoint was a sustained virologic response at 12 weeks (SVR12). The total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels and LDL-C/HDL-C (L/H) ratio were measured every two weeks. Patients This study included 101 patients. Seventeen cases of liver cirrhosis and nine cases of DAA retreatment were registered. The G/P treatment period was 8 weeks in 74 cases and 12 weeks in 27 cases. Results SVR12 was evaluated in 96 patients. The rate of achievement of SVR12 in the evaluable cases was 100%. We found significantly elevated TC and LDL-C levels over the observation period compared to baseline. The serum levels of HDL-C did not change during treatment but were significantly increased after treatment compared to baseline. The L/H ratio was significantly increased two weeks after the start of treatment but returned to the baseline after treatment. Conclusion The primary endpoint of the SVR12 achievement rate was 100%. G/P treatment changed the serum lipid levels. Specifically, the TC and LDL-C levels increased during and after treatment, and the HDL-C levels increased after treatment. G/P treatment may be associated with a reduced thrombotic risk. Therefore, validation in large trials is recommended.

Double small bowel cancers leading to the diagnosis of Lynch syndrome with germline MSH6 mutation in an elderly patient.

A female patient in her 80s was referred to our hospital because of an ileal tumor identified by capsule endoscopy. FDG-PET suggested double intestinal tumors not only in the ileum but also in the jejunum. The patient has cancer past history including sigmoid colon, rectum, and endometrium, and also had cancer family history fulfilling the revised Amsterdam criteria. Double balloon enteroscopy disclosed two ulcerated tumors in the jejunum and the ileum. Biopsy was diagnosed as adenocarcinoma pathologically, and microsatellite instability-high (MSI-H) genetically. Surgical resection was performed, and the jejunal and the ileal tumors were tubular (T2N0M0) and mucinous adenocarcinoma (T4N0M0), respectively. Germline mutation analysis revealed a pathogenic splice-site mutation in MSH6.

Rare case of idiopathic sclerosing cholangitis, which was difficult to distinguish from cholangiocarcinoma: A case report.

It is often difficult to correctly diagnose patients who present with dilation of the bile duct. Cholangiocarcinoma, primary sclerosing cholangitis (PSC) and immunoglobulin (Ig)G4-related sclerosing cholangitis must be considered as potential diagnoses for these cases. The current study presents a 73-year-old female patient who presented with a high fever and abdominal pain. Contrast-enhanced computed tomography and magnetic resonance cholangiopancreatography revealed stenosis and dilation of the intrahepatic bile duct without solid components. It was suspected that the patient had intrahepatic cholangiocarcinoma. A left liver lobectomy, cholecystectomy and distal gastrectomy combined with a D2 lymph node dissection were performed. A pathological examination of the liver revealed increased fibrosis in the stroma, irregular bile duct dilation and clusters of inflamed lymph cells. No carcinoma or IgG4-positive plasma cells were observed and the typical findings of PSC were not detected. Based on these clinical and pathological results, the diagnosis was idiopathic sclerosing cholangitis, which is particularly rare. It is often difficult to preoperatively differentiate between cholangiocarcinoma and benign bile duct stenosis.

Feasibility study of postoperative adjuvant chemotherapy with S-1 in patients with biliary tract cancer.

BACKGROUND: The role of adjuvant chemotherapy has not yet been established for patients with resected biliary tract cancer. S-1 has been shown to exert activity against advanced biliary tract cancer. Therefore, we evaluated the feasibility of adjuvant chemotherapy with S-1 in patients with resected biliary tract cancer. METHODS: Patients with complete macroscopic resection of intrahepatic/extrahepatic bile duct, gall bladder, or ampullary cancer were eligible. S-1 was administered orally twice daily for 4 weeks every 6 weeks, up to 4 cycles. The treatment was continued up to 24 weeks or until recurrence/appearance of unacceptable toxicity. The primary endpoint was the treatment completion rate, which was defined as the percentage of patients who received a relative dose intensity of ≥ 75%. This trial was registered as UMIN000004051. RESULTS: Thirty-three patients were enrolled between June 2010 and March 2011. The relative dose intensity was ≥ 75% in 27 patients representing a treatment completion rate of 81.8%. The most common grade 3/4 adverse event was neutropenia (18%). Grade 2 nausea or diarrhea was observed in 12%. The 3-year relapse-free survival rate was 39.4%. The 3-year survival rate was 54.5%. CONCLUSION: Adjuvant chemotherapy with S-1 is feasible treatment in patients with resected biliary tract cancer. It is necessary to conduct a phase III study to confirm the efficacy of adjuvant therapy of S-1 in patients with resected BTC.

A randomized Phase III trial of adjuvant S-1 therapy vs. observation alone in resected biliary tract cancer: Japan Clinical Oncology Group Study (JCOG1202, ASCOT).

No standard adjuvant treatment has been established for patients with curatively resected biliary tract cancer. S-1 has been reported to show promising efficacy with mild toxicity profiles in patients with advanced biliary tract cancer, and adjuvant S-1 therapy has been demonstrated to provide survival benefit in patients with resected gastric cancer and pancreatic cancer. The aim of this open-label, multicenter, randomized Phase III trial is to confirm that adjuvant chemotherapy with S-1 would prolong overall survival in patients with resected biliary tract cancer. This study was activated in September 2013. A total of 350 patients planned to be enrolled from 36 Japanese institutions over a period of 4 years. At July 2017, the protocol was revised to increase power from 70% to 80%. Therefore, the planned total sample size is 440. The primary endpoint is overall survival. This trial is registered with the UMIN Clinical Trials Registry as UMIN000011688.

Phase II study of the GPC3-derived peptide vaccine as an adjuvant therapy for hepatocellular carcinoma patients.

The recurrence rates of Hepatocellular carcinoma (HCC) are high, necessitating novel and effective adjuvant therapies. Therefore, we conducted a phase II study of glypican-3 (GPC3) peptide vaccine as an adjuvant therapy for HCC patients. Forty-one patients with initial HCC who had undergone surgery or radiofrequency ablation (RFA) were analyzed in this phase II, open-label, single-arm trial. Ten vaccinations were performed for 1 y after curative treatment. We also investigated case-control subjects, where selected patients treated surgically during the same period were analyzed. The expression of GPC3 in the available primary tumors was determined by immunohistochemical analysis. Six patients received RFA therapy while 35 received surgery. The recurrence rate tended to be lower in the 35 patients treated with surgery plus vaccination compared to 33 patients who underwent surgery alone (28.6% vs. 54.3% and 39.4% vs. 54.5% at 1 and 2 y, respectively; p = 0.346, 0.983). Twenty-five patients treated with surgery and vaccination had GPC3-positive tumors; the recurrence rate in this group was significantly lower compared to that in 21 GPC3-positive patients who received surgery only (24% vs. 48% and 52.4% vs. 61.9% at 1 and 2 y, respectively; p = 0.047, 0.387). The GPC3 peptide vaccine improved the 1-y recurrence rate in patients with GPC3-positive tumors. This study demonstrated that GPC3 expression by the primary tumor may be used as a biomarker in a putative larger randomized clinical trial to determine the efficacy of the GPC3-derived peptide vaccine.

Serum HER2 as an adjunct to assess HER2 status for advanced gastric cancer: A prospective multicenter trial (SHERLOCK).

BACKGROUND: Intratumoral human epidermal growth factor receptor 2 (HER2) heterogeneity of gastric cancer can be an obstacle to accurate HER2 assessment. Serum HER2, concentrations of the HER2 extracellular domain shed into the bloodstream, has a potential to compensate HER2 immunohistochemistry (IHC) but has not been scrutinized in gastric cancer. This study sought to explore the clinical utility of serum HER2 in gastric cancer. METHODS: We performed a prospective multicenter trial (SHERLOCK trial) involving patients with all-stage gastric or gastro-esophageal junction cancer. Serum HER2 was measured using direct chemiluminescence while tissue HER2 status was determined using IHC and fluorescent in situ hybridization. For stage IV cases, concordance between local and central laboratories in tissue HER2 assessment was also evaluated. RESULTS: Of 224 patients enrolled, both tissue HER2 status and serum HER2 levels were successfully determined in 212 patients and 21% (45/212) were tissue HER2-positive. Serum HER2 levels, ranged from 4.5 to 148.0 ng/ml (median 10.3), correlated with tissue HER2 status (p = 0.003). At a cut-off level of 28.0 ng/ml determined by receiver operating characteristics analysis, sensitivity, specificity, positive and negative predictive values of serum HER2 were 22.6%, 100%, 100% and 82.3%, respectively. All nine cases with elevated serum HER2 were tissue HER2-positive stage IV cases. Among 61 stage IV cases, the agreement rate for IHC scoring between the local and the central laboratories was 82% and tissue HER2 judgment was conflicting in five (8.2%) cases. Of these five cases, four were confirmed as false-negative and two of these four patients demonstrated elevated serum HER2. CONCLUSIONS: Serum HER2 levels correlated with tissue HER2 status in gastric cancer. Although the low sensitivity is a drawback, serum HER2 might be a useful adjunct tool to detect tissue HER2 false-negative gastric cancer.

Peretinoin after curative therapy of hepatitis C-related hepatocellular carcinoma: a randomized double-blind placebo-controlled study.

BACKGROUND: Effective prophylactic therapies have not been established for hepatocellular carcinoma recurrence. Peretinoin represents one novel option for patients with hepatitis C virus-related hepatocellular carcinoma (HCV-HCC), and it was tested in a multicenter, randomized, double-blind, placebo-controlled study. METHODS: Patients with curative therapy were assigned to one of the following regimens: peretinoin 600, 300 mg/day, or placebo for up to 96 weeks. The primary outcome was recurrence-free survival (RFS). RESULTS: Of the 401 patients initially enrolled, 377 patients were analyzed for efficacy. The RFS rates in the 600-mg group, the 300-mg group, and the placebo group were 71.9, 63.6, and 66.0 % at 1 year, and 43.7, 24.9, and 29.3 % at 3 years, respectively. The primary comparison of peretinoin (300 and 600-mg) with placebo was not significant (P = 0.434). The dose-response relationship based on the hypothesis that "efficacy begins to increase at 600 mg/day" was significant (P = 0.023, multiplicity-adjusted P = 0.048). The hazard ratios for RFS in the 600-mg group vs. the placebo group were 0.73 [95 % confidence interval (CI) 0.51-1.03] for the entire study period and 0.27 (95 % CI 0.07-0.96) after 2 years of the randomization. Common adverse events included ascites, increased blood pressure, headache, presence of urine albumin, and increased transaminases. CONCLUSIONS: Although the superiority of peretinoin to placebo could not be validated, 600 mg/day was shown to be the optimal dose, and treatment may possibly reduce the recurrence of HCV-HCC, particularly after 2 years. The efficacy and safety of peretinoin 600 mg/day should continue to be evaluated in further studies.

Phase I study on the safety, pharmacokinetic profile, and efficacy of the combination of TSU-68, an oral antiangiogenic agent, and S-1 in patients with advanced hepatocellular carcinoma.

PURPOSE: We aimed to investigate the recommended dose for the combination of TSU-68, a multiple-receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2 and platelet-derived growth factor receptor-ß, and S-1, an oral fluoropyrimidine, in patients with advanced hepatocellular carcinoma (HCC) based on its associated dose-limiting toxicity (DLT) frequency. We also determined the safety, tolerability, pharmacokinetics (PK), and efficacy of the combination treatment. PATIENTS AND METHODS: Patients without any prior systemic therapy received 400 mg/day TSU-68 orally and 80 mg/day (level 1) or 100 mg/day (level 2) S-1 for 4 or 2 weeks followed by a 2- or 1-week rest period (groups A and B, respectively). According to the treatment, patients progressed from level 1B to level 2A, then level 2B. Safety and response rates were assessed. RESULTS: Eighteen patients were enrolled. Two patients at levels 1B and 2A but none at level 2B showed DLTs. The common adverse drug reactions were a decrease in hemoglobin levels, hypoalbuminemia, and anorexia, which were mild in severity (grades 1-2). PK data from levels 1B and 2A indicated that the area under the curve for TSU-68 and 5-fluorouracil was unlikely to be affected by the combination treatment. Response rate, disease control rate, median time to progression, and median overall survival were 27.8 %, 61.1 %, 5.3 months, and 12.8 months, respectively. CONCLUSION: The recommended dose for advanced HCC should be 400 mg/day TSU-68 and 100 mg/day S-1 for 4 weeks followed by 2-week rest.

Phase I study of combination chemotherapy using sorafenib and transcatheter arterial infusion with cisplatin for advanced hepatocellular carcinoma.

The aims of this study were to evaluate the frequency of dose-limiting toxicities and to find the recommended dose of combination chemotherapy with sorafenib and transcatheter arterial infusion (TAI) using cisplatin for patients with advanced hepatocellular carcinoma (HCC), for whom surgical resection, local ablation therapy, or transcatheter arterial chemoembolization were not indicated. Patients received 800 mg sorafenib daily. Cisplatin was given at one of three dosages (level 1, 35 mg/m(2) /cycle; level 2, 50 mg/m(2) /cycle; and level 3, 65 mg/m(2) /cycle) from feeding arteries to the HCC. The treatment was repeated every 4-6 weeks up to a maximum of six cycles, until there were signs of tumor progression or unacceptable toxicity. The dose-limiting toxicities experienced by the 20 enrolled patients were grade 4 increased aspartate aminotransferase at level 1, grade 3 gastrointestinal hemorrhaging at level 1, and grade 3 hypertension at level 3. The common drug-related adverse events that were of severity grade 3 or 4 included the elevation of aspartate aminotransferase (30%), alanine aminotransferase (20%), amylase (30%), and lipase (30%). Partial response was seen in four patients (20%), and 13 patients (65%) had stable disease. The median overall survival and progression-free survival were 9.1 and 3.3 months, respectively. The combination of sorafenib at 800 mg/day with TAI of cisplatin at 65 mg/m(2) /cycle was determined to be the recommended regimen. A randomized phase II trial of sorafenib alone versus sorafenib plus TAI of cisplatin is currently underway. This study was registered at UMIN as trial number UMIN000001496.

Treatment outcome for systemic chemotherapy for recurrent pancreatic cancer after postoperative adjuvant chemotherapy.

OBJECTIVES: A global consensus on how to treat recurrent pancreatic cancer after adjuvant chemotherapy with gemcitabine (ADJ-GEM) does not exist. METHODS: We retrospectively reviewed the clinical data of 41 patients with recurrences who were subsequently treated with chemotherapy. RESULTS: The patients were divided into two groups according to the time until recurrence after the completion of ADJ-GEM (ADJ-Rec): patients with an ADJ-Rec < 6 months (n = 25) and those with an ADJ-Rec ≥ 6 months (n = 16). The disease control rate, the progression-free survival after treatment for recurrence and the overall survival after recurrence for these two groups were 68 and 94% (P = 0.066), 5.5 and 8.2 months (P = 0.186), and 13.7 and 19.8 months (P = 0.009), respectively. Furthermore, we divided the patients with an ADJ-Rec < 6 months into two groups: patients treated with gemcitabine (n = 6) and those treated with alternative regimens including fluoropyrimidine-containing regimens (n = 19) for recurrent disease. Patients treated with the alternative regimens had a better outcome than those treated with gemcitabine. CONCLUSIONS: Fluoropyrimidine-containing regimens may be a reasonable strategy for recurrent disease after ADJ-GEM and an ADJ-Rec < 6 months.

Everolimus for advanced pancreatic neuroendocrine tumours: a subgroup analysis evaluating Japanese patients in the RADIANT-3 trial.

OBJECTIVE: Everolimus, an inhibitor of the mammalian target of rapamycin, has recently demonstrated efficacy and safety in a Phase III, double-blind, randomized trial (RADIANT-3) in 410 patients with low- or intermediate-grade advanced pancreatic neuroendocrine tumours. Everolimus 10 mg/day provided a 2.4-fold improvement compared with placebo in progression-free survival, representing a 65% risk reduction for progression. The purpose of this analysis was to investigate the efficacy and safety of everolimus in the Japanese subgroup enrolled in the RADIANT-3 study. METHODS: Subgroup analysis of the Japanese patients was performed comparing efficacy and safety between everolimus 10 mg/day orally (n = 23) and matching placebo (n = 17). The primary endpoint was progression-free survival. Safety was evaluated on the basis of the incidence of adverse drug reactions. RESULTS: Progression-free survival was significantly prolonged with everolimus compared with placebo. The median progression-free survival was 19.45 months (95% confidence interval, 8.31-not available) with everolimus vs 2.83 months (95% confidence interval, 2.46-8.34) with placebo, resulting in an 81% risk reduction in progression (hazard ratio, 0.19; 95% confidence interval, 0.08-0.48; P< 0.001). Adverse drug reactions occurred in all 23 (100%) Japanese patients receiving everolimus and in 13 (77%) patients receiving placebo; most were grade 1/2 in severity. The most common adverse drug reactions in the everolimus group were rash (n = 20; 87%), stomatitis (n = 17; 74%), infections (n = 15; 65%), nail disorders (n = 12; 52%), epistaxis (n = 10; 44%) and pneumonitis (n = 10; 44%). CONCLUSIONS: These results support the use of everolimus as a valuable treatment option for Japanese patients with advanced pancreatic neuroendocrine tumours.