Neuroprotective Effect of Cudrania tricuspidata Fruit Extracts on Scopolamine-Induced Learning and Memory Impairment.

Cudrania tricuspidata has diverse biological activities, such as antioxidant, anti-inflammatory, anticancer, and neuroprotective effects. This study investigated the protective effects of C. tricuspidata fruit extracts (CTFE) against scopolamine (SCO)-induced neuron impairment. The neuroprotective effects of CTFE on SCO-induced memory dysfunction were confirmed in mice using the Barnes maze test. The results showed that co-treatment of SCO and CTFE increased the stay time in the target zone compared with SCO treatment alone. Similarly, the results obtained by the fear conditioning test revealed that SCO-CTFE co-treatment induced the freezing action time under both the contextual fear condition and the cued fear condition compared with SCO treatment alone. Moreover, we showed that CTFE reduced the SCO-induced acetylcholinesterase (AChE) activity, thereby increasing the acetylcholine concentration in mice hippocampal tissues. Consistent with the improvement of memory and recognition function in vivo, our in vitro results showed that CTFE induced cAMP response element binding protein (CREB) and extracellular regulated kinase 1/2 (ERK1/2) activity in PC12 cells and reduced SCO-induced AChE activity. In addition, the microarray results of the hippocampal tissue support our data showing that CTFE affects gene expressions associated with neurogenesis and neuronal cell differentiation markers such as spp1 and klk6. Overall, CTFE exerts a neuroprotective effect via regulation of the CREB and ERK1/2 signaling pathways and could be a therapeutic candidate for neurodegenerative diseases.

Clinical and molecular distinctions in patients with refractory colon cancer who benefit from regorafenib treatment.

Regorafenib (Stivarga, BAY 73-4506; Bayer Pharma AG, Berlin, Germany) is a novel oral multikinase inhibitor that blocks the activity of several protein kinases. However, few guidelines exist for novel biomarkers to select patients who will likely benefit from regorafenib treatment. Metastatic colorectal cancer (mCRC) patients treated with regorafenib were evaluated in this study. Tumor tissues of these patients were subjected to next-generation sequencing-based cancer panel tests. The relationship between molecular profiling and efficacy of regorafenib was analyzed. Among the 76 mCRC patients, the median age was 58 years (range 22-79 years), and 73.7% received regorafenib as a third-line therapy. The primary tumor locations were the right side (n = 15, 19.8%) and the left side (n = 61, 80.2%). Most patients (97.4%) had received prior anti-angiogenetic agents, and a prior anti-Epidermal Growth Factor Receptor (EGFR) agent had been administered to 32.9%. Of these 76 patients, 65 were evaluated to determine the efficacy of treatment. We observed zero complete responses, seven confirmed partial responses (PR 9.2%), 26 stable disease states (34.2%), and 32 disease progressions (42.1%). The overall confirmed response rate and the disease control rate were 9.2% and 43.4%, respectively. Genomic analysis revealed that APC mutations were significant in patients who demonstrated a tumor response to regorafenib (p < 0.05). Interestingly, FGFR1 amplification was detected in only three of 76 patients (3.9%), and these three patients achieved a PR to regorafenib. The median progression-free survival time was 2.8 months (95% Confidence Interval [CI] 1.6-4.0). Patients with BRAF mutation and/or SMAD4 mutation had significantly worse progression-free survival (PFS) than those without such a mutation. On pathway analysis, Tumor Growth Factor (TGF)-beta pathways were significantly associated with worse PFS. We found that efficacy of regorafenib might be correlated with specific genetic aberrations, such as APC mutation and FGFR1 amplification. In addition, SMAD4 mutation and TGF-beta pathway were associated with worse PFS after regorafenib. We found that efficacy of regorafenib might be correlated with specific genetic aberrations, such as APC mutation and FGFR1 amplification. In addition, SMAD4 mutation and the TGF-beta pathway were associated with worse PFS after regorafenib.

Oxaliplatin-Based Adjuvant Chemotherapy for Rectal Cancer After Preoperative Chemoradiotherapy (ADORE): Long-Term Results of a Randomized Controlled Trial.

PURPOSE: We evaluated the role of oxaliplatin as adjuvant chemotherapy in patients with rectal cancer who received preoperative chemoradiotherapy (CRT) with fluoropyrimidine monotherapy and total mesorectal excision (TME). METHODS: The ADORE trial (adjuvant oxaliplatin in rectal cancer) is a multicenter, randomized trial in patients with postoperative ypStage II (ypT3-4N0) or III (ypTanyN1-2) rectal cancer after fluoropyrimidine-based preoperative CRT and TME. Patients were randomly assigned (1:1) to receive adjuvant chemotherapy either with FL (fluorouracil 380 mg/m2 and leucovorin 20 mg/m2) or FOLFOX (oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, and fluorouracil bolus 400 mg/m2 on day 1, fluorouracil infusion 2,400 mg/m2 for 46 hours). Stratification factors included ypStage and participating center. Primary end point was disease-free survival (DFS). RESULTS: A total of 321 patients were enrolled between November 19, 2008, and June 12, 2012. Six-year DFS rates were 68.2% in the FOLFOX arm versus 56.8% in the FL arm, with a stratified hazard ratio of 0.63 (95% CI, 0.43 to 0.93; P = .018) by intention-to-treat analysis. In the subgroup analysis for DFS, FOLFOX was favorable versus FL in patients with ypStage III, ypN1b, ypN2, high-grade histology, minimally regressed tumor, and an absence of lymphovascular or perineural invasion. Six-year overall survival rate was 78.1% in the FOLFOX arm versus76.4% in the FL arm (hazard ratio, 0.73; 95% CI, 0.45 to 1.19; P = .21). In the subgroup analysis for OS, FOLFOX was favorable versus FL in patients with ypN2 and minimally regressed tumor. CONCLUSION: Adjuvant FOLFOX improved DFS in patients with rectal cancer with ypStage II and III disease after preoperative CRT. Adjuvant FOLFOX may be considered on the basis of the postoperative pathologic stage in those who received preoperative CRT and TME.

TAS-118 (S-1 plus leucovorin) versus S-1 in patients with gemcitabine-refractory advanced pancreatic cancer: a randomised, open-label, phase 3 study (GRAPE trial).

BACKGROUND: In our previous randomised phase 2 study for patients with gemcitabine-refractory advanced pancreatic cancer, S-1 plus leucovorin improved progression-free survival compared with S-1 alone. Here, we evaluated the efficacy of TAS-118 (S-1 plus leucovorin) versus S-1 in overall survival (OS). PATIENTS AND METHODS: This randomised, open-label, phase 3 study was conducted at 58 centres in Japan and Korea. Patients with metastatic pancreatic cancer that progressed during first-line gemcitabine-based chemotherapy or recurred during or after post-operative gemcitabine-based adjuvant treatment were randomly assigned (1:1) to receive either S-1 (40-60 mg, twice daily for 4 weeks in a 6-week cycle) or TAS-118 (S-1 40-60 mg plus leucovorin 25 mg, twice daily for 1 week in a 2-week cycle). The primary end-point was OS. RESULTS: A total of 603 patients were randomised, and 300 and 301 patients received TAS-118 and S-1, respectively. There was no difference in OS between groups (median OS for TAS-118 versus S-1, 7.6 months versus 7.9 months; hazard ratio [HR], 0.98 [95% confidence interval (CI), 0.82-1.16]; P = 0.756). Progression-free survival was significantly longer with TAS-118 than S-1 (median, 3.9 months versus 2.8 months; HR, 0.80 [95% CI, 0.67-0.95]; P = 0.009). There were interactions between Japan and Korea (P = 0.004) and between unresectable and recurrent disease (P = 0.025) in OS. Incidence, profile and severity of adverse events were similar between groups. CONCLUSION: TAS-118 did not improve OS in patients with gemcitabine-refractory advanced pancreatic cancer compared to S-1. Further studies are needed to find patients who have benefit from adding leucovorin to S-1.

Pemetrexed Monotherapy as Salvage Treatment in Patients with Metastatic Colorectal Cancer Refractory to Standard Chemotherapy: A Phase II Single-arm Prospective Trial.

Background: We designed a single-arm, open-label phase II study to determine the efficacy and toxicity of pemetrexed monotherapy with vitamin supplementation in patients with refractory colorectal cancer (CRC) that failed to respond to standard treatments including 5-fluorouracil, oxaliplatin, and irinotecan with or without biologic agents. Methods: Patients were treated with pemetrexed 500 mg/m2 on day 1 every 3 weeks, with folic acid and vitamin B12 supplementation. Treatment was continued until disease progression or intolerable toxicity. Between June 2016 and October 2016, 24 patients were enrolled in this study. Results: One patient withdrew consent, leaving a total of 23 patients for evaluation. The median age of the patients was 54.0 years (range, 23.0 to 67.0), and the median ECOG performance status was 1 (1-2). The median number of previous systemic chemotherapies was 3 (range, 2 to 5). There was no patient with complete response (CR) or partial response (PR). However, stable disease was observed in 10 patients (43.4%) and maintained more than 6 months in 7 of 10 patients. The median progression-free survival was 1.6 months (95% CI, 1.1-2.0) and the median overall survival was 9.8 months (95% CI, 5.9-13.6). Grade 3 treatment-related adverse events occurred in one patient with elevated liver enzymes and hematologic adverse event of grade 2 anemia was observed in one patient. There were no cases of dose reduction or treatment-related deaths and all toxicities were manageable. Conclusions: Pemetrexed monotherapy showed moderate disease control and acceptable toxicity profile as salvage therapy for refractory CRC.

Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib: Patient-focused outcome results from the randomised phase III REACH study.

PURPOSE: To report patient-focused outcomes as measured by quality of life (QoL) and performance status (PS) in REACH, a phase III placebo-controlled randomised study, assessing ramucirumab in advanced hepatocellular carcinoma (HCC) patients who received prior sorafenib. METHODS: Eligible patients had advanced HCC, Child-Pugh A, PS 0 or 1 and prior sorafenib. Patients received ramucirumab (8 mg/kg) or placebo (1:1) on day 1 of a 2-week cycle. QoL was assessed by FACT Hepatobiliary Symptom Index (FHSI)-8 and EuroQoL (EQ-5D) at baseline; cycles 4, 10, and 16; and end of treatment. PS was assessed at baseline, each cycle, and end of treatment. Deterioration in FHSI-8 was defined as a ≥3-point decrease from baseline and PS deterioration was defined as a change of ≥2. Both intention-to-treat and pre-specified subgroup of patients with baseline serum alpha-fetoprotein (AFP) ≥400 ng/mL were assessed. RESULTS: There were 565 patients randomised to ramucirumab and placebo. Compliance with FHSI and EQ-5D was high and similar between groups. In the ITT population, deterioration in FHSI-8, EQ-5D, and PS was similar between ramucirumab and placebo. In patients with baseline AFP ≥400 ng/mL, ramucirumab significantly reduced deterioration in FHSI-8 at the end of treatment compared with placebo (P = 0.0381), and there was a trend towards a delay in the deterioration of symptoms in FHSI-8 (HR 0.690; P = 0.054) and PS (HR 0.642; P = 0.057) in favour of ramucirumab. CONCLUSIONS: We report one of the most comprehensive data sets of QoL and symptom burden in patients undergoing systemic therapy for advanced HCC. Ramucirumab was associated with no worsening of QoL. In patients with baseline AFP ≥400 ng/mL, the significant survival benefit observed in patients treated with ramucirumab was coupled with a trend in patient-focused outcome benefits. CLINICAL TRIAL REGISTRATION: NCT01140347.

Is There a Role for Adjuvant Therapy in R0 Resected Gallbladder Cancer?: A Propensity Score-Matched Analysis.

PURPOSE: The purpose of this study is to assess the role of adjuvant therapy in stage I-III gallbladder cancer (GBC) patients who have undergone R0 resection. MATERIALS AND METHODS: Clinical data were collected on 441 consecutive patients who underwent R0 resection for stage I-III GBC. Eligible patients were classified into adjuvant therapy and surveillance only groups. Propensity score matching (PSM) between the two groups was performed, adjusting clinical factors. RESULTS: In total, 84 and 279 patients treated with adjuvant therapy and followed up with surveillance only, respectively, were included in the analysis. Before PSM, the 5-year relapse-free survival (RFS) rate was lower in the adjuvant therapy group than in the surveillance only group (50.8% vs. 74.8%, p < 0.001), although there was no statistically significant difference in the 5-year overall survival (OS) rate (66.2% vs. 79.5%, p=0.089). After the PSM, baseline characteristics became comparable and there were no differences in the 5-year RFS (50.8% vs. 64.8%, p=0.319) and OS (66.2% vs. 70.4%, p=0.703) rates between the two groups. CONCLUSION: The results suggest that fluoropyrimidine-based adjuvant therapy is not indicated in stage I-III GBC patients who have undergone R0 resection.

Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial.

BACKGROUND: VEGF and VEGF receptor-2-mediated angiogenesis contribute to hepatocellular carcinoma pathogenesis. Ramucirumab is a recombinant IgG1 monoclonal antibody and VEGF receptor-2 antagonist. We aimed to assess the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma following first-line therapy with sorafenib. METHODS: In this randomised, placebo-controlled, double-blind, multicentre, phase 3 trial (REACH), patients were enrolled from 154 centres in 27 countries. Eligible patients were aged 18 years or older, had hepatocellular carcinoma with Barcelona Clinic Liver Cancer stage C disease or stage B disease that was refractory or not amenable to locoregional therapy, had Child-Pugh A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, had previously received sorafenib (stopped because of progression or intolerance), and had adequate haematological and biochemical parameters. Patients were randomly assigned (1:1) to receive intravenous ramucirumab (8 mg/kg) or placebo every 2 weeks, plus best supportive care, until disease progression, unacceptable toxicity, or death. Randomisation was stratified by geographic region and cause of liver disease with a stratified permuted block method. Patients, medical staff, investigators, and the funder were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01140347. FINDINGS: Between Nov 4, 2010, and April 18, 2013, 565 patients were enrolled, of whom 283 were assigned to ramucirumab and 282 were assigned to placebo. Median overall survival for the ramucirumab group was 9·2 months (95% CI 8·0-10·6) versus 7·6 months (6·0-9·3) for the placebo group (HR 0·87 [95% CI 0·72-1·05]; p=0·14). Grade 3 or greater adverse events occurring in 5% or more of patients in either treatment group were ascites (13 [5%] of 277 patients treated with ramucirumab vs 11 [4%] of 276 patients treated with placebo), hypertension (34 [12%] vs ten [4%]), asthenia (14 [5%] vs five [2%]), malignant neoplasm progression (18 [6%] vs 11 [4%]), increased aspartate aminotransferase concentration (15 [5%] vs 23 [8%]), thrombocytopenia (13 [5%] vs one [<1%]), hyperbilirubinaemia (three [1%] vs 13 [5%]), and increased blood bilirubin (five [2%] vs 14 [5%]). The most frequently reported (≥1%) treatment-emergent serious adverse event of any grade or grade 3 or more was malignant neoplasm progression. INTERPRETATION: Second-line treatment with ramucirumab did not significantly improve survival over placebo in patients with advanced hepatocellular carcinoma. No new safety signals were noted in eligible patients and the safety profile is manageable. FUNDING: Eli Lilly and Co.

Adjuvant chemoradiation with 5-fluorouracil/leucovorin versus S-1 in gastric cancer patients following D2 lymph node dissection surgery: a feasibility study.

PURPOSE: We retrospectively analyzed the feasibility and adverse events for two regimens, postoperative chemoradiation (CRT) with 5-fluorouracil/leucovorin (5-FU/LV) compared to S-1 in D2-resected gastric cancer patients. PATIENTS AND METHODS: The study included 405 gastric cancer patients who underwent curative gastrectomy with D2 lymph node dissection and received adjuvant therapy between January 2008 and July 2009. Feasibility and adverse events for the CRT and S-1 regimens were analyzed. RESULTS: Out of the 405 patients, 244 (60.2%) had CRT and 161 (39.8%) had S-1 treatment. The regimen was selected based on the preferences of the physician and the patient. S-1 was more frequently administered to patients with older age (age≥70) and those with early-stage disease (stage II). The stage was significantly more advanced in the CRT group compared to the S-1 group (S-1 vs. CRT: stage II, 59.6% vs. 36.1%; stage III/IV, 28.0% vs. 48.3%, respectively; p<0.001). The completion rate of the planned therapy was significantly higher in the CRT group than in the S-1 group (95.1% vs. 72.8%, respectively; p<0.001). Regarding severe adverse events (grade 3-4), neutropenia (CRT vs. S-1; 40.2% vs. 8.7%, respectively, p<0.001), nausea (CRT vs. S-1; 5.7% vs. 0%, respectively; p=0.002) and stomatitis (CRT vs. S-1; 7.4% vs. 2.5%, respectively; p=0.034) were significantly more frequent in the CRT cohort compared to the S-1 group. CONCLUSION: Both adjuvant CRT with 5-FU/LV and adjuvant S-1 are safe and feasible in D2-resected gastric cancer patients. Patients with old age or early stage disease tend to prefer S-1 therapy to chemoradiation.

Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after preoperative chemoradiotherapy (ADORE): an open-label, multicentre, phase 2, randomised controlled trial.

BACKGROUND: The role of adjuvant chemotherapy for patients with rectal cancer is controversial, especially when used after preoperative chemoradiotherapy. Fluoropyrimidine-based adjuvant chemotherapy, including fluorouracil and leucovorin, has been widely used; however, the addition of oxaliplatin to fluorouracil and leucovorin (FOLFOX), a standard adjuvant regimen for colon cancer, has not been tested in rectal cancer. We aimed to compare the efficacy and safety of adjuvant fluorouracil and leucovorin with that of FOLFOX in patients with locally advanced rectal cancer after preoperative chemoradiotherapy. METHODS: In this open-label, multicentre, phase 2, randomised trial, patients with postoperative pathological stage II (ypT3-4N0) or III (ypTanyN1-2) rectal cancer after preoperative fluoropyrimidine-based chemoradiotherapy and total mesorectal excision were recruited and randomly assigned (1:1) via a web-based software platform to receive adjuvant chemotherapy with either four cycles of fluorouracil and leucovorin (fluorouracil 380 mg/m(2) and leucovorin 20 mg/m(2) on days 1-5, every 4 weeks) or eight cycles of FOLFOX (oxaliplatin 85 mg/m(2), leucovorin 200 mg/m(2), and fluorouracil bolus 400 mg/m(2) on day 1, and fluorouracil infusion 2400 mg/m(2) for 46 h, every 2 weeks). Stratification factors were pathological stage (II vs III) and centre. Neither patients nor investigators were masked to group assignment. The primary endpoint was 3-year disease-free survival, analysed by intention to treat. This study is fully enrolled, is in long-term follow-up, and is registered with ClinicalTrials.gov, number NCT00807911. FINDINGS: Between Nov 19, 2008, and June 12, 2012, 321 patients were randomly assigned to fluorouracil and leucovorin (n=161) and FOLFOX (n=160). 141 (95%) of 149 patients in the fluorouracil plus leucovorin group and 141 (97%) of 146 in the FOLFOX group completed all planned cycles of adjuvant treatment. Median follow-up was 38·2 months (IQR 26·4-50·6). 3-year disease-free survival was 71·6% (95% CI 64·6-78·6) in the FOLFOX group and 62·9% (55·4-70·4) in the fluorouracil plus leucovorin group (hazard ratio 0·657, 95% CI 0·434-0·994; p=0·047). Any grade neutropenia, thrombocytopenia, fatigue, nausea, and sensory neuropathy were significantly more common in the FOLFOX group than in the fluorouracil plus leucovorin group; however, we noted no significant difference in the frequency of these events at grade 3 or 4. The most common grade 3 or worse adverse events were neutropenia (38 [26%] of 149 patients in the fluorouracil plus leucovorin group vs 52 [36%] of 146 patients in the FOLFOX group), leucopenia (eight [5%] vs 12 [8%]), febrile neutropenia (four [3%] vs one [<1%]), diarrhoea (four [3%] vs two [1%]), and nausea (one [<1%] vs two [1%]). INTERPRETATION: Adjuvant FOLFOX improves disease-free survival compared with fluorouracil plus leucovorin in patients with locally advanced rectal cancer after preoperative chemoradiotherapy and total mesorectal excision, and warrants further investigation. FUNDING: Korea Healthcare Technology R&D Project (South Korean Ministry of Health and Welfare).

Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial.

BACKGROUND: Patients with advanced gastric cancer have a poor prognosis and few efficacious treatment options. We aimed to assess the addition of cetuximab to capecitabine-cisplatin chemotherapy in patients with advanced gastric or gastro-oesophageal junction cancer. METHODS: In our open-label, randomised phase 3 trial (EXPAND), we enrolled adults aged 18 years or older with histologically confirmed locally advanced unresectable (M0) or metastatic (M1) adenocarcinoma of the stomach or gastro-oesophageal junction. We enrolled patients at 164 sites (teaching hospitals and clinics) in 25 countries, and randomly assigned eligible participants (1:1) to receive first-line chemotherapy with or without cetuximab. Randomisation was done with a permuted block randomisation procedure (variable block size), stratified by disease stage (M0 vs M1), previous oesophagectomy or gastrectomy (yes vs no), and previous (neo)adjuvant (radio)chemotherapy (yes vs no). Treatment consisted of 3-week cycles of twice-daily capecitabine 1000 mg/m(2) (on days 1-14) and intravenous cisplatin 80 mg/m(2) (on day 1), with or without weekly cetuximab (400 mg/m(2) initial infusion on day 1 followed by 250 mg/m(2) per week thereafter). The primary endpoint was progression-free survival (PFS), assessed by a masked independent review committee in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. This study is registered at EudraCT, number 2007-004219-75. FINDINGS: Between June 30, 2008, and Dec 15, 2010, we enrolled 904 patients. Median PFS for 455 patients allocated capecitabine-cisplatin plus cetuximab was 4.4 months (95% CI 4.2-5.5) compared with 5.6 months (5.1-5.7) for 449 patients who were allocated to receive capecitabine-cisplatin alone (hazard ratio 1.09, 95% CI 0.92-1.29; p=0.32). 369 (83%) of 446 patients in the chemotherapy plus cetuximab group and 337 (77%) of 436 patients in the chemotherapy group had grade 3-4 adverse events, including grade 3-4 diarrhoea, hypokalaemia, hypomagnesaemia, rash, and hand-foot syndrome. Grade 3-4 neutropenia was more common in controls than in patients who received cetuximab. Incidence of grade 3-4 skin reactions and acne-like rash was substantially higher in the cetuximab-containing regimen than in the control regimen. 239 (54%) of 446 in the cetuximab group and 194 (44%) of 436 in the control group had any grade of serious adverse event. INTERPRETATION: Addition of cetuximab to capecitabine-cisplatin provided no additional benefit to chemotherapy alone in the first-line treatment of advanced gastric cancer in our trial. FUNDING: Merck KGaA.

Safety and efficacy of adjuvant chemoradiation therapy with capecitabine after resection of pancreatic ductal adenocarcinoma: a retrospective review.

PURPOSE: To evaluate clinical outcomes and safety of adjuvant chemoradiation therapy (CRT) with capecitabine after resection of pancreatic adenocarcinoma at a single institution. PATIENTS AND METHODS: A retrospective analysis of patients undergoing adjuvant CRT with capecitabine after resection of pancreatic ductal adenocarcinoma between 2004 and 2007 yielded a total of 55 patients. Capecitabine was administered at 850 mg/m(2) twice daily every day per week radiotherapy (45 Gy in 25 fractions) over the 5 weeks. Sixteen percent of patients (N=9) went on to receive gemcitabine. RESULTS: Of 55 patients, 42 had curative (R0) resection and 13 had incomplete resection (R1). Median overall survival (OS) and progression free survival were 18.3 and 8.0 months for all patients, respectively. Patients receiving additional gemcitabine after adjuvant CRT with capecitabine showed better OS and progression free survival than those not receiving additional gemcitabine (P<0.05). In multivariate analysis, lymphovascular invasion (present vs. absent) and addition gemcitabine therapy (yes vs. no) were significant independent prognostic factors for OS (P<0.05). Local recurrence was observed in 10 patients, and distant recurrence in 26 patients, synchronously accounting for 6 recurrences. Ten patients (18.2%) had severe grade 3 toxicities. CONCLUSIONS: Capecitabine-based CRT after resection of pancreatic adenocarcinoma showed favorable outcomes and tolerable toxicity profiles.

Phase 1 trial of S-1 in combination with sorafenib for patients with advanced hepatocellular carcinoma.

PURPOSE: Sorafenib is a multi-kinase inhibitor, which was approved as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). We conducted a phase 1 study of sorafenib plus S-1 in patients with advanced HCC. EXPERIMENTAL DESIGN: We designed to escalate S-1 at 4 different dose levels with fixed dose of sorafenib. Four dose levels were as follows: level 1, D1-14 S-1 50 mg/m(2)/day + D1-21 sorafenib 400 mg bid; level 2, D1-14 S-1 60 mg/m(2)/day + D1-21 sorafenib 400 mg bid; level 3,, D1-14 S-1 70 mg/m(2)/day + D1-21 sorafenib 400 mg bid; level 4, D1-14 S-1 80 mg/m(2)/day + D1-21 sorafenib 400 mg bid. The treatment was repeated every 3 weeks. RESULTS: From August 2009 to July 2010, 20 patients with advanced HCC were enrolled. The median age was 48 years (range, 29-74). Eighteen (90%) patients had hepatitis B viral infection and 19 (95%) patients were rated as Child-Pugh class A. The dose-limiting toxicities were grade 4 infection and thrombocytopenia. After a median follow-up duration of 8.6 months (range, 3.7-14.2 months), median PFS was 3.9 months (95% CI, 0.8-7.0 months) and median OS was 10.4 months (95% CI, 0-22.4 months). In pharmacokinetic analysis, there was no statistically significant drug interaction between sorafenib and S-1. CONCLUSIONS: The combination of sorafenib and S-1 showed tolerable toxicity profile and modest clinical efficacy in patients with advanced HCC. The recommended dose of sorafenib and S-1 was 400 mg twice daily and 40 mg/m(2) twice daily, respectively.

The effect of postoperative pelvic irradiation after complete resection of metastatic rectal cancer.

BACKGROUND AND OBJECTIVES: The 2010 NCCN clinical practice guidelines recommend radiation as a part of the standard adjuvant or neoadjuvant treatment for stage IV rectal cancer patients. This study evaluated the oncologic efficacy of postoperative radiotherapy (RTx) in loco-regional control after complete removal of primary and metastatic lesions in stage IV rectal cancer. METHODS: Sixty-eight patients with metastatic rectal cancer were enrolled and analyzed. Twenty-eight of the enrolled patients received concurrent postoperative RTx with chemotherapy (RTx group) and the remaining 40 received only postoperative systemic chemotherapy (CTx) without RTx (non-RTx group). The eligibility criteria were as follows: a primary rectal tumor located in the low or mid-rectum, no postoperative macroscopic and microscopic evidence of residual tumor in primary and metastatic sites, and no history of prior CTx or pelvic RTx. RESULTS: The recurrence rates were 75.0% in the RTx group and 72.5% in the non-RTx group. Local recurrence rates were 7.1% (RTx group) and 22.5% (non-RTx group) (P = 0.108). There were no differences in overall survival (OS), local recurrence-free survival, and disease-free survival between the two groups. The 2-year OS rates were 78.9% (RTx group) and 74.1% (non-RTx group) (P = 0.395). CONCLUSIONS: Survival benefit of postoperative RTx in stage IV rectal cancer after complete removal of tumors was not apparent. RTx could be recommended for selected patients at high risk of local recurrence or for palliation of symptoms.

Polymorphic markers associated with severe oxaliplatin-induced, chronic peripheral neuropathy in colon cancer patients.

BACKGROUND: To identify potential genetic markers for severe oxaliplatin-induced chronic peripheral neuropathy (OXCPN), the authors performed a genome-wide association analysis of patients with colon cancer who received oxaliplatin-based chemotherapy. METHODS: This was a prospective study in which DNA was purified in peripheral blood from patients with colon cancer who received oxaliplatin. The primary endpoint was the development of severe (grade 2 lasting for >7 days or grade 3) OXCPN. For the discovery set, genotyping was done for 96 patients who received adjuvant fluorouracil and oxaliplatin using the a genome-wide human single-nucleotide polymorphism (SNP) array. An association between polymorphisms and severe OXCPN was investigated. At the same time, 247 patients who received oxaliplatin-based, first-line chemotherapy for advanced disease were enrolled as a validation set. RESULTS: Among the 32 genotyped candidate SNPs selected from the discovery set, 9 SNPs in 8 genes (tachykinin, precursor 1[TAC1]; forkhead box C1 [FOXC1]; integrin, alpha 1 [ITGA1]; acylphosphatase 2, muscle type [ACYP2]; deleted in lymphocytic leukemia, 7 [DLEU7]; B-cell translocation gene 4 [BTG4]; calcium/calmodulin-dependent protein kinase II inhibitor 1 [CAMK2N1]; and phenylalanyl-tRNA synthase 2 [FARS2]) had nominal replication (P < .05). The most significant association was observed at reference SNP number (rs)10486003 in TAC1 (P = 4.84 × 10(-7)) in combined data from 2 sets. Five SNPs (rs10486003, rs2338, rs830884, rs843748, and rs797519) were significant in a multiple regression analysis (P < .05). Overall prediction accuracy calculated by the regression model was 72.8% (95% confidence interval, 65.8%-79.9%) in the model development and 75.9% (95% confidence interval, 66.9%-84.9%) in the model evaluation. CONCLUSIONS: The current results indicated that a genome-wide pharmacogenomic approach is useful for identifying novel polymorphism predictors of severe OXCPN that may be used in personalized chemotherapy.

Phase III trial comparing capecitabine plus cisplatin versus capecitabine plus cisplatin with concurrent capecitabine radiotherapy in completely resected gastric cancer with D2 lymph node dissection: the ARTIST trial.

PURPOSE: The ARTIST (Adjuvant Chemoradiation Therapy in Stomach Cancer) trial was the first study to our knowledge to investigate the role of postoperative chemoradiotherapy therapy in patients with curatively resected gastric cancer with D2 lymph node dissection. This trial was designed to compare postoperative treatment with capecitabine plus cisplatin (XP) versus XP plus radiotherapy with capecitabine (XP/XRT/XP). PATIENTS AND METHODS: The XP arm received six cycles of XP (capecitabine 2,000 mg/m2 per day on days 1 to 14 and cisplatin 60 mg/m2 on day 1, repeated every 3 weeks) chemotherapy. The XP/XRT/XP arm received two cycles of XP followed by 45-Gy XRT (capecitabine 1,650 mg/m2 per day for 5 weeks) and two cycles of XP. RESULTS: Of 458 patients, 228 were randomly assigned to the XP arm and 230 to the XP/XRT/XP arm. Treatment was completed as planned by 75.4% of patients (172 of 228) in the XP arm and 81.7% (188 of 230) in the XP/XRT/XP arm. Overall, the addition of XRT to XP chemotherapy did not significantly prolong disease-free survival (DFS; P = .0862). However, in the subgroup of patients with pathologic lymph node metastasis at the time of surgery (n = 396), patients randomly assigned to the XP/XRT/XP arm experienced superior DFS when compared with those who received XP alone (P = .0365), and the statistical significance was retained at multivariate analysis (estimated hazard ratio, 0.6865; 95% CI, 0.4735 to 0.9952; P = .0471). CONCLUSION The addition of XRT to XP chemotherapy did not significantly reduce recurrence after curative resection and D2 lymph node dissection in gastric cancer. A subsequent trial (ARTIST-II) in patients with lymph node-positive gastric cancer is planned.

Prognostic factors in patients with advanced hepatocellular carcinoma treated with sorafenib: a retrospective comparison with previously known prognostic models.

BACKGROUND: Sorafenib, a multitargeted tyrosine kinase inhibitor, is now the treatment of choice for systemic therapy of patients with advanced hepatocellular carcinoma (HCC). Herein, we present the clinical characteristics and outcomes of patients with advanced HCC who were treated with sorafenib. METHODS: Data of 201 sorafenib-treated, metastatic HCC patients were collected from a single institution tumor registry. The primary and secondary endpoints were overall survival (OS) and failure-free survival (FFS). RESULTS: Chronic hepatitis B was the predominant cause of HCC (84%). Of 162 evaluable patients, 4 partial responses were recorded. With a median follow-up of 15.7 months, the median FFS and OS were 2.5 months (95% CI 2.3-2.7) and 5.3 months (95% CI 4.4-6.3), respectively. In multivariate analysis, the prognostic factors associated with FFS were the presence of ascites, portal venous thrombosis, serum α-fetoprotein ≥400 ng/ml, albumin, bilirubin, tumor size and number, and performance status. Likewise, the presence of ascites, portal venous thrombosis, tumor size and number, performance status and baseline levels of α-fetoprotein, albumin and bilirubin were significantly related with OS. After adjusting for performance status, the Cancer of the Liver Italian Program scoring system and Okuda stages can better predict the hazard of failure or death than the Child-Pugh classification. CONCLUSIONS: Our results suggest that Cancer of the Liver Italian Program scores or Okuda stages, along with performance status, can be useful in stratifying patients with advanced HCC treated with sorafenib.

Clinical impact of microsatellite instability in colon cancer following adjuvant FOLFOX therapy.

PURPOSE: Colon cancer with DNA mismatch repair (MMR) defects reveals indistinguishable clinical and pathologic aspects, including better prognosis and reduced response to 5-fluorouracil (5-FU)-based chemotherapy. There has been no consensus for p53 as a prognostic marker in colorectal cancer. This study investigated the clinical implication of MSI-H/MMR-D and p53 expression in R0-resected colon cancer patients who received adjuvant oxaliplatin/5-FU/leucovorin (FOLFOX) therapy. EXPERIMENTAL DESIGN: We analyzed 135 patients, who had been treated by adjuvant chemotherapy containing 5-FU and oxaliplatin (FOLFOX) after curative resection (R0) for colon adenocarcinoma between May 2004 and November 2007. Tumor expression of the MMR proteins, MLH1 and MSH2, was detected by immunohistochemistry (IHC) in surgically resected tumor specimens. MSI was analyzed by polymerase chain reaction (PCR) amplification using fluorescent dye-labeled primers specific for microsatellite loci. Tumors with MMR defects were defined as those demonstrating loss of MMR protein expression (MMR-D) and/or microsatellite instability high (MSI-H) genotype. Expression patterns of p53 were determined in a semiquantitative manner by light microscopy. RESULTS: There were 13 (9.6%) patients with stage II, 108 (80%) with stage III, and 14 (10.4%) with stage IV. Fourteen patients with stage IV (10.3%) had metastases to liver only, all of whom underwent complete metastasectomy for liver metastases. In total, 134 tumor specimens were genotyped, 115 specimens were tested by IHC and 113 cases had both genotyping and IHC results available for analysis. Genotyping results demonstrated that 12 (9.0%) cases were MSI-H and 122 (91.0%) were MSI-L/S. By IHC, 11 (9.6%) patients were MMR-D and 104 (90.4%) were MMR-I. The methods were in agreement in 108 patients (94.7%). We assessed 114 patients for p53 expression by immunostaining. MMR status was not significantly associated with DFS (P = 0.56) or OS (P = 0.61) in patients with colon cancer (n = 135) receiving adjuvant FOLFOX. According to p53 status, there was also no significant difference for DFS (P = 0.11) and OS (P = 0.94). For patients with genotyping/IHC agreement (n = 108), there was no difference in DFS (P = 0.57) and OS (P = 0.98) between patients with MSI-H/MMR-D and MSI-L/S/MMR-I tumors. CONCLUSION: The MMR status or p53 positivity was not significantly associated with outcomes to FOLFOX as adjuvant chemotherapy in colon cancer patients with R0 resection. Adding oxaliplatin in adjuvant chemotherapy may overcome negative impact of 5-FU on colon cancers with MSI-H/MMR-D.

Definitive chemoradiation therapy with capecitabine in locally advanced pancreatic cancer.

We evaluated safety and efficacy of concurrent chemoradiotherapy (CCRT) with capecitabine in patients with locally advanced pancreatic cancer (LAPC). Between January 2004 and January 2008, 39 patients with LAPC treated with capecitabine CCRT were reviewed. Capecitabine was administered at 850 mg/m twice daily every day with 5 days per week radiotherapy (1.8 Gy fractions) over the 5 weeks. Thirty-seven (94.8%) patients completed CCRT. Of the 36 evaluable patients, 15 (41.7%) and 13 (36.1%) patients achieved partial response and stable disease, and eight (28.6%) among them received gemcitabine-based post-CCRT chemotherapy without dose reduction or delay. The overall survival was 14.3 months [95% confidence interval (CI): 10.6-17.9 months]. Median progression-free survival was 11.1 months for all patients, and 7.9 months for those patients who had not received post-CCRT chemotherapy. Eight patients (21.6%) had severe grade 3 toxicities, seven (18.9%) with gastrointestinal toxicity, and one (2.7%) with hematologic toxicity. Prognostic factors for survival were serum albumin (P = 0.014; relative risk: 3.4; 95% CI: 1.4-9.7), and adjuvant gemcitabine treatment (P=0.005; relative risk: 3.5; 95% CI: 1.2-10.6). Combined therapy with capecitabine CCRT was well tolerated and seems to be a promising regimen, in terms of response, survival, and adverse effects.