Gemcitabine with or without continuous infusion 5-FU in advanced pancreatic cancer: a randomised phase II trial of the Italian oncology group for clinical research (GOIRC) Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer Phase II randomised proof-of-concept study of the urokinase inhibitor upamostat (WX-671) in combination with gemcitabine compared with gemcitabine alone in patients with non-resectable, locally advanced pancreatic cancer A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer A randomized multi-center phase II trial of the angiogenesis inhibitor Cilengitide (EMD 121974) and gemcitabine compared with gemcitabine alone in advanced unresectable pancreatic cancer Comparison of single-agent epirubicin and 5-fluorouracil/epirubicin/mitomycin in patients with advanced adenocarcinoma of the pancreas. Comparison of 5-fluorouracil, doxorubicin and mitomycin C with 5-fluorouracil alone in the treatment of pancreatic-biliary carcinomas. A Phase II Randomized, Double‐Blind, Placebo‐Controlled Study of Simtuzumab or Placebo in Combination with Gemcitabine for the First‐Line Treatment of Pancreatic Adenocarcinoma Randomized phase II/III clinical trial of elpamotide for patients with advanced pancreatic cancer: PEGASUS-PC Study Capecitabine plus oxaliplatin (CapOx) versus capecitabine plus gemcitabine (CapGem) versus gemcitabine plus oxaliplatin (mGemOx): final results of a multicenter randomized phase II trial in advanced pancreatic cancer. Gemcitabine-based or capecitabine-based chemoradiotherapy for locally advanced pancreatic cancer (SCALOP): a multicentre, randomised, phase 2 trial Randomized phase II study of gemcitabine (G) plus anti-IGF-1R antibody MK-0646, G plus erlotinib (E) plus MK-0646 and G plus E for advanced pancreatic cancer. Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Randomized phase II study evaluating oxaliplatin alone, oxaliplatin combined with infusional 5-FU, and infusional 5-FU alone in advanced pancreatic carcinoma patients. Oxaliplatin combined with 5-FU in second line treatment of advanced pancreatic adenocarcinoma. Results of a phase II trial. Randomised Phase I/II trial assessing the safety and efficacy of radiolabelled anti-carcinoembryonic antigen I131 KAb201 antibodies given intra-arterially or intravenously in patients with unresectable pancreatic adenocarcinoma Randomized phase II study of gemcitabine and S-1 combination versus gemcitabine alone in the treatment of unresectable advanced pancreatic cancer (Japan Clinical Cancer Research Organization PC-01 study) A 4-week versus a 3-week schedule of gemcitabine monotherapy for advanced pancreatic cancer: a randomized phase II study to evaluate toxicity and dose intensity A randomized, placebo-controlled phase III trial of masitinib plus gemcitabine in the treatment of advanced pancreatic cancer Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Chemotherapy for advanced pancreatic cancer. A comparison of 5‐fluorouracil, adriamycin, and mitomycin (fam) with 5‐fluorouracil, streptozotocin, and mitomycin (fsm) A comparison of three chemotherapeutic regimens in the treatment of advanced pancreatic and gastric carcinoma. Fluorouracil vs fluorouracil and doxorubicin vs fluorouracil, doxorubicin, and mitomycin. Chemotherapy prolongs survival in inoperable pancreatic carcinoma Length and quality of survival after external-beam radiotherapy with concurrent continuous 5-fluorouracil infusion for locally unresectable pancreatic cancer. Randomized prospective trial comparing 5-fluorouracil (NSC-19893) to 5-fluorouracil and methyl-CCNU (NSC-95441) in advanced gastrointestinal cancer. Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer: an open-label randomised phase II study Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. A multicentre randomised phase II trial of gemcitabine alone vs gemcitabine and S-1 combination therapy in advanced pancreatic cancer: GEMSAP study Chemoradiotherapy with concurrent gemcitabine and cisplatin with or without sequential chemotherapy with gemcitabine/cisplatin vs chemoradiotherapy with concurrent 5-fluorouracil in patients with locally advanced pancreatic cancer – a multi-centre randomised phase II study Treatment of locally unresectable cancer of the stomach and pancreas: a randomized comparison of 5-fluorouracil alone with radiation plus concurrent and maintenance 5-fluorouracil--an Eastern Cooperative Oncology Group study. Docetaxel- and 5-FU-concurrent radiotherapy in patients presenting unresectable locally advanced pancreatic cancer: a FNCLCC-ACCORD/0201 randomized phase II trial's pre-planned analysis and case report of a 5.5-year disease-free survival Irinotecan plus raltitrexed vs raltitrexed alone in patients with gemcitabine-pretreated advanced pancreatic adenocarcinoma Erlotinib is effective in pancreatic cancer with epidermal growth factor receptor mutations: a randomized, open-label, prospective trial Addition of an induction regimen of antiangiogenesis and antitumor immunity to standard chemotherapy improves survival in advanced malignancies Prospective randomised evaluation of traditional Chinese medicine combined with chemotherapy: a randomised phase II study of wild toad extract plus gemcitabine in patients with advanced pancreatic adenocarcinomas Combined immunopharmaceutical therapy of patients with unresectable pancreatic carcinoma. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001. [Effects of Guben Yiliu II combined with arterial perfusion with chemotherapeutic agent in treating advanced pancreatic cancer]. A multicenter, phase II study of infliximab plus gemcitabine in pancreatic cancer cachexia. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. A controlled trial of combination chemotherapy with 5-FU and BCNU in pancreatic cancer. Prospective randomized clinical trial of two drug delivery pathway in the treatment of inoperable advanced pancreatic carcinoma. Treatment of unresectable pancreatic carcinoma with 5-fluorouracil, vincristine, and CCNU. Phase III results of exatecan (DX-8951f) versus gemcitabine (Gem) in chemotherapy-naïve patients with advanced pancreatic cancer (APC). Randomized controlled study of gemcitabine plus S-1 combination chemotherapy versus gemcitabine for unresectable pancreatic cancer NSC-631570 (Ukrain) in the palliative treatment of pancreatic cancer A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea Multi-drug chemotherapy with and without radiation for carcinoma of the stomach and pancreas: a prospective randomized trial. Therapy of locally unresectable pancreatic carcinoma: A randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5‐fluorouracil), and high dose radiation + 5‐fluorouracil. The gastrointestinal tumor study group Phase II evaluation of recombinant gamma-interferon in patients with advanced pancreatic carcinoma: a Southwest Oncology Group study. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). The tyrosine kinase inhibitor imatinib fails to inhibit pancreatic cancer progression. Pharmacokinetic study and clinical evaluation of a slow-release 5-fluorouracil implant in pancreatic cancer patients Gemcitabine versus FLEC regimen given intra-arterially to patients with unresectable pancreatic cancer: a prospective, randomized phase III trial of the Italian Society for Integrated Locoregional Therapy in Oncology. Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. [Comparative study of UFT plus mitomycin C and UFT plus doxorubicin in adenocarcinoma. Hirosaki Cooperative Group of Cancer Chemotherapy]. Comparison of helium-ion radiation therapy and split-course megavoltage irradiation for unresectable adenocarcinoma of the pancreas. Final report of a Northern California Oncology Group randomized prospective clinical trial. An explorative randomised phase II study of sequential chemotherapy in advanced upper gastrointestinal cancer Outcome of upfront combination chemotherapy followed by chemoradiation for locally advanced pancreatic adenocarcinoma Sorafenib does not improve efficacy of chemotherapy in advanced pancreatic cancer: A GISCAD randomized phase II study. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. A randomised trial comparing 5-FU with 5-FU plus cisplatin in advanced pancreatic carcinoma. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. Evaluation of cell mediated immunity in advanced pancreatic carcinoma before and after treatment with interleukin-2 (IL-2). Randomized phase III multi-institutional study of TNFerade biologic with fluorouracil and radiotherapy for locally advanced pancreatic cancer: final results. Randomized study of 5‐FU and ccnu in pancreatic cancer: Report of the veterans administration surgical adjuvant cancer chemotherapy study group Phase III Trial of Radiosensitizer PR-350 Combined With Intraoperative Radiotherapy for the Treatment of Locally Advanced Pancreatic Cancer Evaluation of Ipilimumab in Combination With Allogeneic Pancreatic Tumor Cells Transfected With a GM-CSF Gene in Previously Treated Pancreatic Cancer A phase III trial on the therapy of advanced pancreatic carcinoma evaluations of the mallinson regimen and combined 5‐fluorouracil, doxorubicin, and cisplatin A prospective randomized study of gemcitabine with doxifluridine versus paclitaxel with doxifluridine in concurrent chemoradiotherapy for locally advanced pancreatic cancer. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. Randomized, dose‐finding phase III study of lithium gamolenate in patients with advanced pancreatic adenocarcinoma A phase III comparison trial of streptozotocin, mitomycin, and 5‐fluorouracil with cisplatin, cytosine arabinoside, and caffeine in patients with advanced pancreatic carcinoma Evaluation of combination chemotherapy and phase II agents in pancreatic adenocarcinoma. A southwest oncology group study A phase III trial of virulizin plus gemcitabine vs. gemcitabine alone in advanced pancreatic cancer: Results of subgroup analysis. Cationic liposomal paclitaxel plus gemcitabine or gemcitabine alone in patients with advanced pancreatic cancer: a randomized controlled phase II trial. BAYPAN study: a double-blind phase III randomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer. Chemotherapy of gastric and pancreatic carcinoma: a controlled evaluation of combinations of 5-fluorouracil with nitrosoureas and "lactones". Docetaxel plus gemcitabine or docetaxel plus cisplatin in advanced pancreatic carcinoma: randomized phase II study 40984 of the European Organisation for Research and Treatment of Cancer Gastrointestinal Group. Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. Randomized Double-Blind Phase II Trial Comparing Gemcitabine Plus LY293111 Versus Gemcitabine Plus Placebo in Advanced Adenocarcinoma of the Pancreas A randomized phase II trial of two different 4-drug combinations in advanced pancreatic adenocarcinoma: cisplatin, capecitabine, gemcitabine plus either epirubicin or docetaxel (PEXG or PDXG regimen) A randomized phase III study of rubitecan (ORA) vs. best choice (BC) in 409 patients with refractory pancreatic cancer report from a North-American multi-center study. Randomized controlled trial of gemcitabine in combination with UFT versus gemcitabine alone in patients with advanced pancreatic cancer. [Intraoperative 125I brachytherapy combined with chemotherapy for pancreatic cancer]. A prospective randomised phase-II trial with gemcitabine versus gemcitabine plus sunitinib in advanced pancreatic cancer: a study of the CESAR Central European Society for Anticancer Drug Research-EWIV. Multicenter randomized phase III trial comparing protracted venous infusion (PVI) fluorouracil (5-FU) with PVI 5-FU plus mitomycin in inoperable pancreatic cancer. Concurrent chemoradiotherapy treatment of locally advanced pancreatic cancer: gemcitabine versus 5-fluorouracil, a randomized controlled study. A randomized phase II study of PX-12, an inhibitor of thioredoxin in patients with advanced cancer of the pancreas following progression after a gemcitabine-containing combination Randomized phase II clinical trial of adriamycin, methotrexate, and actinomycin‐d in advanced measurable pancreatic carcinoma. A gastrointestinal tumor study group report Randomized trial of 5‐fluorouracil and mitomycin C with or without streptozotocin for advanced pancreatic cancer. A Southwest oncology group study Randomized trial of 5-fluorouracil, leucovorin and cisplatin in advanced pancreatic cancer. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. Randomized phase III study of exatecan and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic cancer. Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial. Phase II, randomized, biomarker identification trial (MARK) for erlotinib in patients with advanced pancreatic carcinoma. Prospective randomized trial of 5-fluorouracil, doxorubicin, and mitomycin C for non-resectable pancreatic and biliary carcinoma: multicenter randomized trial. A phase II/III study comparing intravenous ZD9331 with gemcitabine in patients with pancreatic cancer. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. Chemotherapy in pancreatic cancer: results of a controlled, prospective, randomised, multicentre trial. The PACT trial: Interim results of a randomized trial of TNFerade biologic plus chemoradiation (CRT) compared to CRT alone in locally advanced pancreatic cancer (LAPC). [Effect of qi replenishing and blood circulation activating drugs in treatment of middle-advanced pancreatic cancer with radio- and chemotherapy]. A randomized phase I and II study of short-term infusion of high-dose fluorouracil with or without N-(phosphonacetyl)-L-aspartic acid in patients with advanced pancreatic and colorectal cancers. 618PDA PHASE 2 RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED STUDY OF SIMTUZUMAB OR PLACEBO IN COMBINATION WITH GEMCITABINE FOR THE FIRST LINE TREATMENT OF PANCREATIC ADENOCARCINOMA. Trials of single-agent and combination chemotherapy for advanced cancer of the pancreas. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. A randomized phase III study of radiotherapy alone or with 5-fluorouracil and mitomycin-C in patients with locally advanced adenocarcinoma of the pancreas: Eastern Cooperative Oncology Group study E8282. Regional versus systemic chemotherapy for advanced pancreatic cancer: a randomized study. Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. Randomized phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. An International Multicenter Randomized Controlled Trial of G17DT in Patients With Pancreatic Cancer Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000-01 FFCD/SFRO study. Gemcitabine plus erlotinib followed by capecitabine versus capecitabine plus erlotinib followed by gemcitabine in advanced pancreatic cancer: final results of a randomised phase 3 trial of the ‘Arbeitsgemeinschaft Internistische Onkologie’ (AIO-PK0104) Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group.
This study was performed to determine the activity of adding continuous infusion ( CI ) of 5-fluorouracil ( 5-FU ) to gemcitabine ( GEM ) vs GEM alone in advanced pancreatic cancer ( APC ) . In all , 94 chemo-naïve patients with APC were r and omised to receive GEM alone ( arm A : 1000 mg m−2 per week for 7 weeks followed by a 2 week rest period , then weekly for 3 consecutive weeks out of every 4 weeks ) or in combination with CI 5-FU ( arm B : CI 5-FU 200 mg m−2 day−1 for 6 weeks followed by a 2 week rest period , then for 3 weeks every 4 weeks ) . Overall response rate ( RR ) was the primary end point and criteria for decision were planned according to the Simon 's optimal two-stage design . The overall RR was 8 % ( arm A ) and 11 % ( arm B ) ( 95 % confidence interval : 0.5–16 % and 2–22 % ) , respectively , and stable disease was 29 and 28 % . The median duration of RR was 34 weeks ( range 25–101 weeks ) for GEM and 26 weeks ( range 16–46 weeks ) for the combination . The median progression-free survival ( PFS ) was 14 weeks ( range 2–65 weeks ) and 18 weeks ( range 4–51 weeks ) , respectively . The median overall survival ( OS ) was 31 weeks ( range 1–101 weeks ) and 30 weeks ( 1–101 weeks ) . Toxicity was mild in both arms . This study does not show promising activity in terms of RR , PFS and OS for the double combination arm in APC PURPOSE This phase III trial compared the efficacy and safety of gemcitabine ( Gem ) plus capecitabine ( GemCap ) versus single-agent Gem in advanced/metastatic pancreatic cancer . PATIENTS AND METHODS Patients were r and omly assigned to receive GemCap ( oral capecitabine 650 mg/m2 twice daily on days 1 to 14 plus Gem 1,000 mg/m2 by 30-minute infusion on days 1 and 8 every 3 weeks ) or Gem ( 1,000 mg/m2 by 30-minute infusion weekly for 7 weeks , followed by a 1-week break , and then weekly for 3 weeks every 4 weeks ) . Patients were stratified according to center , Karnofsky performance score ( KPS ) , presence of pain , and disease extent . RESULTS A total of 319 patients were enrolled between June 2001 and June 2004 .  Median overall survival ( OS ) time , the primary end point , was 8.4 and 7.2 months in the GemCap and Gem arms , respectively ( P = .234 ) . Post hoc analysis in patients with good KPS ( score of 90 to 100 ) showed a significant prolongation of median OS time in the GemCap arm compared with the Gem arm ( 10.1 v 7.4 months , respectively ; P = .014 ) . The overall frequency of grade 3 or 4 adverse events was similar in each arm . Neutropenia was the most frequent grade 3 or 4 adverse event in both arms . CONCLUSION GemCap failed to improve OS at a statistically significant level compared with st and ard Gem treatment . The safety of GemCap and Gem was similar . In the subgroup of patients with good performance status , median OS was improved significantly . GemCap is a practical regimen that may be considered as an alternative to single-agent Gem for the treatment of advanced/metastatic pancreatic cancer patients with a good performance status Pancreatic cancer is the fifth most common cause of cancer death in the western world and the prognosis for unresectable disease remains poor . Recent advances in conventional chemotherapy and the development of novel ‘ molecular ’ treatment strategies with different toxicity profiles warrant investigation as combination treatment strategies . This r and omised study in pancreatic cancer compares marimastat ( orally administered matrix metalloproteinase inhibitor ) in combination with gemcitabine to gemcitabine alone .  Two hundred and thirty-nine patients with unresectable pancreatic cancer were r and omised to receive gemcitabine ( 1000 mg m−2 ) in combination with either marimastat or placebo . The primary end-point was survival . Objective tumour response and duration of response , time to treatment failure and disease progression , quality of life and safety were also assessed . There was no significant difference in survival between gemcitabine and marimastat and gemcitabine and placebo ( P=0.95 log-rank test ) . Median survival times were 165.5 and 164 days and 1-year survival was 18 % and 17 % respectively . There were no significant differences in overall response rates ( 11 and 16 % respectively ) , progression-free survival ( P=0.68 log-rank test ) or time to treatment failure ( P=0.70 log-rank test ) between the treatment arms . The gemcitabine and marimastat combination was well tolerated with only 2.5 % of patients withdrawn due to presumed marimastat toxicity . Grade 3 or 4 musculoskeletal toxicities were reported in only 4 % of the marimastat treated patients , although 59 % of marimastat treated patients reported some musculoskeletal events . The results of this study provide no evidence to support a combination of marimastat with gemcitabine in patients with advanced pancreatic cancer . The combination of marimastat with gemcitabine was well tolerated . Further studies of marimastat as a maintenance treatment following a response or stable disease on gemcitabine may be justified Background : To evaluate the efficacy and tolerability of the urokinase plasminogen activator ( uPA ) inhibitor upamostat in combination with gemcitabine in locally advanced pancreatic adenocarcinoma ( LAPC ) . Methods : Within a prospect i ve multicenter study , LAPC patients were r and omly assigned to receive 1000 mg m−2 of gemcitabine IV weekly either alone ( arm A ) or in combination with 200 mg ( arm B ) or 400 mg ( arm C ) oral upamostat daily . Efficacy endpoints of this proof-of-concept study included response rate , time to first metastasis , progression-free and overall survival ( OS ) . Results : Of the 95 enroled patients , 85 were evaluable for response and 93 for safety . Median OS was 12.5 months ( 95 % CI 8.2–18.2 ) in arm C , 9.7 months ( 95 % CI 8.4–17.1 ) in arm B and 9.9 months ( 95 % CI 7.4–12.1 ) in arm A ; corresponding 1-year survival rates were 50.6 % , 40.7 % and 33.9 % , respectively . More patients achieved a partial remission ( confirmed responses by RECIST ) with upamostat combination therapy ( arm C : 12.9 % ; arm B : 7.1 % ; arm A : 3.8 % ) . Overall , only 12 patients progressed by developing detectable distant metastasis ( arm A : 4 , arm B : 6 , arm C : 2 ) . The most common adverse events considered to be related to upamostat  were asthenia , fever and nausea . Conclusion : In this proof-of-concept study targeting the uPA system in LAPC , the addition of upamostat to gemcitabine was tolerated well ; similar survival results were observed for the three treatment arms Background : Only a few clinical trials have been conducted in patients with advanced pancreatic cancer after failure of first-line gemcitabine-based chemotherapy . Therefore , there is no current consensus on the treatment of these patients . We conducted a r and omised phase II study of the modified FOLFIRI.3 ( mFOLFIRI.3 ; a regimen combining 5-fluorouracil ( 5-FU ) , folinic acid , and irinotecan ) and modified FOLFOX ( mFOLFOX ; a regimen combining folinic acid , 5-FU , and oxaliplatin ) regimens as second-line treatments in patients with gemcitabine-refractory pancreatic cancer . Methods : The primary end point was the 6-month overall survival rate . The mFOlFIRI.3 regimen consisted of irinotecan ( 70 mg m−2 ; days 1 and 3 ) , leucovorin ( 400 mg m−2 ; day 1 ) , and 5-FU ( 2000 mg m−2 ; days 1 and 2 ) every 2 weeks . The mFOLFOX regimen was composed of oxaliplatin ( 85 mg m−2 ; day 1 ) , leucovorin ( 400 mg m−2 ; day 1 ) , and 5-FU ( 2000 mg m−2 ; days 1 and 2 ) every 2 weeks . Results : Sixty-one patients were r and omised to mFOLFIRI.3 ( n=31 ) or mFOLFOX ( n=30 ) regimen .  The six-month survival rates were 27 % ( 95 % confidence interval (CI)=13–46 % ) and 30 % ( 95 % CI=15–49 % ) , respectively . The median overall survival periods were 16.6 and 14.9 weeks , respectively . Disease control was achieved in 23 % ( 95 % CI=10–42 % ) and 17 % patients ( 95 % CI=6–35 % ) , respectively . The number of patients with at least one grade 3/4 toxicity was identical ( 11 patients , 38 % ) in both groups : neutropenia ( 7 patients under mFOLFIRI.3 regimen vs 6 patients under mFOLFOX regimen ) , asthaenia ( 1 vs 4 ) , vomiting ( 3 in both ) , diarrhoea ( 2 vs 0 ) , and mucositis ( 1 vs 2 ) . Conclusion : Both mFOLFIRI.3 and mFOLFOX regimens were tolerated with manageable toxicity , offering modest activities as second-line treatments for patients with advanced pancreatic cancer , previously treated with gemcitabine Background Anti-angiogenic treatment is believed to have at least cystostatic effects in highly vascularized tumours like pancreatic cancer . In this study , the treatment effects of the angiogenesis inhibitor Cilengitide and gemcitabine were compared with gemcitabine alone in patients with advanced unresectable pancreatic cancer . Methods A multi-national , open-label , controlled , r and omized , parallel-group , phase II pilot study was conducted in 20 centers in 7 countries .  Cilengitide was administered at 600 mg/m2 twice weekly for 4 weeks per cycle and gemcitabine at 1000 mg/m2 for 3 weeks followed by a week of rest per cycle . The planned treatment period was 6 four-week cycles . The primary endpoint of the study was overall survival and the secondary endpoints were progression-free survival ( PFS ) , response rate , quality of life ( QoL ) , effects on biological markers of disease ( CA 19.9 ) and angiogenesis ( vascular endothelial growth factor and basic fibroblast growth factor ) , and safety . An ancillary study investigated the pharmacokinetics of both drugs in a subset of patients . Results Eighty-nine patients were r and omized . The median overall survival was 6.7 months for Cilengitide and gemcitabine and 7.7 months for gemcitabine alone . The median PFS times were 3.6 months and 3.8 months , respectively . The overall response rates were 17 % and 14 % , and the tumor growth control rates were 54 % and 56 % , respectively . Changes in the levels of CA 19.9 went in line with the clinical course of the disease , but no apparent relationships were seen with the biological markers of angiogenesis . QoL and safety evaluations were comparable between treatment groups . Pharmacokinetic studies showed no influence of gemcitabine on the pharmacokinetic parameters of Cilengitide and vice versa . Conclusion There were no clinical ly important differences observed regarding efficacy , safety and QoL between the groups . The observations lay in the range of other clinical studies in this setting . The combination regimen was well tolerated with no adverse effects on the safety , tolerability and pharmacokinetics of either agent In a r and omized trial we compared single-agent epirubicin with the FEM ( 5-fluorouracil/epirubicin/mitomycin ) combination in patients with locally advanced and /or metastatic adenocarcinoma of the pancreas . Sixty patients previously untreated with radiotherapy or chemotherapy  were r and omly assigned to receive either 100 mg/m2 epirubicin or FEM in the following doses : 5-fluorouracil , 600 mg/m2 to a maximum of 1 g ; epirubicin , 50 mg/m2 ; mitomycin , 6 mg/m2 to a maximum of 10 mg . Treatment was given every 28 days via intravenous bolus ; because of its association with delayed myelotoxicity , mitomycin was given every other cycle . A total of 47 patients are evaluable for toxicity and survival  , 22 who received FEM and 25 epirubicin . Preliminary results of this ongoing study show no difference in survival between the two arms . Toxicity has been easily managed . A similar number of patients in each arm had elevated serum bilirubin levels , but dose reductions of 50 % allowed all these patients to continue treatment In this multicenter r and omized trial , the efficacy of combination chemotherapy using 5-fluorouracil , doxorubicin and mitomycin C ( arm A ) was compared with that of 5-fluorouracil alone ( arm B ) in 81 patients with nonresectable carcinomas of the pancreas or biliary tract . There were no significant differences between treatment arms regarding the median time to progressive disease , median survival time , palliative effects or toxicities . It was concluded that combination chemotherapy is feasible but can not be recommended Abstract Lessons Learned . The safety profile in the gemcitabine/simtuzumab group was similar to that in the gemcitabine/placebo group . The addition of simtuzumab to gemcitabine does not improve clinical outcomes in patients with metastatic pancreatic adenocarcinoma Background . The humanized IgG4 monoclonal antibody simtuzumab inhibits the extracellular matrix‐remodeling enzyme lysyl oxidase‐like 2 maintaining pathological stroma in tumors . Methods . Adult patients with metastatic pancreatic adenocarcinoma ( mPaCa ) were r and omly assigned to receive intravenous gemcitabine , 1,000 mg/m2 , in combination with 200 or 700 mg simtuzumab or placebo . Primary endpoint was progression‐free survival ( PFS ) , secondary endpoints included overall survival ( OS ) , objective response rate ( ORR ) , and safety . Results . Of 240 patients , 80 were r and omly assigned to  gemcitabine/simtuzumab 700 mg , 79 to gemcitabine/simtuzumab 200 mg , and 81 to gemcitabine/placebo . After a median follow‐up of 3.0 , 1.9 , and 3.4 months for gemcitabine/simtuzumab 700 mg , gemcitabine/simtuzumab 200 mg , and gemcitabine/placebo , respectively , the median PFS was 3.7 months ( adjusted hazard ratio [ HR ] , 95 % confidence interval [ CI ] , p value vs placebo : 1.09 [ 0.74–1.61 ] ; p = .73 ) , 3.5 months ( 1.13 [ 0.76–1.66 ] , p = .61 ] ) , and 3.7 months , respectively . Median OS was 7.6 months ( 0.83 [ 0.57–1.22 ] ; p = .28 ) , 5.9 months ( 1.07 [ 0.73–1.55 ] ; p = .69 ) , and 5.7 months , respectively . ORRs were 13.9 % , 14.5 % , and 23.5 % , respectively . Simtuzumab was well tolerated . Conclusion . The addition of simtuzumab to gemcitabine did not improve clinical outcomes in patients with mPaCa Gemcitabine is a key drug for the treatment of pancreatic cancer ; however , with its limitation in clinical benefits , the development of another potent therapeutic is necessary . Vascular endothelial growth factor receptor 2 is an essential target for tumor angiogenesis , and we have conducted a phase I clinical trial using gemcitabine and vascular endothelial growth factor receptor 2 peptide ( elpamotide ) . Based on the promising results of this phase I trial , a multicenter , r and omized , placebo‐controlled , double‐blind phase II/III clinical trial has been carried out for pancreatic cancer . The eligibility criteria included locally advanced or metastatic pancreatic cancer . Patients were assigned to either the Active group ( elpamotide + gemcitabine ) or Placebo group ( placebo + gemcitabine ) in a 2:1 ratio by the dynamic allocation method . The primary endpoint was overall survival . The Harrington – Fleming test was applied to the statistical analysis in this study to evaluate the time‐lagged effect of immunotherapy appropriately . A total of 153 patients ( Active group , n = 100 ; Placebo group , n = 53 ) were included in the analysis . No statistically significant differences were found between the two groups in the prolongation of overall survival ( Harrington – Fleming P‐value , 0.918 ; log – rank P‐value , 0.897 ; hazard ratio , 0.87 , 95 % confidence interval [ CI ] , 0.486–1.557 ) . Median survival time was 8.36 months ( 95 % CI , 7.46–10.18 ) for the Active group and 8.54 months ( 95 % CI , 7.33–10.84 ) for the Placebo group . The toxicity observed in both groups was manageable . Combination therapy of elpamotide with gemcitabine was well tolerated . Despite the lack of benefit in overall survival , subgroup analysis suggested that the patients who experienced severe injection site reaction , such as ulceration and erosion , might have better survival BACKGROUND To compare the efficacy and safety of three different chemotherapy doublets in the treatment of advanced pancreatic cancer ( PC ) . PATIENTS AND METHODS At total of 190 patients were r and omly assigned to receive capecitabine 1000 mg/m(2 ) twice daily on days 1 - 14 plus oxaliplatin 130 mg/m(2 ) on day 1 ( CapOx ) , capecitabine 825 mg/m(2 ) twice daily on days 1 - 14 plus gemcitabine 1000 mg/m(2 ) on days 1 and 8 ( CapGem ) or gemcitabine 1000 mg/m(2 ) on days 1 and 8 plus oxaliplatin 130 mg/m(2 ) on day 8 ( mGemOx ) . Treatment cycles were repeated every three weeks . The primary end point was progression-free survival ( PFS ) rate at 3 months ; secondary end points included objective response rate , carbohydrate antigen 19 - 9 response , clinical benefit response , overall survival and toxicity . RESULTS The PFS rate after 3 months was 51 % in the CapOx arm , 64 % in the CapGem arm and 60 % in the mGemOx arm . Median PFS was estimated with 4.2 months , 5.7 months and 3.9 months , respectively ( P = 0.67 ) . Corresponding median survival times were : 8.1 months ( CapOx ) , 9.0 months ( CapGem ) and 6.9 months ( mGemOx ) ( P = 0.56 ) . Grade 3/4 hematological toxicities were more frequent in the two Gem-containing arms ; grade 3/4 non-hematological toxicity rates did not exceed 15 % in any arm . CONCLUSION CapOx , CapGem and mGemOx have similar clinical efficacy in advanced PC . Each regimen has a distinct but manageable tolerability profile Summary Background In the UK , chemotherapy is the st and ard treatment for inoperable , locally advanced , non-metastatic pancreatic cancer .  Chemoradiotherapy is also an acceptable treatment option , for which gemcitabine , fluorouracil , or capecitabine can be used as concurrent chemotherapy agents . We aim ed to assess the activity , safety , and feasibility of both gemcitabine-based and capecitabine-based chemoradiotherapy after induction chemotherapy for patients with locally advanced pancreatic cancer . Methods In this open-label , r and omised , two-arm , phase 2 trial , patients aged 18 years or older with histologically proven , locally advanced pancreatic cancer ( with a tumour diameter of 7 cm or less ) were recruited from 28 UK centres between Dec 24 , 2009 and Oct 25 , 2011 . After 12 weeks of induction gemcitabine and capecitabine chemotherapy ( three cycles of gemcitabine [ 1000 mg/m2 on days 1 , 8 , 15 of a 28-day cycle ] and capecitabine [ 830 mg/m2 twice daily on days 1–21 of a 28-day cycle ] ) , patients with stable or responding disease , tumour diameter of 6 cm or less , and WHO performance status 0–1 were r and omly assigned to receive a further cycle of gemcitabine and capecitabine chemotherapy followed by either gemcitabine ( 300 mg/m2 once per week ) or capecitabine ( 830 mg/m2 twice daily , Monday to Friday only ) , both in combination with radiation ( 50·4 Gy in 28 fractions ) . R and omisation ( 1:1 ) was done via a central computerised system and used stratified minimisation . The primary endpoint was 9-month progression-free survival , analysed by intention to treat including only those patients with valid CT assessment s. This trial is registered with IS RCT N , number 96169987 . Findings 114 patients were registered and 74 were r and omly allocated ( 38 to the gemcitabine group and 36 to the capecitabine group ) . After 9 months , 22 of 35 assessable patients ( 62·9 % , 80 % CI 50·6–73·9 ) in the capecitabine group and 18 of 35 assessable patients ( 51·4 % , 39·4–63·4 ) in the gemcitabine group had not progressed . Median overall survival was 15·2 months ( 95 % CI 13·9–19·2 ) in the capecitabine group and 13·4 months ( 95 % CI 11·0–15·7 ) in the gemcitabine group ( adjusted hazard ratio [ HR ] 0·39 , 95 % CI 0·18–0·81 ; p=0·012 ) . 12-month overall survival was 79·2 % ( 95 % CI 61·1–89·5 ) in the capecitabine group and 64·2 ( 95 % CI 46·4–77·5 ) in the gemcitabine group . Median progression-free survival was 12·0 months ( 95 % CI 10·2–14·6 ) in the capecitabine group and 10·4 months ( 95 % CI 8·9–12·5 ) in the gemcitabine group ( adjusted HR 0·60 , 95 % CI 0·32–1·12 ; p=0·11 ) . Eight patients in the capecitabine group had an objective response at 26 weeks , as did seven in the gemcitabine group . More patients in the gemcitabine group than in the capecitabine group had grade 3–4 haematological toxic effects ( seven [ 18 % ] vs none , p=0·008 ) and non-haematological toxic effects ( ten [ 26 % ] vs four [ 12 % ] , p=0·12 ) during chemoradiation treatment ; the most frequent events were leucopenia , neutropenia , and fatigue . Two patients in the capecitabine group progressed during the fourth cycle of induction chemotherapy . Of the 34 patients in the capecitabine group who received chemoradiotherapy , 25 ( 74 % ) received the full protocol dose of radiotherapy , compared with 26 ( 68 % ) of 38 patients in the gemcitabine group . Quality -of-life scores were not significantly different between the treatment groups . Interpretation Our results suggest that a capecitabine-based regimen might be preferable to a gemcitabine-based regimen in the context of consolidation chemoradiotherapy after a course of induction chemotherapy for locally advanced pancreatic cancer . However , these findings should be interpreted with caution because the difference in the primary endpoint was non-significant and the number of patients in the trial was small . Funding Cancer Research UK 4026 Background : IGF-1R activation results in the phosphorylation of IRS-1 and the PI3-Kinase/Akt , mTOR and S6 kinase pathways in pancreatic cancer . Monoclonal antibody MK-0646 blocks IGF-1-receptor interaction , internalizes and de grade s IGF-1R . Receptor cross-talk between IGF-1R and EGFR and IGF-1R-induced PI3-kinase mediates resistance to anti-EGFR agents . Prior phase I established the maximal tolerated dose of MK-0646 as 10 mg/kg with G and 5 mg/kg with G+E. METHODS Patients ( pts ) with stage IV , previously untreated pancreatic cancer , ECOG performance status ( PS ) 0 - 1 , adequate hematologic and organ function were enrolled . Uncontrolled hyperglycemia or cardio-respiratory conditions were exclusions . Phase II study has 3 arms and uses adaptive r and omized design with progression-free survival ( PFS ) as primary endpoint : Arm A ( G + MK-0646 ) , Arm B ( G + E + MK-0646 ) and Arm C ( G + E ) . G was administered as 1,000 mg/m2 over 100 min , weekly x 3 , MK-0646 weekly x 4 and E 100 mg daily . Cycles repeated q 4 weeks . On progression , arm C pts crossed over to arm B. Secondary endpoints : overall survival ( OS ) , response rate and toxicity . RESULTS 58 pts enrolled ( 53 evaluable ) , 34 males , 3 prior Whipple , 48 PS 1 , 5 PS 0 . Median of 2 cycles administered ( range 1 , 12 + ) . Accrual : Arm A= 20 , B=23 , C=10 pts . Median follow up A=48 , B=30 , C=26 weeks . Grade 3 - 4 toxic events/ arm : neutropenia 9/A , 26/B , 1/C ; platelets 5/A , 10/B ; anemia 2/B ; AST 3/B,3/C ; hyponatremia 1/A , 5/B ; hyperglycemia 3/A , 3/B ; dehydration 1/B ; thrombus 2/B and infection 2/B. Partial responses : 20 % Arm A , 25 % Arm B , 10 % Arm C. Median PFS Arm A=17 weeks ( CI:7,34 ) , Arm B=8 weeks ( 8,18 ) , Arm C= 8 weeks ( 3,22 ) ; PFS was significant in favor of arm A ( p=0.0425 ) . OS arm A=48 wks ( 14,82 ) , B=30 wks ( 18,56 ) , C=26 wks ( 8,40 ) . No significant difference noted in OS in the 3 arms ( p=0.4 ) in this cross-over study . Sustained responses ( > 8 weeks ) occurred in arms A and B only ; greater proportion of arm A pts survived > 40 weeks ( p=0.04 ) . CONCLUSIONS MK-0646 is tolerable in combination with G ; toxicities were higher with G+ E+ MK-0646 .  Sustained PRs , limited toxicity and encouraging survival were noted with G+ MK-0646 ( arm A ) in this preliminary analysis BACKGROUND Pre clinical data have suggested a synergistic effect of cetuximab combined with gemcitabine and cisplatin and clinical data have shown a substantial improvement in response and survival when gemcitabine is combined with a platinum analogue compared with gemcitabine alone . The aim of this study was to assess the activity and feasibility of a combination of cetuximab with gemcitabine and cisplatin compared with use of gemcitabine and cisplatin alone for the treatment of advanced pancreatic cancer . METHODS In a multicentre , r and omised phase II trial , 84 patients with advanced pancreatic cancer were r and omly assigned to either 250 mg/m2 cetuximab weekly , after a loading dose of 400 mg/m2 , plus 1000 mg/m2 gemcitabine and 35 mg/m2 cisplatin on days 1 and 8 of a 21-day cycle or to the same chemotherapeutic regimen without cetuximab . The primary endpoint was objective response ( defined as the proportion of patients whose best response was either partial response or complete response ) . Secondary endpoints included disease control ( defined as the proportion of patients whose best response was either partial response , complete response , or stable disease ) , progression-free survival , and overall survival . All assessment s of response at each site were done blindly by a local experienced radiologist who was not directly involved in the trial . Responses were measured according to an intention-to-treat analysis . This trial is registered with the Clinical Trial registry , number NCT00536614 . FINDINGS 29 men and 13 women were r and omly assigned to cetuximab plus gemcitabine and cisplatin ( median age 61 years [ range 38 - 78 ] ) and 22 men and 20 women were r and omly assigned to gemcitabine and cisplatin ( median age 64 years [ range 40 - 76 ] ) . Seven of 40 ( 17.5 % ) patients had an objective response in the cetuximab group ( 95 % CI 7.3 - 32.8 ) and five of 41 ( 12.2 % ) patients had an objective response in the non-cetuximab group ( 95 % CI 4.1 - 26.2 ) . No significant difference was noted between the groups both for objective response ( 5.3 % higher in the cetuximab group [ 95 % CI -16.5 to 27.1 ] ; chi2 test=0.360 ; p=0.549 ) or for disease control ( 3.5 % higher in the non-cetuximab group [ -34.0 % to 27.0 % ] ; 0.446 ; p=0.504 ) . Overall median follow-up was 11.8 months ( range 2.5 - 18.5 ) . No significant differences between the groups were noted in median progression-free survival ( hazard ratio 0.96 , 95 % CI 0.60 - 1.52 , p=0.847 ) or in median overall survival ( 0.91 , 0.54 - 1.55 , p=0.739 ) : median progression-free survival was 3.4 months ( 95 % CI 2.4 - 5.1 ) in the cetuximab group and 4.2 months ( 2.6 - 5.4 ) in the non-cetuximab group ; median overall survival was 7.5 months ( 5.1 - 8.8 ) and 7.8 months ( 5.3 - 15.0 ) , respectively . 33 patients from both groups had at least one grade 3 - 4 toxic effect . INTERPRETATION The addition of cetuximab to a combination of gemcitabine and cisplatin does not increase response or survival for patients with advanced pancreatic cancer . Although toxic effects were not increased by cetuximab , this combination should not be further assessed in phase III trials BACKGROUND A r and omized phase II , open-label multicenter study evaluating oxaliplatin alone ( OXA ) , infusional 5-fluorouracil alone ( 5-FU ) and an oxaliplatin/infusional 5-FU combination ( OXFU ) in untreated , advanced pancreatic carcinoma ( APC ) . PATIENTS AND METHODS Chemotherapy-naïve patients with advanced or metastatic , histologically/cytologically proven pancreatic carcinoma with measurable disease , received OXA [ 130 mg/m2 , 2-h intravenous ( i.v . ) infusion ] alone , OXA combined with 5-FU ( 1000 mg/m2/day , continuous i.v . , days 1 - 4 ) , or 5-FU alone , every 3 weeks . RESULTS Sixty-three patients ( 42 males/21 females ) were treated : 17 patients /52 cycles OXA , 31 patients / 175 cycles OXFU , 15 patients /41 cycles 5-FU , with a median of three , six and two cycles/patient , respectively . Patient characteristics were similar in all arms . Median age was 57 years ( range 21 - 75 ) , and 83 % of patients had PS 0 - 1 . Most patients ( 62 % ) had moderate to well-differentiated tumors , 90 % had metastatic disease , 81 % with liver metastases . All responses ( three partial responses ; WHO ) occurred in the OXFU arm ( 10 % response rate ) . Five of 32 patients evaluable for clinical benefit were responders ( OXA , 14 % ; OXFU , 21 % ) . Median time to progression and overall survival were higher in the combination arm ( 4.2 and 9.0 months , respectively ) than either single-agent arm ( OXA , 2.0 and 3.4 months ; 5-FU , 1.5 and 2.4 months , respectively ) . Moderate hematotoxicity without morbidity was seen in all arms . Two OXFU patients had grade 3 oxaliplatin neurosensory toxicity . CONCLUSIONS With a 10 % response rate , median overall survival of 9 months and an encouraging safety profile , the OXFU combination is effective , appears superior to infusional 5-FU and warrants further studies in APC patients BACKGROUND The efficacy and benefit of second-line chemotherapy in advanced pancreatic adenocarcinoma has never been demonstrated although it is regularly used . PATIENTS AND METHODS A r and omized phase II study evaluating oxaliplatin alone ( OXA ) , infusional 5-fluorouracil alone ( 5-FU ) and an oxaliplatin/infusional 5-FU combination ( OXFU ) in untreated advanced pancreatic adenocarcinoma has been conducted . In this trial , a second-line treatment with the OXFU regimen ( OXA 130 mg/m2 2-h intravenous ( i.v . ) infusion combined with 5-FU ( 1000 mg/m2/day , continuous i.v . , days 1 - 4 ) , every 3 weeks ) was offered to patients progressing after single agent treatment . RESULTS Eighteen out of 32 patients ( 12 males , median age 57 years ) treated in the single agent arms received the OXFU combination in second-line treatment . WHO performance status was at least 2 in 61 % of the patients . There was no objective response and 3 patients ( 17 % ) had a disease stabilisation . Median time to progression from the start of second-line treatment was 0.9 months . Median overall survival was 4.9 months from the start of front-line therapy and 1.3 months from the start of second-line therapy . CONCLUSION The results of this trial bring arguments to support a modest value of second-line chemotherapy for advanced pancreatic adenocarcinoma Background Advanced pancreatic cancer has a poor prognosis , and the current st and ard of care ( gemcitabine based chemotherapy ) provides a small survival advantage . However the drawback is the accompanying systemic toxicity , which targeted treatments may overcome . This study aim ed to evaluate the safety and tolerability of KAb201 , an anti-carcinoembryonic antigen monoclonal antibody , labelled with I131 in pancreatic cancer ( IS RCT N 16857581 ) . Methods Patients with histological/cytological proven inoperable adenocarcinoma of the head of pancreas were r and omised to receive KAb 201 via either the intra-arterial or intravenous delivery route . The dose limiting toxicities within each group were determined . Patients were assessed for safety and efficacy and followed up until death . Results Between February 2003 and July 2005 , 25 patients were enrolled . Nineteen patients were r and omised , 9 to the intravenous and 10 to the intra-arterial arms . In the intra-arterial arm , dose limiting toxicity was seen in 2/6 ( 33 % ) patients at 50 mCi whereas in the intravenous arm , dose limiting toxicity was noted in 1/6 patients at 50 mCi , but did not occur at 75 mCi (0/3).The overall response rate was 6 % ( 1/18 ) . Median overall survival was 5.2 months ( 95 % confidence interval = 3.3 to 9 months ) , with no significant difference between the intravenous and intra-arterial arms ( log rank test p = 0.79 ) . One patient was still alive at the time of this analysis . Conclusion Dose limiting toxicity for KAb201 with I131 by the intra-arterial route was 50 mCi , while dose limiting toxicity was not reached in the intravenous arm Purpose To evaluate the efficacy and safety of the combination of gemcitabine ( GEM ) and S-1 ( GS ) in comparison to GEM alone ( G ) for unresectable pancreatic cancer . Methods In this multicenter r and omized phase II study , we r and omly assigned unresectable pancreatic cancer patients to either the GS group or the G group . The GS group regimen consists of intravenous 1,000 mg/m2 GEM during 30 min on days 1 and 8 , combined with 80 mg/m2 oral S-1 twice daily on days 1–14 , repeated every 3 weeks . On the other h and , the G group regimen consists of intravenous 1,000 mg/m2 GEM on days 1 , 8 , and 15 , repeated every 4 weeks . The primary endpoint was objective response rate ( ORR ) . Secondary end points included treatment toxicity , clinical response benefit , progression-free survival ( PFS ) , and overall survival . Results We registered 117 patients from 16 institutions between June 2007 and August , 2010 . The ORR of the GS group was 28.3 % , whereas that of the G group was 6.8 % . This difference was statistically significant ( P = 0.005 ) . The disease control rate was 64.2 % in the GS group and 44.1 % in the G group . Median PFS was 6.15 months in the GS group and 3.78 month in the G group . This was also statistically significant ( P = 0.0007 ) . Moreover , the median overall survival ( OS ) of the GS group was significantly longer than that of the G group ( 13.7 months vs. 8.0 months ; P = 0.035 ) . The major grade 3–4 adverse events were neutropenia ( 54.7 % in the GS group and 22.0 % in the G group ) , thrombocytopenia ( 15.1 % in the GS group and 5.1 % in the G group ) , and skin rash ( 9.4 % in the GS group ) . Conclusions The GS group showed stronger anticancer activity than the G group , suggesting the need for a large r and omized phase III study to confirm GS advantages in a specific subset Background This r and omized phase II study compared the efficacy and toxicity between 4-week and 3-week schedules of gemcitabine monotherapy in advanced pancreatic cancer . Methods Patients with advanced pancreatic cancer were r and omly assigned to either a 4-week schedule ( gemcitabine at 1000 mg/m² as a 30-min infusion weekly for 3 consecutive weeks every 4 weeks ) or a 3-week schedule ( gemcitabine at 1000 mg/m² as a 30-min infusion weekly for 2 consecutive weeks every 3 weeks ) . The primary endpoint was the compliance rate during the first 8 weeks between the two groups . Results A total of 90 patients were enrolled . The compliance rate during the first 8 weeks was the same ( 53.3 % ) . For the 4- and 3-week schedules , the tumor response rates were 14.2 and 17.1 % ( p = 0.92 ) , median progression free survival was 112 and 114 days ( p = 0.82 ) , and median overall survival was 206 and 250 days ( p = 0.84 ) , respectively . Grade 3–4 neutropenia was the major adverse event in both schedules : 37.7 and 35.5 % ( p = 0.82 ) . In contrast , thrombocytopenia ( platelet count < 70000/mm³ ) was significantly higher for the 4-week schedule : 26.6 and 4.4 % ( p = 0.008 ) . The mean received dose intensity was equal : 588 and 550 mg/m²/week ( p = 0.14 ) . Conclusions The 3-week schedule of gemcitabine did not improve the compliance rate during 8 weeks compared with the 4-week schedule , but it attained a comparable efficacy with lower toxicity . Further investigation will be needed to introduce it into daily practice . Clinical trial registration number : UMIN ID 974 Two subgroups showing significantly poor survival when treated with single-agent gemcitabine have been identified ; one is defined by an overexpression of ACOX1 in blood , and the other via a pain intensity threshold . Masitinib in combination with gemcitabine appears to have a positive benefit – risk ratio in both subgroups . These findings could influence future trial design in pancreatic cancer BACKGROUND Gemcitabine usually given until progressive disease ( PD ) is the main first-line treatment option for patients with inoperable advanced pancreatic cancer ( APC ) . Currently there is no accepted active regimen for second-line chemotherapy . Previous phase II studies suggest clinical relevant activity of oxaliplatin , folinic acid and 5-FU ( OFF ) . We initiated a phase III multicentre study comparing OFF versus best supportive care ( BSC ) in patients with APC progressing while on gemcitabine therapy . METHODS In this open r and omized study , patients with CT and /or MRI confirmed progressive disease while on gemcitabine therapy  were r and omized 1:1 to OFF or BSC . Stratification included duration of first-line therapy ( <3 , 3 to 6 and > 6 months ) , performance status ( KPS 70 - 80 % ; 90 - 100 % ) and tumour stage ( M1/M0 ) . OFF consisted of folinic acid 200mg/m(2 ) followed by 5-fluorouracil 2g/m(2 ) ( 24h ) on d1 , d8 , d15 , d22 and oxaliplatin 85 mg/m(2 ) on days 8 and 22 . After a rest of 3 weeks the next cycle was started on d43 . A total of 165 patients were calculated to demonstrate a doubling of survival time after progression on first-line therapy . RESULTS After inclusion of forty six patients the trial was terminated according to predefined protocol regulations due to insufficient accrual ( lack of acceptance of BSC by patients and physicians . Patient characteristics were well balanced between both study arms . The OFF regimen was well tolerated with more patients with grade I/II paraesthesia and grade II/III nausea/emesis and diarrhoea . Median second-line survival was 4.82 [ 95 % Confidence Interval ; 4.29 - 5.35 ] months for OFF treatment and 2.30 [ 95 % CI ; 1.76 - 2.83 ] months with BSC alone ( 0.45 [ 95 % CI : 0.24 - 0.83 ] , p = 0.008 ) . Median overall survival for the sequence GEM-OFF was 9.09 [ 95 % CI : 6.97 - 11.21 ] and 7.90 [ 95 % CI : 4.95 - 10.84 ] months for GEM-BSC ( 0.50 [ 95 % CI : 0.27 - 0.95 ] , p = 0.031 ) respectively . INTERPRETATION Although stopped prematurely , this r and omized trial provides at first time evidence for the benefit of second-line chemotherapy as compared to BSC alone for patients with APC . OFF significantly prolonged survival time compared to BSC alone after failure of first-line therapy with gemcitabine One hundred ninety‐six patients with advanced pancreatic cancer were r and omized to receive one of two combination chemotherapy programs : FAM ( 5‐fluorouracil , Adriamycin [ doxorubicin ] , mitomycin ) or FSM ( 5‐fluorouracil , streptozotocin , mitomycin ) . Patient characteristics were comparable in both groups . Overall response rates for those with measurable disease ( 14 % on FAM , 4 % on FSM ) were not significantly different ( P = 0.07 ) . There was no significant difference in overall survival between patients treated with FAM and FSM ( median survivals of 26 and 18 weeks , respectively ) . Survival benefits of FAM were significant only for patients with measurable disease . Toxicity of both regimens was acceptable and comparable , aside from greater renal toxicity and more nausea and vomiting with FSM . The results failed to confirm the 35 % to 40 % response rates previously reported for FAM and FSM in advanced pancreatic cancer Three hundred five patients with advanced pancreatic and gastric carcinoma were r and omly assigned to treatment with fluorouracil , fluorouracil plus doxorubicin ( Adriamycin ) ( FA ) , or fluorouracil plus doxorubicin plus mitomycin ( mitomycin C ) ( FAM ) . All regimens were equivalent with regard to patient survival . There is no reasonable likelihood that either the FA or FAM regimen could produce a meaningful survival advantage over fluorouracil alone . Interval to disease progression , objective response rates , and palliative effects ( improved performance , body weight , or symptoms ) were essentially equivalent among the three regimens . With regard to toxicity , the FAM regimen produced more anorexia , nausea , vomiting , leukopenia , thrombocytopenia , and cumulative bone marrow suppression . Fluorouracil alone produced more stomatitis and diarrhea . Because of a failure to produce improved survival or palliation , unrewarded toxicity , and excessive cost , neither the FA nor FAM regimen can be recommended for the treatment of advanced pancreatic or gastric cancer Forty‐three patients with irresectable advanced pancreatic cancer were r and omized to receive chemotherapy using a combination of 5‐fluorouracil , Adriamycin and mitomycin or no chemotherapy . Groups were well matched with regard to age , extent of disease and performance status on entry . Chemotherapy was well tolerated and , although common , side‐effects were usually mild . Psychological measurements based on the Hospital Anxiety and Depression score were made in 31 patients . These showed significantly less depression but not anxiety in the treated group immediately after r and omization and following 2 months of chemotherapy . Median survival in the treated group was 33 ( range 9–80 ) weeks compared with 15 ( range 1–62 ) weeks in the untreated group ( P < 0·002 ) . Chemotherapy should be considered in all patients presenting with advanced inoperable pancreatic cancer PURPOSE The purpose of this study was to evaluate whether external-beam radiotherapy ( EBRT ) with concurrent continuous 5-fluorouracil ( 5-FU ) infusion affects the length and quality of survival in patients with locally unresectable pancreatic cancer . METHODS Thirty-one patients with histologically proven locally advanced and unresectable pancreatic cancer without distant metastases were evaluated in this prospect i ve r and omized trial . Sixteen patients received EBRT ( 50.4 Gy/28 fractions ) with concurrent continuous infusion of 5-FU ( 200 mg/m(2)/day ) , whereas 15 patients received no chemoradiation . The length and quality of survival was analyzed and compared for the two groups . RESULTS The median survival of 13.2 months and the 1-year survival rate of 53.3 % in the chemoradiation group were significantly better than the respective 6.4 months and 0 % in the group without chemoradiotherapy ( p = 0.0009 ) . The average monthly Karnofsky score , a quality of life indicator , was 77.1 in the chemoradiation group , which was significantly higher than the 65.5 in the group without chemoradiotherapy ( p < 0.0001 ) . The number of hospital days per month of survival was significantly less in the chemoradiation than in the no-therapy group ( 12.3 vs. 19.0 days , p < 0.05 ) . In the chemoradiation group , 5 patients ( 31 % ) had a partial response , and 9 ( 56 % ) had radiologically stable disease at a median duration of 6.1 months . The patients who had chemoradiation had a lower rate of liver and peritoneal metastases than patients without chemoradiotherapy ( 31 % vs. 64 % ) . Of 10 patients who experienced pain before chemoradiation , 8 ( 80 % ) received pain relief that lasted a median of 5.2 months . CONCLUSIONS EBRT with concurrent continuous 5-FU infusion increased the length and quality of survival as compared to no chemoradiotherapy and provided a definite palliative benefit for patients with unresectable pancreatic cancer The Southwest Oncology Group has confirmed the superiority of 5-fluorouracil ( 5-FU ) and methyl-CCNU versus 5-FU weekly as treatment for patients with advanced gastrointestinal cancers . The drug combination produced a PR rate of 29.3 % compared to the single-drug arm rate of 10.6 % ; however , the two-drug arm produced much more toxicity . Despite the improved response rate no improvement in survival was observed BACKGROUND Axitinib ( AG-013736 ) is a potent and selective oral inhibitor of vascular endothelial growth factor receptors 1 , 2 , and 3 , which have an important role in pancreatic cancer . The aim of this study was to assess the safety and efficacy of gemcitabine plus axitinib versus gemcitabine alone . METHODS Between January and August , 2006 , 103 patients with unresectable , locally advanced , or metastatic pancreatic cancer were r and omly assigned in a two to one ratio to receive gemcitabine ( 1000 mg/m(2 ) ) plus axitinib 5 mg twice daily ( n=69 ) or gemcitabine ( 1000 mg/m(2 ) ) alone ( n=34 ) by a central ised registration system . The primary endpoint was overall survival . Analyses were done by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00219557 . FINDINGS All r and omised patients were included in the efficacy analyses . Median overall survival was longer with gemcitabine plus axitinib than with gemcitabine alone ( 6.9 [ 95 % CI 5.3 - 10.1 ] months vs 5.6 [ 3.9 - 8.8 ] months ) . The hazard ratio for survival with gemcitabine plus axitinib versus with gemcitabine alone , adjusted for stratification factors , was 0.71 ( 95 % CI 0.44 - 1.13 ) . The most common grade 3 or worse adverse events were fatigue ( 15 [ 22 % ] patients in the gemcitabine plus axitinib group vs one [ 3 % ] in the gemcitabine alone group ) , abdominal pain ( eight [ 12 % ] vs five [ 16 % ] ) , and asthenia ( eight [ 12 % ] vs one [ 3 % ] ) . INTERPRETATION Gemcitabine plus axitinib showed a similar safety profile to gemcitabine alone ; the small , non-statistically significant gain in overall survival needs to be assessed in a r and omised phase III trial BACKGROUND Axitinib is a potent , selective inhibitor of vascular endothelial growth factor ( VEGF ) receptors 1 , 2 , and 3 . A r and omised phase 2 trial of gemcitabine with or without axitinib in advanced pancreatic cancer suggested increased overall survival in axitinib-treated patients . On the basis of these results , we aim ed to assess the effect of treatment with gemcitabine plus axitinib on overall survival in a phase 3 trial . METHODS In this double-blind , placebo-controlled , phase 3 study , eligible patients had metastatic or locally advanced pancreatic adenocarcinoma , no uncontrolled hypertension or venous thrombosis , and Eastern Cooperative Oncology Group performance status 0 or 1 . Patients , stratified by disease extent ( metastatic vs locally advanced ) , were r and omly assigned ( 1:1 ) to receive gemcitabine 1000 mg/m(2 ) intravenously on days 1 , 8 , and 15 every 28 days plus either axitinib or placebo . Axitinib or placebo were administered orally with food at a starting dose of 5 mg twice a day , which could be dose-titrated up to 10 mg twice daily if well tolerated . A central ised r and omisation procedure was used to assign patients to each treatment group , with r and omised permuted blocks within strata . Patients , investigators , and the trial sponsor were masked to treatment assignments . The primary endpoint was overall survival . All efficacy analyses were done in all patients assigned to treatment groups for whom data were available ; safety and treatment administration and compliance assessment s were based on treatment received . This study is registered at Clinical Trials.gov , number NCT00471146 . FINDINGS Between July 27 , 2007 , and Oct 31 , 2008 , 632 patients were enrolled and assigned to treatment groups  ( 316 axitinib , 316 placebo ) . At an interim analysis in January , 2009 , the independent data monitoring committee concluded that the futility boundary had been crossed . Median overall survival was 8·5 months ( 95 % CI 6·9 - 9·5 ) for gemcitabine plus axitinib ( n=314 , data missing for two patients ) and 8·3 months ( 6·9 - 10·3 ) for gemcitabine plus placebo ( n=316 ; hazard ratio 1·014 , 95 % CI 0·786 - 1·309 ; one-sided p=0·5436 ) . The most common grade 3 or higher adverse events  for gemcitabine plus axitinib and gemcitabine plus placebo were hypertension ( 20 [ 7 % ] and 5 [ 2 % ] events , respectively ) , abdominal pain ( 20 [ 7 % ] and 17 [ 6 % ] ) , fatigue ( 27 [ 9 % ] and 21 [ 7 % ] ) , and anorexia ( 19 [ 6 % ] and 11 [ 4 % ] ) . INTERPRETATION The addition of axitinib to gemcitabine does not improve overall survival in advanced pancreatic cancer . These results add to increasing evidence that targeting of VEGF signalling is an ineffective strategy in this disease . FUNDING Pfizer Background : This r and omised phase II trial compared gemcitabine alone vs gemcitabine and S-1 combination therapy in advanced pancreatic cancer . Methods : Patients were r and omly assigned to 4-week treatment with gemcitabine alone ( 1000 , mg m−2 gemcitabine by 30-min infusion on days 1 , 8 , and 15 ) or gemcitabine and S-1 combination therapy ( 1000 , mg m−2 gemcitabine by 30-min infusion on days 1 and 15 and 40 mg m−2 S-1 orally twice daily on days 1–15 ) . The primary end point was progression-free survival ( PFS ) . Results : Between July 2006 and February 2009 , 106 patients were enrolled .  The PFS  in gemcitabine and S-1 combination arm was significantly longer than in gemcitabine arm ( 5.4 vs 3.6 months ) , with a hazard ratio of 0.64 ( P=0.036 ) . Overall survival ( OS ) for gemcitabine and S-1 combination was longer than that for gemcitabine monotherapy ( 13.5 vs 8.8 months ) , with a hazard ratio of 0.72 ( P=0.104 ) . Overall , grade 3 or 4 adverse events were similar in both arms . Conclusion : Gemcitabine and S-1 combination therapy  demonstrated longer PFS in advanced pancreatic cancer . Improved OS duration of 4.7 months was found for gemcitabine and S-1 combination therapy , though this was not statistically significant Background : No st and ard treatment for locally advanced pancreatic cancer ( LAPC ) is defined . Patients and methods Within a multi-centre , r and omised phase II trial , 95 patients with LAPC were assigned to three different chemoradiotherapy ( CRT ) regimens : patients received conventionally fractionated radiotherapy of 50 Gy and were r and omised to concurrent 5-fluorouracil ( 350 mg m−2 per day on each day of radiotherapy , RT-5-FU arm ) , concurrent gemcitabine ( 300 mg m−2 ) , and cisplatin ( 30 mg m−2 ) on days 1 , 8 , 22 , and 29 ( RT-GC arm ) , or the same concurrent treatment followed by sequential full-dose gemcitabine ( 1000 mg m−2 ) and cisplatin ( 50 mg m−2 ) every 2 weeks ( RT-GC+GC arm ) . Primary end point was the overall survival ( OS ) rate after 9 months . Results : The 9-month OS rate was 58 % in the RT-5-FU arm , 52 % in the RT-GC arm , and 45 % in the RT-GC+GC arm . Corresponding median survival times were 9.6 , 9.3 , and 7.3 months ( P=0.61 ) respectively . The intent-to-treat response rate was 19 , 22 , and 13 % respectively . Median progression-free survival was estimated with 4.0 , 5.6 , and 6.0 months ( P=0.21 ) . Grade 3/4 haematological toxicities were more frequent in the two GC-containing arms , no grade 3/4 febrile neutropaenia was observed . Conclusion : None of the three CRT regimens tested met the investigators ' definition for efficacy ; the median OS was similar to those previously reported with gemcitabine alone in LAPC One hundred ninety-one patients with pathologically confirmed , locally unresectable adenocarcinoma of the stomach ( 57 patients ) and pancreas ( 91 patients ) , were r and omly allocated to therapy with 5-fluorouracil ( 5-FU ) alone , 600 mg/m2 intravenously ( IV ) once weekly , or radiation therapy , 4,000 rad , plus adjuvant 5-FU , 600 mg/m2 IV , the first three days of radiotherapy , then follow-up maintenance 5-FU , 600 mg/m2 , weekly . Forty-three patients ( 22 % ) could not be analyzed because of in eligibility or cancellation , thus 148 patients were evaluable . The median survival time was similar for both treatment programs and for both types of primary carcinoma , and was as follows : gastric primary carcinoma , 5-FU , 9.3 months ; 5-FU plus radiotherapy , 8.2 months ; pancreatic primary carcinoma , 5-FU , 8.2 months ; 5-FU plus radiotherapy , 8.3 months . Substantially more toxicity was experienced by patients treated with the combined modality arm than by those patients receiving 5-FU alone . Severe or worse toxicity experienced by patients with gastric primary carcinoma treated by 5-FU was 19 % , and the combined modality arm was 31 % . The toxicity experienced by patients with pancreatic primary carcinoma treated with 5-FU was 27 % , and the combined modality arm was 51 % . Significant prognostic variables included : weight loss in stomach-cancer patients ; and performance status , degree of anaplasia , and reduced appetite in pancreas-cancer patients Background To explore possible improvement in the treatment of locally advanced pancreatic carcinoma ( LAPC ) we performed a r and omized , non-comparative phase II study evaluating docetaxel - plus either daily continuous 5 FU or weekly cisplatin concurrent to radiotherapy . We report here the results of the docetaxel plus 5 FU regimen stopped according to the interim analysis . The docetaxel plus cisplatin arm was continued . Methods Forty ( 40 ) chemotherapy-naive patients with unresectable LAPC were r and omly assigned ( 1:1 ) to either continuous fluorouracil ( 5-FU ) 200 mg/m2/day ( protracted IV ) and docetaxel ( DCT ) 20 mg/m2/week or DCT 20 mg/m2 and cisplatin ( CDDP ) 20 mg/m2 , plus concurrent radiotherapy for a period of 6 weeks . The radiation dose to the primary tumor was 54 Gy in 30 fractions . The trial 's primary endpoint was the 6-month crude non-progression rate ( NPR ) . Secondary endpoints were tolerance , objective response rate , and overall survival . Accrual was to be stopped if at 6 months more than 13 disease progressions were observed in 20 patients . Results Eighteen ( 18 ) progressions occurred at 6 months in the 5-FU-DCT arm . Six-month NPR was 10 % ( 95%CI : 0 - 23 ) . Six and 12-month survivals were 85 % ( 95%CI : 64 - 95 ) and 40 % ( 95%CI : 22 - 61 ) ; median overall survival was 10.1 months . Median progression-free survival was 4.3 months . We report the case of one patient who was amenable to surgery and has been in complete response ( CR ) for 5.5 years . Toxicities grade ≥ 3 were reported in 75 % of patients ; no treatment-related death occurred . Severe toxicities were mainly vomiting ( 35 % ) , abdominal pain ( 10 % ) and fatigue ( 10 % ) . Conclusions Combination of 5-FU , docetaxel and radiotherapy has inadequate efficacy in the treatment of LAPC despite good tolerance for the 5-FU-DCT regimen . Trial Registration Clinical Trials.gov : There is no established second-line treatment for advanced pancreatic cancer after gemcitabine failure . In view of the urgent need for such therapy , and since pre clinical and phase I clinical data suggest an encouraging , potentially synergistic activity between raltitrexed and irinotecan , the present r and omised phase II study was initiated . A total of 38 patients with metastatic pancreatic adenocarcinoma , who progressed while receiving or within 6 months after discontinuation of palliative first-line chemotherapy with gemcitabine , were enrolled in this study . They were r and omised to 3-weekly courses of raltitrexed 3 mg m−2 on day 1 ( arm A ) or irinotecan 200 mg m−2 on day 1 plus raltitrexed 3 mg m−2 on day 2 ( arm B ) . The primary study end point was objective response , secondary end points included progression-free survival ( PFS ) and overall survival ( OS ) , as well as clinical benefit response in symptomatic patients ( n=28 ) . In the combination arm , the IRC-confirmed objective response rate was 16 % ( three out of 19 patients had a partial remission ; 95 % CI , 3–40 % ) , which was clearly superior to that in the comparator/control arm with raltitrexed alone , in which no response was obtained . Therefore , the trial was already stopped at the first stage of accrual . Also , the secondary study end points , median PFS ( 2.5 vs 4.0 months ) , OS ( 4.3 vs 6.5 months ) , and clinical benefit response ( 8 vs 29 % ) were superior in the combination arm . The objective and subjective benefits of raltitrexed+irinotecan were not negated by severe , clinical ly relevant treatment-related toxicities : gastrointestinal symptoms ( 42 vs 68 % ) , partial alopecia ( 0 vs 42 % ) , and cholinergic syndrome ( 0 vs 21 % ) were more commonly noted in arm B ; however , grade 3 adverse events occurred in only three patients in both treatment groups . Our data indicate that combined raltitrexed+irinotecan seems to be an effective salvage regimen in patients with gemcitabine-pretreated pancreatic cancer . The superior response activity , PFS and OS ( when compared to raltitrexed ) , as well as its tolerability and ease of administration suggest that future trials with this combination are warranted Objective To analyze the efficacy of gemcitabine with or without erlotinib for pancreatic cancer , and to determine the predictive role of epidermal growth factor receptor ( EGFR ) and KRAS mutations in these patients . Methods This was a single-center , r and omized , open-label , prospect i ve trial . Eighty-eight chemotherapy-naïve metastatic pancreatic cancer patients were r and omized for treatment with gemcitabine or gemcitabine plus erlotinib . EGFR and KRAS mutations were analyzed , respectively . The primary endpoint was the disease control rate . Results Disease control rate ( 64 % vs. 25 % ; P < 0.001 ) , progression-free survival ( median 3.8 vs. 2.4 months ; P < 0.001 ) , and overall survival ( median 7.2 vs. 4.4 months ; P < 0.001 ) were better in the gemcitabine plus erlotinib group than in the gemcitabine alone group . In the gemcitabine plus erlotinib group , disease control ( 85 % vs. 33 % ; P = 0.001 ) , progression-free survival ( median 5.9 vs. 2.4 months ; P = 0.004 ) , and overall survival ( median 8.7 vs. 6.0 months ; P = 0.044 ) were better in patients with EGFR mutations than in those without EGFR mutations . KRAS mutation was not associated with treatment response or survival . Conclusions Gemcitabine plus erlotinib is more effective than gemcitabine alone for treating metastatic pancreatic cancer patients , especially those with EGFR mutations . Clinical Trials.gov number , NCT01608841 Studies have shown that cancer requires two conditions for tumor progression : cancer cell proliferation and an environment permissive to and conditioned by malignancy . Chemotherapy aims to control the number and proliferation of cancer cells , but it does not effectively control the two best-known conditions of the tumor-permissive environment : neoangiogenesis and tolerogenic immunity . Many malignant diseases exhibit poor outcomes after treatment with chemotherapy . Therefore , we investigated the potential benefits of adding an induction regimen of antiangiogenesis and antitumor immunity to chemotherapy in poor outcome disease . In a prospect i ve , r and omized trial , we included patients with advanced , unresectable pancreatic adenocarcinomas , non-small cell lung cancer , or prostate cancer . Two groups of each primary condition were compared : group 1 ( G1 ) , n = 30 , was treated with the st and ard chemotherapy and used as a control , and group 2 ( G2 ) , n = 30 , was treated with chemotherapy plus an induction regimen of antiangiogenesis and antitumor immunity . This induction regimen included a low dose of metronomic cyclophosphamide , a high dose of Cox-2 inhibitor , granulocyte colony-stimulating factor , a sulfhydryl ( SH ) donor , and a hemoderivative that contained autologous tumor antigens released from patient tumors into the blood . After treatment , the G2 group demonstrated significantly longer survival , lower blood level of neoangiogenesis and immune-tolerance mediators , and higher blood levels of antiangiogenesis and antitumor immunity mediators compared with the G1 group . Toxicity and quality of life were not significantly different between the groups . In conclusion , in several advanced malignancies of different primary localizations , an increase in survival was observed by adding an induction regimen of antiangiogenesis and antitumor immunity to st and ard chemotherapy Background : An intravenous formulated extract of the venom of the wild toad Bufo bufo gargarizans Cantor or Bufo melanostictus Schneider , huachansu , is currently used in China for the treatment of lung , liver , pancreatic , and colorectal cancers . We performed a r and omised , single-blinded , phase II clinical study of huachansu plus gemcitabine versus placebo plus gemcitabine in patients with locally advanced and /or metastatic pancreatic adenocarcinomas . Methods : Patients with tissue-proven locally advanced and /or metastatic pancreatic adenocarinoma were r and omly assigned to receive either gemcitabine 1000 mg m−2 on days 1 , 8 , and 15 with huachansu 20 ml m−2 daily for 21 days ( arm A ) or placebo ( arm B ) ; treatment cycles were 28 days in length . Primary end point was 4-month progression-free overall survival ( PFS ) ; secondary end points were objective radiographical response rate ( ORR ) , time to progression ( TTP ) , and toxicity . Results : A total of 80 subjects were enrolled ; 76 patients were evaluable ( received at least 1 week therapy ) . Median overall survival was 160 days for arm A and 156 days for arm B ( P=0.339 ) ; ORR was 9 and 3 % in arms A and B , respectively ( P=0.332 ) , median TTP was 98 and 115 days , respectively ( P=0.825 ) ; the median 4-month PFS was 99 and 98 days , respectively ( P=0.679 ) . Conclusion : Huachansu when combined with gemcitabine did not improve the outcome of patients with locally advanced and /or metastatic pancreatic cancer BACKGROUND / AIMS This paper presents the results of a prospect i ve r and omized study of targeting locoregional chemotherapy and targeting locoregional immunostimulation therapy implemented in 36 , out of 66 , patients with a histological diagnosis of pancreatic duct carcinoma seen by our group from 1991 to Sept. 1994 . METHOD AND MATERIAL S Sixty-six patients with unresectable pancreatic duct carcinoma were separated into two groups . The first group received laparotomy ( n = 30 ) , with palliative gastric bypass ( n = 8) or with palliative biliary bypass ( n = 18 ) . The second group received laparotomy ( n = 36 ) , with palliative gastric bypass ( n = 9 ) or with palliative biliary bypass ( n = 20 ) , supplemented with locoregional immunostimulation and locoregional chemotherapy . This therapy consisted of ten days of infusion with Proleukin ( IL2 ) and Imukin ( gamma-IFN ) , emulsified in Lipidiol-Urographin . This infusion was performed five days trans-splenically and five days trans-tumorally . Fifteen days later , targeting locoregional chemotherapy was administered , again emulsified in Lipidiol-Urographin . RESULTS All the patients in the first group are dead , with a mean survival of 4.5 months , as of November 1995 . Presently , 47 % ( n = 17 ) of the second group have achieved a positive objective response , with a mean survival of 14.1 months . During re-exploration , eight patients became tumor free after pancreatic resection , which became feasible after our therapy and six are alive and have remained tumor free to date . CONCLUSION Targeting locoregional immunotherapy , combined with locoregional chemotherapy appears to be a promising therapy , meriting further consideration for clinical application in patients with unresectable pancreatic ductal carcinoma PURPOSE To compare clinical benefit response ( CBR ) and quality of life ( QOL ) in patients receiving gemcitabine ( Gem ) plus capecitabine ( Cap ) versus  single-agent Gem for advanced/metastatic pancreatic cancer . PATIENTS AND METHODS Patients were r and omly assigned to receive GemCap ( oral Cap 650 mg/m(2 ) twice daily on days 1 through 14 plus Gem 1,000 mg/m(2 ) in a 30-minute infusion on days 1 and 8 every 3 weeks ) or Gem ( 1,000 mg/m(2 ) in a 30-minute infusion weekly for 7 weeks , followed by a 1-week break , and then weekly for 3 weeks every 4 weeks ) for 24 weeks or until progression . CBR criteria and QOL indicators were assessed over this period . CBR was defined as improvement from baseline for > or= 4 consecutive weeks in pain ( pain intensity or analgesic consumption ) and Karnofsky performance status , stability in one but improvement in the other , or stability in pain and performance status but improvement in weight . RESULTS Of 319 patients , 19 % treated with GemCap and 20 % treated with Gem experienced a CBR , with a median duration of 9.5 and 6.5 weeks , respectively ( P < .02 ) ; 54 % of patients treated with GemCap and 60 % treated with Gem had no CBR ( remaining patients were not assessable ) . There was no treatment difference in QOL ( n = 311 ) . QOL indicators were improving under chemotherapy ( P < .05 ) . These changes differed by the time to failure , with a worsening 1 to 2 months before treatment failure ( all P < .05 ) . CONCLUSION There is no indication of a difference in CBR or QOL between GemCap and Gem . Regardless of their initial condition , some patients experience an improvement in QOL on chemotherapy , followed by a worsening before treatment failure OBJECTIVE To observe the effects ot Guben Yiliu II ( GY II ) combined with arterial perfusion with chemotherapeutic agent on advanced pancreatic cancer ( APC ) . METHODS Sixty-five APC patients were r and omly assigned to the treated group ( 35 cases ) given GY II and arterial perfusion with chemotherapeutic agent and the control group ( 30 cases ) with chemotherapeutic agent alone . RESULTS The clinical beneficial rate was 54.2 % in the treated group and 40.0 % in the control group , with significant difference between them ( P < 0.05 ) , the overall effective rate being 17.1 % and 13.3 % , and the effective rate in relieving pain being 64.5 % and 59.2 % in the treated and the control group respectively , all showed insignificant difference between groups ( P > 0.05 ) . Furthermore , in the treated group after treatment , the blood hypercoagulation state ameliorated , cellular immunity elevated , the toxic and side- effects of chemical medicine relieved , and the quality of life improved . CONCLUSION GY II is effective in enhancing clinical effects and relieving toxic and side-effects of chemotherapy , and so , better efficacy could be obtained by therapy of GY II and arterial perfusion with chemotherapeutic agent for treatment of APC To evaluate the safety and efficacy of infliximab administered with gemcitabine to treat cancer cachexia and to explore a functional measure of clinical benefit , investigators involved in this multicenter , phase II ,  placebo-controlled study r and omized 89 patients with stage II-IV pancreatic cancer and cachexia to receive either placebo or 3 mg/ kg or 5 mg/kg of infliximab at weeks 0 , 2 , and 4 and then every 4 weeks to week 24 ; patients also received 1,000 mg/m2 of gemcitabine weekly from weeks 0 - 6 and then for 3 of every 4 weeks until their disease progressed . The primary endpoint was change in lean body mass ( LBM ) at 8 weeks from baseline ; major secondary endpoints included overall survival , progression-free survival , Karnofsky performance status , and 6-minute walk test distance . In addition , quality of life was measured . The mean change in LBM at 8 weeks was + 0.4 kg for patients receiving placebo , + 0.3 kg for those receiving 3 mg/kg of infliximab , and + 1.7 kg for those receiving 5 mg/kg of infliximab . No statistically significant differences in LBM or secondary endpoints were observed among the groups . Safety findings were similar in all groups . Adding infliximab to gemcitabine to treat cachexia in advanced pancreatic cancer patients was not associated with statistically significant differences in safety or efficacy when compared with placebo PURPOSE The purpose of this trial was to evaluate the role of radiation therapy with concurrent gemcitabine ( GEM ) compared with GEM alone in patients with localized unresectable pancreatic cancer . PATIENTS AND METHODS Patients with localized unresectable adenocarcinoma of the pancreas were r and omly assigned to receive GEM alone ( at 1,000 mg/m(2)/wk for weeks 1 to 6 , followed by 1 week rest , then for 3 of 4 weeks ) or GEM ( 600 mg/m(2)/wk for weeks 1 to 5 , then 4 weeks later 1,000 mg/m(2 ) for 3 of 4 weeks ) plus radiotherapy ( starting on day 1 , 1.8 Gy/Fx for total of 50.4 Gy ) . Measurement of quality of life using the Functional Assessment of Cancer Therapy-Hepatobiliary question naire was also performed . RESULTS Of 74 patients entered on trial and r and omly assigned to receive GEM alone ( arm A ; n = 37 ) or GEM plus radiation ( arm B ; n = 34 ) , patients in arm B had greater incidence of grade s 4 and 5 toxicities ( 41 % v 9 % ) , but grade s 3 and 4 toxicities combined were similar ( 77 % in A v 79 % in B ) . No statistical differences were seen in quality of life measurements at 6 , 15 to 16 , and 36 weeks . The primary end point was survival , which was 9.2 months ( 95 % CI , 7.9 to 11.4 months ) and 11.1 months ( 95 % CI , 7.6 to 15.5 months ) for arms A and B , respectively ( one-sided P = .017 by stratified log-rank test ) . CONCLUSION This trial demonstrates improved overall survival with the addition of radiation therapy to GEM in patients with localized unresectable pancreatic cancer , with acceptable toxicity Combined chemotherapy with 5-FU and BCNU was compared with placebo in a triple-blind , r and omized study of 40 patients with pancreatic adenocarcinoma . There were no significant differences between the groups with regard to survival , tumor size , or quality of life OBJECTIVES Evaluate the effect of an implanted percutaneous left subclavian artery port-catheter drug delivery system for regional chemotherapy of inoperable pancreatic carcinoma . METHODS One hundred and forty patients with inoperable pancreatic carcinoma were enrolled and r and omized into two groups to receive the FAM regimen on a 6-day cycle at 1-month intervals : 70 patients in the regional interventional chemotherapy group in which treatment was infused directly into the common hepatic artery , and 70 patients who received the same chemotherapy regimen via the peripheral vein . RESULT In the interventional chemotherapy group , there were 5 cases of complete remission ( CR ) and 49 cases of partial remission ( PR ) , giving a response rate ( CR+PR ) of 77.1 % ; pain control was effective in 95.7 % cases ; survival time was 3 - 34 months ( median 13.5 ) . There was no case of CR in the systemic chemotherapy group , and 25 cases of PR , giving a response rate of 35.7 % ; pain control was effective in 35.7 % , and survival time was 1 - 13 months ( median 6.2 ) . The differences between the two groups in response rate and survival were statistically significant ( P < 0.005 ) . Nausea and vomiting occurred in 48.6 % of the interventional chemotherapy group and 41.3 % of the systemic chemotherapy group ( NS ) . There were three cases of serious myelosuppression in the systemic chemotherapy group and one case died . There was a significant difference between the two groups in white blood cell count after the chemotherapy , indicating that the myelosuppressive effect was serious in the systemic chemotherapy group . CONCLUSION Interventional arterial infusion chemotherapy could significantly improve quality of life and prolong the survival of patients with inoperable pancreatic carcinoma Forty-seven patients with unoperable pancreatic cancer were included in a controlled , prospect i ve study of combination chemotherapy . Twenty-five of the patients were allocated to cyclic treatment with 5-fluorouracil , CCNU , and vincristine in accordance with a special schedule . The other 22 patients served as untreated controls .  There were no differences between the two groups with regard to survival time or quality of life . Side effects of the drugs given were common in the treatment group 4005 Background : Ensiv ( Exatecan ) is a novel hexacyclic , water-soluble , topoisomerase-1 inhibitor . Ensiv has single-agent and combination activity with Gem in APC ( D'Adamo , et al. ProcASCO , 2001 ; O'Reilly , et al. ProcASCO , 2002 ) . METHODS A multi-centre r and omised phase III trial comparing Ensiv with gemcitabine in APC has been completed . Eligibility included KPS ≥ 60 % ; locally advanced or metastatic disease ; no prior chemotherapy . Patients ( pts ) were r and omised in a 1:1 ratio to Ensiv ( 0.5 mg/m2 daily x 5 q3w ) or gemcitabine ( 1000 mg/m2 weekly x 7 then 1 week rest , then weekly x 3 q4w ) . Treatment continued until disease progression or  intolerable toxicity . Primary endpoint was overall survival ( OS ) . Study was powered to demonstrate a 50 % increase in OS from 5.1 to 7.65 months . Analysis will be conducted based on 263 events ( deaths ) having occurred . An independent data safety monitoring board monitored the trial . RESULTS Altogether , an Intent To Treat ( ITT ) population of 339 pts ( Ensiv 169 , Gem 170 ) were r and omised at 67 sites between July 2001 and Jan 2003 . Of these 330 ( 165 Ensiv ; 165 Gem ) received treatment . Demographic factors were well balanced for age , sex , PS and disease extent . In the ITT population for Ensiv 139 pts died and 30 were censored ( gem 137 ; 33 ) at data cut-off following the 263 event ocurrence as prescribed in the statistical analysis plan . Survival : Median Survival Times ( MST ) were Ensiv 151 days ; Gem 197 days ) , 6-month Survival rates Ensiv 44.1 % ; Gem 51.1 % , and 12-month Survival rates Ensiv 17.9 % ; Gem 22.1 % . Response rates seen were : Ensiv 0CR , 1PR , 75 SD ; Gem 3CR , 10PR , 78 SD . Median Time to Tumor Progression ( TTP ) was ; Ensiv 85 days ; Gem 132 days . Gem was superior to Ensiv in both weight loss and pain worsening ( weight loss ; Ensiv 69 days vs Gem 114 days ; pain VAS ; 112 days vs 236 days ; analgesic consumption increase ; 69 days vs 114 days ) as well as in QOL evaluation . Treatment emergent toxicities are tabulated below : Conclusions : Single agent Ensiv did not show the expected increase in survival or clinical benefit over gemcitabine in this study [ Figure : see text ] [ Table : see text ] Purpose The aim of this study was to evaluate efficacy and safety of gemcitabine plus S-1 ( GS ) combination chemotherapy in patients with unresectable pancreatic cancer . Methods Patients were r and omly assigned to receive GS ( oral S-1 60 mg/m2 daily on days 1–15 every 3 weeks and gemcitabine 1,000 mg/m2 on days 8 and 15 ) or gemcitabine ( 1,000 mg/m2 on days 1 , 8 , and 15 every 4 weeks ) . The primary endpoint was progression-free survival ( PFS ) . Results One hundred and one patients were r and omly assigned . PFS was significantly longer in the GS arm with an estimated hazard ratio ( HR ) of 0.65 ( 95 % CI 0.43–0.98 ; P = 0.039 ; median 5.3 vs 3.8 months ) . Objective response rate ( ORR ) was also better in the GS arm ( 21.6 vs 6 % , P = 0.048 ) . Median survival was 8.6 months for GS and 8.6 months for GEM ( HR 0.93 ; 95 % CI 0.61–1.41 ; P = 0.714 ) . Grade 3–4 neutropenia ( 44 vs 19.6 % , P = 0.011 ) and thrombocytopenia ( 26 vs 8.7 % , P = 0.051 ) were more frequent in the GS arm . Conclusions GS therapy improved PFS and ORR with acceptable toxicity profile in patients with unresectable pancreatic cancer Background : NSC-631570 ( Ukrain ) is a semisynthetic compound of thiophosphoric acid and the alkaloid chelidonine from the plant Chelidonium majus . It has been used in complementary herbal medicine for more than 20 years for the treatment of benign and malignant tumors . Patients / methods : Between August 1999 and June 2001 , 90 patients with histologically proven unresectable pancreatic cancer were r and omized in a monocentric , controlled , r and omized study . Patients in arm A received 1000 mg gemcitabine/m2 , those in arm B received 20 mg NSC-631570 , and those in arm C received 1000 mg gemcitabine/m2 followed by 20 mg NSC-631570 weekly . End point of the study was overall survival . Results : In all three arms therapy was well tolerated and toxicity was moderate . At the first re-evaluation in arm A 32 % , in arm B 75 % , and in arm C 82 % showed no change or partial remission according to WHO criteria ( arm A versus arm B : P<0.01 , arm A versus arm C : P<0.001 ) . Median survival according to Kaplan-Meier analysis was in arm A 5.2 months , in arm B 7.9 months , and in arm C 10.4 months ( arm A versus arm B : P<0.01 , arm A versus arm C : P<0.01 ) . Actuarial survival rates after 6 months were 26 % , 65 % and 74 % in arms A B and C , respectively ( arm A versus arm B : P<0.05 , arm A versus arm C P<0.01 ) . Conclusion : We could show that in unresectable advanced pancreatic cancer , NSC-631570 alone and in combination with gemcitabine nearly doubled the median survival times in patients suffering from advanced pancreatic cancer Background : This phase III trial compared the efficacy and safety of gemcitabine plus capecitabine ( GemCap ) versus single-agent gemcitabine ( Gem ) in advanced pancreatic cancer as first-line chemotherapy . Methods : A total of 214 advanced pancreatic cancer patients were enrolled from 16 hospitals in South Korea between 2007 and 2011 . Patients were r and omly assigned to receive GemCap ( oral capecitabine 1660 mg/m2 plus Gem 1000 mg/m2 by 30-minute intravenous infusion weekly for 3 weeks followed by a 1-week break every 4 weeks ) or Gem ( by 30-minute intravenous infusion weekly for 3 weeks every 4 weeks ) . Results : Median overall survival ( OS ) time , the primary end point , was 10.3 and 7.5 months in the GemCap and Gem arms , respectively ( P = 0.06 ) . Progression-free survival was 6.2 and 5.3 months in the GemCap and Gem arms , respectively ( P = 0.08 ) . GemCap significantly improved overall response rate compared with Gem alone ( 43.7 % vs 17.6 % ; P = 0.001 ) . Overall frequency of grade 3 or 4 toxicities was similar in each group . Neutropenia was the most frequent grade 3 or 4 toxicity in both groups . Conclusion : GemCap failed to improve OS at a statistically significant level compared to Gem treatment . This study showed a trend toward improved OS compared to Gem alone . GemCap and Gem both exhibited similar safety profiles A prospect ively r and omized trial in advanced gastric and pancreatic carcinoma compared multi-drug chemotherapy , with and without radiotherapy to the local lesion , in terms of median survival and toxicity . Of 29 patients with gastric adenocarcinoma , 14 were r and omized to receive 5-FU and Methyl-CCNU , and 15 to receive 5-FU and local radiotherapy to a dose of 4600 rad , and then Methyl-CCNU .  Thirty patients with advanced adenocarcinoma of the pancreas were similarly r and omized . There was no significant difference between the two arms of the gastric or pancreatic adenocarcinoma groups , with a median survival of 13 months and 11.5 months respectively in gastric carcinoma , and 7.8 months and 7.3 months in pancreatic carcinoma . Complications were minimal in both groups . There was more hematopoietic depression in the radiation-treated patients , but none had radiotherapy discontinued because of toxicity One‐hundred‐ninety‐four eligible and evaluable patients with histologically confirmed locally unresectable adenocarcinoma of the pancreas were r and omly assigned to therapy with high‐dose ( 6000 rads ) radiation therapy alone , to moderate‐dose ( 4000 rads ) radiation + 5‐fluorouracil ( 5‐FU ) , and to high‐dose radiation plus 5‐FU .  Median survival with radiation alone was only 51/2 months from date of diagnosis . Both 5‐FU‐containing treatment regimens produced a highly significant survival improvement when compared with radiation alone . Forty percent of patients treated with the combined regimens were still living at one year compared with 10 % of patients treated with radiation only . Survival differences between 4000 rads plus 5‐FU and 6000 rads plus 5‐FU were not significant with an overall median survival of ten months . Significant prognostic variables , in addition to treatment , were pretreatment performance status and pretreatment CEA level Thirty evaluable patients with advanced carcinoma of the pancreas received treatment with either daily x 5 bolus or continuous infusion x 5 days recombinant gamma-interferon . No responses were noted . Major toxicities included fever , hypotension , and flu-like symptoms .  gamma-Interferon does not appear to be an active single agent for patients with advanced pancreatic cancer PURPOSE The combination of gemcitabine plus bevacizumab produced a 21 % response rate and a median survival of 8.8 months in a multicenter phase II trial in patients with metastatic pancreatic cancer . These encouraging data led Cancer and Leukemia Group B ( CALGB ) to conduct a double-blind , placebo-controlled , r and omized phase III trial of gemcitabine/bevacizumab versus gemcitabine/placebo in advanced pancreatic cancer patients . PATIENTS AND METHODS Eligible patients had no prior therapy for advanced disease , Eastern Cooperative Oncology Group ( ECOG ) performance status 0 to 2 , no tumor invasion of adjacent organs , and no increased bleeding risk . The primary end point was overall survival . Patients were stratified by performance status , extent of disease , and prior radiotherapy . Patients received gemcitabine at 1,000 mg/m(2 ) over 30 minutes on days 1 , 8 , and 15 every 28 days and bevacizumab at 10 mg/kg or placebo on days 1 and 15 every 28 days . RESULTS Between June 2004 and April 2006 , 602 patients were enrolled onto the study and 535 were treated .  Median overall survival was 5.8 months for gemcitabine/bevacizumab and 5.9 months for gemcitabine/placebo ( P = .95 ) . Median progression-free survival was 3.8 and 2.9 months , respectively ( P = .07 ) . Overall response rates were 13 % and 10 % , respectively . Patients with a performance status of 0 , 1 , and 2 survived a median of 7.9 , 4.8 , and 2.4 months , respectively . The only statistically significant differences in grade s 3 and 4 toxicity occurred for hypertension ( 10 % v 3 % ; P < .001 ) and proteinuria ( 5 % v 1 % ; P = .002 ) ; venous thrombosis grade > or = 3 was equivalent in both arms ( 14 % and 15 % , respectively ) . CONCLUSION The addition of bevacizumab to gemcitabine does not improve survival in advanced pancreatic cancer patients Imatinib targets KIT and platelet-derived growth factor receptors ( PDGFR ) and is highly effective in the treatment of CML and GIST patients . Pancreatic cancers express KIT and PDGFRs . Therefore , 26 patients with unresectable pancreatic cancer were r and omized to either gemcitabine ( 1000 mg/m2 weekly ) or imatinib ( 2x400 mg po ) treatment daily . Pancreatic adenocarcinoma was confirmed histologically and expression of KIT and PDGFRbeta was determined immunohistochemically in the biopsy specimens . Quality of life was assessed with two st and ard question naires . No objective responses were seen in either group . Median time to progression was 77 and 29 days ( P=0.411 ) and median survival time was 140 and 60 days ( P=0.517 ) for gemcitabine and imatinib , respectively . Survival and treatment responses were independent of KIT and PDGFRbeta expression in patients treated with imatinib .  Grade 3/4 toxicities of imatinib treatment were anemia , elevated liver enzymes , vomiting , and dyspnea . Patients treated with imatinib  reported diarrhoea and /or altered bowel function more frequently , which were treatable symptomatically . Quality of life was similar in both groups . In this small series of pancreatic cancer patients , treatment with imatinib was not associated with a significant control of cancer progression The aim of this research was to study the pharmacokinetic characteristics of a slow-release 5-fluorouracil implant as well as to evaluate the clinical drug activity of this preparation in pancreatic cancer patients . Pharmacokinetic characteristics of the slow-release 5-fluorouracil implant were evaluated by examining the half-life time ( T1/2 ) and apparent volume of distribution ( Vd ) in pancreatic cancer patients ; the slow-release 5-fluorouracil implant was administered through interstitial chemotherapy ( tumor interstitium implantation ) . In the drug activity study , 36 locally advanced unresectable pancreatic cancer patients were divided r and omly into an experimental treatment group ( n=18 ) and a st and ard treatment group ( n=18 ) . The experimental treatment group was treated with interstitial chemotherapy of a slow-release 5-fluorouracil implant combined with systemic chemotherapy of gemcitabine ; the st and ard treatment group was treated with systemic chemotherapy of gemcitabine . An internal drainage procedure was used when biliary and /or gastrointestinal tract obstruction occurred in the two groups . Clinical benefit response , including pain ( visual analogue scale ) , analgesic drug use , general conditions ( Karnofsky performance score ) , weight changes , and survival status , was observed . T1/2 of the slow-release 5-fluorouracil implant was 5475.8±136.4 min , whereas Vd was 45275.0±1028.6 l. Clinical benefit response in the experimental treatment group was better than that in the st and ard treatment group . The experimental treatment group had longer median survival time compared with the st and ard treatment group . The slow-release 5-fluorouracil implant could deliver drugs mainly in the regional area of the tumor and prolong the drug action time  ; interstitial chemotherapy of a 5-fluorouracil implant combined with systemic chemotherapy of gemcitabine could improve the quality of life and survival status of pancreatic cancer patients . The method was promising and worthy of in-depth investigations Gemcitabine is considered the gold st and ard treatment for unresectable pancreatic adenocarcinoma . Intra-arterial drug administration had shown some interesting results in small phase II studies . In this study , patients were r and omly assigned to receive gemcitabine at a dose of 1,000 mg/m2 over 30 minutes intravenously weekly for 7 weeks , followed by 1 week of rest , then weekly for 3 weeks every 4 weeks or FLEC : 5-fluoruracil 1,000 mg/m2 , leucovorin 100 mg/m2 , epirubicin 60 mg/m2 , carboplatin 300 mg/m2 infused bolus intra-arterially into celiac axis at a 3-week interval 3 times or 5-fluorouracil 400 mg/m2 plus folinic acid 20 mg/m2 for 5 days every 4 weeks for 6 cycles . The primary endpoint was overall survival , while time to treatment failure , response rate , clinical benefit response were secondary endpoints . Sixty-seven patients were r and omly allocated gemcitabine  and 71 were allocated  FLEC  intra-arterially . Patients treated with FLEC lived for significantly longer than patients on gemcitabine ( p=0.036 ) . Survival at 1 year increased from 21 % in the gemcitabine group to 35 % in the FLEC group . Median survival was 7.9 months in the FLEC group and 5.8 months in the gemcitabine group . Median time to treatment failure was longer with FLEC ( 5.3 vs 4.2 months for FLEC vs gemcitabine respectively ; p=0.013 ) . Clinical benefit was similar in both groups ( 17.9 % for gemcitabine and 26.7 % for FLEC ; p = NS ) . CT-scan partial response was similar in both groups ( 5.9 % for gemcitabine and 14 % for FLEC ; p = NS ) . Toxicity profiles were different . Compared with gemcitabine , the FLEC regimen given intra-arterially improved survival in patients with unresectable pancreatic adenocarcinoma PURPOSE Gemcitabine is generally considered to constitute first-line therapy for pancreatic cancer . To determine whether the addition of fluorouracil ( 5-FU ) improves on the results from single-agent gemcitabine , the Eastern Cooperative Oncology Group ( ECOG ) compared gemcitabine plus bolus 5-FU with gemcitabine alone for patients with advanced pancreatic carcinoma . PATIENTS AND METHODS This trial involved patients with biopsy-proven , advanced carcinoma of the pancreas not amenable to surgical resection . Patients were r and omized to receive either gemcitabine alone ( 1,000 mg/m(2)/wk ) weekly for 3 weeks of every 4 or to receive gemcitabine ( 1,000 mg/m(2)/wk ) followed by 5-FU ( 600 mg/m(2)/wk ) weekly on the same schedule . The primary end point of the trial was survival , with secondary end points of time to progression and response rate . RESULTS Of 327 patients enrolled over 18 months , 322 were eligible . Overall , the median survival was 5.4 months for gemcitabine alone and 6.7 months for gemcitabine plus 5-FU ( P = .09 ) . Progression-free survival for gemcitabine alone was 2.2 months , compared with 3.4 months for gemcitabine plus 5-FU ( P = .022 ) . Objective responses were uncommon and were observed in only 5.6 % of patients treated with gemcitabine and 6.9 % of patients treated with gemcitabine plus 5-FU . Most toxicities were hematologic or gastrointestinal ; no significant differences were noted between the two treatment arms . CONCLUSION 5-FU , administered in conjunction with gemcitabine , did not improve the median survival of patients with advanced pancreatic carcinoma compared with single-agent gemcitabine . Further studies with other combinations of gemcitabine and 5-FU are not compelling , and clinical trial re sources should address other combinations and novel agents A multicenter cooperative study was conducted to compare the clinical efficacy of UFT-M ( UFT , Mitomycin C ( MMC ) ) and UFT-D ( UFT , Doxorubicin ( DXR ) ) . A total of 62 cases with adenocarcinoma were enrolled in this study . Eligible cases included 25 patients with gastric cancer , 22 with pancreas or biliary tract cancer and 10 with other cancers . They were divided into two groups ; 30 in UFT-M and 27 in UFT-D. The treatment schedules were as follows : UFT 400 - 600 mg/day orally every day , MMC 4 - 6 mg/m2 , IV , every week ( UFT-M ) ; UFT 400 - 600 mg/day orally every day , DXR 20 mg/m2 , IV , every 3 weeks ( UFT-D ) . For gastric cancer , 3 of 17 cases treated by UFT-M showed PR , whereas no case showed PR in UFT-D. As for toxicity , bone marrow suppression was more commonly observed in UFT-M than in UFT-D. There was no statistical difference in survival between the two treatment regimens . These results suggested that UFT-D was not effective but UFT-M was a more promising combination therapy against advanced gastric cancer Forty-nine patients with locally advanced carcinoma of the pancreas were treated in a r and omized , prospect i ve study comparing definitive helium ion radiation therapy with conventional split-course megavoltage photon irradiation . Patients in each treatment arm underwent exploratory staging laparotomy followed by concurrent radiation therapy and 5-fluorouracil chemotherapy . Patients treated with photons received 6,000 cGy over a period of 10 weeks ; patients treated with helium irradiation received a 6,000 - 7,000-cGy-equivalent dose over a period of 8 - 9 weeks . There was no significant difference in overall survival between patients in the two treatment arms ( P = .29 ) . Patients treated with helium ions had a slightly longer median survival ( 7.8 months ) than the photon-treated patients ( 6.5 months ) . Local control rates were slightly higher in the helium-treated patients ( 10 % vs 5 % ) . Complications included one chemotherapy-related death . Four of the five helium-treated patients who survived longer than 18 months died of local failure without distant metastases . These results suggest that more aggressive local therapy could result in improved survival in helium-treated patients The feasibility , safety , and efficacy of planned sequential administration of docetaxel and irinotecan with 5-fluorouracil (5-FU)/leucovorin in advanced upper gastrointestinal adenocarcinoma ( UGIA ) are unknown . Seventy-three patients with gastric ( GC ; n = 22 ) , pancreatic ( PC ; n = 28 ) or biliary cancer ( BC ; n = 23 ) were r and omised to start with  45  mg/m2 docetaxel or 180 mg/m2 irinotecan combined with 5-FU/leucovorin  every 2nd week . After every 2nd course , the patients were crossed over to the other combination . Treatment was given for a maximum of 12 courses . Quality -of-life ( QoL ) was evaluated during the first two months using the EORTC QLQ-C30 . Eighteen patients ( 25 % ; GC 32 % , PC 21 % , BC 22 % ) demonstrated partial response ( PR ) and 21 ( 29 % ) had prolonged stable disease . Mean QoL scores were low at baseline . Twenty-three ( 32 % ) patients had improved QoL using a summary measure and 13 were stable . Median time to progression was 4.4 months and overall survival 8.2 months . The treatments were reasonably well tolerated . Grade 3–4 toxicities were slightly more common for the docetaxel combination . There were two treatment-related deaths . Planned sequential treatment with docetaxel or irinotecan with 5-FU/leucovorin is feasible , reasonably tolerable and appears active in advanced UGIA Purpose The role and timing of chemotherapy and radiation for treating stage III pancreatic adenocarcinoma remains controversial . Methods Treatment-naive patients with stage III non-resectable pancreatic adenocarcinoma were treated with PEFG/PEXG ( cisplatin , epirubicin , 5-fluorouracil (F)/capecitabine ( X ) , gemcitabine ) or PDXG ( docetaxel substituting epirubicin ) regimen for 6 months followed by radiotherapy ( 50–60 Gy ) with concurrent F or X or G. Results Ninety-one patients were registered between April 1997 and December 2007 . Forty-three patients ( 47 % ) had a partial remission and 38 ( 42 % ) had a stable disease . Thirteen patients ( 14 % ) were radically resected yielding one pathologic complete remission . Median survival ( OS ) was 16.2 months . Median progression-free survival was 9.9 months . Pattern of failure consisted of isolated local failure ( N = 26 , 35 % ) ; both local and systemic failure ( N = 14 , 19 % ) ; isolated systemic failure ( N = 35 , 47 % ) . Conclusion Combination chemotherapy with four-drug regimens followed by chemoradiation was a feasible strategy showing relevant results in stage III pancreatic adenocarcinoma BACKGROUND The RAF-MEK-ERK pathway is commonly activated in pancreatic cancer because of a high frequency of KRAS-BRAF mutations . A phase II r and omized trial was design ed to investigate the activity of sorafenib in combination with chemotherapy in advanced pancreatic cancer . METHODS Locally advanced or metastatic pancreatic adenocarcinoma patients were r and omized in a 1:1 ratio to receive cisplatin plus gemcitabine with sorafenib 400 mg bid ( arm A ) or without sorafenib ( arm B ) . RESULTS One hundred and fourteen patients were enrolled ; of these , 43 ( 74.6 % ) patients progressed in arm A and 44 ( 82.4 % ) in arm B. Median progression-free survival was 4.3 months ( 95 % CI : 2.7 - 6.5 ) and 4.5 months ( 95 % CI : 2.5 - 5.2 ) , respectively ( HR=0.92 ; 95 % CI : 0.62 - 1.35 ) . Median overall survival was 7.5 ( 95 % CI : 5.6 - 9.7 ) and 8.3 months ( 95 % CI : 6.2 - 8.7 ) , respectively ( HR=0.95 ; 95 % CI : 0.62 - 1.48 ) . Response rates were 3.4 % in arm A and 3.6 % in arm B. CONCLUSIONS Sorafenib does not significantly enhance activity of chemotherapy in advanced pancreatic cancer patients , and therefore should not be assessed in phase III trials PURPOSE To determine whether addition of the farnesyltransferase inhibitor tipifarnib ( Zarnestra , R115777 ; Johnson and Johnson Pharmaceutical Research and Development , Beerse , Belgium ) to st and ard gemcitabine therapy improves overall survival in advanced pancreatic cancer . PATIENTS AND METHODS This r and omized , double-blind , placebo-controlled study compared gemcitabine + tipifarnib versus gemcitabine + placebo in patients with advanced pancreatic adenocarcinoma previously untreated with systemic therapy .  Tipifarnib was given at 200 mg bid orally continuously ; gemcitabine was given at 1,000 mg/m(2 ) intravenously weekly x 7 for 8 weeks , then weekly x 3 every 4 weeks . The primary end point was overall survival ; secondary end points included 6-month and 1-year survival rates , progression-free survival , response rate , safety , and quality of life . RESULTS Six hundred eighty-eight patients were enrolled . Baseline characteristics were well balanced between the two treatment arms . No statistically significant differences in survival parameters were observed . The median overall survival for the experimental arm was 193 v 182 days for the control arm ( P = .75 ) ; 6-month and 1-year survival rates were 53 % and 27 % v 49 % and 24 % for the control arm , respectively ; median progression-free survival was 112 v 109 days for the control arm . Ten drug-related deaths were reported for the experimental arm and seven for the control arm . Neutropenia and thrombocytopenia grade > or = 3 were observed in 40 % and 15 % in the experimental arm versus 30 % and 12 % in the control arm . Incidences of nonhematologic adverse events were similar in two groups . CONCLUSION The combination of gemcitabine and tipifarnib has an acceptable toxicity profile but does not prolong overall survival in advanced pancreatic cancer compared with single-agent gemcitabine BACKGROUND Chemotherapy is moderately efficient as a treatment for pancreatic adenocarcinoma , but patient survival and quality of life has improved with this modality in some trials . In a previous phase II trial , 5-fluorouracil ( 5-FU ) plus cisplatin ( FUP ) yielded a 26.5 % response rate and a 29 % survival rate at 1 year . The present study aim ed to compare FUP with 5-FU alone , which was the control arm in former Mayo Clinic trials . PATIENTS AND METHODS Patients with untreated cytologically or histologically proven metastatic or locally advanced adenocarcinoma of the pancreas were deemed measurable or evaluable . Chemotherapy regimens consisted of a control FU arm ( 5-FU 500 mg/m(2)/day for 5 days ) and the investigational FUP arm ( continuous 5-FU 1000 mg/m(2)/day for 5 days plus cisplatin 100 mg/m(2 ) on day 1 or day 2 ) . In both arms , chemotherapy was repeated at day 29 . RESULTS Two-hundred and seven patients from 18 centres were r and omised : 103 in the FU arm and 104 in FUP arm . Treatment arms were balanced with respect to performance status grade 0 - 1 ( 83 % versus 86 % , respectively ) and the presence of metastases ( 92 % versus 89 % , respectively ) . The median number of cycles administered was two in both arms ( range 0 - 14 ) . Five patients did not receive any chemotherapy and 45 received only one cycle . Toxicity ( WHO grade 3 - 4 ) was lower with FU than with FUP ( 20 % versus 48 % , P < 0.001 ) , as was neutropenia ( 6 % versus 23 % ) , vomiting ( 4 % versus 17 % ) and toxicity-related deaths ( one versus four early in the trial ) . The response rate was low in both arms , but superior in the FUP arm : 12 % versus 0 % ( intention-to-treat analysis , P < 0.01 ) . The survival rates at 6 months were 28 % and 38 % for the FU and FUP arms , respectively , and 1-year survival rates were 9 % and 17 % ( log-rank test , P = 0.10 ) . One-year progression-free survival was 0 % with FU versus 10 % with FUP ( log-rank test , P = 0.0001 ) . CONCLUSIONS In advanced pancreatic carcinomas with a poor prognosis , FUP was superior to FU in terms of response and progression-free survival , but not in terms of overall survival . The low response rate is partly related to the number of patients who received only one cycle of chemotherapy . A more effective , better tolerated version of this FUP combination is needed PURPOSE Patients with advanced pancreas cancer present with disease that is poorly responsive to conventional therapies . Pre clinical and early clinical evidence has supported targeting the epidermal growth factor receptor ( EGFR ) signaling pathway in patients with pancreas cancer . This trial was conducted to evaluate the contribution of an EGFR-targeted agent to st and ard gemcitabine therapy . Cetuximab is a monoclonal antibody against the lig and -binding domain of the receptor . PATIENTS AND METHODS Patients with unresectable locally advanced or metastatic pancreatic adenocarcinoma were r and omly assigned to receive gemcitabine alone or gemcitabine plus cetuximab . The primary end point was overall survival . Secondary end points included progression-free survival , time to treatment failure , objective response , and toxicity . RESULTS A total of 745 eligible patients were accrued . No significant difference was seen between the two arms of the study with respect to the median survival time ( 6.3 months for the gemcitabine plus cetuximab arm v 5.9 months for the gemcitabine alone arm ; hazard ratio = 1.06 ; 95 % CI , 0.91 to 1.23 ; P = .23 , one-sided ) . Objective responses and progression-free survival were similar in both arms of the study . Although time to treatment failure was longer in patients on gemcitabine plus cetuximab ( P = .006 ) , the difference in length of treatment was only 2 weeks longer in the combination arm . Among patients who were studied for tumoral EGFR expression , 90 % were positive , with no treatment benefit detected in this patient subset . CONCLUSION In patients with advanced pancreas cancer , the anti-EGFR monoclonal antibody cetuximab did not improve the outcome compared with patients treated with gemcitabine alone . Alternate targets other than EGFR should be evaluated for new drug development BACKGROUND / AIMS The administration of high doses of Interleukin-2 ( IL-2 ) either alone or in combination with other cytokines demonstrated that immunologic manipulation is capable of mediating the regression of established cancer in humans . Thus , there is an urgent need to develop and evaluate the effect of treatment with IL-2 on immunological parameters and outcome of patients with inoperable pancreatic carcinoma . METHODOLOGY Twenty-one patients with advanced pancreatic cancer were the subjects of this study and all patients were diagnosed as unresectable pancreatic carcinoma on a clinical , surgical , radiological and laboratory basis . The patients were classified as group I : 10 patients treated by  IL-2  , and group II : 11 non-treated patients . We used a novel method of intra-arterial therapy . Patients in group I were subjected to surgical exploration for assessing the inoperability and catheterization of the splenic artery , gastroduodenal artery and hepatic artery in patients with liver metastasis . The course of therapy that started 15 days after catheterization included the following for 10 days , lipiodol 2.5ml , 0.5ml urographin 58 % , and IL-2 1ml . After 15 days of immunostimulation bolus injection of chemotherapy was given including , lipiodol 10ml , urographin 2ml , mitomycin C 0.2mg/kg , carboplatin 1.5mg/kg , farmorubicin 1mg/kg , 5-fluorouracil 10mg/kg , and leukovorin 1.5mg/kg . Forty-five days following locoregional chemotherapy , the same procedure was followed in the same sequence with 10 daily courses of locoregional immunotherapy . RESULTS The results showed that there is a 70 % relief of pain in group I compared to 0 % in group II . Also , there is an improvement in body weight in 50 % of group I in comparison to group II . Tumor size was decreased in 70 % of the cases in group I. The mean survival was 11.9+/-4.9 months in group I compared to 5.6+/-1.5 in group II ( p<0.0008 ) . A highly significant increase of CD3 ( p<0.0001 ) , CD4 ( p<0.001 ) , CD8 ( p<0.0001 ) , CD16 ( p<0.001 ) , CD14 ( p<0.0001 ) , NK cytotoxicity ( p<0.0001 ) , T cell cytotoxicity ( p<0.001 ) , ICAM-1 ( p<0.001 ) , TNFalpha ( p=0.001 ) IL-2 ( p<0.001 ) , and IL-2R ( p=0.001 ) was seen in group I patients compared to group II patients . CONCLUSIONS Immunotherapy is a new modality for treatment of pancreatic carcinoma . Local administration of therapy seems to be an attractive way for delivering the optimum concentration of IL-2 target tissues avoiding the toxic side effects associated with high dose systemic treatment PURPOSE TNFerade biologic is a novel means of delivering tumor necrosis factor alpha to tumor cells by gene transfer . We herein report final results of the largest r and omized phase III trial performed to date among patients with locally advanced pancreatic cancer ( LAPC ) and the first to test gene transfer against this malignancy . PATIENTS AND METHODS In all , 304 patients were r and omly assigned 2:1 to st and ard of care plus TNFerade ( SOC + TNFerade ) versus st and ard of care alone ( SOC ) . SOC consisted of 50.4 Gy in 28 fractions with concurrent fluorouracil ( 200 mg/m(2 ) per day continuous infusion ) . TNFerade was injected intratumorally before the first fraction of radiotherapy each week at a dose of 4 × 10(11 ) particle units by using either a percutaneous transabdominal or an endoscopic ultrasound approach . Four weeks after chemoradiotherapy , patients began gemcitabine ( 1,000 mg/m(2 ) intravenously ) with or without erlotinib ( 100 to 150 mg per day orally ) until progression or toxicity . RESULTS The analysis included 187 patients r and omly assigned to  SOC + TNFerade  and  90 to SOC  by using a modified intention-to-treat approach . Median follow-up was 9.1 months ( range , 0.1 to 50.5 months ) . Median survival was 10.0 months for patients in both the SOC + TNFerade and SOC arms ( hazard ratio [ HR ] , 0.90 ; 95 % CI , 0.66 to 1.22 ; P = .26 ) . Median progression-free survival ( PFS ) was 6.8 months for SOC + TNFerade versus 7.0 months for SOC ( HR , 0.96 ; 95 % CI , 0.69 to 1.32 ; P = .51 ) . Among patients treated on the SOC + TNFerade arm , multivariate analysis showed that TNFerade injection by an endoscopic ultrasound-guided transgastric/transduodenal approach rather than a percutaneous transabdominal approach was a risk factor for inferior PFS ( HR , 2.08 ; 95 % CI , 1.06 to 4.06 ; P = .032 ) . The patients in the SOC + TNFerade arm experienced more grade 1 to 2 fever and chills than those in the SOC arm ( P < .001 ) but both arms had similar rates of grade 3 to 4 toxicities ( all P > .05 ) . CONCLUSION SOC + TNFerade  is safe but not effective for prolonging survival in patients with LAPC Between the years 1973–1977 , 152 male patients from 28 participating Veterans Hospitals with histologically proven nonresectable cancer of the pancreas were r and omized in a two‐arm study . The treated group was to receive combination chemotherapy with 5‐FU and CCNU , and the controls were to receive no chemotherapy .  Both groups were comparable with respect to age , amount of weight loss , extent of histologically proved metastases , and operation performed . In the treatment group , drug therapy was begun between 10 and 60 days postoperatively . Intravenous 5‐FU , 9 mg/kg , was administered on five consecutive days , and CCNU , 70 mg/m2 , was given orally on the first day of each course . In the absence of toxicity , the course was repeated every six weeks for life ; 146 drug courses were given . The incidence of toxicity was not great . One or more toxic reactions were reported for one‐third of the drug courses administered , but for the most part , these were mild . The most frequent toxic reaction was vomiting in 17 % of the courses , and hematologic toxicity — primarily leukopenia — in 15 % of the drug courses . There was no evidence of a beneficial effect on survival from drug treatment in the group as a whole or in any subgroup analyzed . The median survival of the control group was 3.9 months , and of the drug‐treated group , 3.0 months Abstract : A r and omized , controlled trial was conducted to clarify the effect of novel radiosensitizer , PR-350 , accompanied by intraoperative radiology ( IOR ) on locally advanced pancreatic cancer . Between July 1999 and March 2002 , 48 patients were enrolled in this clinical trial and received either  PR-350 or placebo . Any differences between the PR-350 group ( n = 22 ) and control group ( n = 25 ) were not statically significant . All patients were evaluated , and none of them showed toxicity , with the exception of 1 patient from the control group , and the PR-350 compound was considered to be safe . The efficacy of IOR with PR-350 was evaluated using CT examination . The committee responsible for evaluating efficacy reported that 47.4 % of the PR-350 group showed the effective response , compared with 21.7 % of the control group ( P = 0.1067 , Fisher analysis ) . At 6 months following treatment , the tumor mass reduction rate in the PR-350 group was significantly improved ( P = 0.0274 ) . By the time of the last follow-up in July 2003 , 17 PR-350 patients and 24 control patients group had died of the disease . The median survival period of the PR-350 group was thus 318.5 days and that of the control group is 303.0 days . One-year survival rates of the PR-350 group and control group were 36.4 % and 32.0 % , respectively . Although the PR-350 group did not demonstrate significantly better survival than the control group , 4 of 22 PR-350 patients were still living more than 2 years after the end of the trial , compared with only 1 of 25 patients from the control group . The mechanism of this increased therapeutic response to radiotherapy using PR-350 must be clarified to establish more effective strategy for pancreatic cancer treatment Pre clinical reports support the concept of synergy between cancer vaccines and immune checkpoint blockade in nonimmunogenic tumors . In particular , cytotoxic T lymphocyte-associated antigen-4 ( CTLA-4 ) antibodies have been successfully combined with GM-CSF cell-based vaccines ( GVAX ) . Ipilimumab ( anti-CTLA-4 ) has been tested as a single agent in patients with pancreatic ductal adenocarcinoma ( PDA ) result ing in a delayed response at a dose of 3 mg/kg . Our study evaluated ipilimumab 10 mg/kg ( arm 1 ) and ipilimumab 10 mg/kg+GVAX ( arm 2 ) . A total of 30 patients with previously treated advanced PDA were r and omized ( 1:1 ) . Induction doses were administered every 3 weeks for a total of 4 doses followed by maintenance dosing every 12 weeks . Two patients in arm 1 showed evidence of stable disease ( 7 and 22 wk ) but none demonstrated CA19 - 9 biochemical responses . In contrast , 3 patients in arm 2 had evidence of prolonged disease stabilization ( 31 , 71 , and 81 wk ) and 7 patients experienced CA19 - 9 declines . In 2 of these patients , disease stabilization occurred after an initial period of progression . The median overall survival ( OS ) ( 3.6 vs. 5.7 mo , hazards ratio : 0.51 , P=0.072 ) and 1 year OS ( 7 vs. 27 % ) favored arm 2 . Similar to prior ipilimumab studies , 20 % of patients in each arm had grade 3/4 immune-related adverse events . Among patients with OS>4.3 months , there was an increase in the peak mesothelin-specific T cells ( P=0.014 ) and enhancement of the T-cell repertoire ( P=0.031 ) . In conclusion , checkpoint blockade in combination with GVAX has the potential for clinical benefit and should be evaluated in a larger study One hundred eighty‐seven patients with histologically proven advanced pancreatic adenocarcinoma were r and omly assigned to therapy with 5‐fluorouracil ( 5‐FU ) alone , to the Mallinson regimen ( combined and sequential 5‐FU , cyclophosphamide , methotrexate , vincristine , and mitomycin C ) , or to combined 5‐FU , doxorubicin , and cisplatin ( FAP ) .  Patients with both measurable and nonmeasurable disease were included and the primary study end point was survival . Among 41 patients with measurable disease  , objective response rates were 7 % for 5‐FU alone , 21 % for the Mallinson regimen , and 15 % for FAP . The median interval to progression for each of the three regimens was 2.5 months . Survival curves intertwined with the median survival times for 5‐FU alone and the Mallinson regimen at 4.5 months and for FAP at 3.5 months . Compared with 5‐FU alone , both the Mallinson regimen and FAP  produced significantly more toxicity . Neither the Mallinson regimen nor FAP can be recommended as therapy for advanced pancreatic carcinoma . Any chemotherapy for this disease should remain an experimental endeavor PURPOSE The objective of this study was to compare the efficacy and toxicity of gemcitabine-based concurrent chemoradiotherapy ( CCRT ) with paclitaxel-based CCRT in patients with locally advanced pancreatic cancer . METHODS AND MATERIAL S A total of 48 patients who had received no prior therapy were enrolled . The patients were treated with 4500 cGy radiation in 25 fractions over 5 weeks concomitant with gemcitabine 1000 mg/m(2)/week/intravenously ( IV ) and doxifluridine 600 mg/m(2)/day/by mouth ( PO ) , or paclitaxel 50 mg/m(2)/week/IV and doxifluridine 600 mg/m(2)/day/PO . After a 4-week rest , the responses were evaluated and maintenance therapies ( operation or chemotherapy ) ( gemcitabine 1000 mg/m(2)/week/IV and doxifluridine 600 mg/m(2)/day/PO ) were conducted . RESULTS The median survival was 12 months in the gemcitabine group vs. 14 months in the paclitaxel group . The response rate was 13.6 % vs. 25 % , and the median time to progression was 12 months vs. 12.5 months , respectively . The positive rate of the clinical benefit response was 59.1 % vs. 41.7 % , respectively . Toxicities were acceptable in both groups . CONCLUSION In this trial , we demonstrated that the gemcitabine-based CCRT and the paclitaxel-based CCRT in combination of doxifluridine are clearly acceptable treatment strategy , and appear more effective than the 5 fluorouracil-based CCRT for locally advanced pancreatic cancer with comparable tolerability . Furthermore , the paclitaxel-based CCRT showed similar efficacy and toxicities to the gemcitabine-based treatment when it was combined with 5-fluorouracil PURPOSE Most patients with advanced pancreas cancer experience pain and must limit their daily activities because of tumor-related symptoms . To date , no treatment has had a significant impact on the disease . In early studies with gemcitabine , patients with pancreas cancer experienced an improvement in disease-related symptoms . Based on those findings , a definitive trial was performed to assess the effectiveness of gemcitabine in patients with newly diagnosed advanced pancreas cancer . PATIENTS AND METHODS One hundred twenty-six patients with advanced symptomatic pancreas cancer completed a lead-in period to characterize and stabilize pain and were r and omized to receive either gemcitabine 1,000 mg/m2 weekly x 7 followed by 1 week of rest , then weekly x 3 every 4 weeks thereafter ( 63 patients ) , or to fluorouracil ( 5-FU ) 600 mg/m2 once weekly ( 63 patients ) . The primary efficacy measure was clinical benefit response , which was a composite of measurements of pain ( analgesic consumption and pain intensity ) , Karnofsky performance status , and weight . Clinical benefit required a sustained ( > or = 4 weeks ) improvement in at least one parameter without worsening in any others . Other measures of efficacy included response rate , time to progressive disease , and survival . RESULTS Clinical benefit response was experienced by 23.8 % of gemcitabine-treated patients compared with 4.8 % of 5-FU-treated patients ( P = .0022 ) . The median survival duration s were 5.65 and 4.41 months for gemcitabine-treated and 5-FU-treated patients , respectively ( P = .0025 ) . The survival rate at 12 months was 18 % for gemcitabine patients and 2 % for 5-FU patients . Treatment was well tolerated . CONCLUSION This study demonstrates that gemcitabine is more effective than 5-FU in alleviation of some disease-related symptoms in patients with advanced , symptomatic pancreas cancer .  Gemcitabine also confers a modest survival advantage over treatment with 5-FU Chemotherapy for pancreatic cancer offers small survival benefits and considerable side‐effects .  Unsaturated fatty acids have an antitumour effect in experimental studies ; in phase II studies few side‐effects were seen Conventional chemotherapy for unresectable or metastatic adenocarcinoma of the pancreas has had little effect on palliation or survival . Almost all studies of systemic therapy have involved empiric use of a variety of Phase II or conventional agents alone or in combination . On the basis of recent studies using a human tumor pancreatic cancer ( PC ) xenograft in nude mice , a Phase I clinical trial of cisplatin , high‐dose cytosine arabinoside ( Ara‐C ) , and caffeine ( CAC ) was performed in patients with advanced incurable PC . A tolerable dose and schedule of the three agents were developed . Seven of 18 patients with measurable disease in this Phase I trial had partial responses to CAC . A Phase III comparison of CAC versus st and ard treatment using streptozotocin , mitomycin , and 5‐fluorouracil ( SMF ) was performed . Eighty‐two patients with advanced PC were entered into this r and om assignment trial . The two treatment arms were well balanced for the usual prognostic factors . Although the acute ( e.g. , nausea and vomiting ) toxicities of CAC were greater than those of SMF , both groups of patients tolerated treatment reasonably well . Ninety percent of patients were evaluable for response . Two patients ( 5.5 % ) on the CAC treatment arm ( 95 % confidence interval [ CI ] , 0 % to 15 % ) and four patients ( 10.2 % ) on the SMF treatment arm ( 95 % CI , 1 % to 22 % ) had objective responses ( partial response in measurable disease or improvement in evaluable disease ) . No complete remissions were observed . The 95 % confidence limits of response for CAC and SMF overlapped . The median duration of survival for all patients on the SMF treatment arm was 10 months , although it was 5 months on the CAC treatment arm ( P = 0.008 ) . In this Phase III comparison , CAC was not superior to conventional therapy with SMF in terms of response and was inferior for survival . Neither regimen is effective treatment for advanced PC Background . Pancreatic carcinoma responds poorly to conventional chemotherapy . To identify potentially useful agents , a sequence of clinical trials were done 4116 Background : Virulizin ( V ) is a novel antitumor immune modulator that improves survival in pancreatic cancer patients ( pts ) as monotherapy . A double-blind , multicenter , r and omized , phase III study was conducted to evaluate the survival benefits and safety of V in combination with gemcitabine ( G ) in pts with advanced pancreatic cancer . METHODS Chemo-naive pts with locally advanced or metastatic pancreatic cancer with ECOG Performance Status ( PS ) of 0 , 1 or 2 were enrolled . Pts were r and omized to receive intramuscular injections of either V or placebo ( P ) 3 times weekly + G ( 1,000 mg/m2 weekly ×7 with 1 week rest , then weekly ×3 q4w ) . R and omization was stratified according to ECOG PS ( 0 or 1 , and 2 ) and extent of disease ( locally advanced and metastatic ) . Pts who showed no clinical benefit or were intolerant to G entered 2nd-line therapy ( stage 3 ) , in which pts continued to receive either V or P alone or with 5-FU , or best supportive care . The primary endpoint was survival , defined as time from baseline/treatment day 1 to time of death from any cause . RESULTS The intent to treat ( ITT ) population comprised 434 pts , of which 377 were efficacy evaluable ( EE ) . Median overall survival for V + G was 6.3 months for the ITT population ( 6.8 months for EE pts ) and 6 months for P + G for both ITT and EE pts . While differences in survival times were not statistically significant , exploratory analysis showed encouraging results in specific subgroups treated with V + G ( table ) . Importantly , a significant difference was found in stage 3 pts who received V in a salvage setting compared to pts who received P. CONCLUSIONS Pancreatic cancer pts with either low ECOG PS or metastatic cancer showed a survival benefit when treated with V + G , which was significant in pts who continued to receive V as a salvage therapy . Further studies in these targeted patient population s are being considered . [ Table : see text ] No significant financial relationships to disclose BACKGROUND Paclitaxel embedded in cationic liposomes ( EndoTAG ™ -1 ; ET ) is an innovative agent targeting tumor endothelial cells . This r and omized controlled phase II trial evaluated the safety and efficacy of ET in combination with gemcitabine ( GEM ) in advanced pancreatic cancer ( PDAC ) . PATIENTS AND METHODS Chemotherapy-naive patients with locally advanced or metastatic disease were r and omly assigned to receive weekly GEM 1000 mg/m(2 ) or GEM plus twice-weekly ET 11 , 22 or 44 mg/m(2 ) for 7 weeks . After a safety run-in of 100 patients , a second cohort continued treatment . End points included overall survival ( OS ) , progression-free survival ( PFS ) , tumor response and safety . RESULTS Two hundred and twelve patients were r and omly allocated to the study and 200 were treated ( 80 % metastatic , 20 % locally advanced ) . Adverse events were manageable and reversible . Transient thrombocytopenia and infusion reactions with chills and pyrexia mostly grade 1 or 2 occurred in the ET groups . Disease control rate after the first treatment cycle was 43 % with GEM and 60 % , 65 % and 52 % in the GEM + ET  cohorts . Median PFS reached 2.7 compared with 4.1 , 4.6 and 4.4 months , respectively . Median OS was 6.8 compared with 8.1 , 8.7 and 9.3 months , respectively . CONCLUSIONS Treatment of advanced PDAC with GEM + ET was generally well tolerated . GEM + ET  showed beneficial survival and efficacy . A r and omized phase III trial should confirm this positive trend BACKGROUND Sorafenib is an oral anticancer agent targeting Ras-dependent signaling and angiogenic pathways . A phase I trial demonstrated that the combination of gemcitabine and sorafenib was well tolerated and had activity in advanced pancreatic cancer ( APC ) patients . The BAYPAN study was a multicentric , placebo-controlled , double-blind , r and omized phase III trial comparing gemcitabine/sorafenib and gemcitabine/placebo in the treatment of APC . PATIENTS AND METHODS The patient eligibility criteria were locally advanced or metastatic pancreatic adenocarcinoma , no prior therapy for advanced disease and a performance status of zero to two . The primary end point was progression-free survival ( PFS ) . The patients received gemcitabine 1000 mg/m(2 ) i.v . , weekly seven times followed by 1 rest week , then weekly three times every 4 weeks plus sorafenib 200 mg or placebo , two tablets p.o . , twice daily continuously . RESULTS Between December 2006 and September 2009 , 104 patients were enrolled on the study ( 52 pts in each arm ) and 102 patients were treated . The median and the 6-month PFS were 5.7 months and 48 % for gemcitabine/placebo and 3.8 months and 33 % for gemcitabine/sorafenib ( P = 0.902 , stratified log-rank test ) , respectively . The median overall survivals were 9.2 and 8 months , respectively ( P = 0.231 , log-rank test ) . The overall response rates were similar ( 19 and 23 % , respectively ) . CONCLUSION The addition of sorafenib to gemcitabine does not improve PFS in APC patients By r and om assignment a total of 176 eligible patients with advanced nonmeasurable pancreatic carcinoma were treated with 5-fluorouracil ( 5-FU ) either alone or in combination with a nitrosourea ( streptozotocin ) , in combination with a " lactone " ( spironolactone ) , or in combination with both . By r and om assignment a total of 179 patients with advanced nonmeasurable gastric carcinoma were treated with 5-FU either alone or in combination with a nitrosourea ( methyl CCNU ) , in combination with a lactone ( testolactone ) , or in combination with both . The median survival period for all pancreatic carcinoma patients was 17 weeks , and for all gastric carcinoma patients 30 weeks . The addition of the nitrosoureas or the lactones or a combination of both produced no improvement in length of patient survival for either primary carcinoma when compared to treatment with 5-FU alone PURPOSE To define the efficacy and toxicity of docetaxel plus gemcitabine or docetaxel plus cisplatin for advanced pancreatic carcinoma . PATIENTS AND METHODS Chemotherapy-naive patients with measurable disease and WHO performance status less than 2 were r and omly assigned to receive 21-day cycles of gemcitabine 800 mg/m2 on days 1 and 8 plus docetaxel 85 mg/m2 on day 8 ( arm A ) or docetaxel 75 mg/m2 on day 1 plus cisplatin 75 mg/m2 on day 1 ( arm B ) . Primary end points were tumor response and rate of febrile neutropenia grade . RESULTS Of 96 r and omly assigned patients ( 49 patients in arm A and 47 patients in arm B ) , 70 patients were analyzed for response ( 36 in arm A and 34 in arm B ) and 89 patients were analyzed for safety ( 45 in arm A and 44 in arm B ) . Confirmed responses were observed in 19.4 % ( 95 % CI , 8.2 % to 36.0 % ) of patients in arm A and 23.5 % ( 95 % CI , 10.7 % to 41.2 % ) in arm B. In arm A , the median progression-free survival ( PFS ) was 3.9 months ( 95 % CI , 3.0 to 4.7 months ) , median survival was 7.4 months ( 95 % CI , 5.6 to 11.0 months ) , and 1-year survival was 30 % . In arm B , the median PFS was 2.8 months ( 95 % CI , 2.6 to 4.6 months ) , median survival was 7.1 months ( 95 % CI , 4.8 to 8.7 months ) , and 1-year survival was 16 % . Febrile neutropenia occurred in 9 % and 16 % of patients in arms A and B , respectively . CONCLUSION Both regimens are well tolerated and show activity in advanced pancreatic carcinoma . The safety profile and survival analyses favor docetaxel plus gemcitabine for further evaluation PURPOSE The prognosis for unresectable pancreatic cancer remains dismal ( 1-year survival rate , < 10 % ; 5-year survival rate , < 5 % ) . Recent advances in conventional chemotherapy and novel molecular treatment strategies warrant investigation . This , the largest r and omized study in pancreatic cancer performed to date , compares marimastat , the first of a new class of agents , with gemcitabine . PATIENTS AND METHODS Four hundred fourteen patients with unresectable pancreatic cancer were r and omized to receive marimastat 5 , 10 , or 25 mg bid or gemcitabine 1,000 mg/m2 . The primary end point was survival . Progression-free survival , patient benefit , and safety were also assessed . RESULTS There was no significant difference in survival between 5 , 10 , or 25 mg of marimastat and gemcitabine ( P = .19 ) . Median survival times were 111 , 105 , 125 , and 167 days , respectively , and 1-year survival rates were 14 % , 14 % , 20 % , and 19 % , respectively . There was a significant difference in survival rates between patients treated with gemcitabine and marimastat 5 and 10 mg ( P < .003 ) . Both agents were well tolerated , although grade 3 or 4 toxicities were reported in 22 % and 12 % of the gemcitabine- and marimastat-treated patients , respectively . The major toxicity of marimastat was musculoskeletal ( 44 % of marimastat patients , compared with 12 % of gemcitabine patients ; musculoskeletal toxicity was severe in only 8 % of marimastat patients ) . CONCLUSION The results of this study provide evidence of a dose response for marimastat in patients with advanced pancreatic cancer . The 1-year survival rate for patients receiving marimastat 25 mg was similar to that of patients receiving gemcitabine . In view of the manageable tolerability of marimastat and its ease of administration , further studies are warranted Background : LY293111 ( LY ) is a novel oral anticancer agent with leukotriene B4 receptor antagonist and peroxisome proliferator-activated receptor gamma agonist properties , producing promising results alone and in combination with gemcitabine in pancreatic cancer xenograft models . A phase I study proved that the combination ( gemcitabine plus LY ) is safe and well tolerated . Patients and Methods : Chemotherapy-naive patients with histologically confirmed locally advanced or metastatic adenocarcinoma of the pancreas were r and omly assigned to gemcitabine 1000 mg/m2 on days 1 , 8 , and 15 of a 28-day cycle and continuously administered LY 600 mg twice daily or gemcitabine 1000 mg/m2 on days 1 , 8 , and 15 of a 28-day cycle and daily oral placebo . Arms were balanced for Eastern Cooperative Oncology Group performance status and disease stage . The primary end point was 6-month survival ; secondary objectives include response rate ( RR ) , progression-free survival , and overall survival . Results : Six-month survival was not different between groups ( P > 0.2 , 1-sided ) ; progression-free survival and RR were not different ( P > 0.05 , 2-sided ) . RR was also not impacted . LY did not increase grade s 3–4 hematologic toxicities , but was associated with a trend toward more , grade s 3–4 diarrhea . Conclusions : These results do not demonstrate any benefit to adding LY to gemcitabine in unpretreated patients with advanced pancreatic carcinoma Purpose PEFG regimen ( P : cisplatin , E : epirubicin , F:5-fluorouracil , G : gemcitabine ) significantly prolonged progression-free ( PFS ) and overall survival ( OS ) of patients with advanced pancreatic adenocarcinoma ( PA ) with respect to st and ard gemcitabine . The current trial was aim ed at assessing whether the replacement of E with docetaxel ( D ) may improve 6 months PFS ( PFS6 ) . Methods Chemo-naive patients with stage III or metastatic PA received P ( 30 mg/m2 day 1 and 15 ) , G ( 800 mg/m2 day 1 and 15 ) , and capecitabine ( 1,250 mg/m2/day days 1–28 , without a break ) and were r and omized to receive either D at 25–30 mg/m2 day 1 and 15 ( arm A : PDXG regimen ) or E at 30 mg/m2 day 1 and 15 ( arm B : PEXG regimen ) . Cycles were repeated every 28 days for a maximum of 6 months . The Fleming design was used to calculate the sample size on the probability of being PFS6 . Assuming P0 = 40 % and P1 = 60 % , α = 0.05 and β = 0.10 ; the study was to enroll 52 patients per arm . Results Between July 2005 and September 2008 , 105 patients were enrolled , stratified by stage and r and omized . Patients ’ characteristics were ( A/B ) the following : median age 61/59 , PS > 70 92/88 % , metastatic disease 66/65 % . PFS6 was 58 % , and median OS was 11 months in both arms . A partial response was observed in 60/37 % of patients . Main per cycle G3 - 4 toxicity was the following : neutropenia 4/13 % , thrombocytopenia 2/4 % , anemia 4/4 % , and fatigue 6/3 % . Conclusions The inclusion of D instead of E yielded more objective response and less G3 - 4 neutropenia but did not improve PFS and OS . The present trial confirms the relevant impact on outcome of advanced PA of 4-drug regimens 4013 Background : Rubitecan ( Orathecin ) , an oral topoisomerase I inhibitor , showed promising activity in pancreatic cancer in previous single-center Phase 2 studies in US and Europe . Our objective was to compare ORA with BC ( physicians ' best choice of treatment or care ) . Primary end-point : Median survival ( MS ) . Secondary endpoints : Response rate ( RR ) , progression- free survival ( PFS ) and safety . METHODS ORA was administered orally at a dose of 1.5 mg/m2 for 5 consecutive days each week for 8 or more weeks . BC consisted of st and ard regimens of best alternative chemotherapy ( 89 % ) or supportive care ( 11 % ) . CT scans were followed every 8 weeks . RESULTS 198 patients ( pts ) were r and omized to ORA and 211 to BC . More than 90 % were resistant to prior chemotherapy and 70 % were refractory to 2 or more prior regimens . 49 % of BC patients crossed over to rescue therapy with ORA at time of failure . No significant difference was noted in MS time ( ORA : 108 days , BC 94 days , p = 0.626 ) , whereas a significant survival advantage was observed for BC pts crossed over to ORA vs. BC non-rescue pts , 147 days vs. 60 days ( P<0.0001 ) . In pts with measurable disease ( 59 % ) , there were 12 independently verified ( blinded radiology review ) responders for ORA ( 2 CR and 10 PR ) for a RR of 11 % , compared to one responder ( < 1 % ; 1 CR ) for BC ( p < 0.001 ) . Stable disease ( SD ) was also more common on ORA ( 44 pts vs. 27 pts ) . On an Intent-To-Treat basis , more than 2-fold more pts on ORA ( 28 % vs. 13 % ) achieved tumor growth control ( CR + PR + SD ) , a primary objective for palliative treatment in this disease ( Heinemann et al. , Oncology 60:8 - 18 , 2001 ) . Median PFS was significantly longer for ORA , 58 days vs. 48 days ( p = 0.003 ) . ORA was well tolerated as < 5 % discontinued treatment due to toxicity . Grade 3 - 4 toxicity was more common for ORA ( neutropenia 28 % vs. 14 % ; anemia 21 % vs. 9 % ; nausea/vomiting 14 % vs. 9 % ; diarrhea 12 % vs. 5 % ) . CONCLUSIONS The results of this study support the notion that rubitecan , a new oral medication with an acceptable risk-benefit ratio , is convenient to use , and can achieve tumor growth control in a disease with few treatment options . [ Table : see text ] 4131 Background : GEM is a st and ard drug for chemotherapy in patients with APC . But they should be offered better therapy aim ed more effective response and prolonging survival .  UFT is also available for treatment of APC . In order to evaluate the efficacy of GEM in combination with UFT , we performed following study . METHODS Eligibility : no pretreatment ( chemotherapy and irradiation ) , good performance status ( 50 - 100 in Karnofsky Performance Status ) and less than 75 years old in APC patients such as locally advanced or with distant metastasis . The study is r and omized trial comparing two arms , arm A in which patients are treated by GEM plus UFT ( day 1 , 8 , 15 : gemcitabine 1000 mg/m2 , d.i.v./30min ; everyday : UFT 300 mg/day , oral ; every 4 weeks as 1 course ) , arm B in which patients are treated by GEM alone ( day 1 , 8 , 15 : gemcitabine 1000 mg/m2 , div/30min ; every 4 weeks as 1 course ) . Primary endpoints are response rate ( RR ) and survival time ( MST ) . Time to progression ( TTP ) and Clinical benefit response ( CBR ) were also evaluated . RESULTS During July in 2001 to March in 2003 , 19 patients ( A : B=10 : 9 ) were r and omized from two centers.depends on document review Pretreatment characteristics were well balanced between the two groups ; A vs B as median age , 60.5 vs 58.4 , stage ( locally advanced : metastatic ) , 3:7 vs 2:7 , sex difference ( male : female ) , 7:3 vs 7:2 . RR ( 0/10 vs 3/9 ) and MST ( 5.0±0.6 months vs 7.6±2.1 ) were not significant ( NS ) . CBR ( 25 % vs 33.3 % ) was NS . But TTP ( 1.9±0.5 months vs 5.0±1.5 ) was significantly different ( p=0.0408 , Logrank ) . So , from a point of ethics , the study has already stopped . Toxicity ( NCI-CTC grade 3/4 ) ; leucocytes ( 20.0%:33.3 % ) , neutrophils ( 10.0%:11.1 % ) , platelets ( 10.0%:0 % ) , diarrhea ( 10.0%:0 % ) , anorexia ( 40.0%:11.1 % ) Conclusions : The chemotherapy by GEM plus UFT in this method may not be effective compared with GEM alone . No significant financial relationships to disclose OBJECTIVE To evaluate the efficacy , toxicity and survival of intraoperative 125I brachytherapy combined with chemotherapy for advanced pancreatic cancer . METHODS Thirty-six patients with advanced pancreatic cancer were r and omized to two groups : brachy-chemotherapy group ( n = 18 ) and control group ( n = 18 ) . For the combined group , intraoperative 125I implantation and gemcitabine , 5-Fu were given . For the control group , intratumoral injection of absolute alcohol was done . RESULTS The CR + PR rate of brachy-chemotherapy group was 38.9 % with pain relief in 77.8 % , while that of control group was 0 with pain relief in 22.2 % ( P < 0.05 ) . Although there were some toxicity in brachy-chemotherapy group , treatment was well tolerated . The 6- , 12-month survival rates of brachy-chemotherapy group were 71.4 % and 21.4 % and those of control group were 38.5 % and 7.7 % , respectively . The median survival time was 10.6 months and 5.2 months for the two groups , between which the difference was significant ( P < 0.05 ) . CONCLUSION Interoperative 125I brachytherapy combined with chemotherapy for advanced pancreatic cancer can control tumor , relieve pain and improve quality of life . It is safe and effective BACKGROUND Pancreatic ductal adenocarcinoma ( PDAC ) is one of the most common malignant tumours and is still associated with a poor prognosis in advanced disease . To improve the st and ard therapy with gemcitabine , we initiated a prospect i ve r and omised phase-II trial with gemcitabine ( GEM ) versus gemcitabine plus sunitinib ( SUNGEM ) based on data of in vitro trials and phase-I data for the combination treatment . The rational of adding sunitinib was its putative antiangiogenic mechanism of action . METHODS A total of 106 eligible patients with locally advanced , unresectable or metastatic PDAC without previous system therapy were r and omised to receive GEM at a dosage of 1.000mg/m(2 ) d1 , 8 , 15 q28 versus a combination of SUNGEM at a dosage of GEM 1.000mg/m(2 ) d1 + 8 and sunitinib 50 mg p.o . d1 - 14 , q21d . The primary end-point was progression free survival ( PFS ) , secondary end-points were overall survival ( OS ) , toxicity and overall response rate ( ORR ) . RESULTS The confirmatory analysis of PFS was based on the intend-to-treat ( ITT ) population ( N=106 ) . The median PFS was 13.3 weeks ( 95 % confidence interval ( 95%-CI ) : 10.4 - 18.1 weeks ) for GEM and 11.6 weeks for SUNGEM ( 95%-CI : 7.0 - 18.0 weeks ; p=0.78 one-sided log-rank ) . The ORR was 6.1 % ( 95%-CI : 0.7 - 20.2 % ) for GEM and for 7.1 % ( 95%-CI : 0.9 - 23.5 % ) for SUNGEM ( p=0.87 ) . The median time to progression ( TTP ) was 14.0 weeks ( 95%-CI : 12.4 - 22.3 weeks ) for GEM and 18.0 weeks ( 95%-CI : 11.3 - 19.3 weeks ) for SUNGEM ( p=0.60 ; two-sided log-rank ) . The median OS was 36.7 weeks ( 95%-CI : 20.6 - 49.0 weeks ) for the GEM arm and 30.4 weeks ( 95%-CI : 18.1 - 37.6 weeks ) for the SUNGEM ( p=0.78 , one-sided log-rank ) . In regard to toxicities , suspected SAEs were reported in 53.7 % in the GEM arm and 71.2 % in the SUNGEM arm . Grade 3 and 4 neutropenia was statistically significantly higher in the SUNGEM arm with 48.1 % versus 27.8 % in the GEM arm ( p=0.045 , two sided log-rank ) . CONCLUSIONS The combination SUNGEM was not sufficient superior in locally advanced or metastatic PDAC compared to GEM alone in regard to efficacy but was associated with more toxicity PURPOSE To compare protracted venous infusion ( PVI ) fluorouracil ( 5-FU ) with PVI 5-FU plus mitomycin ( MMC ) in patients with advanced pancreatic cancer in a multicenter , prospect ively r and omized study . PATIENTS AND METHODS Two hundred eight patients were r and omized to PVI 5-FU ( 300 mg/m(2)/d for a maximum of 24 weeks ) or  PVI 5-FU plus MMC  ( 7 mg/m(2 ) every 6 weeks for four courses ) . The major end points were tumor response , survival , toxicity , and quality of life ( QOL ) . RESULTS The two treatment groups were balanced for baseline demographic factors , and 62 % had metastatic disease . The overall response rate was 8.4 % ( 95 % confidence interval [ CI ] ) 3.2 % to 13.7 % for patients treated with PVI 5-FU alone compared with 17.6 % ; 95 % CI 10.3 % to 25.1 % for PVI 5-FU plus MMC ( P = .04 ) . Median failure-free survival was 2.8 months for PVI 5-FU and 3.8 months for PVI 5-FU plus MMC ( P = .14 ) . Median survival was 5.1 months for PVI 5-FU and 6.5 months for PVI 5-FU plus MMC ( P = .34 ) . Toxicities in both arms were mild . There was an increased incidence of neutropenia in the 5-FU plus MMC arm ( P < .01 ) , although no differences in infection were seen . No patients developed hemolytic uremic syndrome . Global QOL improved significantly after 24 weeks of treatment compared with baseline for patients receiving 5-FU plus MMC , although there was no statistically significant difference in QOL between arms . CONCLUSION PVI 5-FU plus MMC result ed in a superior response rate in comparison with PVI 5-FU alone in advanced pancreatic cancer , but this did not translate into a survival advantage . These results emphasize the importance of chemotherapy in this setting and the continuing value of the fluoropyrimidines in pancreatic cancer PURPOSE To determine the efficacy and tolerability of gemcitabine (GEM)-concurrent chemoradiotherapy ( CCRT ) vs. 5-fluorouracil ( 5-FU ) CCRT for locally advanced pancreatic cancer . METHODS AND MATERIAL S Thirty-four patients with locally advanced pancreatic cancer were studied . Eighteen patients were r and omized to receive GEM CCRT ( 600 mg/m(2)/wk for 6 weeks ) and 16 patients to receive bolus 5-FU CCRT ( 500 mg/m(2)/d for 3 days repeated every 2 weeks for 6 weeks ) . All patients were to receive 3D-CRT 50.4 - 61.2 Gy at 1.8-Gy/d fractions and GEM ( 1000 mg/m(2 ) weekly for 3 weeks repeated every 4 weeks ) after RT . RESULTS The median survival and median time to progression were 14.5 months and 7.1 months for the GEM CCRT group and 6.7 months and 2.7 months for the 5-FU CCRT group ( p = 0.027 and p = 0.019 , respectively ) . The quality -adjusted life month survival time was 11.2 + /- 0.5 months for GEM CCRT and 6.0 + /- 0.3 months for 5-FU CCRT patients ( p < 0.001 ) . The response rate was 50 % ( four complete responses and five partial responses ) for GEM CCRT and 13 % ( two partial responses ) for 5-FU CCRT ( p = 0.005 ) . Pain control was 39 % for GEM CCRT and 6 % for 5-FU CCRT ( p = 0.043 ) . Grade 3 - 4 neutropenia ( 34 % vs. 19 % ) , thrombocytopenia ( 0 % vs. 7 % ) , nausea ( 33 % vs. 31 % ) , vomiting ( 17 % vs. 19 % ) , hospitalization days per month of survival ( 7.4 + /- 1.7 days vs. 8.0 + /- 1.3 days ) , and full dose of RT received ( 78 % vs. 75 % ) were not significantly different between the GEM CCRT and 5-FU CCRT patients . CONCLUSION GEM CCRT appears more effective than 5-FU CCRT for locally advanced pancreatic cancer and has comparable tolerability Purpose This study evaluated PX-12 , a novel small molecule inhibitor of the proto-oncogene ( Trx-1 ) , in patients with previously treated advanced pancreatic cancer ( APC ) . Methods PX-12 ( 54 or 128 mg/m2 ) was administered by 3-hour IV infusion daily ×5 days every 21 days ( n = 17 ) . Patients were r and omized to either 54 or 128 mg/m2 and then stratified based on CA 19 - 9 level ( ≥1,000 vs. < 1,000 U/ml ) and SUV values on PET scans ( ≥7.0 vs. < 7.0 ) . The primary endpoint was based on a progression-free survival ( PFS ) at 4 months in ≥40 % of patients , and required 40 patients in each arm . An amendment required elevated Trx-1 levels ( > 18 ng/ml ) as an entry criteria after the first 17 patients were accrued . Results Plasma Trx-1 levels were elevated in 3/28 ( 11 % ) patients screened for study . The grade of the expired metabolite odor was higher in the 128 mg/m2 arm . Therapy was well tolerated , and Grade ≥3 adverse events were uncommon . The best response was stable disease in 2 patients . There was no consistent decrease in SUV , Trx-1 levels or CA 19 - 9 levels with therapy . No patients had a PFS of > 4 months . Median PFS and survival were 0.9 months ( 95 % CI 0.5–1.2 ) and 3.2 months ( 95 % CI 2.4–4.2 ) , respectively . Conclusions Due to the lack of significant antitumor activity and unexpectedly low baseline Trx-1 levels , the study was terminated early . PX-12 does not appear to be active in unselected patients with previously treated APC Sixty‐six patients with advanced pancreatic carcinoma were r and omized to receive single agent chemotherapy with either adriamycin , methotrexate , or actinomycin‐D using conventional dose , route and schedule of administration . All patients had measurable lesions which were used for objective assessment of response . For adriamycin , 2 of 25 patients ( 8 % ) evidence d a partial response ( 2 of 15 ( 13 % ) previously untreated patients ) . One of 25 patients treated with methotrexate and one of 28 who received actinomycin‐D responded . The duration of responses ranged from 43–64 days for those patients with no chemotherapy prior to study entry . The median survival of patients who received adriamycin as initial treatment was 12 weeks compared to 8 weeks for methotrexate and 6 weeks for actinomycin‐D therapy A prospect i ve r and omized trial comparing streptozotocin , mitomycin C , and 5‐FU ( SMF ) with mitomycin C and 5‐FU ( MF ) in patients with advanced pancreatic cancer was performed . In patients with measurable disease the response rates were 34 % ( 19/56 ) to SMF , and 8 % ( 5/60 ) to MF ( P = 0.009 ) . Median survivals were similar , however , 18 versus 17 weeks ( P = 0.356 ) . Median survival of patients responding to chemotherapy was 33 weeks , and for nonresponders it was 17 weeks ( P = 0.002 ) . In patients with nonmeasurable disease  , median survivals were 21 weeks ( SMF ) and 18 weeks ( MF ) ( P = 0.797 ) . Patients surviving ⩾48 weeks , however , appeared to be increased in the SMF arm ( 14 patients ) compared to the MF ( 7 patients ) . Toxicity was moderate for both regimens , with SMF having greater gastrointestinal and renal toxicity . Chemotherapy with SMF appears to produce objective responses in patients with pancreatic cancer , but does not improve survival compared to MF BACKGROUND / AIMS Phase II trials of combined 5 fluorouracil , leucovorin and cisplatin have demonstrated an 18 - 28 % response rate in advanced pancreatic carcinomas . We investigated the effect of this chemotherapy regime on patients ' survival .  METHODOLOGY Patients included gave informed consent . They had an advanced and proven pancreatic adenocarcinoma . The trial was multicentric , prospect i ve and r and omized . It compared a 5-day course of leucovorin ( 200 mg/m2/day ) , 5-fluorouracil ( 375 mg/m2/day ) and cisplatin ( 15 mg/m2/day ) repeated every 21 days ( 23 patients ) with a  control group ( 22 patients ) . The main end points were survival time ( Kaplan-Meier and log-rank methods ) a[not readable : see text]side effects of chemotherapy . RESULTS Association of leucovorin , 5-fluorouracil and cisplatin failed to demonstrate any advantage of this regimen compared with supported care alone . Median survival times were 8.6 months ( SD + /- 1.8 ) and 7.0 months ( SD + /- 0.6 ) , respectively . The modulation of 5-fluorouracil by leucovorin and cisplatin was well tolerated with moderate toxic effects . CONCLUSIONS This multicentric trial failed to demonstrate any advantage of the evaluated chemotherapy regime in the palliative treatment of cancer of the exocrine pancreas . Other trials including gemcitabine and /or radiotherapy are needed in advanced pancreatic adenocarcinoma PURPOSE Patients with advanced pancreatic cancer have a poor prognosis and there have been no improvements in survival since the introduction of gemcitabine in 1996 . Pancreatic tumors often overexpress human epidermal growth factor receptor type 1 ( HER1/EGFR ) and this is associated with a worse prognosis . We studied the effects of adding the HER1/EGFR-targeted agent erlotinib to gemcitabine in patients with unresectable , locally advanced , or metastatic pancreatic cancer . PATIENTS AND METHODS Patients were r and omly assigned 1:1 to receive st and ard gemcitabine plus erlotinib ( 100 or 150 mg/d orally ) or gemcitabine plus placebo in a double-blind , international phase III trial . The primary end point was overall survival . RESULTS A total of 569 patients were r and omly assigned .  Overall survival based on an intent-to-treat analysis was significantly prolonged on the erlotinib/gemcitabine arm with a hazard ratio ( HR ) of 0.82 ( 95 % CI , 0.69 to 0.99 ; P = .038 , adjusted for stratification factors ; median 6.24 months v 5.91 months ) . One-year survival was also greater with erlotinib plus gemcitabine ( 23 % v 17 % ; P = .023 ) . Progression-free survival was significantly longer with erlotinib plus gemcitabine with an estimated HR of 0.77 ( 95 % CI , 0.64 to 0.92 ; P = .004 ) . Objective response rates were not significantly different between the arms , although more patients on erlotinib had disease stabilization . There was a higher incidence of some adverse events with erlotinib plus gemcitabine , but most were grade 1 or 2 . CONCLUSION To our knowledge , this r and omized phase III trial is the first to demonstrate statistically significantly improved survival in advanced pancreatic cancer by adding any agent to gemcitabine . The recommended dose of erlotinib with gemcitabine for this indication is 100 mg/d PURPOSE Exatecan mesylate is a hexacyclic , water-soluble , topoisomerase-1 inhibitor . Exatecan has single-agent and combination activity with gemcitabine in advanced pancreatic cancer . A multicenter , r and omized , phase III trial comparing exatecan plus gemcitabine versus gemcitabine alone in advanced pancreatic cancer was conducted . PATIENTS AND METHODS Eligibility criteria included Karnofsky performance status > or = 60 % , locally advanced or metastatic pancreatic adenocarcinoma , and no prior chemotherapy .  Radiation alone for locally advanced disease was permitted . Patients were r and omly assigned on a 1:1 basis . For the exatecan plus gemcitabine arm , exatecan 2.0 mg/m2 and gemcitabine 1,000 mg/m2 were administered on days 1 and 8 , every 3 weeks . Gemcitabine alone was dosed at 1,000 mg/m2 up to 7 weeks in the first cycle , then once a week for the first 3 weeks of a 4-week cycle . Tumor assessment was performed every 6 weeks . The primary end point was overall survival . An intent-to-treat analysis was used . RESULTS From August 2001 to January 2003 , 349 patients were r and omly assigned , 175 to exatecan plus gemcitabine and 174 to gemcitabine alone . Twenty-four patients ( 6.9 % ) were not treated . The median survival time was 6.7 months for exatecan plus gemcitabine and 6.2 months for gemcitabine alone ( P = .52 ) . One complete response ( CR ; < 1 % ) and 11 partial responses ( PRs ; 6.3 % ) were observed in the exatecan plus gemcitabine treatment group , and one CR ( < 1 % ) and eight PRs ( 4.6 % ) were observed in the gemcitabine-alone group . Grade 3 and 4 toxicities were higher for the exatecan plus gemcitabine arm versus the gemcitabine alone arm ; neutropenia ( 30 % v 15 % ) and thrombocytopenia ( 15 % v 4 % ) . CONCLUSION Exatecan plus gemcitabine was not superior to gemcitabine alone with respect to overall survival in the first-line treatment of advanced pancreatic cancer BACKGROUND Patients with advanced pancreatic adenocarcinoma have a  poor response , progression-free survival , and overall survival with st and ard treatment . We aim ed to assess whether a four-drug regimen could improve 4 month progression-free survival compared with gemcitabine alone . METHODS In a r and omised multicentre phase III trial , 52 patients were r and omly assigned to 40 mg/m2 cisplatin and 40 mg/m2 epirubicin both given on day 1 , 600 mg/m2 gemcitabine given intravenously over 1 h on days 1 and 8 , and 200 mg/m2 fluorouracil a day given by continuous infusion on days 1 - 28 of a 4-week cycle ( PEFG regimen ) , and 47 were assigned to 1000 mg/m2 gemcitabine given intravenously over 30 min once a week for 7 of 8 consecutive weeks in cycle 1 and for 3 of 4 weeks thereafter . The primary endpoint was 4-month progression-free survival . Secondary endpoints were overall survival , objective response , safety , and quality of life . Analyses were by intention to treat . FINDINGS 51 patients assigned PEFG  and 46 assigned  gemcitabine  alone had disease progression . 49 patients in the PEFG group and 46 in the gemcitabine group died from progressive disease . More patients allocated PEFG than gemcitabine alone were alive without progressive disease at 4 months ( 60 % [ 95 % CI 46 - 72 ] vs 28 % [ 17 - 42 ] ; hazard ratio [ HR ] 0.46 [ 0.26 - 0.79 ] ) . 1-year overall survival in the PEFG group was 38.5 % ( 25.3 - 51.7 ) and in the gemcitabine group was 21.3 % ( 9.6 - 33.0 ; HR 0.68 [ 0.42 - 1.09 ] ) . More patients assigned PEFG showed disease response than did those assigned gemcitabine ( 38.5 % [ 25.3 - 51.7 ] vs 8.5 % [ 0.5 - 16.5 ] ; odds ratio 6.60 [ 2.11 - 20.60 ] , p=0.0008 ) . More patients in the PEFG group had grade 3 - 4 neutropenia and thrombocytopenia than in the gemcitabine group ( p<0.0001 ) . INTERPRETATION The PEFG regimen could be considered for treatment of advanced pancreatic adenocarcinoma BACKGROUND A prospect i ve , r and omized phase II study , with m and atory tumor sampling at current disease stage , aim ed to identify biomarkers predictive of improved progression-free survival ( PFS ) in patients with pancreatic cancer treated with erlotinib .  PATIENTS AND METHODS Patients with histologically/cytologically confirmed , unresectable , locally advanced/metastatic pancreatic cancer , who had failed on or were unsuitable for first-line chemotherapy , underwent a tumor biopsy  and were then r and omized to receive once-daily erlotinib 150 mg or placebo . The primary end point was identification of biomarkers predicting improved PFS with erlotinib . Secondary end points included PFS , overall survival , response and toxicity . RESULTS At data cut-off , 207 patients were enrolled and analyzed . Prespecified biomarker analyses of EGFR protein expression , EGFR gene copy number/mutations/polymorphisms and KRAS mutations did not identify any subgroups with a detrimental effect or a strong benefit for PFS with erlotinib . In the primary analysis , the median PFS was 6.1 versus 5.9 weeks in the erlotinib and placebo arms , respectively [ hazard ratio ( HR ) 0.83 ; 95 % confidence interval ( CI ) 0.63 - 1.10 ; P = 0.1909 ] . However , observed baseline imbalances indicated worse prognosis in the erlotinib arm . After adjustment for baseline characteristics , a significant PFS benefit for erlotinib was observed ( HR 0.68 ; 95 % CI 0.50 - 0.91 ; P = 0.0102 ) . Exploratory biomarker analyses showed patients with high baseline serum amphiregulin levels might benefit from erlotinib . CONCLUSION This study in patients with inoperable pancreatic cancer did not identify any prespecified biomarkers predictive of PFS benefit with erlotinib . Exploratory analyses suggested high amphiregulin might predict PFS benefit  from erlotinib . CLINICAL TRIALSGOV NUMBER NCT00674973 BACKGROUND / AIMS The efficacy of combination chemotherapy , which consists of fluorouracil , doxorubicin and mitomycin , was compared with that of palliative surgery-only in patients ( control ) having non-resectable pancreatic and biliary carcinomas in a multicenter r and omized trial . METHODOLOGY The patients were assigned to combination chemotherapy consisting of concomitant 5-fluorouracil 200 mg/m2 , doxorubicin 15 mg/m2 , and mitomycin 5 mg/m2 by intravenous administration . This combination chemotherapy was given concurrently as the initial dose within 1 week after palliative operation , and this regimen was repeated for at least 2 whole courses at 4-week intervals before the next course of therapy . Forty-two cases of this combination chemotherapy group and 41 of the control group were completely eligible for analysis . RESULTS Regarding the overall 50 % inhibition of tumor progression and that of gallbladder carcinoma , there were significantly better outcomes in the modified FAM therapy group . In this group , tumor reduction was achieved in 1 complete response ( CR ) and 2 partial response ( PR ) patients . With respect to the overall and differentiated survival times according to the tumor sites and the clinical efficacy , there was no difference between the groups . The most frequent adverse reactions were gastrointestinal manifestations such as anorexia , nausea , vomiting , and diarrhea ; also noted was alopecia . CONCLUSIONS Since this combination chemotherapy inhibited the tumor progression for significantly longer duration and , to a lesser extent , reduced the tumor size in non-resectable gallbladder carcinomas compared to a non-administrated chemotherapy group , this study will function as the basis for pursuing a more effective chemotherapy ZD9331 is a novel antifolate inhibitor of thymidylate synthase ( TS ) . This multicentre , r and omised , phase II/III study compared the efficacy and safety of ZD9331 with gemcitabine in 55 patients with chemonai;ve , locally advanced or metastatic pancreatic cancer . Patients received intravenous ( i.v . ) ZD9331 ( n=30 ) , on days 1 and 8 of a 3-week cycle or i.v . gemcitabine ( n=25 ) , once a week for 7 weeks followed by a 1-week rest , then on days 1 , 8 and 15 of a 4-week cycle . Objective tumour response and clinical benefit response ( CBR ) were similar for both groups . More ZD9331 patients were alive at the data cut-off point compared with gemcitabine patients ( 13 and 8 % , respectively ) . Median survival ( 152 versus 109 days , respectively ) and time to progression ( 70 versus 58 days , respectively ) were longer in the ZD9331 group . Nausea and vomiting ( grade 1/2 ) were the most common toxicities in both groups . These results suggest that , in pancreatic cancer , ZD9331 is equivalent to gemcitabine and may offer a promising alternative to current therapies PURPOSE Both gemcitabine ( GEM ) and fluoropyrimidines are valuable treatment for advanced pancreatic cancer . This open-label study was design ed to compare the overall survival ( OS ) of patients r and omly assigned to GEM alone or GEM plus capecitabine ( GEM-CAP ) .  PATIENTS AND METHODS Patients with previously untreated histologically or cytologically proven locally advanced or metastatic carcinoma of the pancreas with a performance status < or= 2 were recruited . Patients were r and omly assigned to GEM or GEM-CAP . The primary outcome measure was survival . Meta- analysis of published studies was also conducted . RESULTS Between May 2002 and January 2005 , 533 patients were r and omly assigned to GEM  ( n = 266 ) and  GEM-CAP  ( n = 267 ) arms . GEM-CAP significantly improved objective response rate ( 19.1 % v 12.4 % ; P = .034 ) and progression-free survival ( hazard ratio [ HR ] , 0.78 ; 95 % CI , 0.66 to 0.93 ; P = .004 ) and was associated with a trend toward improved OS ( HR , 0.86 ; 95 % CI , 0.72 to 1.02 ; P = .08 ) compared with GEM alone . This trend for OS benefit for GEM-CAP was consistent across different prognostic subgroups according to baseline stratification factors ( stage and performance status ) and remained after adjusting for these stratification factors ( P = .077 ) . Moreover , the meta- analysis of two additional studies involving 935 patients showed a significant survival benefit in favor of GEM-CAP ( HR , 0.86 ; 95 % CI , 0.75 to 0.98 ; P = .02 ) with no intertrial heterogeneity . CONCLUSION On the basis of our trial and the meta- analysis , GEM-CAP should be considered as one of the st and ard first-line options in locally advanced and metastatic pancreatic cancer Forty patients with inoperable pancreatic cancer were included in a prospect i ve , r and omised , controlled trial of multiple chemotherapy . The survival of 19 untreated control patients was compared with that of 21 patients who received an initiation course of intravenous fluorouracil , cyclophosphamide , methotrexate , and vincristine given over five days followed by intravenous fluorouracil and mitomycin given over three or five days at six-week intervals thereafter . Median survival in treated patients was 44 weeks , which was significantly longer than the nine weeks seen in controls . In patients without metastases  median survival was 48 weeks in the treated group and 12 weeks in controls . In patients with metastases it was 30 weeks in treated patients and seven weeks in controls . The treatment was well tolerated and seemed to confer a significant prolongation of survival , comparing favourably with previous reports of chemotherapy with or without radiotherapy . If the results are confirmed this regimen may be useful in district general hospital practice 4102 Background : TNFerade is a second-generation replication-deficient adenovector , carrying the transgene encoding human TNF-α , regulated by the stress-inducible promoter Egr-1 . In a phase I trial of TNFerade + radiation in 36 patients with advanced or refractory solid tumors , a 47 % objective tumor response rate was observed , including 100 % complete responses in 3 stage 4 melanoma patients , with 2/3 disease-free at > 3.5 years . METHODS This controlled phase II trial r and omizes 74 patients with newly diagnosed unresectable LAPC to 5-wks of TNFerade ( 4 × 1011 pu via weekly intratumoral injection ) + CRT ( 5-FU [ 200 mg/m2/day CIV × 5 days/wk ] and 50.4 Gy radiation ) or CRT alone .  All patients receive maintenance gemcitabine . ENDPOINTS Progression-free survival , safety , radiographic tumor response , CA 19 - 9 and survival . RESULTS In dose escalation ( n=50 ) dose-limiting toxicities occurred in 3 patients at 1 × 1012 pu ( pancreatitis in 2 and biliary obstruction ) , setting the MTD at 4 × 1011 pu . Compared with the first two cohorts ( n=30 ) , the MTD ( n = 11 ) was associated with greater locoregional control and progression-free survival , a higher rate of stable or decreasing CA 19 - 9 , improved overall survival ( median = 11.2 ) , and a high ( 45 % ) resection rate . Accrual continues in the r and omized phase of the study at 20 + centers . The most frequent adverse events in the first 16 enrolled patients have been nausea ( 75 % ) , abdominal pain ( 63 % ) , constipation ( 50 % ) , anemia ( 38 % ) , diarrhea ( 38 % ) , vomiting ( 38 % ) , and weight loss ( 38 % ) , with no significant difference in severity or frequency between the TNFerade + CRT and CRT groups . No thromboembolic events have been reported . Serum TNF-alpha levels have remained low ( peak = 45.3 pg/mL , in a CRT patient ) . CA 19 - 9 has been stable ( no change > 100 U/mL ) or decreased in all but one CRT patient . CONCLUSIONS These initial data indicate that TNFerade plus CRT , given as weekly intratumoral injections to patients with LAPC , is feasible and tolerable compared to CRT alone . With continued accrual , comparative tumor response and toxicity data will be available and up date d. No significant financial relationships to disclose OBJECTIVE To study the effect of Qi replenishing and blood circulation activating drugs ( QRBCAD ) in treatment of middle-advanced pancreatic cancer with radio- and chemotherapy . METHODS Patients were divided r and omly into two groups , 28 patients treated with radiotherapy and intervention treatment as Group A and 30 patients treated with the same therapy but with additional QRBCAD medication  as the Group B , and the effects in the two groups were compared . RESULTS The short-term effective rate in Group A and B was 53.6 % and 67.6 % respectively ( P < 0.05 ) . The remission rates of jaundice and abdominal pain in Group A were 57.1 % and 50.0 % respectively , while in Group B , 83.3 % and 76.7 % respectively , there was significant difference between the two groups , P < 0.05 . The gastroenteric reaction occurred in Group B was significantly lesser than that in Group A , P < 0.05 . The 1- and 2-year survival rate in Group A were 50 % and 21.4 % , and in Group B , 80.0 % and 46.6 % respectively , significant difference ( P < 0.05 ) showed in comparison of the two groups . CONCLUSION QRBCAD could alleviate the gastroenteric reaction caused by radio- and chemotherapy , raise the clinical symptomatic effective rate of treatment , and prolong the 1- and 2-year survival rate of patients Fifty-two patients with advanced gastrointestinal ( GI ) malignancies who had not received previous chemotherapy or radiation therapy  were r and omized to be treated either with 24-hour infusion of weekly fluorouracil ( 5-FU ) or the same plus N-(phosphonacetyl)-L-aspartic acid ( PALA ) .  Forty-seven patients were evaluable for the assessment of toxicity and antitumor activity .  PALA was administered as an intravenous ( IV ) bolus over 15 minutes at a fixed dose , 250 mg/m2 . The latter agent was administered 24 hours before the start of 5-FU infusion . 5-FU was initially administered at 750 mg/m2 and was incrementally increased to 3,400 mg/m2 . In both arms of the r and omized study , the courses were repeated every week . In both arms of the study , ataxia and myelosuppression were the dose-limiting toxic effects . At 5-FU dose of 3,400 mg/m2 , one patient in each arm developed grade 3 hematologic toxicity . Other reversible side effects included grade 2 skin changes , nausea , and vomiting . During the administration of 2,600 mg/m2 of 5-FU over 24 hours , the steady state plasma 5-FU concentration was approximately 20 mumol/L. The maximum tolerated dose ( MTD ) for 5-FU for protracted treatment is 2,600 mg/m2 in either arm of the study . Therapeutic response was predominantly seen in the combination arm : there were two patients with complete response ( CR ) and 11 patients with partial response ( PR ) of 28 patients in the study . In the 5-FU alone arm there were four PR and 19 patients in the study ABSTRACT Aim : Simtuzumab ( SIM ) is a humanized antibody that inhibits lysyl oxidase-like molecule 2 ( LOXL2 ) , an extracellular matrix enzyme that catalyzes the covalent cross-linking of collagen and is widely expressed across desmoplastic tumors . Inhibiting LOXL2 is expected to block formation of desmoplasia , which is thought to play an important role in tumor progression and metastasis . In the Phase 1 study , SIM was safe and well-tolerated in patients ( pts ) with advanced solid tumors and showed early evidence of efficacy . Based on these results , a r and omized , double-blind , placebo-controlled phase 2 study of SIM + gemcitabine ( Gem ) vs. placebo ( pbo ) + Gem in pts with metastatic pancreatic adenocarcinoma was initiated . Methods : Eligible pts had no prior systemic therapy for advanced disease and Eastern Cooperative Oncology Group performance status of 0 or 1 . The primary endpoint was progression free survival ( PFS ) . Pts were r and omized to 200 mg SIM , 700 mg SIM , or pbo at a 1:1:1 ratio in combination with Gem in cycles of 28 days . In each cycle , pts received IV SIM or pbo infused on Days 1 and 15 , and IV Gem ( 1000 mg/m2 ) on Days 1 , 8 , and 15 . Results : Between 3/28/12 and 5/15/13 , 236 pts were r and omized and treated ; 76 pts ( 200 mg SIM/Gem ) , 79 pts ( 700 mg SIM/Gem ) , and 81 pts ( pbo/Gem ) . Median PFS was 3.5 ( HR 1.12 ; p = 0.63 vs pbo ) , 3.7 ( HR 1.08 ; p = 0.75 vs pbo ) , and 3.7 months for 200 mg SIM/Gem , 700 mg SIM/Gem , and pbo/Gem arms , respectively . Median overall survival ( OS ) was 5.9 ( HR 1.05 ; p = 0.76 vs pbo ) , 7.6 ( HR 0.83 ; p = 0.26 vs pbo ) , and 5.7 months , respectively . Gemcitabine-related expected toxicities included anemia , thrombocytopenia , neutropenia , and nausea . There were no differences in the safety profile of the SIM plus Gem groups versus pbo plus Gem group . Conclusions : The addition of SIM to Gem does not improve PFS or OS in advanced pancreatic cancer pts . Disclosure : H. Dong : is an employee of Gilead Sciences , the sponsor of the clinical study , and holds shares of Gilead stock ; D. Thai : is an employee of Gilead Sciences , the sponsor of the clinical study , and holds shares of Gilead stock . All other authors have declared no conflicts of interest In a study of 127 patients with advanced measurable pancreatic cancer , objective response rates of 2 % ( melphalan ) , 10 % ( 5-FU and methyl-CCNU ) , and 7 % ( 5-FU , methyl-CCNU , and streptozocin ) were achieved . No responses occurred in the 28 patients treated with VP-16 - 213 who had already received prior chemotherapy .  Toxicity was greater for the two- and three-drug combinations than for melphalan . There was no difference in survival following use of the three treatment regimens . Further studies are needed to develop effective chemotherapy for patients with cancer of the pancreas BACKGROUND In certain patients with pancreatic and biliary cancer , chemotherapy may relieve tumour-related symptoms , improve quality of life and possibly prolong survival . The extent of these improvements is not completely known in spite of the extensive use of this treatment modality . The aim of this study was to estimate any gain in the quantity and quality of life produced by chemotherapy in patients with pancreatic and biliary cancer . PATIENTS AND METHODS Between January 1991 and February 1995 , 90 eligible patients with pancreatic or biliary cancer were r and omized to either  chemotherapy in addition to best supportive care or to best supportive care . Chemotherapy was allowed in the latter group if the supportive measures did not lead to palliation . Chemotherapy was either sequential 5-fluorouracil/leucovorin combined with etoposide ( FELv ) or , in elderly and poor performance patients , the same regimen without etoposide ( FLv ) .  Quality of life was evaluated with the EORTC-QLQ-C30 instrument . RESULTS Mean scale scores in the QLQ-C30 improved more often/deteriorated less frequently in the chemotherapy group than in the best supportive care group . More patients in the chemotherapy group ( 36 % , 17/49 ) had an improved or prolonged high quality of life for a minimum period of 4 months compared to those in the best supportive care group ( 10 % , 4/41 , P < 0.01 ) . Overall survival was significantly longer in the chemotherapy group ( median 6 vs. 2.5 months , P < 0.01 ) . Also , the quality -adjusted survival time was longer for patients r and omized to chemotherapy ( median 4 vs. 1 months , P < 0.01 ) . The effects were seen both in pancreatic and biliary cancer . CONCLUSIONS The results show that chemotherapy can add to both quantity and quality of life in advanced pancreatic and biliary cancer . The number of patients who benefit from treatment is , however , still limited ; for this reason careful selection before , and close monitoring during , treatment are necessary PURPOSE The median survival time of patients with locally advanced adenocarcinoma of the pancreas is 8 - 10 months . Radiation therapy has been used to improve local control and palliate symptoms . This r and omized study was undertaken to determine whether the addition of 5-fluorouracil ( 5-FU ) and mitomycin-C ( MMC ) to radiation therapy improves outcome in this patient population . PATIENTS AND METHODS One hundred fourteen patients were r and omized to receive 59.4 Gy external beam radiotherapy in 1.8 Gy fractions alone or in combination with 5-FU ( 1,000 mg/m2/day for 4 days by continuous infusion Days 2 - 5 and 28 - 31 ) and MMC ( 10 mg/m2 on Day 2 ) . RESULTS One hundred four patients were evaluable for efficacy . Hematologic and nonhematologic toxicities were more common in the combination arm . The response rates were 6 % in the radiation therapy arm and 9 % in the combination arm . There were no differences in median disease-free survival time ( DFS ) or overall survival time ( OS ) between the combination and radiation therapy alone arms : 5.1 vs. 5.0 months , respectively , for DFS ( p = 0.19 ) and 8.4 vs. 7.1 months , respectively , for OS ( p = 0.16 ) . CONCLUSION The addition of 5-FU and MMC to radiotherapy increased toxicity without improving DFS or OS in patients with locally advanced pancreatic cancer . Alternative drugs for radiosensitization may improve outcome BACKGROUND / AIMS In an attempt to improve treatment protocol s for advanced pancreatic cancer , the value of regional chemotherapy compared with systemic chemotherapy was investigated in this r and omized study . METHODOLOGY Fourteen patients with advanced non-resectable pancreatic adenocarcinoma were r and omized receiving either systemic chemotherapy with mitomycin , mitoxanthrone and cisplatin ( 5pts . ) or celiac axis infusion regional chemotherapy with SpherexR microembolization . In the systemic group one patient was stage III , four patients were stage IV , in the intraarterial group two patients were specified stage III and seven were stage IV . RESULTS In the systemic group one stable disease and four progressive diseases were noted , in the regional group two stable diseases and seven partial responses were noted . Median survival was 11 weeks in the systemically treated patients versus 33 weeks in the patients treated with intraarterial infusion ( p=0.001 ) . One patient became resectable ( R0 ) . CONCLUSIONS Performance status improved during regional chemotherapy whilst it steadily decreased in the patients treated systemically . The study was terminated at that point PURPOSE Single-agent gemcitabine became st and ard first-line treatment for advanced pancreatic cancer after demonstration of superiority compared with fluorouracil . The Gruppo Italiano Pancreas 1 r and omized phase III trial aim ed to compare gemcitabine plus cisplatin versus gemcitabine alone ( Clinical Trials.gov ID NCT00813696 ) . PATIENTS AND METHODS Patients with locally advanced or metastatic pancreatic cancer , age 18 to 75 years , and Karnofsky performance status ( KPS ) > or = 50 , were r and omly assigned to receive gemcitabine ( arm A ) or gemcitabine plus cisplatin ( arm B ) . Arm A : gemcitabine 1,000 mg/m(2 ) weekly for 7 weeks , and , after a 1-week rest , on days 1 , 8 , and 15 every 4 weeks . Arm B : cisplatin 25 mg/m(2 ) added weekly to gemcitabine , except cycle 1 day 22 . Primary end point was overall survival . To have 8 % power of detecting a 0.74 hazard ratio ( HR ) of death , with bilateral alpha .05 , 355 events were needed and 400 patients planned . RESULTS Four hundred patients were enrolled ( arm A : 199 ; arm B : 201 ) . Median age was 63 , 59 % were male , 84 % had stage IV , and 83 % had KPS > or = 80 .  Median overall survival was 8.3 months versus 7.2 months in arm A and B , respectively ( HR , 1.10 ; 95 % CI , 0.89 to 1.35 ; P = .38 ) . Median progression-free survival was 3.9 months versus 3.8 months in arm A and B , respectively ( HR , 0.97 ; 95 % CI , 0.80 to 1.19 ; P = .80 ) . The objective response rate was 10.1 % in A and 12.9 % in B ( P = .37 ) . Clinical benefit was experienced by 23.0 % in A and 15.1 % in B ( P = .057 ) . Combination therapy produced more hematologic toxicity , without relevant differences in nonhematologic toxicity . CONCLUSION The addition of weekly cisplatin to gemcitabine failed to demonstrate any improvement as first-line treatment of advanced pancreatic cancer PURPOSE To conduct a r and omized phase II trial of dose-intense gemcitabine using a st and ard 30-minute infusion or the fixed dose rate ( FDR ) infusion ( 10 mg/m2/min ) in patients with pancreatic adenocarcinoma . PATIENTS AND METHODS In this prospect i ve trial , patients with locally advanced and metastatic pancreatic adenocarcinoma were treated with 2,200 mg/m2 gemcitabine over 30 minutes ( st and ard arm ) or 1,500 mg/m2 gemcitabine over 150 minutes ( FDR arm ) on days 1 , 8 , and 15 of every 4-week cycle . The primary end point of this trial was time to treatment failure . Secondary end points included time to progression , median survival , safety , and pharmacokinetic studies of gemcitabine  . RESULTS Ninety-two patients were enrolled onto this study ; 91 % of the patients had metastatic disease .  Time to treatment failure was comparable in both treatment groups ; however , the median survival for all patients was 5.0 months in the st and ard arm and 8.0 months in the FDR arm ( P = .013 ) . For patients with metastases , the median survival was 4.9 months in the st and ard arm and 7.3 months in FDR arm ( P = .094 ) . The 1- and 2-year survival rates for all patients were 9 % ( st and ard arm ) versus 28.8 % ( FDR ; P = .014 ) and 2.2 % ( st and ard arm ) versus 18.3 % ( FDR ; P = .007 ) , respectively . Patients in the FDR infusion arm experienced consistently more hematologic toxicity . Pharmacokinetic analyses demonstrated a two-fold increase in intracellular gemcitabine triphosphate concentration in the FDR arm ( P = .046 ) . CONCLUSION Pharmacokinetic and clinical data in this trial supports the continued evaluation of the FDR infusion strategy with gemcitabine PURPOSE To compare the effectiveness and tolerability of gemcitabine plus cisplatin with single-agent gemcitabine as first-line chemotherapy for locally advanced or metastatic pancreatic cancer . PATIENTS AND METHODS Patients with advanced adenocarcinoma of the pancreas were r and omly assigned to receive either gemcitabine 1,000 mg/m2 and cisplatin 50 mg/m2 given on days 1 and 15 of a 4-week cycle ( GemCis arm ) or gemcitabine alone at a dose of 1,000 mg/m2 on days 1 , 8 , and 15 of a 4-week regimen ( Gem arm ) . The primary end point was overall survival ; secondary end points were progression-free survival , response rate , safety , and quality of life . RESULTS One hundred ninety-five patients were enrolled and showed baseline characteristics well balanced between treatment arms . Combination treatment in the GemCis arm was associated with a prolonged median progression-free survival ( 5.3 months v 3.1 months ; hazard ratio [ HR ] = 0.75 ; P = .053 ) . Also , median overall survival was superior for patients treated in the GemCis arm as compared with the Gem arm ( 7.5 v 6.0 months ) , an advantage which did not , however , reach statistical significance ( HR = 0.80 ; P = .15 ) . Tumor response rates were comparable between treatment arms ( 10.2 % v 8.2 % ) . The rate of stable disease was , however , greater in the combination arm ( 60.2 % v 40.2 % ; P < .001 ) . Grade 3 to 4 hematologic toxicity did not exceed 15 % in both treatment arms . CONCLUSION These results support the efficacy and safety of an every-2-weeks treatment with gemcitabine plus cisplatin .  Median overall survival and progression-free survival were more favorable in the combination arm as compared with gemcitabine alone , although the difference did not attain statistical significance Objectives This study aim ed to investigate G17DT , an immunogen producing neutralizing antibodies against the tumor growth factors ami date d and glycine-extended forms of gastrin-17 , in the treatment of pancreatic cancer . Methods A r and omized , double-blind , placebo-controlled , group-sequential multicenter trial of G17DT in patients with advanced pancreatic cancer unsuitable for or unwilling to take chemotherapy . Inclusion criteria were a Karnofsky performance score of 60 or higher and a life expectancy of more than 2 months . Patients received G17DT or placebo emulsion at weeks 0 , 1 , 3 , 24 , and 52 . The primary end point was survival , and secondary end points were tolerability , Karnofsky performance . Results A total of 154 patients were recruited : 79 G17DT and 75 placebo .  A final analysis of the intention-to-treat population , using a proportional hazards model , stratifying by disease stage and adjusting for interim analysis , gave a hazard ratio for mortality of 0.75 ( 95 % confidence interval , 0.51–1.10 , P = 0.138 ; G17DT/placebo ) . A conventional analysis without adjustment for disease stage or interim analysis , censoring for chemotherapy and excluding protocol violators , gave median survival periods of 151 ( G17DT ) and 82 days ( placebo ) ( log-rank test , P = 0.03 ) . Patients developing anti-G17DT responses ( 73.8 % ) survived longer than nonresponders or those on placebo ( median survival , 176 vs 63 vs 83 ; log-rank test , P = 0.003 ) . G17DT was well tolerated . Abbreviations HR - hazard ratio , ITT - intention to treat , CI - confidence BACKGROUND The role of chemoradiation with systemic chemotherapy compared with chemotherapy alone in locally advanced pancreatic cancer ( LAPC ) is uncertain . PATIENTS AND METHODS One hundred and nineteen patients with LAPC , World Health Organization performance status of zero to two were r and omly assigned to either the induction CHRT group ( 60 Gy , 2 Gy/fraction ; concomitant 5-fluorouracil infusion , 300 mg/m(2)/day , days 1 - 5 for 6 weeks ; cisplatin , 20 mg/m(2)/day , days 1 - 5 during weeks 1 and 5 ) or the induction gemcitabine group ( GEM : 1000 mg/m(2 ) weekly for 7 weeks ) . Maintenance gemcitabine ( 1000 mg/m(2 ) weekly , 3/4 weeks ) was given in both arms until disease progression or toxicity . RESULTS Overall survival was shorter in the CHRT than in GEM arm [ median survival 8.6 ( 99 % confidence interval 7.1 - 11.4 ) and 13 months ( 8.7 - 18.1 ) , P = 0.03 ] . One-year survival was , respectively , 32 % and 53 % . These results were confirmed in a per- protocol analysis for patients who received 75 % or more of the planned dose of radiotherapy . More overall grade s 3 - 4 toxic effects were recorded in the CHRT arm , both during induction ( 36 versus 22 % ) and maintenance ( 32 versus 18 % ) . CONCLUSION This intensive induction schedule of CHRT was more toxic and less effective than gemcitabine alone Objective AIO-PK0104 investigated two treatment strategies in advanced pancreatic cancer ( PC ) : a reference sequence of gemcitabine/erlotinib followed by 2nd-line capecitabine was compared with a reverse experimental sequence of capecitabine/erlotinib followed by gemcitabine . Methods 281 patients with PC were r and omly assigned to 1st-line treatment with either gemcitabine plus erlotinib or capecitabine plus erlotinib . In case of treatment failure ( eg , disease progression or toxicity ) , patients were allocated to 2nd-line treatment with the comparator cytostatic drug without erlotinib . The primary study endpoint was time to treatment failure ( TTF ) after 1st- and 2nd-line therapy ( TTF2 ; non-inferiority design ) . KRAS exon 2 mutations were analysed in archival tumour tissue from 173 of the r and omised patients . Results Of the 274 eligible patients , 43 had locally advanced and 231 had metastatic disease ; 140 ( 51 % ) received 2nd-line chemotherapy .  Median TTF2 was estimated with 4.2 months in both arms ; median overall survival was 6.2 months with gemcitabine/erlotinib followed by capecitabine and 6.9 months with capecitabine/erlotinib followed by gemcitabine , respectively ( HR 1.02 , p=0.90 ) . TTF for 1st-line therapy ( TTF1 ) was significantly prolonged with gemcitabine/erlotinib compared to capecitabine/erlotinib ( 3.2 vs 2.2 months ; HR 0.69 , p=0.0034 ) . Skin rash was associated with both TTF2 ( rash grade 0/1/2–4:2.9/4.3/6.7 months , p<0.0001 ) and survival ( 3.4/7.0/9.6 months , p<0.0001 ) . Each arm showed a safe and manageable toxicity profile during 1st- and 2nd-line therapy . A KRAS wild-type status ( 52/173 patients , 30 % ) was associated with an improved overall survival ( HR 1.68 , p=0.005 ) . Conclusion Both treatment strategies are feasible and demonstrated comparable efficacy ; KRAS may serve as biomarker in patients with advanced PC treated with erlotinib . Trial registration number This study was registered at Clinical Trials.gov , number NCT00440167 . Significance of this study What is already known on this subject ? Gemcitabine-based chemotherapy remains an international st and ard of care for patients with non-resectable , advanced pancreatic cancer ( PC ) .  Anti-EGFR treatment with the tyrosine kinase inhibitor erlotinib , as well as chemotherapy intensification by application of the FOLFIRINOX regimen , both significantly improved overall survival in r and omised phase 3 trials . The optimal ( sequential ) regimen for the use of gemcitabine , erlotinib and the oral fluoropyrimidine capecitabine remains unclear in advanced PC . Molecular predictors for the efficacy of anti-EGFR treatments in PC have not been defined up to now . What are the new findings ? The sequential use of gemcitabine , erlotinib and capecitabine is safe and equally effective in PC ; gemcitabine appears to be more effective in 1st- and 2nd-line therapy than capecitabine and therefore remains the preferred combination partner for erlotinib .  Skin rash is strongly correlated with efficacy outcome measures in PC patients treated with erlotinib . KRAS wild-type status appears to be associated with improved overall survival in patients treated with erlotinib in this AIO study . Significance of this study How might it impact on clinical practice in the foreseeable future ? The benefit of adding erlotinib to chemotherapy is restricted to patients that experience skin rash during treatment ; non-rash patients are characterised by a very poor outcome and need to be offered novel treatment strategies . Second-line salvage chemotherapy is effective and safe in selected PC patients . KRAS could serve as the first biomarker for improved survival in erlotinib-treated patients ; the predictive value of KRAS for erlotinib efficacy remains to be defined prospect ively PURPOSE Single-agent gemcitabine ( GEM ) is st and ard treatment of metastatic pancreatic cancer . Fixed-dose rate ( FDR ) GEM and GEM plus oxaliplatin have shown promise in early clinical trials . E6201 was design ed to compare overall survival ( OS ) of st and ard weekly GEM 1,000 mg/m(2)/30 minutes versus GEM FDR 1,500 mg/m(2)/150 minutes or GEM 1,000 mg/m(2)/100 minutes/day 1 plus oxaliplatin 100 mg/m(2)/day 2 every 14 days ( GEMOX ) . METHODS This trial included patients with metastatic or locally advanced pancreatic cancer , normal organ function , and performance status of 0 to 2 . The study was design ed to detect a 33 % difference in median survival ( hazard ratio [ HR ] < or = 0.75 for either of the experimental arms ) with 81 % power while maintaining a significance level of 2.5 % in a two-sided test for each of the two primary comparisons . RESULTS Eight hundred thirty-two patients were enrolled . The median survival and 1-year survival were 4.9 months ( 95 % CI , 4.5 to 5.6 ) and 16 % for GEM , 6.2 months ( 95 % CI , 5.4 to 6.9 ) , and 21 % for GEM FDR ( HR , 0.83 ; stratified log-rank P = .04 ) , and 5.7 months ( 95 % CI , 4.9 to 6.5 ) and 21 % for GEMOX ( HR , 0.88 ; stratified log-rank P = .22 ) . Neither of these differences met the prespecified criteria for significance . Survival was 9.2 months for patients with locally advanced disease , and 5.4 months for those with metastatic disease . Grade 3/4 neutropenia and thrombocytopenia were greatest with GEM FDR . GEMOX caused higher rates of nausea , vomiting , and neuropathy . CONCLUSION Neither GEM FDR nor GEMOX result ed in substantially improved survival or symptom benefit over st and ard GEM in patients with advanced pancreatic cancer
BACKGROUND Pancreatic cancer ( PC ) is a highly lethal disease with few effective treatment options .
Over the past few decades , many anti-cancer therapies have been tested in the locally advanced and metastatic setting , with mixed results .
This review attempts to synthesis e all the r and omised data available to help better inform patient and clinician decision-making when dealing with this difficult disease .
OBJECTIVES To assess the effect of chemotherapy , radiotherapy or both for first-line treatment of advanced pancreatic cancer .
Our primary outcome was overall survival , while secondary outcomes include progression-free survival , grade 3/4 adverse events , therapy response and quality of life .