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. Gemcitabine-based polychemotherapy for advanced pancreatic cancer (APC): Is it ready for prime time? A pooled analysis of 3,682 patients (pts) enrolled in 12 phase III trials. 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. Increased survival using platinum analog combined with gemcitabine as compared to single-agent gemcitabine in advanced pancreatic cancer: pooled analysis of two randomized trials, the GERCOR/GISCAD intergroup study and a German multicenter study. 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. A randomised trial comparing 5-FU with 5-FU plus cisplatin in advanced pancreatic carcinoma. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial.
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 4118 Background : Since the introduction of gemcitabine ( G ) , attempts have been made to develop G-based combination regimens to improve the dismal outcome of APC pts . Results of r and omized trials , however , have been conflicting and single-agent G presently remains the st and ard of care for such pts . METHODS All prospect i ve phase III trials comparing  single-agent G with G-based polychemotherapy regimens ( poly-G ) were considered eligible . A pooled analysis was performed and event-based relative risk ratios ( RR ) with 95 % CI were derived through both a fixed- and a r and om-effect model approach , exploring OS as the primary outcome and PFS and ORR as secondary outcomes . Heterogeneity between different trials was also taken into account . RESULTS Twelve trials involving 3682 pts were identified . The analysis was conducted considering three different subgroups : 1 ) overall population ( 3682 patients , 12 trials ) , 2 ) platinum-containing poly-G ( PG ) vs G ( 768 pts , 5 trials ) , and 3 ) fluoropyrimidine-containing poly-G ( FG ) vs G ( 1640 pts , 4 trials ) . As shown in the table , no significant differences in the primary outcome ( OS ) were observed in any of the three groups analyzed . Conversely , a significant advantage for poly-G was evident with regard to both PFS and ORR in the overall population as well as in the PG vs G subgroup , although with some heterogeneity . A heterogeneous non-significant trend towards a better PFS and ORR outcome was also observed in the FG vs G subgroup . CONCLUSIONS Single-agent G remains the treatment of choice in APC pts . However , the addition of platinum compounds to G appears to significantly improve PFS and ORR , possibly justifying the use of platinum-based poly-G in younger and fit patients . [ Table : see text ] No significant financial relationships to disclose 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 BACKGROUND The aim was to evaluate the efficacy of gemcitabine combined with a platinum agent compared to single-agent gemcitabine in a pooled analysis of two r and omized trials . METHODS The French Multidisciplinary Clinical Research Group (GERCOR)/Italian Group for the Study of Gastrointestinal Tract Cancer ( GISCAD ) intergroup study comparing gemcitabine plus oxaliplatin to gemcitabine and a German multicenter trial comparing gemcitabine plus cisplatin versus gemcitabine were included in a pooled analysis based on individual patient data . RESULTS Among 503 evaluable patients , 252 received gemcitabine plus a platinum analog ( GP )  , while 251 patients were treated with gemcitabine alone . For progression-free survival ( PFS ) , the pooled univariate analysis indicated a hazard ratio ( HR ) of 0.75 ( P = 0.0030 ) in favour of the GP combination . The benefit from the GP combination was greatest in the subgroup of patients with performance status ( PS ) = 0 ( HR = 0.64 ; P = 0.013 ) . Also overall survival was significantly superior in patients receiving the GP combination ( HR = 0.81 ; P = 0.031 ) . Again , patients with PS = 0 appeared to have a greater benefit from treatment intensification ( HR = 0.72 ; P = 0.063 ) . CONCLUSION The pooled analysis of the GERCOR/GISCAD intergroup study and the German multicenter study indicates that the combination of gemcitabine with a platinum analog such as oxaliplatin or cisplatin significantly improves progression-free survival and overall survival as compared to single-agent gemcitabine in advanced pancreatic cancer . The benefit seems to prevail in patients with a good performance status 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 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 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
In advanced pancreatic cancer , level one evidence has established a significant survival advantage with chemotherapy , compared to best supportive care .
The treatment-associated toxicity needs to be evaluated .
This study examines the secondary outcome measures for chemotherapy  in advanced pancreatic cancer using meta-analyses .