Josep Tabernero|Teresa Macarulla
Changing the Paradigm in Conducting Randomized Clinical Studies in Advanced Pancreatic Cancer: An Opportunity for Better Clinical Development
Vall d'Hebron Hospital Universitari|Vall d'Hebron Hospital Universitari
pancreatic cancer constitutes fourth leading cause cancerrelated deaths united states symptoms typically occur late patients diagnosed advanced disease thus prognosis population patients remains poor estimated median overall survival mos 2 5 months supportive care gemcitabine considered standard treatment patients advanced pancreatic cancer since burris et al demonstrated pivotal study patients treated gemcitabine modest yet statistically significant improvement mos 565 v 441 months p 0025 significant clinical benefit 238 v 48 p 0022 compared patients treated fluorouracil however singleagent gemcitabine multiple trials consistently achieves mos figures approximately 6 months finding clearly indicates need development new treatment strategies various cytotoxic agents clinically investigated combination gemcitabine phase phase ii trials promising activity nevertheless gemcitabinebased combinations evaluated randomized phase iii trials compared singleagent gemcitabine results globally disappointing combinations resulted improvement objective response rate rr progressionfree survival pfs translated statistically clinically meaningful impact os case combinations gemcitabine platinum analogs contrast phase iii studies completely negative without suggestion increased efficacy combinations gemcitabine cytotoxic agents exatecan pemetrexed targeted agents tipifarnib marimastat capecitabine oral fluoropyrimidine evaluated combination gemcitabine one randomized phase ii two phase iii studies issue journal clinical oncology jco cunningham et al published results one largest studies metastatic pancreatic cancer conducted united kingdom medical research council comparing combination gemcitabine capecitabine gemcitabine single agent latter considered standard care setting although initial results study presented 2005 biannual european cancer organisation meeting positive primary end point study os mature data study published show combination gemcitabine capecitabine increased rr 191 v 124 p 034 statistically significant increase pfs hazard ratio hr 078 95 ci 066 093 p 004 trend towards improvement os hr 085 95 ci 072 102 p 08 singleagent gemcitabine treatment potential caveats study related wide range inclusion criteria patients either locally advanced metastatic disease enteredhaving two populations patients different prognosisas well patients either performance status 0 1 2 shown patients poor prognosis status benefit treatment advanced disease two factors among others may contributed dilute potential benefit combination gemcitabine single agent herrmann et al published results phase iii study evaluating similar gemcitabine capecitabine combination singleagent gemcitabine study also failed demonstrate advantage os primary objective similarly scheithauer et al also previously published results randomized phase ii study comparing combination gemcitabine plus capecitabine gemcitabine single agent study showing efficacy differences two arms note two additional studies capecitabine administered lower dose intensity sample size studies quite smaller cunningham et al study study cunningham et al issue jco authors addition performed metaanalysis also including patients two previously published studies evaluating combination gemcitabine capecitabine results metaanalysis total 935 patients demonstrate significant benefit os favoring combination arm hr 086 95 ci 075 098 p 002 gemcitabine single agent basis results authors concluded combination gemcitabine capecitabine considered new treatment option patients advanced pancreatic cancer nevertheless caution raised conclusion schedules dose intensities gemcitabine capecitabine three studies composed metaanalysis completely different three trials considered individually show significant advantage os combination arm journal clinical oncology e r l volume 27 number 33 november 2