There are preliminary results and ongoing studies with EGFR inhibitors (erlotinib, cetuximab), farnesyltransferase inhibitors (tipifarnib), figure 1 leukotriene B4 receptor antagonists (LY293111), antiangiogenic agents (axitinib, cilengitide), matrix metalloproteinase inhibitors (marimastat), vascular endothelial growth factor A inhibitors (bevacizumab), and histone deacetylase inhibitors (CI-994). However, most of these trials showed negative results. In the present analysis, nine trials including 3, 342 patients evaluated gemcitabine combined with targeted therapy (Table (Table3).3). Although the results of the most recent trials (Philip 2010, Kindler 2010) are now available, which evaluated gemcitabine combined with C-225 or bevacizumab, so far Moore’s trial is still the only study to demonstrate a significant improvement in survival in LA/MPC as a result of adding a targeted agent to gemcitabine.
Therefore, the addition of other targeted agents is not recommended for the treatment of LA/MPC in the current clinical setting outside of a clinical trials. Table 3 Median OS and DFS in trials comparing gemcitabine combined with targeted therapy with gemcitabine alone. Trials discussing gemcitabine doublets plus a third targeted reagent Two trials (Cascino 2008, Vervenne 2008) including 691 patients evaluated a gemcitabine doublet with or without a third targeted reagent. In Cascino’s multicenter randomized phase II trial, the addition of cetuximab to the gemcitabine/cisplatin combination did not increase PFS (hazard ratio 0.96, 95% CI, 0.60-1.52, p = 0.847) or OS (hazard ratio 0.
91, 95% CI, 0.54-1.55, p = 0.739). In 2008, Vervenne compared the efficacy and safety of adding bevacizumab to erlotinib and gemcitabine in patients with metastatic pancreatic cancer. The results showed that addition of bevacizumab to erlotinib and gemcitabine did not significantly prolong OS, but there was a significant improvement in PFS (p = 0.0002). This combination requires further investigation in larger-scale clinical trials to assess efficacy and cost effectiveness. Pooled analysis revealed slightly better disease control by adding a third reagent to the gemcitabine doublet, with an ORs of 1.62 (95% CI, 1.00 to 2.62), but this was not statistically significant (p = 0.05). Furthermore, the OS observed in the triplet group was disappointing (ORs, -0.79; 95% CI, -0.90 to -0.
60; p < 0.00001). Drug_discovery Discussion Pancreatic adenocarcinoma is among the most challenging of solid malignancies to treat on account of its propensity for late presentation with inoperable disease, aggressive tumor biology and resistance to chemotherapy [43,44]. Gemcitabine monotherapy has become a cornerstone of therapy for patients with LA/MPC since Burris et al reported their phase III trial results.