First-line Therapy in Metastatic PDAC

Pancreatic ductal adenocarcinoma (PDAC) remains an almost uniformly lethal disease. Although there has been significant progress in understanding of the underlying molecular biology of pancreatic cancer, this progress has not translated into substantially better outcome. Alarmingly, the number of pancreatic cancer cases is constantly rising and pancreatic cancer will be the second most frequent cause of cancer related death by 2030. Accordingly, novel therapeutic strategies for patients with pancreatic cancer are desperately needed. Recently, the combination of gemcitabine and nab-paclitaxel proofed to be superior when compared to single agent gemcitabine (overall survival \[OS\] 8.7 months in the nab-paclitaxel/gemcitabine group versus 6.6 months in the gemcitabine group; hazard ratio for death, 0.72; 95% confidence interval \[CI\], 0.62 to 0.83; P\<0.001). Consequently, this combination therapy is now regarded as a standard treatment option for patients with metastatic pancreatic cancer and should therefore serve as control for future clinical studies. Furthermore, the combination of 5-fluorouracil (5-FU), irinotecan and oxaliplatin (FOLFIRINOX) was found to be more effective in the treatment of metastatic pancreatic cancer when compared to gemcitabine monotherapy (overall survival 11.1 month in the FOLFIRINOX group versus 6.8 months in the gemcitabine group - hazard ratio for death, 0.57; 95% confidence interval \[CI\], 0.45 to 0.73; P\<0.001). However, this increased activity came at the cost of higher treatment-related side effects. Recently, the NAPOLI-1 trial yielded promising results for the combination of liposomal irinotecan (nal-Iri) in combination with 5-FU/folinic acid (FA) in patients pretreated with a gemcitabine-based first-line regimen. Finally, Phase II data show promising efficacy and favorable toxicity with conventional FOLFIRI.3 in the treatment of advanced pancreatic cancer. Furthermore, studies in colorectal cancer demonstrated a comparable efficacy and favorable toxicity when comparing conventional FOLFOXIRI (+ bevacizumab) and sequential FOLFOXIRI (alternating FOLFOX and FOLFIRI) in combination with bevacizumab. With these novel treatment options at hand it is imperative to define the optimal first-line treatment modality in order to allow for an optimized treatment sequence to ensure for maximal success with acceptable toxicity.