Chemotherapy – available drugs, mechanisms and toxicity

Pancreatic ductal adenocarcinoma has historically been considered refractory to systemic chemotherapy. The past two decades have seen the step-wise development of active regimens in the setting of advanced disease. From the emergence of gemcitabine monotherapy in 1997, through the development of active gemcitabine-based doublet combinations, we have arrived at FOLFIRINOX, currently the most active regimen in this disease. The choice of regimen is largely based on an individual patient’s performance status after weighing up the potential benefits, toxicities and impact on quality of life. Second-line chemotherapy options have also emerged for patients remaining fit enough to consider additional chemotherapy. In this era of precision medicine, the first indication of benefit has been seen in the improvement in progression-free survival in patients with germline mutation in BRCA-1/-2 after induction platinum-based chemotherapy, highlighting the importance of germline testing in this disease. Many challenges remain in this highly-aggressive malignancy including development of highly-efficacious therapies targeting intracellular pathways as well as the tumour stroma, and learning to harness the immune response.