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Pancreatic cancer remains a vexing treatment challenge, with a cure rate that remains just 7%. Two effective regimens—gemcitabine/nab-paclitaxel and FOLFIRINOX—have improved outcomes and are being used earlier in the disease. However, meaningful differences in outcomes may not be realized without novel strategies. Targeting of the immune system is an active area of research.

Outcomes for pancreatic cancer are becoming less discouraging with the refinement of molecular profiling, both germline and somatic, and beneficial effects seen with adjuvant chemotherapy. The NCCN Guidelines for Pancreatic Adenocarcinoma reflect these advances, and recommend that clinicians consider germline testing for all patients with pancreatic cancer and consider a molecular analysis for those with metastatic disease. The guidelines further recommend that clinicians consider adjuvant therapy with modified FOLFIRINOX (leucovorin/5-FU/irinotecan/oxaliplatin) for patients who are able to tolerate it.

Although we are “winning the war against cancer,” pancreatic malignancies are expected to be the most common cause of cancer-related death by 2040. Several systemic therapies, such as oxaliplatin + irinotecan/fluorouracil/leucovorin (FOLFIRINOX) and gemcitabine + nab-paclitaxel, have shown activity in the adjuvant and neoadjuvant settings. The current NCCN Guidelines reflect the most up-to-date, evidence-based data relating to the evaluation and management of pancreatic adenocarcinoma. They were recently updated to recommend germline testing for any patient with pancreatic cancer and molecular analysis of any metastatic pancreatic tumor.

Pancreatic adenocarcinoma represents the fourth-leading cause of cancer-related mortality in the United States. The vast majority of patients are diagnosed at advanced stages of the disease when surgery is no longer an option. For these patients, systemic therapy remains the mainstay of care. Although single-agent gemcitabine has remained the standard of care since its approval in 1997, improvements in patient outcomes may potentially be realized by (1) applying pharmacokinetic principles to optimize drug delivery, such as the administration of gemcitabine at a “fixed-dose rate” infusion; (2) combining gemcitabine with other cytotoxic agents for which evidence of synergy exists, such as platinum compounds; and (3) integrating novel targeted agents such as bevacizumab, erlotinib, and cetuximab into treatment paradigms, based on an increasing understanding of the molecular pathways that govern pancreatic tumor growth and maintenance. This article provides the evidence to support each of these approaches and highlights future directions in the management of metastatic pancreatic cancer.