Novel directions in neoadjuvant therapy for pancreas adenocarcinoma

Abstract

Surgical resection of pancreatic carcinoma has long represented the only viable option for a potential cure of pancreas cancer. The use of adjuvant chemotherapy post-resection has been established in treating micro metastases and prolonging disease-free survival. However, studies of neoadjuvant therapy have not come to any definitive conclusion regarding the overall efficacy of such treatment, despite the theoretical benefits. In this review, we examine the historical precedent as well as the current state of affairs regarding neoadjuvant therapy in resectable and borderline resectable pancreatic adenocarcinoma. In addition, we review the definitions for resectable and borderline resectable disease and highlight key areas of clinical investigation in the field and summarize the major ongoing neoadjuvant studies focused on resectable pancreatic adenocarcinoma.

Keywords:

• adjuvant
• borderline respectable
• FOLFIRINOX
• gemcitabine
• neoadjuvant
• pancreatic cancer

Financial & competing interests disclosure

EM O’Reilly has received support from Celgene, AduroBiotech, Sanofi-Aventis, Merrimack and Beyer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Neoadjuvant therapy has several theoretical advantages over adjuvant therapy, including the ability to downstage tumors, treat distant micrometastases and avoid surgery in patients with evolving systemic disease.

• The evidence for neoadjuvant therapy in resectable pancreatic adenocarcinoma has historically been sparse due to low patient numbers, lack of homogenous inclusion criteria regarding resectable versus borderline resectable pancreatic cancer and the use of older systemic regimens.

• Defining the entities of borderline resectable disease has been challenging due to a lack of a single consensus definition and the subjectivity involved in adjudication of resectable versus borderline resectable.

• The evidence supports the neoadjuvant role of systemic therapy in borderline resectable disease, although specific standard combination therapies do not currently exist and the role of radiation remains to be defined in this disease setting.

• There are few completed prospective studies examining newer agents such as FOLFIRINOX or nab-paclitaxel combined with gemcitabine, although an increasing number of trials with these cytotoxic backbones are underway.

• Novel neoadjuvant therapies over the next 5 years are likely to incorporate both traditional systemic agents and to integrate immunotherapeutic approaches, of which several strategies include checkpoint blockade, enhanced ras vaccination strategies and other vaccine-based approaches.