Pancreatic cancer is the fourth leading cause of cancer related death among both genders in the United States. Despite advances in diagnostic and treatment strategies, there has been little improvement in overall survival in the last 30 years. 43,920 new cases are projected to occur in the United States in 2012, accounting for 6% of all incident cancer cases and 13% of all cancer-related deaths (1
). The only treatment modality proven to have curative potential is surgical resection; however only 10-20% of cases are potentially resectable at presentation (2
Neoadjuvant chemotherapy has been proposed to downstage unresectable LAPC and enable surgical intervention, reduce the incidence of late relapse and decrease the rate of positive margins. A meta-analysis published in 2011 suggested that approximately 40% of patients with unresectable disease receiving neoadjuvant therapy underwent surgical resection. In that series, however, criteria for resectable disease were broad and in many cases were not defined (3
Current National Comprehensive Cancer Network (NCCN) guidelines suggest GEM-based combination chemotherapy plus or minus chemoradiation as an option in LAPC patients with good performance status. Other options include clinical trials, FOLFIRINOX, single agent GEM, GEM plus erlotinib, or fluoropyrimidine-based chemotherapy (4
). GEM is a cytotoxic agent that is potent against pancreatic adenocarcinoma cells in vitro
with known short half-life. Nab-P, an albumin bound formulation of paclitaxel particles, appears to have advantages over the soluble formulation, with less toxicity and increased local concentration targeting stromal-rich tumors. In a mouse model, it has been shown to decrease levels of cytidine deaminase, the primary gemcitabine catabolic enzyme, through the generation of reactive oxygen species, thereby increasing sensitivity to GEM (5
). This suggests potential benefit from the combination of both agents.
A phase I/II trial exploring GEM plus nab-P in metastatic pancreatic adenocarcinoma showed substantial antitumor activity with tolerable side effects. At a maximum tolerated dose of 1,000 mg/m2
of GEM and 125 mg/m2
of nab-P administered once a week for 3 weeks every 28 days, there was a 48% response rate and a 48% 1-year survival (6
). At this time, no phase III studies evaluating this combination in pancreatic cancer have been published.
A single center retrospective review evaluated 13 patients with LAPC undergoing neoadjuvant chemotherapy with GEM/nab-P plus or minus chemoradiation. The regimen was given as cycles of GEM 1,000 mg/m2
and nab-P 100 mg/m2
weekly, 3 weeks on and one week off, with appropriate modifications. 77% of patients received chemoradiation and 38% underwent resection. Overall survival was 85% at six months and 77% at twelve months. Progression-free survival at six months was 100% and 88% in the resected and non-resected groups, respectively (7
The timing for surgical exploration after neo-adjuvant therapy remains debatable. Some centers reserve surgical exploration only for patients with evidence of tumor downsizing. Other centers consider exploration for patients with radiographic stable disease and normalization of CA19-9 (8
The decision whether to offer patients the possibility of surgery and cure and avoid prolonged courses of neoadjuvant treatments requires a multidisciplinary approach and the development of clearer guidelines. Other investigators observations and well-designed phase II trials using this combination with or without chemoradiation will go a long way in defining its efficacy in LAPC and its possible role as neoadjuvant or definitive therapy in locally advanced disease.