A Pilot Study of Neoadjuvant and Adjuvant mFOLFIRINOX in Localized, Resectable Pancreatic Adenocarcinoma

Pancreatic ductal adenocarcinoma is a highly lethal disease. It is estimated that in 2010 there were approximately 43,140 new cases in the United States and 36,800 deaths which ranks fourth among cancer related deaths . At diagnosis, roughly 17,000 of the initial 43,000 patients have disease which appears to be localized to the pancreatic bed, but unfortunately, only a minority of these patients (15-20%) are immediately operable (on imaging studies their disease appears to be both localized to the pancreas and technically resectable with clear margins, and at surgery no unexpected findings preclude an R0 resection ). It should be noted that of those patients deemed immediately operable on clinical grounds, between 20 and 57% are found to have inoperable disease on exploration depending on the series and on the extent and nature of preoperative staging. The majority of patients have locally advanced, borderline resectable or unresectable disease owing to involvement of critical structures, most particularly sentinel blood vessels such as the SMA, celiac axis, hepatic artery, SMV, or portal vein. Furthermore, despite recent advances in systemic therapy, even those fortunate few able to undergo immediate surgery remain largely incurable, with a five year survival of slightly less than 20%.

The current standard of care for adjuvant therapy in resectable pancreatic cancer is based on the CONKO-001 study which randomized patients to 6 cycles of postoperative adjuvant therapy with gemcitabine versus observation alone. Results favored adjuvant gemcitabine in both disease free survival (13.4 vs 6.9 months, p<0.001) and overall survival (24.2 months vs 20.5 months p=0.02) strongly supporting the use of adjuvant gemcitabine in the setting of both R0 and R1 resections. An RTOG study - 97-04 - concluded that gemcitabine was probably superior to 5FU when used pre and postoperatively in combination with 5FU/RT, with a HR of 0.82. The role of radiation therapy in this setting remains controversial, with studies such as the GITSG trial (pro) and ESPAC 1 (con) criticized either for questionable design, outdated chemotherapy or unconventional radiation therapy. Current studies in progress examining postoperative therapy include RTOG 0848 (phase III looking at adjuvant gemcitabine versus gemcitabine plus erlotinib plus/minus chemo/RT using fluorouracil), ACOSOG Z5041 evaluating gemcitabine plus erlotinib in the pre and postoperative setting and ESPAC 4 evaluating gemcitabine versus gemcitabine plus capecitabine.

Many studies have explored the use of neoadjuvant therapy in initially resectable, borderline resectable and unresectable disease. The majority of these have been single arm, single institution phase I/II studies, and results have been mixed. Potential benefits of a neoadjuvant approach include: downstaging of disease with an increased percentage of margin negative and lymph node negative resections; no delay in systemic therapy aimed at eradicating micrometastatic disease; the detection of biologically aggressive tumors, as evidenced by early progression/metastases during this phase of therapy, thereby avoiding inappropriate surgery; and the greater likelihood of completing all intended therapy as opposed to postoperative treatment, where fully 22 - 35% of patients do not complete their intended program.

A comprehensive meta-analysis and systematic review of neoadjuvant therapy in both resectable and unresectable pancreatic cancer has recently been published. The conclusion reached in resectable patients was that resection frequency and survival following neoadjuvant therapy was similar to that in patients undergoing primary resection followed by adjuvant therapy. In patients with initially unresectable disease, fully one third had resectable tumors following neoadjuvant therapy with survival comparable to initially resectable patients. In aggregate, these observations indicate that a neoadjuvant approach is feasible and effective, and that this sequence does not compromise resectability or survival, even in those patients with the best prognosis.

With respect to specific studies in resectable disease, investigators at MD Anderson Cancer Center have published their most recent results. In their first study, 86 patients with resectable disease in the head of the pancreas received radiation therapy (30 Gy in 10 fractions over 2 weeks) plus 7 weekly infusions of gemcitabine at 400 mg/m2/week. 85% of these patients were taken to surgery and 74% were able to undergo the intended pancreaticoduodenectomy. Median survival for patients whose disease was resected was 34 months, but it was only 7 months for those whose disease could not be resected. In a second study of patients with resectable adenocarcinoma of the pancreatic head, 90 patients were enrolled with the goal of administering chemotherapy alone for eight weeks, using gemcitabine and cisplatin, followed by combined low dose gemcitabine and radiation therapy (30 Gy in 10 fractions). Ultimately, 79 (88%) patients completed the full course of preoperative therapy and 62 of these (78%) patients were taken to surgery. 52 (66%) had their disease resected with a median survival of 31 months for those who had surgery, versus 10.5 months for those who did not. They concluded that initial combination chemotherapy with gemcitabine and cisplatin followed by chemotherapy/RT did not improve on the results achieved with chemotherapy/RT alone. This result is perhaps not surprising as gemcitabine, both alone and in doublet combinations, has simply not been active enough to materially impact on the outcome of this disease. Interestingly, the longer preoperative interval did not result in local tumor progression.