Systemic Therapy With a Loco-regional Treatment in Patients With Locally Advanced Pancreatic Cancer: The SMART Study

Current Knowledge and Rationale

Pancreatic cancer is one of the most lethal malignancies, with an overall 5-year survival rate of less than 10%. It is the 12th most common cancer and 7th most frequent cause of cancer-related death worldwide and 4th leading cause of cancer death among men and women in Canada. Surgery is the only curative option, however, less than 20% of patients have resectable disease at the time of diagnosis and the remainder have either locally advanced or metastatic cancer. Approximately 40 percent of patients with pancreatic cancer present with locally advanced or surgically unresectable pancreatic cancer. The optimal management of patients with locally advanced pancreatic cancer remains unknown. Treatment options include chemotherapy alone, radiation alone, or combination of chemotherapy and radiation. Despites absence of metastatic disease at the time of diagnosis, patients with locally advanced pancreatic cancer have poor prognosis with a median overall survival of about 12 months.

For many years single agent gemcitabine remained the standard therapy for patients with locally advanced and metastatic pancreatic cancer (6). Two randomized trials showed benefit of combination chemotherapy over single agent gemcitabine. For example, the ACCORD II trial demonstrated the efficacy of FOLFIRINOX (5-FU, leucovorin, irinotecan, and oxaliplatin) over gemcitabine in patients with metastatic pancreatic cancer. The median progression-free survival (PFS) and overall survival (OS) with FOLFIRNOX were 6.4 months and 11.1 months, respectively, compared with 3.3 months and 6.8 months, respectively, with gemcitabine alone. The MPACT trial demonstrated the superiority of the combination of gemcitabine plus nab-paclitaxel over gemcitabine alone in patients with metastatic pancreatic cancer. The median PFS and OS were 5.5 months and 8.5 months, respectively, in the gemcitabine/nab-paclitaxel group, compared with 3.7 and 6.7 months in the gemcitabine group, respectively. Based on the improved activity and survival of both regimens in patients with metastatic pancreatic cancer, FOLFIRINOX (5-FU, leucovorin, irinotecan, and oxaliplatin) and gemcitabine plus nab-paclitaxel have become standard chemotherapy regimens in the management of patients with locally advanced pancreatic cancer. In the investigators' world experience of patients with locally advanced pancreatic cancer who were treated with either FOLFIRINOX (5-FU, leucovorin, irinotecan, and oxaliplatin) or gemcitabine plus nab-paclitaxel over a five year period in Saskatchewan had a median OS of 12.0 months.

Because patients with locally advanced pancreatic cancer have localized disease, loco-regional therapies such as radiation treatment have been employed with limited success. For example, in a randomized trial involving 449 patients with locally advanced pancreatic cancer with stable disease after 4 months of induction chemotherapy, there was no significant difference in overall survival with chemoradiotherapy compared with chemotherapy alone. The median OS of patients who received chemotherapy was 16.5 months compared with 15.2 months it combination of chemotherapy and radiation (p=0.83). Currently, in most institutions outside the setting of a clinical trial, patients with locally advanced pancreatic cancer, are primarily treated with combination of chemotherapy. Other conventional ablative therapies such thermal ablation have limited role due to collateral damage to the adjacent vital structure such as blood vessels and bile duct. These limitations could be overcome by irreversible electroporation (IRE), a novel, non-thermal ablative method that has been examined in the treatment of various solid organ cancers.

IRE also known as NanoKnife® is a unique treatment modality as it ablates tumor cells without using heat or radiation and hence does not cause injury to nearby blood vessels, ducts, and bowel. This makes it particularly appealing for the treatment of locally advanced unresectable pancreatic cancers. This local treatment for cancer involves delivering brief pulses of high voltage electrical current across the tumor (either percutaneously or open surgery), which results in the formation of tiny holes (nanopores) in the cell membranes. The loss of electrolytes and the gain of fluid into the cell from these pores causes the cells to die an apoptotic death. The collagen scaffolding is unaffected because IRE ablation occurs without heat, and this allows for destruction of tumors without collateral thermal injury. IRE is therefore an ideal ablation strategy for the pancreas, which is intimate with the common bile duct, the portal vein, and the duodenum, all of which are injured if heat ablation or even radiation are used.