Standard Versus Prolonged Neoadjuvant (Conversion) Chemotherapy to Prolong Survival of Patients With Borderline and Locally Advanced Pancreatic Cancer: a Phase III Randomized Controlled

The prognosis of the large majority cancer types has gradually improved over the past decades. Pancreatic cancer (PC) is one of the few exceptions where the 5-year survival still lies under the 10% threshold. Surgery is the only treatment modality that can contribute to long-term survival. However, only about 20% of the patients qualify for surgery since PC often presents as spread disease at the time of diagnosis. Even after curatively intended surgery the prognosis is still dismal, with a 5-year survival of about 20%. Chemotherapy can reduce the risk for recurrence after surgery.

A factor that complicates surgery is the anatomical location of the pancreas. It overlies the large abdominal vessels, which provide blood supply to the liver and the small bowel. Approximately 25% of the patients present at diagnosis with what is labeled as borderline (BR) or locally advanced pancreatic cancer (LAPC). BR and LAPC refer to different degree of tumoral involvement of the large abdominal vessels. Previously, resection of tumors with this type of vascular involvement has not been a treatment alternative, since the postoperative complication rate has been unacceptably high and there has not been a potent oncologic treatment to address potential micrometastatic spread. Therefore, the survival of patients with BR/LAPC has for long been almost as short as the survival of patients with spread PC.

The introduction of the potent combination chemotherapy FOLFIRINOX significantly improved the survival of patients with BR/LAPC and metastatic PC compared to the previous standard gemcitabine. Patients with BR/LAPC who could be resected after induction chemotherapy with FOLFIRINOX had furthermore chance for long-term term survival compared to unresected patients. Even other types of combination therapy, such as gemcitabine-nab-paclitaxel, have shown to lead to long-tern survival of patients with BR/LAPC who could be resected after initial chemotherapy.

Generally, the larger the tumor size the higher the risk for vascular invasion, lymph node metastases and elevated CA19-9, all associated with worse prognosis. Neoadjuvant chemotherapy contributes to decreased tumor size, lower probably for lymph node metastases and lower CA19-9. In this way the risk for recurrence decreases while the potential benefit of surgery increases. Theoretically, repeated cycles of chemotherapy under longer period would have the possibility to destroy more cancer cells. In studies it has been shown that the duration of chemotherapy is correlated with better histologic tumor regression and chance for negative lymph nodes. On the contrary, it could also be that longer treatment periods induce resistant cell clones which can reverse the previous beneficial treatment effects and decondition the patients. Often there is a limit to what the patient can tolerate in terms of side effects and general condition.

Since the outcome of technically advanced pancreatic surgery has been shown to correlate with volume, a national level structure has been implemented in Sweden, limiting the surgical treatment of BR/LAPC to two national centers with the intention to increase patient safely and improve postoperative outcome. Regarding the length of preoperative chemotherapy, two alternative regimens have been used by the two centers - either six cycles of modified FOLFIRINOX or four cycles of gemcitabine-nab-paclitaxel. Previously published data confirmed that long-term survival can be achieved by these treatment setups. However, internationally it is more common to apply eight or more cycles of FOLFIRINOX for BR/LAPC. In larger international multicenter studies, showing the efficacy of FOLFIRINOX when used with palliative intent or as adjuvant treatment, the aimed number of treatment cycles has been set to twelve. When gemcitabine-nab-paclitaxel has been intended for the treatment of LAPC, six cycles have been administered.