Trial Investigates Alternative Approach to Resectable Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDA) that is deemed resectable is typically treated with surgery followed by chemotherapy, but clinical outcomes remain suboptimal and most patients have systemic recurrence. As newer multi-agent regimens continue to show promise in the metastatic setting, an ongoing randomized phase II study is investigating whether preoperative chemotherapy might represent a viable strategy to improve outcomes in patients with resectable PDA.

Oncologist Davendra Sohal, MD, MPH, Director of the Clinical Genomics Program at Cleveland Clinic’s Taussig Cancer Center, is heading the study. He offers three compelling reasons for investigating presurgical chemotherapy at this juncture: “First, surgery followed by chemotherapy results in more deaths than successes, so we felt that we needed to change our approach. Second, trying to improve outcomes by adding more chemotherapy after major surgery is difficult; post-operatively these patients are sicker and weaker and so aggressive systemic therapy is not usually feasible. Third, testing chemotherapy perioperatively may offer advantages in the future by allowing us to study chemotherapy resistance, evaluate prospective biomarkers and gain the benefits of early detection of treatment success or failure using different regimens,” he says.

A description of this study, which is sponsored by SWOG and the National Cancer Institute, was accepted for poster presentation at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago. The trial opened late in 2015 and continues to enroll patients.

‘Pick the winner’ design being used

“The main question is: Should giving aggressive chemotherapy before surgery be adopted as a better approach compared to what we do today, which is surgery first?” says Dr. Sohal. Toward that goal, the aim of this phase II study is to choose the most promising perioperative regimen to test in a larger trial.

Two multi-agent chemotherapy regimens – mFOLFIRINOX (5-fluorouracil, irinotecan, oxaliplatin – without bolus 5-FU and leucovorin) and gemcitabine/nab-paclitaxel – have been successful in improving overall survival rates in patients with advanced metastatic pancreatic cancer, and they may hold promise in the curative setting as well.

In the current study, mFOLFIRINOX and gemcitabine/nab-paclitaxel will be administered in two randomized treatment groups. However, the aim of the study is not to conduct a head-to-head comparison. Rather, investigators are using a “pick the winner” design, with the goal of first determining if preoperative chemotherapy is superior to the conventional sequence. Then, the regimen that shows more promise will be picked for use in future trials.

The study began in late 2015, with most hospitals activating it in the early spring. Eligibility requirements include adult patients with an ECOG performance status of 0 or 1, a confirmed histopathologic diagnosis of PDA and resectable disease confirmed by central radiology review. The study opened nationwide, and the planned total number of patients is 112.

Treatment includes 12 weeks (either six doses of mFOLFIRINOX or nine doses of gemcitabine/nab-paclitaxel, on standard schedules) of preoperative chemotherapy, followed by surgical resection and 12 weeks of identical postoperative chemotherapy. The primary outcome is two-year overall survival that will use the aforementioned “pick the winner” design, with a minimum two-year overall survival rate of 40 percent.

Active recruitment in progress

Upon completion, study results are expected to provide valuable data on the effectiveness of this preoperative strategy and which chemotherapy regimen elicits more positive outcomes.

According to Dr. Sohal, “If this study demonstrates that we can administer these chemotherapy drugs before surgery safely and with some success, then we should build on that platform in larger studies. These results also will help us identify which of the two regimens we should pick for these future studies,” he says.

“We’re still very early in the study, and our goal is to have a complete set of 112 patients by mid-2017 and to finish it within 1-2 years,” he says. “I encourage all physicians in the field to consider this study for any patients who may be eligible, as the faster we acquire our study group, the faster we will be able to answer our questions.”