July 1, 2022
Oncologists continue to debate the use of preoperative (neoadjuvant) chemotherapy in patients with resectable pancreatic cancer. Potential benefits and shortcomings of neoadjuvant chemotherapy for pancreatic cancer have been well documented.1,2
For resectable pancreatic cancer, recent data also have shed light on the lower-than-expected survival outcomes seen in patients receiving multiagent neoadjuvant chemotherapy.3 Data from the SWOG (formerly known as the Southwest Oncology Group) S1505 phase II trial demonstrated a median overall survival time of only 22.4 months in patients treated with mFOLFIRNOX and 23.6 months in patients treated with gemcitabine and nab-paclitaxel.3
These outcomes were strikingly lower than the median overall survival time of 54.4 months seen in the PRODIGE (Partenariat de Recherche en Oncologie Digestive) 24/CCTG PA.6 trial for patients with good performance status who were randomized after R0/R1 resection to receive mFOLFIRINOX in the postoperative or adjuvant setting.4 Furthermore, only 25% of patients treated with neoadjuvant mFOLFIRINOX in the SWOG S1505 trial demonstrated a significant or complete pathologic response on histologic analysis.3
A noteworthy 36% of all patients did not reach surgery because of disease progression during neoadjuvant therapy.5 These results have raised questions regarding the neoadjuvant treatment strategy for technically resectable patients and have added significant equipoise to the issue.
ALLIANCE A021806 (NCT 04340141), a randomized phase III trial to evaluate the use of perioperative therapy in resectable pancreatic cancer, opened to accrual in July 2020. This landmark study aims to better understand the role of perioperative therapy in resectable pancreatic cancer. Patients will be randomized to treatment with perioperative mFOLFIRINOX (perioperative arm) or upfront surgery followed by postoperative mFOLFIRINOX (adjuvant arm). Patients randomized to the perioperative arm undergo eight cycles of neoadjuvant mFOLFIRINOX followed by a curative-intent resection. These patients then will receive four additional cycles of mFOLFIRINOX in the postoperative setting. Patients randomized to the adjuvant arm undergo 12 cycles of adjuvant mFOLFIRINOX following pancreatectomy (Figure 1). This study team plans to enroll 353 patients with resectable pancreatic cancer from the US and Canada.
To qualify for trial enrollment, patients must have biopsy-proven pancreatic adenocarcinoma and imaging must demonstrate resectable disease as defined by the National Comprehensive Cancer Network definition of resectable pancreatic cancer. This definition includes pancreatic cancer in any location within the pancreas without evidence of involvement of the celiac artery, common hepatic artery, superior mesenteric artery, or, if present, a replaced right hepatic artery. Splenic arterial involvement is permitted. Venous involvement of less than or equal to 180° of the portal vein and/or superior mesenteric vein vessel wall with patency of the portal vein/splenic vein confluence also is permitted.
Patients must not have definitive evidence of distant metastases. Patients must have good performance status (ECOG 0 or 1) and be candidates to receive mFOLFIRINOX. All patients who are eligible for the trial undergo a prospective central radiologic eligibility review as a method of quality control to confirm that patients enrolled in the trial fall within a consistent definition of resectable pancreatic cancer.
The primary endpoint of the trial is 2-year overall survival. The trial also will compare clinical outcomes such as disease-free survival, margin-negative resection rates, tolerability of chemotherapy, and health-related quality of life. To date, accrual has been robust; however, the need for continued support of this trial will be important in order to standardize treatment for this patient population. It is anticipated that the results of this trial will be practice-changing and will establish the standard of care for patients with resectable pancreatic cancer.
Dr. Akhil Chawla is a hepatopancreatobiliary surgical oncologist at Northwestern Medicine and clinical assistant professor of surgery, Northwestern University Feinberg School of Medicine, Chicago, IL. He is co-chair, Alliance A021806 Clinical Trial.