Editor’s note: This article was initiated as part of a series of feature stories developed and written by members of the American College of Surgeons Cancer Research Program to inform Bulletin readers about research and issues that affect cancer surgeons and patients.
Surgical outcomes and systemic therapy for pancreatic adenocarcinoma have significantly improved over the last decade. This improvement in systemic therapy has increased the number of patients with borderline resectable and locally advanced pancreatic adenocarcinoma who are able to have their cancer surgically resected with negative margins. Advances in neoadjuvant therapy.
Data from Phase II trials have demonstrated surgical resection rates of 65 to 70 percent for patients who present with borderline and locally advanced pancreatic ductal adenocarcinoma (PDAC) and receive neoadjuvant therapy with FOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and irinotecan).1,2 These findings have led to the standardization of neoadjuvant chemotherapy in the treatment of borderline resectable and locally advanced pancreatic cancer for this subset of patients and is reflected in the latest National Comprehensive Cancer Network (NCCN) Guidelines in Oncology for Pancreatic Adenocarcinoma.3 With the success of neoadjuvant FOLFIRINOX in borderline and locally advanced patients, the PRODIGE 24/CCTG PA.6 (Partenariat de Recherche en Oncologie Digestive) trial established modified adjuvant FOLFIRINOX (mFOLFIRINOX) as a new standard of care in the adjuvant setting, with an increased median overall survival from 35 months to 54.4 months, particularly for patients with good performance status.4
For patients who present with surgically resectable pancreas cancer, practice patterns vary widely. At present, a standard of care for patients with primary resectable pancreatic cancer that can be treated surgically is upfront resection followed by adjuvant chemotherapy.3 However, some academic institutions across the nation routinely use a strategy involving neoadjuvant chemotherapy for resectable disease. No level one evidence is available to guide the use of neoadjuvant chemotherapy for patients with a resectable pancreatic adenocarcinoma.
While multiple potential benefits have been ascribed to neoadjuvant chemotherapy—including improved compliance with multidrug treatment regimens, a potentially better understanding of the biology of the cancer, and fewer delays in therapy because of post-pancreatectomy complications—some patients will experience significant toxicity from chemotherapy and not undergo resection. Moreover, patients may develop disease progression during the neoadjuvant period rendering their cancer unresectable as the result of local or distant disease. Consequently, the window of opportunity for performing surgical resection may close.
Delivering neoadjuvant chemotherapy to patients with technically resectable disease also requires a pretherapy tissue biopsy. Furthermore, in patients who present with obstructive jaundice, delivery of neoadjuvant chemotherapy requires the use of biliary stents, which can leave patients susceptible to stent occlusion during the neoadjuvant period and increase vulnerability to infectious complications in the perioperative period. Neoadjuvant therapy also may be delayed while waiting for serum bilirubin to decrease to a level acceptable for chemotherapeutic agents.
Survival rates: Comparative data
Preliminary data from the SWOG S1505 phase II trial recently was presented at the 2020 meeting of the American Society of Clinical Oncology (ASCO). This trial sought to determine the most promising chemotherapy regimen (gemcitabine/nab-paclitaxel or mFOLFIRINOX) for patients with resectable pancreatic cancer who undergo neoadjuvant therapy. Surprisingly, the study showed no difference in overall survival for resectable pancreatic cancer in patients who received gemcitabine/nab-paclitaxel or mFOLFIRINOX.5
More surprising were the overall survival outcomes for all patients in this trial. Among the 55 patients who received perioperative mFOLFIRINOX, median overall survival was 22.4 months versus 23.6 months for the 47 patients who received perioperative gemcitabine/nab-paclitaxel. This survival time is far lower than the survival outcomes seen in the PRODIGE 24/CCTG PA.6 trial for patients who received mFOLFIRINOX (54.4 months) after surgery.
In addition, patients treated with mFOLFIRINOX in the S1505 trial demonstrated major or complete pathologic response rates of 25 percent.5 These results raise many unanswered questions regarding the utility of delivering perioperative chemotherapy. A large-scale prospective phase III trial is urgently needed to define the role of neoadjuvant chemotherapy in patients with resectable PDAC.
Given the pros and cons, as well as the available data, there is considerable equipoise to the question of delivering neoadjuvant chemotherapy to patients who present with resectable pancreatic cancer. Although institutional and individual provider bias plays a role in the decision to use neoadjuvant therapy in resectable pancreatic cancer, it is clear that we have only begun to scratch the surface with respect to a consensus on the debate of neoadjuvant therapy in resectable PDAC. The differences in opinion on this question were highlighted at the ASCO 2019 Gastrointestinal Cancers Symposium. An audience poll showed opinions were nearly split, with 142 respondents choosing an operation first followed by adjuvant chemotherapy and 141 respondents opting for neoadjuvant chemotherapy followed by an operation.
ALLIANCE A021806 trial aims to provide definitive answers
The definitive trial to address this question is now open and is being run through the National Clinical Trials Network. To answer this question, the ALLIANCE A021806 (NCT 04340141) is an actively accruing randomized phase III trial of patients with resectable pancreatic cancer, randomized to perioperative mFOLFIRINOX or upfront surgery followed by adjuvant therapy with mFOLFIRINOX. The primary endpoint is two-year overall survival.
Patients with biopsy-proven, localized resectable pancreatic adenocarcinoma (as defined by the NCCN definition for Resectable Pancreatic Cancer) are eligible for the trial. This definition includes imaging demonstrating a lack of any tumor involvement of the celiac artery, common hepatic artery, superior mesenteric artery, and, if present, a replaced right hepatic artery. Involvement of the tumor with up to 180 degrees or less of the portal vein and/or superior mesenteric vein vessel wall is permitted. In addition, the portal vein/splenic vein confluence on imaging should be patent.
Patients must have good performance status (ECOG 0 or 1) and be a candidate to receive mFOLFIRINOX. All patients who are eligible for the trial will then undergo central radiologic eligibility review to confirm that patients enrolled in the trial fall within a consistent definition of resectable pancreatic cancer by imaging criteria. After imaging confirmation, patients then will be randomized to either the perioperative arm or the adjuvant arm (see Figure 1). The perioperative arm includes delivery of eight cycles of neoadjuvant mFOLFIRINOX followed by resection, followed by four additional cycles of adjuvant mFOLFIRINOX. Patients in the adjuvant arm will undergo upfront resection within 12 weeks of diagnosis, followed by 12 cycles of mFOLFIRINOX after surgery.
The primary endpoint of the trial is two-year overall survival with secondary endpoints including disease-free survival and margin-negative resection rates. The ability to tolerate chemotherapy in the perioperative versus adjuvant setting also will be clarified as planned secondary endpoints. The PRODIGE 24/CCTG PA.6 trial randomized patients postoperatively, whereas the ALLIANCE A021806 trial will randomize patients at diagnosis, allowing for a better understanding of the percentage of patients who are able to tolerate 12 cycles of adjuvant FOLFIRINOX, as well as patients who do not undergo resection because of disease progression. Additional secondary endpoints include the rate of surgical complications and chemotherapeutic adverse events as well as the dose-intensity and number of cycles of mFOLFIRINOX delivered in each arm.
Add to our understanding of effective pancreatic cancer care
The ALLIANCE A021806 trial is timely and has the potential to standardize how to best treat this subgroup of patients, which is particularly important given the wide variability in practice patterns. The results of this trial may be practice-changing and may transform the standard of care for patients with resectable PDAC.
The importance of investigating this strategy in the upfront resectable disease population is underscored by poor long-term survival outcomes in patients who present with resectable pancreatic cancer. As we evolve through a new era of multimodality treatment for PDAC, there is great emphasis on further understanding the need to prioritize systemic therapy in all patients with pancreatic cancer prior to surgical resection. We anticipate this trial will yield a definitive answer regarding the use of neoadjuvant chemotherapy and will allow for the standardization of treatment algorithms.
For questions related to this trial, contact Cristina Ferrone, MD, FACS, at cferrone@mgh.harvard.edu.
References
- Murphy JE, Wo JY, Ryan DP, et al. Total neoadjuvant therapy with FOLFIRINOX followed by individualized chemoradiotherapy for borderline resectable pancreatic adenocarcinoma: A phase 2 clinical trial. JAMA Oncol. 2018;4(7):963-969.
- Murphy JE, Wo JY, Ryan DP, et al. Total neoadjuvant therapy with FOLFIRINOX in combination with losartan followed by chemoradiotherapy for locally advanced pancreatic cancer: A phase 2 clinical trial. JAMA Oncol. 2019;5(7):1020-1027.
- NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Pancreatic Adenocarcinoma. Version 1.2020. National Comprehensive Cancer Network® (NCCN®). Available at: www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. (Log-in required.) Accessed July 25, 2020.
- Conroy T, Hammel P, Hebbar M, et al. Unicancer GI PRODIGE 24/CCTG PA.6 trial: A multicenter international randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine (gem) in patients with resected pancreatic ductal adenocarcinomas. J Clin Oncol. 2018;36(18_suppl):LBA4001.
- Sohal D, Duong MT, Ahmad SA, et al. SWOG S1505: Results of perioperative chemotherapy (peri-op CTx) with mfolfirinox versus gemcitabine/nab-paclitaxel (Gem/nabP) for resectable pancreatic ductal adenocarcinoma (PDA). J Clin Oncol. 2020;38(15_suppl):4504.
