Pancreatic adenocarcinoma remains one of the deadliest cancers in the U.S.; however, margin-negative surgical resection, when feasible, may lead to cure. One of the most challenging situations for patients and surgeons is when they are faced with borderline resectable tumors that involve a portion of the adjacent mesenteric vasculature. In this situation, achieving a margin-negative resection may not be possible; resection of these tumors is also technically challenging and may be associated with significant postoperative morbidity. Use of neoadjuvant therapy with chemotherapy and radiation prior to surgery has been hypothesized to improve rates of complete surgical resection.
Pilot study A021101
A pilot study was designed to assess the feasibility of administering neoadjuvant chemotherapy and chemoradiation in patients with borderline resectable pancreatic cancer in a multicenter setting. Alliance A021101, Neoadjuvant FOLFIRINOX and Chemoradiation Followed by Definitive Surgery and Postoperative Gemcitabine for Patients with Pancreatic Adenocarcinoma: An Intergroup Single-Arm Pilot Study, enrolled 23 patients across 14 selected institutions from May 2013 through February 2014. Initial results from the trial were presented at the 2015 annual meeting of the American Society of Clinical Oncology in June.*
Alliance A021101 evaluated patients with borderline resectable pancreatic cancer defined by one or more of the following centrally reviewed radiographic criteria: (1) a circumferential tumor-vessel interface (TVI) with superior mesenteric/portal vein ≥ 180°; (2) TVI with superior mesenteric artery < 180°; and (3) short-segment TVI with hepatic artery of any degree. These patients received modified FOLFIRINOX (mFOLFIRINOX; oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2 followed by 5-Fluorouracil 2400 mg/m2 for four cycles) and chemoradiation (50.4 Gy in 28 fractions) with concurrent capecitabine (825mg/m2, twice a day) prior to intended surgical resection and postoperative gemcitabine (1000 mg/m2 on days 1, 8, and 15 for two cycles). The three specific aims of the study were to demonstrate the ability to accrue patients from multiple institutions, to demonstrate the safety and tolerability of preoperative mFOLFIRINOX and capecitabine-based chemoradiation, and to evaluate the rate of completion of all preoperative therapy and pancreatectomy.
In all, 14 selected high-volume pancreatic cancer treatment centers enrolled 23 patients in the study, which completed accrual in advance of schedule. Among 22 patients who started protocol therapy, all 22 completed mFOLFIRINOX and 21 (95 percent) completed chemoradiation. By the standards of the Response Evaluation Criteria in Solid Tumors, the best responses to preoperative therapy included complete response (two patients), partial response (four patients), stable disease (14 patients), and progressive disease (two patients).
Seven patients did not undergo planned resection due either to disease progression (six patients) or refusal (one patient). Among the 15 (68 percent) patients who underwent pancreatectomy, 14 (93 percent) operations were margin negative; 80 percent of operations required concomitant vein resection or hepatic artery resection. Five (33 percent) patients had less than 5 percent viable cells in their tumors remaining following neoadjuvant therapy.
Among all patients, 68 percent [95% confidence interval 49%–88%] underwent R0/R1 resections and two (9 percent) patients achieved pathologic complete response (CR). In all, 64 percent of patients experienced at least one grade 3 adverse event (AE) and only one patient experienced at least one grade 4 AE during preoperative therapy. One patient died within 90 days of surgery. These numbers compare favorably to historical data; for example, the rate of negative margins among patients who undergo de novo resection of similar invasive tumors in the absence of preoperative therapy is on the order of 37 percent.†
Trial design leads to robust outcomes
The clinical importance of these results notwithstanding, the most significant product of Alliance A021101 is the design of the trial itself. The efficacy of preoperative chemotherapy and chemoradiation for patients with borderline resectable pancreatic cancer has historically been difficult to establish because most earlier studies have been small retrospective reports or single-institution trials of groups of patients who had a heterogenous local tumor anatomy and who were treated with a variety of modalities in a nonstandardized way.
To address this problem, Alliance A021101 established and used standardized definitions of and procedures for the following:
- The radiographic definition of borderline resectable pancreatic cancer
- Selection criteria for a neoadjuvant strategy
- The indications for operative intervention following induction therapy
- Surgical technique
- Pathologic review of the surgical specimen that will be used in future studies
Indeed, the radiographic criteria used in the study to define tumors as “borderline resectable” have now been endorsed by the National Comprehensive Cancer Network for use in all future clinical trials of borderline resectable pancreatic cancer.‡
Alliance A021101, the first successful cooperative group study of preoperative therapy for patients with borderline resectable pancreatic cancer, has provided much-needed baseline data and a quality-controlled trial framework, which have been used to design a forthcoming Alliance trial that aims to establish a standard preoperative treatment regimen for patients with this stage of disease. This proposed trial, Alliance A021501 (see Figure 1), has been submitted to the National Cancer Institute for approval. This follow-up study will attempt to define a standard multimodality treatment regimen for patients with borderline resectable pancreatic cancer by randomizing patients to eight cycles of systemic mFOLFIRINOX or six cycles of mFOLFIRINOX followed by hypofractionated radiation therapy. The trial will evaluate the rates of 18-month overall survival comparing these two approaches.
Figure 1. Treatment Schema for Alliance A021501
The success of Alliance A021101 was due in large part to the enthusiastic participation of surgeons with their multidisciplinary teams. The future utility of Alliance A021501 also will rely heavily upon surgical oncologist involvement in collaboration with their medical and radiation oncologists. For additional information, contact Matthew H. G. Katz at firstname.lastname@example.org.
*Katz MHG, Shi Q, Ahmad SA, et al. Preoperative modified FOLFIRINOX (mFOLFIRINOX) followed by chemoradiation (CRT) for borderline resectable (BLR) pancreatic cancer (PDAC): Initial results from Alliance Trial A021101 (abstract). J Clin Oncol. 2015;33 (suppl; abstr 4008). Abstract available at: http://meetinglibrary.asco.org/content/147695-156 (Accessed on July 17, 2015). Accessed August 26, 2015.
†Yamada S, Fujii T, Sugimoto H, et al. Aggressive surgery for borderline resectable pancreatic cancer: Evaluation of National Comprehensive Cancer Network guidelines. Pancreas. 2013;42(6):1004-1010.
‡National Comprehensive Cancer Network. NCCN guidelines. Available at: www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed August 26, 2015.