Two studies pave the way for preoperative therapy in pancreatic cancer patients

Pancreatic cancer is the fourth-most common cause of cancer-related death in the U.S. and is predicted to soon be the third-leading cause. Surgical resection with pancreatectomy has historically been viewed as offering the only chance for cure. However, achieving negative margins at surgery can be difficult, with positive surgical margins found in as many as 90 percent of resected specimens.¹ Unfortunately, most patients develop recurrent cancer within two to five years of pancreatectomy due to the growth and dissemination of cancer cells following surgery, both at the operative field and distant sites.

Systemic chemotherapy is classically delivered postoperatively with the goal of reducing the number of cancer cells throughout the body. Chemotherapy definitively prolongs survival following pancreatectomy, but only marginally.² In contrast, the value of postoperative radiation, with the goal of reducing any residual cancer cells left within the surgical field, is controversial. Importantly, only about one-half of patients who should receive either chemotherapy and/or radiation therapy following surgery actually do. Nonetheless, pancreatectomy followed by systemic chemotherapy remains the standard of care worldwide, and the role of additional postoperative radiation therapy is being evaluated in a large phase III trial.³

Positive effects of preoperative therapy

The delivery of chemotherapy and/or radiation in the preoperative setting (before surgical resection, instead of after it) has been hypothesized to improve both rates of margin-negative resection and survival. This alternate strategy has several potential advantages, including the following:

• All cancer cells, both those in the pancreas and any cells distant from the primary tumor, may be treated with early systemic therapy early.
• Treatment may reduce the anatomic extent of the cancer sufficient to facilitate a margin-negative resection.
• Patients with rapidly progressive cancers may be spared a presumably futile operation if they are found to develop metastases during systemic therapy before surgery.

Several single-arm studies have shown that both chemotherapy and radiation can generally be delivered safely before pancreatectomy.

Although the outcomes associated with this general strategy have not been shown to be superior to the standard “surgery first” regimen, preoperative therapy has gained popularity nationwide both for patients with resectable (low-risk for margin-positive resection) and borderline resectable (high-risk for margin-positive resection) pancreatic cancers. Encouraging data using newer systemic chemotherapy and radiation regimens have increased interest in this strategy. Indeed, two of the three treatment trials for patients with non-metastatic pancreatic cancer that are being conducted within the National Clinical Trials Network (NCTN) have been designed to evaluate and optimize preoperative therapy regimens for patients with localized pancreatic cancer.

Trials under way

Until recently, systemic therapy options in pancreatic cancer have been limited and relatively ineffective, thus limiting opportunities for preoperative therapy. Now with two multi-agent regimens available (mFOLFIRINOX and gemcitabine plus nab-paclitaxel) that are more active against pancreatic cancer, systemic therapy can be considered in the preoperative setting. Southwest Oncology Group (SWOG) Trial 1505 (see Figure 1) will test these two regimens in the perioperative setting for patients with resectable tumors. This intergroup study, which has been activated and is open to all NCTN sites, randomizes patients with resectable pancreatic cancer to three cycles of systemic FOLFIRINOX or three cycles of gemcitabine plus nab-paclitaxel. Patients without progression then undergo surgical resection followed by three cycles of the same regimen following surgery. The primary objective of this study is to pick the superior regimen with respect to overall survival.

Figure 1. Schema for SWOG Trial 1505

The Alliance for Clinical Trials in Oncology A021501 trial (see Figure 2), which is expected to activate across NCTN sites in late summer 2016, will compare two more intensive preoperative therapy regimens for patients with more advanced disease. Patients with borderline resectable pancreatic cancer will be randomized to receive either a systemic regimen of modified FOLFIRINOX for eight cycles, or a combination regimen of seven cycles of modified FOLFIRINOX followed by a five-day radiation regimen using either stereotactic body radiation therapy or hypofractionated image-guided radiation therapy.

Figure 2. Schema for Alliance Trial A021501

The chemotherapy component of this trial can be delivered at affiliated treatment sites as long as the incorporated quality control measures can be maintained. The regimens used in this trial are anticipated to improve upon the results of the recently published Alliance A021101 pilot study, in which 68 percent of patients with borderline resectable pancreatic cancer underwent pancreatectomy following FOLFIRINOX and conventional chemoradiation, and 93 percent of operations were associated with microscopically negative margins.^4,5 Like the SWOG trial, the primary objective of the study is to determine the superior regimen with respect to overall survival.

All patients with localized pancreatic cancer should be considered for enrollment in one of these two noncompeting trials. The SWOG study specifically is for patients with technically resectable cancers—cancers that meet the following radiographic criteria:

• No involvement of the celiac artery, common hepatic artery, or superior mesenteric artery
• No involvement, or < 180° interface between tumor and vessel wall, of the portal vein or superior mesenteric vein; and patent portal vein/splenic vein confluence
• No evidence of metastatic disease

In contrast, the Alliance study is specifically for patients with borderline resectable cancers defined by one or more of the following radiographic criteria:

• A circumferential tumor-vessel interface (TVI) with superior mesenteric/portal vein ≥ 180°
• TVI with superior mesenteric artery < 180°
• Short-segment TVI with hepatic artery of any degree

Surgeon/patient participation needed

The ability of these trials to advance the management of pancreatic cancer will depend in large part upon the enthusiastic participation of surgeons and their patients with their multidisciplinary teams. For questions and additional information, contact Matthew H. G. Katz at mhgkatz@mdanderson.org or Syed A. Ahmad at ahmadsy@uc.edu.

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References

1. Verbeke CS, Leitch D, Menon KV, McMahon MJ, Guillou PJ, Anthoney A. Redefining the R1 resection in pancreatic cancer. Br J Surg. 2006;93(10):1232-1237.
2. Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: A randomized controlled trial. JAMA. 2007;297(3):267-277.
3. Abrams RA. RTOG 0848: A phase IIR and a phase III trial evaluating both erlotinib (Ph IIR) and chemoradiation (Ph III) as adjuvant treatment for patients with resected head of pancreas adenocarcinoma. February 2014. Available at: www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=0848. Accessed June 23, 2016.
4. Katz MH, Shi Q, Ahmad SA, et al. Preoperative modified FOLFIRINOX treatment followed by capecitabine-based chemoradiation for borderline resectable pancreatic cancer: Alliance for Clinical Trials in Oncology Trial A021101. JAMA Surg. June 2016 [Epub ahead of print].
5. Katz MH, Ahmad SA, Boughey JC. Improving resection rates in borderline resectable pancreatic cancer: Pilot study shows favorable results. Bull Am Coll Surg. 2015;100(10):39-41. Available at: bulletin.facs.org/2015/10/improving-resection-rates-in-borderline-resectable-pancreatic-cancer-pilot-study-shows-favorable-results/. Accessed June 23, 2016.