Tumor involvement of the major mesenteric vasculature historically has represented a contraindication to the surgical treatment of pancreatic cancer. Unfortunately, most patients with this disease present with primary tumors that abut or encase the superior mesenteric artery, superior mesenteric vein (SMV)/portal vein (PV), or hepatic artery. Therefore, only approximately one-third of patients with localized pancreatic cancers have been considered eligible for surgical therapy.
Studies show that resection is potentially curative for patients with primary tumors that can be resected to negative margins, up to 27 percent of whom can expect to live five years or longer.1 For patients with unresectable tumors, cure is impossible. Most of these individuals will die within 18 months of diagnosis.
However, over the last two decades two clinical observations have increasingly blurred the distinction between resectable and unresectable pancreatic cancers. First, surgeons have recognized that resection and reconstruction of the SMV/PV and the hepatic artery can be performed safely and effectively concurrent with a pancreatectomy in well-selected patients and may lead to an improvement in survival over nonsurgical management. Second, multidisciplinary teams have recognized that, when administered in the preoperative setting, chemotherapy and chemoradiation can exert cytotoxic effects on the primary tumor, enabling surgical oncologists to effectively select patients with favorable tumor biology for the major operations to follow.
Multimodality therapy, including surgical resection, now represents a potential route to long-term survival for a group of patients with so-called “borderline resectable” cancers. These cancers include localized tumors that are technically resectable but at high risk for margin-positive resection due to their close anatomic relationship with the major mesenteric vasculature.
Figure 1: Treatment schema for patients with borderline resectable pancreatic cancer2
A typical treatment schema for patients with borderline resectable disease is shown in Figure 1. Both systemic chemotherapy and chemoradiation are administered first. Patients who are found to have progressive disease on restaging studies receive palliative care, and surgical treatment is no longer considered an option. Patients who have stable disease following completion of preoperative therapy are brought to the operating room (OR) for resection. This approach allows complete resection to be performed in a highly enriched population most likely to benefit from it, and therefore leads to potential cure in patients previously considered unresectable.2
Multi-institutional trials needed
Although this treatment strategy is rational and its use has been accepted by consensus, no multi-institutional trial has been performed to study it.3 Indeed, only one multi-institutional prospective trial has been conducted specifically to study patients with borderline resectable pancreatic cancer, and that trial closed prematurely almost a decade ago largely due to an absence of a well-defined study population and therapeutic and surgical standards.4 Since then, standardization of preoperative assessment and staging, surgical decision making and technique, and integration of drug therapy and chemoradiation has not been accomplished for this group.5 For these reasons, patients with borderline resectable cancer are still often either treated as inoperable, and are therefore denied a chance at cure, or are brought to the OR for massive operations that are unlikely to be of long-term benefit.
The critical need for prospective evaluation of novel therapeutic strategies for patients with borderline resectable cancer is clear. The Alliance for Clinical Trials in Oncology (Alliance), in cooperation with the Southwest Oncology Group, the Eastern Cooperative Oncology Group, and the Radiation Therapy Oncology Group recently obtained the approval of the National Cancer Institute to conduct a feasibility study of preoperative chemotherapy and chemoradiation for this challenging group of patients. This study will be the first involving national and multi-institutional cooperation to look at neoadjuvant therapy for patients with advanced pancreatic cancer.
Study design
Adult patients with biopsy-proven adenocarcinoma of the pancreatic head, a serum CA 19-9 level < 1000 U/ml in the absence of jaundice, and no evidence of metastatic cancer are considered to have borderline resectable disease and are eligible for this study if their primary tumor meets any one or more of the following radiographic criteria:
- An interface between the primary tumor and SMV/PV exists that measures 180º or greater of the circumference of the vessel wall
- Short segment occlusion of the SMV/PV exists with normal vein above and below the level of obstruction that is amenable to resection and venous reconstruction
- Short segment interface (of any degree) between tumor and hepatic artery exists with normal artery proximal and distal to the interface that is amenable to resection and arterial reconstruction
- An interface between the tumor and superior mesenteric artery exists that measures less than 180º of the circumference of the vessel wall
Figure 2: Treatment schema for Alliance trial A0201101
Following central confirmation of the initial staging studies in a pre-registration phase, enrolled patients will be treated with FOLFIRINOX and capecitabine-based chemoradiation (see Figure 2). Patients who maintain their performance status and exhibit no radiographic evidence for tumor progression at completion of therapy will be brought to the OR for planned resection. The primary end points of this initial single-arm pilot study will be to achieve the following: rapidly determine the feasibility of multi-institutional study of borderline resectable pancreatic cancer, develop a standardized clinical and research infrastructure specific to this disease stage that is necessary to study it, and define a new standard of care therapy for patients in whom such a standard does not currently exist to which novel regimens will subsequently be compared. Following rapid completion of this initial feasibility trial, a larger clinical study that includes a robust translational science program will be performed to evaluate this group of patients.
It is anticipated that surgeons will play a critical role in the success of this trial and their active participation is encouraged. For additional information, contact Dr. Katz at mhgkatz@mdanderson.org.
References
- Katz MH, Wang H, Fleming JB, Sun CC, Hwang RF, Wolff RA, Varadhachary G, Abbruzzese JL, Crane CH, Krishnan S, Vauthey JN, Abdalla EK, Lee JE,Pisters PW, Evans DB. Long-term survival after multidisciplinary management of resected pancreatic adenocarcinoma. Ann Surg Oncol. 2009;16(4):836-847.
- Katz MH, Pisters PW, Evans DB, Sun CC, Lee JE, Fleming JB, Vauthey JN, Abdalla EK, Crane CH, Wolff RA, Varadhachary GR, Hwang RF. Borderline resectable pancreatic cancer: The importance of this emerging stage of disease. J Am Coll Surg. 2008;206(5):833-846.
- Abrams RA, Lowy AM, O’Reilly EM, Wolff RA, Picozzi VJ, Pisters PW. Combined modality treatment of resectable and borderline resectable pancreas cancer: Expert consensus statement. Ann Surg Oncol. 2009;16(7):1751-1756.
- Landry J, Catalano PJ, Staley C, Harris W, Hoffman J, Talamonti M, Xu N, Cooper H, Benson AB 3rd. Randomized phase II study of gemcitabine plus radiotherapy versus gemcitabine, 5-fluorouracil, and cisplatin followed by radiotherapy and 5-fluorouracil for patients with locally advanced, potentially resectable pancreatic adenocarcinoma. J Surg Oncol. 2010;101(7):587-592.
- Katz MH, Pisters PW, Lee JE, Fleming JB. Borderline resectable pancreatic cancer: What have we learned and where do we go from here? Ann Surg Oncol. 2011;18(3):608-610.
