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New Treatment Options and Management Considerations in Borderline Resectable Pancreatic Cancer

New Treatment Options and Management Considerations in Borderline Resectable Pancreatic Cancer

Oncology (Williston Park). 31(6):443–452.
Table 1. Radiographic Classification of Borderline Resectable Pancreat...
Figure 1. Image Demonstrating Tumor Abutment of the Superior Mesenteri...
Figure 2. Impact of Neoadjuvant Therapy on Tumor Vasculature in Border...
Figure 3. Surgical Resection of Pancreatic Cancer
Table 2. Selected Published Studies of Borderline Resectable Pancreati...
Table 3. Selected Ongoing Clinical Trials for Patients With Borderline...

In the United States, cancer of the pancreas accounts for nearly 40,000 deaths annually and is the fourth leading cause of cancer-related mortality. The vast majority of patients present with metastatic or unresectable disease. Only 20% of patients are candidates for surgery, and therefore curable. The 5-year survival rate for patients with pancreatic adenocarcinoma is only 6%, with surgical resection being essential for long-term survival. Recent research has identified a precise subset of patients with borderline resectable pancreatic cancer for whom resection yielding durable survival is possible. This population is being actively studied to identify optimal treatment strategies for long-term survival. In this article we will discuss the definitions of resectability, describe the current diagnostic tests for pancreatic cancer, and review strategies for maximizing treatment outcomes in patients with resectable pancreatic cancer.

Introduction

Pancreatic ductal adenocarcinoma persists as a highly lethal disease. Multidisciplinary care that includes surgical resection is the only treatment associated with long-term survival; however, only approximately 20% of patients present with surgically resectable disease.[1,2] The ability of neoadjuvant therapy to reduce both tumor size and the extent of locally advanced disease has improved the treatment outcomes associated with many solid malignancies; this approach has been studied over the past 20 years in patients with pancreatic cancer, and is now being actively investigated. Until the early 2000s, pancreatic adenocarcinomas were defined as being resectable, locally advanced, or metastatic.[3] However, in the past decade, along with recent advances in pancreatic imaging, surgical technique, and—perhaps most importantly—multimodality treatments for pancreatic cancer, a distinct subset of patients has emerged: those with borderline resectable pancreatic cancer.[4] Unlike most other solid malignancies, this distinct category of pancreatic cancer is defined not only by anatomic parameters, but also by the biologic and physiologic state (eg, comorbidities) of the individual patient.

The identification of borderline resectable pancreatic cancer as a distinct clinical entity serves to clarify a divergence along the continuum between technically resectable and locally advanced unresectable cancers. It separates out the subgroup of patients for whom a margin-negative (R0) resection is difficult to achieve without major vascular resection, but who are not truly unresectable from anatomic and biologic standpoints. Patients with resection margin–positive pancreatic tumors have poor overall survival and do not benefit from chemoradiation therapy.[5,6] Multiple studies have demonstrated the association of margin-positive resection with early recurrence and more aggressive pancreatic disease. Therefore, categorizing the resectability of a pancreatic adenocarcinoma is a critical goal of the initial patient evaluation.[7]

As we will discuss, there is currently no uniform definition of borderline resectable pancreatic cancer, and consensus on this diagnostic entity continues to evolve. Many retrospective studies and clinical trials continue to group patients with borderline resectable disease together with patients who have locally advanced disease. Future studies will likely separate the two groups and define them as distinct entities of pancreatic adenocarcinoma. The goal of combining systemic chemotherapy, local radiation therapy (RT), and other local ablative therapies is to optimize clinical outcomes for patients with borderline resectable pancreatic cancer, by achieving negative surgical margins and ultimately improving overall survival. In recent years, biologic and physiologic parameters have been incorporated into the pancreatic cancer staging system, due to the efforts of forward-thinking leaders in the field of pancreatic cancer and the growing recognition of high rates of distant metastatic recurrence after surgical resection of early-stage pancreatic adenocarcinoma.[8,9]

Defining Borderline Resectable Pancreatic Cancer

The current ambiguity of the anatomic definition of borderline resectable pancreatic cancer is evident from the four major published definitions of resectability, developed separately by the National Comprehensive Cancer Network (NCCN), MD Anderson Cancer Center (MDACC), the Americas Hepato-Pancreato-Biliary Association (AHPBA)/Society of Surgical Oncology (SSO)/Society for Surgery of the Alimentary Tract (SSAT), and the Alliance for Clinical Trials in Oncology (Table 1). Therefore, in interpreting results of clinical studies of pancreatic cancer management published in the medical literature, one must be mindful of which guidelines have been followed. As an example, compared with the other three sets of guidelines, the AHPBA/SSO/SSAT criteria are the most conservative, with “borderline” disease classified as any abutment of the superior mesenteric vein (SMV), whereas the NCCN guidelines require the presence of SMV distortion rather than just contact. A patient classified under the AHPBA/SSO/SSAT guidelines as having “borderline” disease may, in fact, be resectable based on the NCCN guidelines. Thus, the existence of differences in the current guidelines on resectability of pancreatic cancer is important to bear in mind until one unified classification system is developed that enables identical resectability criteria to be used in all investigational trials.

Borderline tumors in the pancreatic head and/or uncinate process are defined as those with any of the following:

• Tumor abutment to the superior mesenteric artery (Figure 1).

• Short segment abutment or encasement of the common hepatic artery.

• Occlusion or distortion of the SMV–portal vein confluence (Figure 2), with a vein of the appropriate caliber (internal diameter) above and below the occlusio to allow for vascular reconstruction.

Tumors involving the body and tail of the pancreas are characterized as borderline if they abut the celiac axis by 180 degrees or less (ie, ≤ 50% of contact) or by more than 180 degrees without involvement of the aorta and with an intact and uninvolved gastroduodenal artery. The details of the specific degree of contact or distortion based on the different criteria for left-sided vs right-sided pancreatic cancers are outlined in Table 1.

In an effort to identify patients with borderline resectable pancreatic cancer based on biology and physiology, developers of the MDACC guidelines proposed two additional useful and prognostic categories to consider: type A and type B borderline resectable tumors. Type A is based on the aforementioned anatomic considerations. Patients with type B tumors have clinical findings that are suspicious but not diagnostic for metastatic disease; these may include radiographically indeterminate liver lesions, suspicious but not biopsy-proven distant lymph nodes, a biopsy-proven regional lymph node, or cancer antigen (CA) 19-9 levels greater than 1,000 units/mL (in the presence of normal levels of bilirubin).[4] These findings have been incorporated into the currently accepted definition of borderline resectable pancreatic cancer because they are believed to indicate a particularly high risk for early treatment failure with surgery alone.[10,11]

Further, type C patients with borderline resectable tumors are those with marginal performance status or significant comorbidities that confer higher than usual risk for postoperative morbidity and mortality.[10] In an effort to help this group attain the goal of possible future surgery, patients should be actively managed with physical therapy rehabilitation, nutritional optimization, and consultation with subspecialists in surgery and internal medicine.[4]

Borderline resectable pancreatic cancer is defined not just by the characteristic imaging findings, but also by biologic and physiologic parameters, as described above. This highlights the additional importance of a multidisciplinary high-volume pancreas program for the management of patients with borderline resectable pancreatic cancer.

Diagnostic Evaluation

High-quality thin-slice multiphase CT angiography is the modality most frequently used for determining whether a pancreas cancer is surgically resectable. Although MRI is equally specific and sensitive, limitations of cost and variable institutional quality and availability have rendered it inappropriate for patients who cannot tolerate iodinated dye, as well as those with specific or definite liver metastatic lesions, and/or isoattenuating pancreatic lesions.[12] A pancreas protocol CT ideally will involve acquiring submillimeter (0.5- to 1-mm) tissue sections, with scan acquisition in the pancreatic parenchymal phase at 40 to 50 seconds after intravenous injection and a portal venous phase at 65 to 70 seconds post injection. The early phase also opacifies well the arterial blood supply, allowing for accurate delineation of arterial anatomy. The variation in phases enables better char acterization of the often subtle anatomic relationships between the tumor and the mesenteric vasculature, thereby improving the ability to classify patients into the appropriate subgroups.[13] Although the use of fluorodeoxyglucose positron emission tomography (FDG-PET)/CT is not standard practice in the management of pancreatic cancer, recent data presented at the annual American Society of Clinical Oncology Gastrointestinal Cancers Symposium in early 2017 demonstrate that FDG-PET/CT may be useful in patients with significantly elevated levels of CA 19-9.[14]

The workup of patients with borderline resectable pancre atic cancer who will require neoadjuvant therapy should include evaluation of small hepatic biopsy samples for the presence of malignant biliary obstruction. Endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) has become widely available and is a safe and efficient tool for tissue diagnosis in this setting.[15] The use of EUS-FNA is preferable to CT-FNA, given the smaller likelihood of peritoneal seeding with the former technique, and because EUS enables better assessment of vascular involvement. However, if EUS-FNA is not an option, then CT-FNA is a reasonable alternative. In addition to EUS and CT, multiple brushings of the biliary tree can be performed during endoscopic retrograde cholangiopancreatography, to obtain tissue for diagnosis of cholangiocarcinoma. Unfortunately, since the bile duct is often extrinsically compressed by the pancreatic tumor, these brushings are not diagnostic and thus not the modality of choice for diagnosis of pancreatic cancer. Obstructive jaundice is a common presentation of pancreatic head adenocarcinoma and must be treated promptly by the placement of a biliary stent if patients present with prohibitively high levels of bilirubin or if they will receive neoadjuvant therapy prior to surgical resection.

Placement of a biliary stent is necessary to allow for normalization of hepatic function. With regard to the selection of stent length, most centers that treat large numbers of patients with pancreatic cancer will favor short covered metal stents for this population; because shorter stents are less likely to occlude, they carry a lower risk of inducing cholangitis, and the stent covers provide greater resistance to tumor ingrowth compared with open metal stents.[9] While stent occlusion is a complication to understand, it is neither sufficiently common nor problematic to warrant forgoing the use of stents (particularly metal ones) in the delivery of neoadjuvant therapy.[16] The majority of centers now perform routine diagnostic laparoscopy concurrently with the planned resection, particularly in patients who have received neoadjuvant therapy. This approach is consistent with our institutional practice.

The most important aspect of the workup and diagnosis of borderline resectable pancreatic cancer is the involvement of a multidisciplinary team of medical and radiation oncologists, surgeons, interventional radiologists and gastroenterologists, and specialists in nutritional services and physical therapy. Furthermore, to optimize patient survival and ensure that all appropriate patients are considered as candidates for surgical resection or referral to clinical trials, it is critical that both surgical and medical oncologists participate in the initial patient evaluation.

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