Neoadjuvant Strategies for Pancreatic Cancer

Introduction

Pancreatic cancer is the fifth leading cause of cancer-related death for both US men and women and is responsible for 5% of all cancer-related deaths.[1] In 2001, adenocarcinoma of the exocrine pancreas will account for approximately 28,900 deaths in the United States.[1] Because it is usually difficult to diagnose pancreatic cancer while it is still localized and surgically resectable, incidence rates are virtually equal to mortality rates.

Exocrine pancreatic cancer is characterized by infiltration of surrounding blood vessels and perineural tissues, spread to regional lymph nodes, and early vascular dissemination. Most patients present with subclinical liver metastases at the time of diagnosis, even when findings from imaging studies are normal. Thus, disease recurrence following a potentially curative pancreaticoduodenectomy remains common.

Among patients treated with surgery alone, local recurrence develops in up to 80%, peritoneal recurrence in 25%, and liver metastases in 50% of patients.[2] When surgery and chemoradiation are used to maximize locoregional tumor control, liver metastases become the predominant form of tumor recurrence.[3]

Advantages of Multimodality Therapy

Recent prospective and retrospective data suggest that compared with surgery alone, the combination of pancreaticoduodenectomy with postoperative adjuvant fluorouracil(Drug information on fluorouracil) (5-FU) and external-beam radiation therapy (EBRT) improves survival and locoregional tumor control (Table 1).[4-7] However, the morbidity and often prolonged recovery time associated with pancreaticoduodenectomy prevent the timely delivery of postoperative chemoradiation (chemotherapy and EBRT) in at least 25% to 30% of eligible patients.[6,8] This risk of delaying postoperative adjuvant chemoradiation prompted investigators to assess the efficacy of administering chemoradiation before pancreaticoduodenectomy in patients with potentially resectable adenocarcinoma of the pancreas.[3]

Several considerations support the preoperative use of chemoradiation.[8] First, positive gross or microscopic margins of resection along the right lateral border of the superior mesenteric artery are common following pancreaticoduodenectomy, suggesting that surgery alone may be an inadequate strategy for local tumor control.[9] Second, because chemoradiation is administered before surgery, delayed postoperative recovery does not affect the delivery of multimodality therapy. Third, patients with disseminated disease evident on restaging studies after chemoradiation are not subjected to an unnecessary laparotomy, since surgery would not benefit these individuals. Fourth, recent data suggest that preoperative chemoradiation may decrease the incidence of pancreaticojejunal anastomotic fistula, the most common complication following pancreaticoduodenectomy.[10]

Inconsistent definitions of resectability, variations in surgical technique (often resulting in positive retroperitoneal margins), and the absence of a uniform system for gross and microscopic evaluation of pancreaticoduodenectomy specimens have made much of the available data on the use of multimodality therapy for localized pancreatic cancer impossible to interpret. Thus, standardized approaches to patient selection (pretreatment staging), operative technique, and pathologic evaluation of surgical specimens must be incorporated into clinical trials that are evaluating preoperative or postoperative adjuvant therapy.

This article briefly outlines our system for standardizing these important variables, which are critical to ensuring accurate data in clinical trials, and reviews current and future neoadjuvant chemoradiation strategies for patients with localized adenocarcinoma of the pancreas.

Pretreatment Radiographic Staging

At our institution, high-quality contrast-enhanced helical computed tomography (CT) scanning can accurately assess the relationship of the tumor to the superior mesenteric vessels and the celiac axis. To identify potentially resectable disease (Figure 1), we use the following CT criteria[11]: (1) the absence of extrapancreatic disease; (2) no evidence of direct tumor extension to the superior mesenteric artery or celiac axis, as defined by the presence of a fat plane between the low-density tumor and these arterial structures; and (3) a patent superior mesenteric-portal vein confluence.

The third criterion is based on the assumption that resection and reconstruction of the superior mesenteric vein or superior mesenteric-portal vein confluence are possible. In the absence of extrapancreatic disease, the main goal of preoperative imaging studies is to determine the relationship of the low-density tumor mass to the superior mesenteric artery and celiac axis. This information enables accurate prediction of the likelihood of obtaining a negative retroperitoneal margin of resection. The retroperitoneal margin, also termed the mesenteric margin, corresponds to the tissue along the proximal 3 to 4 cm of the superior mesenteric artery wall (Figure 2).

Data from our institution have confirmed the reliability of these CT criteria in a consecutive series of patients with adenocarcinoma of the pancreatic head or uncinate process who underwent laparotomy for planned pancreaticoduodenectomy.[8] We reported a resectability rate of 80% (94 of 118 patients) and a low (17%) rate of positive microscopic retroperitoneal margins. The accuracy of such CT criteria for predicting unresectability is well established.[2]

Surgical Technique

We have previously reported the six-step operative technique of pancreaticoduodenectomy currently performed at our institution.[12] The most important and difficult part of this operation is step 6, during which the pancreas is divided and the specimen is removed from the superior mesenteric-portal vein confluence and the right lateral border of the superior mesenteric artery. Only after full medial mobilization of the superior mesenteric-portal vein is it possible to identify the superior mesenteric artery (lateral to the venous structure). The pancreatic head and all soft tissue to the right of the superior mesenteric artery are then removed by direct ligation of the inferior pancreaticoduodenal artery or arteries. Failure to mobilize the superior mesenteric-portal vein may result in a positive resection margin due to incomplete removal of the uncinate process and the mesenteric soft tissue adjacent to the superior mesenteric artery.

Pathologic Assessment of Surgical Specimens

Both the evaluation of innovative preoperative treatment strategies and the development of reproducible prognostic predictors of patient survival and treatment failure depend on accurate pathologic assessment of surgical specimens. Retrospective pathologic analysis of archival material does not allow accurate assessment of the margins of resection or the number of lymph nodes retrieved. Pathologic evaluation of the pancreaticoduodenectomy specimen includes frozen-section evaluation of the common bile duct transection margin and the pancreatic transection margin.[13] Either transection margin, if positive, is treated with re-resection.

The retroperitoneal or mesenteric margin is defined as the soft tissue directly adjacent to the proximal 3 to 4 cm of the superior mesenteric artery wall. This margin is evaluated by permanent-section microscopic examination and is identified and inked by the surgeon and pathologist (Figure 3). Re-resection to treat a microscopically positive margin is not possible in the retroperitoneum, where the aorta and superior mesenteric artery origin limit the extent of surgical resection; therefore, frozen-section evaluation of this margin is not performed. Importantly, this margin cannot be evaluated retrospectively after gross evaluation of the specimen has been completed. Samples of multiple areas of each tumor, including the interface between the tumor and the adjacent uninvolved tissue, are submitted for paraffin(Drug information on paraffin)-embedded histologic examination (5 to 10 blocks).

The final pathologic evaluation of permanent sections includes a description of tumor histology and differentiation, gross and microscopic evaluation of the tissue of origin (pancreas, bile duct, ampulla of Vater, or duodenum), an assessment of maximal transverse tumor diameter, and a report of lymph node status. Metastatic disease in regional lymph nodes, poorly differentiated histology, and increased size of the primary tumor have been identified as prognostic indicators for poor survival.[14-16] In patients who receive preoperative chemoradiation, the grade of treatment effect is assessed on permanent sections (Table 2).[17]

The continued success of translational research programs requires that an active pancreatic tumor banking program be maintained. Pathologists should routinely bank tumors for collaborative research efforts. Only through the coordinated efforts of such interdisciplinary programs will new treatments advance from the laboratory to clinical practice. At our institution, small sections of normal pancreas (when possible) and tumor are collected immediately for RNA extraction and additional samples are snap-frozen in liquid nitrogen and stored at 80°C. A representative section of tumor and normal tissue is routinely preserved in 70% ethyl alcohol(Drug information on alcohol) for paraffin block processing, and a hematoxylin-eosin-stained slide is made.