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Neoadjuvant Strategies for Pancreatic Cancer

Neoadjuvant Strategies for Pancreatic Cancer

ABSTRACT: Recent prospective and retrospective data suggest that the use of multimodality therapy combining pancreaticoduodenectomy with postoperative adjuvant chemotherapy (fluorouracil) and external-beam radiation therapy maximizes local tumor control and improves the length of survival in pancreatic cancer patients, compared with surgery alone. Since postoperative chemoradiation is often delayed in these patients due to the morbidity and prolonged recovery time associated with surgery, investigators are assessing the efficacy of administering chemoradiation before pancreaticoduodenectomy in patients with potentially resectable pancreatic adenocarcinoma. When given prior to surgery, chemoradiation is not delayed and patients found to have disease progression after chemoradiation are not subjected to an unnecessary laparotomy. [ONCOLOGY 15(6):727-747, 2001]

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 (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-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 for paraffin block
processing, and a hematoxylin-eosin-stained slide is made.

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