Preoperative therapies for resectable and borderline resectable pancreatic cancer
Department of Gastrointestinal Medical Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas
|
Review Article
|
|
Abstract
In the era of multidetector high quality CT imaging, it is feasible and critical to use objective criteria to define resectable pancreatic cancer. This allows accurate pretreatment staging and the development of stage-specific therapy. Tumors of
borderline resectability have emerged as a distinct subset and the definition has been expanded in the last few years. Borderline
resectable tumors are defined as those with tumor abutment of <180degrees (< 50%) of the SMA or celiac axis,
short segment abutment or encasement of the common hepatic artery typically at the gastroduodenal artery origin, SMVPV
abutment with impingement and narrowing or segmental venous occlusion with sufficient venous flow above and
below the occlusion to allow an option for venous reconstruction. Most of the patients whose cancer meet these CT criteria
are candidates for preoperative systemic chemotherapy followed by chemoradiation since they are at a high risk for
margin positive resection with upfront surgery. Patients whose imaging studies show radiographic stability or regression
proceed to pancreaticoduodenectomy (or pancreatectomy) and this may require vascular resection and reconstruction.
Prospective biomarker and functional imaging enriched studies are warranted to determine the best overall treatment
strategy for these patients.
Key words
pancreatic cancer; borderline resectable tumors; preoperative therapies
J Gastrointest Oncol 2011; 2: 136-142. DOI: 10.3978/j.issn.2078-6891.2011.030
|
|
Introduction
Pancreatic cancer presents as a locally advanced or
metastatic cancer in most patients and only about
20-25% of patients present with a potentially resectable
cancer. Even in these patients, the 5-year survival rate
after a successful pancreaticoduodenectomy (PD) or
pancreatectomy is approximately 15-20% (1). Patients
who undergo a margin positive resection (R2 or R1)
do poorly and their survival is similar to those with
locally advanced disease (2-5). Given the systemic
nature of pancreatic adenocarcinoma, and the morbidity
involved with surgery, it is essential to clearly determine the resectability status at the time of initial staging
evaluation. This is best accomplished by a computerized
tomography (CT) scan optimized for pancreatic imaging
(6). Based on this high quality CT imaging, pancreatic
tumors are classified as resectable, locally advanced
or metastatic. Tumors of “borderline resectability” are
emerging as a distinct subset of pancreatic tumors and
do not easily fit the traditional categories of resectable or
locally advanced pancreatic cancers (7,8). It is important
to make this distinction because these presentations tend
to confound the results of clinical trials and misguide
treating physicians – i.e. in the absence of objective
criteria for preoperative staging, some patients with
borderline resectable pancreatic cancer will be treated as
if they have resectable cancer (with an increased risk of
margin positive resection) while others will be treated as
having locally advanced disease (and suggest ‘dramatic’
downstaging and operability). These patients are poor
candidates for upfront PD given the high rate of margin
positive resection and in selected patients; preoperative
therapy can achieve an R0 resection surgery.
This helps select appropriate patients for surgery who
have the greatest likelihood of a favorable postoperative outcome. This allows the appropriate candidates suited
for surgery to proceed with PD. This article reviews the
definition of borderline resectable tumors and provides a
framework for preoperative therapeutic options of patients
with resectable and borderline resectable pancreatic
cancers.
|
|
Preoperative staging criteria and the changing
paradigm
A multidetector computerized tomography (MDCT)
with 3-dimensional reconstruction is the best modality
to determine local tumor resectability except for its low
sensitivity for low-volume hepatic or peritoneal metastases
(in~20% of patients, CT occult metastatic disease is
found on laparoscopy or exploration) (9-11). Whenever
possible, it is helpful to perform a CT scan prior to
biliary decompression procedures since post-procedure
pancreatitis, if it occurs, may obliterate the vascular planes
and preclude accurate assessment of the extent of disease.
Endoscopic ultrasound (EUS) has a higher sensitivity
compared to a CT scan to detect small tumors and is
indicated in selected patients especially those who are
candidates for preoperative therapy.
The American Joint Committee on Cancer (AJCC) TNM
(Tumor, Nodes, Metastasis) staging for pancreatic cancer
was revised in 2002 (6th edition), to reflect the fact local
tumor resectability can be determined by high quality CT
imaging and these criteria are unchanged in the latest AJCC
edition (12). Based on the AJCC criteria, patients with
stages 3 and 4 pancreatic adenocarcinoma are considered to
have unresectable disease. Criteria for resectability include
the absence of tumor extension to the celiac artery (CA)
and superior mesenteric artery (SMA), a patent superior
mesenteric vein (SMV) and portal vein (PV), and no distant
metastases. Locally advanced, surgically unresectable
tumors are defined as those that encase the adjacent arteries
(celiac axis, SMA, common hepatic artery) or that occlude
the SMV, PV, or SMPV conf luence. With sophisticated
imaging, there is a paradigm shift and a growing category of
borderline resectability and the attempt to standardize the
definition of borderline resectable pancreatic cancer is work
in progress, being modified with time.
|
|
Borderline resectable criteria: NCCN, MDACC
and AHPBA guidelines
Even though there is some consistency in the AJCC
definitions of resectability, these become blur red
when describing borderline resectable pancreatic
adenocarcinoma. At the University of Texas M.D. Anderson Cancer Center (MDACC), patients with (anatomic)
borderline resectable pancreatic cancer were originally
defined to include those whose tumors exhibit: shortsegment
encasement of the hepatic artery which is amenable
to resection and reconstruction without evidence of tumor
extension to the celiac axis; abutment of the SMA to involve
less than or equal to180 degrees of the circumference of
the artery; or short-segment occlusion of the SMV, PV,
or SMPV conf luence with a suitable option for vascular
reconstruction due to a normal SMV below, and PV above
the area of tumor involvement (7). Since then the criteria
have been extended to include additional patients where
the surgery could prove to be technically challenging. The
American hepato-pancreatico-biliary (AHPBA) association
consensus conference on pancreatic cancer (2009)
expanded the venous involvement criteria to allow tumor
abutment of the SMV/PV with or without impingment and
narrowing of the lumen (in addition to venous encasement
or short segment occlusion). NCCN has adopted some of
these AHPBA guidelines in its most recent version (2.2011)
and allows SMV/portal vein abutment with impingment
and narrowing of the lumen (13-16). The criteria for arterial
involvement (SMA and hepatic artery) are clear and similar
across the board.
The above definitions describe the anatomic subset
of borderline resectability that deal only with tumorvessel
orientation (referred to as type A). Katz and
colleagues have described two additional subsets, types
B and C, which attempt to define additional criteria
for borderline resectability beyond the imaging based
principles (17). Most physicians encounter patients with
operable pancreatic cancer who are not quite ready for
immediate surgery and require extra time off to sort out
host or tumor related concerns. Some of these patients
have subtle indeterminate subcentimeter liver lesions
or peritoneal / omental nodules that are suspicious for
metastatic disease they are too small to proceed with
a diagnostic FNA- biopsy or additional imaging tests
(PET-CT or MRI). These patients fit the MDACC type
B definition of borderline resectable pancreatic cancer.
Type B patients may have had a technically resectable
or a borderline resectable primary tumor as defined
on CT images. Another subset of patients is those who
have associated medical comorbidities that need time
to evaluate or a reversible borderline per formance
status (typically ECOG 3). Good examples of these
presentation is a patient who has a small asymptomatic
pulmonary embolism on routine imaging or a patient
with a low prealbumin and decline in nutrition and
performance status in the presence of obstructive
jaundice and cholangitis though progress is noted after biliary decompression and a close eye on nutritional
supplementation. This subset const itutes Type C
category (and patients in this category may also have
had a radiographic potentially resectable or a borderline
resectable primary tumor).
|
|
Rationale for Preoperative therapy in patients with
resectable and borderline resectable (types A, B,
C) pancreatic cancer
The rationale for delivering preoperative therapy in early
pancreatic cancer includes potential for down staging in
order to maximize the chances for an R0/R1 resection,
using this approach to gauge the cancer’s biology and allow
appropriate candidates suited for surgery to proceed with
PD, treat micrometastatic disease early, and lastly, deliver
“adjuvant” therapy in a preoperative setting when it is better
tolerated. This has been studied at several institutions in
a phase II setting (18-22). Our group has completed two
gemcitabine based chemoradiation trials in patients with
potentially resectable pancreatic cancer (18,21). In the 176
patients from both trials (Gem-XRT and Gem-Cis-XRT)
isolated tumor progression at the time of preoperative
restaging was rare with the rate of local tumor progression
precluding surgery 0.6% (1 of 176 patients). We have used
a similar preoperative strategy for borderline resectable
pancreatic cancer with the exception that therpay lasts
longer prior to planned PD (the original dataset of 176
patients did not include any patients with MDACC criteria
for borderline resectability). Since patients with borderline
resectable pancreatic cancer (type A) are at a high risk for
margin positive resection and poor survival, these patients
are ideal candidates for a prolonged course of preoperative
therapy.
Treatment schema
After reviewing the patient’s pancreas protocol CT scan
in a multidisciplinary conference with radiologists and
surgical, medical and radiation oncologists, patients’
cancers are categorized as borderline resectable types
A, B, C or a combination of these. Most patients are
candidates for initial gemcitabine based systemic therapy
for 2-4 months. Patients with an ECOG PS of 0-1 are
considered for combination chemotherapy, often with
gemcitabine and a platinum agent. A restaging CT scan is
reviewed after approximately 8 weeks of systemic therapy
and patients with radiographic response or a biochemical
response in the presence of stable disease are candidates
for more systemic therapy followed by chemoradiation
or may proceed to chemoradiation. After a break of 4-6
weeks from their radiation therapy, patients who continue to show disease stability or response are candidates for
surgery. Gemcitabine or capecitabine are the common
radiation sensitizers used in this setting. After a break
of 4-6 weeks from their radiation therapy, patients
who continue to show disease stability or response are
candidates for surgery.
Given the high rate of systemic relapse in patients with
resected pancreatic cancer, the “best” systemic therapy
available may be applicable in the neoadjuvant setting
in selected patients. The recent phase 3 study published
by Conroy and colleagues reports on FOLFIRINOX
superiority over gemcitabine in the treatment of metastatic
pancreatic cancer and has gathered interest (23). 342
patients with a PS of 0 or 1 were randomly assigned to
receive FOLFIRINOX or gemcitabine. Six months of
chemotherapy were recommended in both groups in
patients who had a response. The primary end point was
overall survival. The median overall survival was 11.1
months in the FOLFIRINOX group as compared with
6.8 months in the gemcitabine group (hazard ratio for
death, 0.57; 95% confidence interval [CI], 0.45 to 0.73;
P<0.001). Median progression-free sur vival was 6.4
months in the FOLFIRINOX group and 3.3 months in the
gemcitabine group (P<0.001). The objective response rate
was 31.6% in the FOLFIRINOX group versus 9.4% in the
gemcitabine group (P<0.001). The authors concluded that
FOLFIRINOX is an option for the treatment of patients
with metastatic pancreatic cancer and good performance
status. There has been some interest from cooperative
groups and single institutions to propose FOLFIRINOX
based systemic therapy followed by chemoradiation for
patients with upfront unresectable (but borderline criteria)
pancreatic cancer to potentially maximize their chance
of resectability and improve survival after preoperative
therapy. Though, it is important to note that beside an
excellent PS, >50% of patients in the FOLFIRINOX study
had pancreatic tail tumors and the triple drug regimen was
not without toxicity (especially in patients with biliary
stents/ those prone to cholangitis).
Katz and colleagues have published the largest to
date retrospective report of 160 patients with borderline
resectable pancreatic cancer (from a prospective
database, 1999 -2006) (17). Of these, 125 (78%) received
preoperative therapy with mostly chemotherapy followed
by chemoradiation and 66 (41%) underwent PD. Twenty
seven percent (18 of 66) required vascular resections
and in 94% of the patients this was an R0 resection.
The median survival was 40 months for patients who
underwent preoperative therapy followed by surgery
and 13 months for patients who did not undergo PD
(p<0.001). Interestingly, the percent change in CA 19-9 over the course of preoperative therapy was associated
with overall survival. When compared to patients who
had a > 50% decrease in serum CA 19-9, patients with
an increase in serum CA 19-9 had a greater than 2-fold
risk of death (HR = 2.4, p = 0.02, 95 % CI [1.2, 4.9]). In
practice, the radiographic stability (or response), patient’
s tolerability to therapy and performance status as well
as the Ca19-9 trend is factored into making a therapy
decision. Prospective data on the role of CA19-9 as a
predictive marker is needed before we consider using it as
a part of the ‘resectability criteria’ in treated patients.
Understandably, there is an inherent selection bias given
that the prolonged course of therapy which selects for better
tumor biology, though the role of radiation in this setting
needs further evaluation. When our systemic agents and
biomarker based techniques to select patients improve,
it will provide additional justification for the need for
prolonged therapy prior to locoregional options.
|
|
Barriers to preoperative therapy for borderline
resectable cancer
It is mandatory for patients with resectable or borderline
resectable pancreatic cancer to proceed with a cytologic
diagnosis of adenocarcinoma (via EUS-guided FNA biopsy)
prior to initiating preoperative therapy (16). On rare
occasion, this can lead to pancreatitis. In the preoperative
therapy setting, when the duration of therapy exceeds
8 weeks, patients with plastic stents are at risk for stent
occlusion and cholangitis (especially in the radiation phase). In a clinical trial of 79 patients undergoing chemotherapy
with Gemcitabine in combination with Cisplatin followed
by Gemcitabine based chemoradiation, at least one stent
exchange was necessary in 46 (75%) of the 61 patients who
entered the protocol with a plastic biliary stent and selfexpandable
metal stents which ultimately were placed in 36
(46%) of 79 patients (18,21).
|
|
Biomarker based selection and sequencing of
preoperative therapies: Are we there yet?
A significant challenge to the management of pancreatic
cancer (PC) patients is resistance to a broad range of
therapies. There is an emerging consensus that poor
intratumoral drug levels may be related to high stromal
density, hypoperfusion, and/or drug transport/metabolism
within the tumor (24). These factors have been evaluated
in animal models but not understood in patients. E.g.
gemcitabine, the standard first-line therapy for advanced
disease and a drug used in our preoperative management
is an incompletely understood drug with little data
demonstrating levels of gemcitabine (dFdC) or its active
metabolite within human tissue or evaluating factors
affecting penetration or lack of activity in many patients. We
have some emerging biomarker data, albeit of retrospective
nature (from prospective trials) and we need to exploit this
information to generate new knowledge and plan elegant
next-generation studies (Figure 1). A few of these are
discussed below:
Human equilibrative nucleoside transporter (hENT1)
protein
The hNET-1 transports gemcitabine into cells (25,26).
Farrell and colleagues studied the predictive value of
hENT1 levels in patients from RTOG9704, a large
prospective randomized adjuvant treatment trial comparing
gemcitabine to 5-f luorouracil (5FU) as systemic therapy
in patients getting 5FU based chemoradiation (27,28).
In this study, 538 patients were assigned randomly, after
surgical resection, to either gemcitabine or 5-FU. HENT1
immunohistochemistry was performed on 229 tissue
microarrays and scored as having no staining, low staining,
or high staining. HENT1 expression was associated with
overall survival in a univariate (P = .02) and multivariate
model in the gemcitabine arm (P= .004) and hENT1
expression was not associated with survival in the 5FU arm.
The authors concluded that this report supports preclinical
data and that hENT1 is relevant predictive marker of benefit
from gemcitabine in patients with resected pancreatic
cancer. Prospective trials in the neoadjuvant and adjuvant
setting are warranted to understand its utility as a predictive
biomarker.
Gemcitabine single nucleotide polymorphisms
Okazaki and colleagues evaluated 17 single nucleotide
polymorphisms (SNPs) of gemcitabine metabolism
genes, including CDA, dCK, DCTD, RRM1, hCNT1,
hCNT2, hCNT3, and hENT1 genes in 154 patients with
potentially resectable pancreatic adenocarcinoma who
were enrolled in clinical trials at the UTMDACC from
February 1999 to January 2006 (29,30). Patients received
neoadjuvant concurrent gemcitabine and radiation therapy
with or without gemcitabine-cisplatin induction therapy.
They found that none of the 17 SNPs, individually, had
a significant association with OS. A combined genotype
effect on OS was observed. Patients carrying 0 to 1 (n = 43),
2 to 3 (n = 77), or 4 to 6 (n = 30) variant alleles had median
survival time of 31.5, 21.4, and 17.5 months, respectively.
The hazard ratio of dying was 1.71 (95% confidence interval,
1.06-2.76) and 3.16 (95% confidence interval, 1.77-5.63)
for patients carrying two to three or four to six at-risk
genotypes (P = 0.028 and P < 0.001), respectively, after
adjusting for clinical predictors. Four SNPs mainly, CDA
C111T, dCK C-1205T, dCK A9846G, and hCNT3 A25G
had a significant association with neutropenia toxicity
(individually and combined). The authors concluded that
these observations suggest that polymorphic variations
of drug metabolic genes may be associated with toxicity
of gemcitabine-based therapy and OS of patients with
resectable pancreatic cancer.
Rapid autopsy based DPC4 data
Recent rapid autopsy data presented by Dr. Iacobuzio-Donahue and colleagues suggest that pancreatic cancers
can present with distinct genetic subtypes with different
patterns of failure (31). In their study, patients with DPC4
intact tumors were more likely to die of locally destructive
disease (30% of patients) and those with DPC4 mutated
tumors with a distant widespread metastatic disease (70%).
These distinct patterns of failure (locally destructive versus
metastatic) were unrelated to clinical stage at presentation,
treatment history, and histopathologic features. There is
significant interest in understanding if this data holds true
in patients being treated (prospectively) and eventually
use this information to guide therapy based on subgroups
of patients (locally destructive or wildly metastatic
phenotypes). The feasibility of determining DPC4 status
on diagnostic cytology specimens was tested recently in
patients with locally advanced pancreatic cancer using
immunohistochemical staining though patient numbers
were small and additional validation studies are warranted
(32).
Fig 1 Schema for borderline resectable pancreatic cancer trials: looking ahead. BRPC: borderline resectable pancreatic cancer; SMV: superior mesenteric vein; SMA: superior mesenteric artery; PC: pancreatic cancer.
|
|
Summary
Preoperative management of pancreatic cancer is an
important and evolving field especially with the enlarging
definition of borderline resectability. Clearly this effort
needs a multidisciplinary working group of surgeons,
radiation and medical oncologists, gastroenterologists,
radiologists and a pathologist committed to research-driven
patient care and is best suited to a high volume center with
surgical expertise in vascular resections and interposition
grafting. Currently, we lack functional imaging or biomarker
based knowledge that can reliably provide data that
suggests or predicts response to therapy. This is important
going forward since it may have an impact on sequencing
of therapies (chemotherapy, chemoradiation) and can help
select patients for specific therapies and for surgery.
|
|
References
Cite this article as:
Varadhachary G. Preoperative therapies for resectable and borderline resectable pancreatic cancer. J Gastrointest Oncol. 2011;2(3):136-142. DOI:10.3978/j.issn.2078-6891.2011.030
|
