Resectable or Borderline Resectable Pancreatic Adenocarcinoma: Initial Treatment Options
Neoadjuvant chemoradiation may benefit patients with resectable or borderline resectable disease
By Sunni Hosemann
Adenocarcinoma of the exocrine pancreas accounts for 95% of pancreatic
cancers. Neuroendocrine pancreatic cancers, which account for the
remaining 5%, differ in their natural history, biology, and treatment
and are not considered here.
Pancreatic adenocarcinomas are initially classified as resectable,
borderline resectable, locally advanced/nonresectable, or
metastatic/disseminated. This discussion centers on resectable and
borderline resectable pancreatic adenocarcinomas, for which decisions
about initial treatment—surgery or neoadjuvant therapy—are the most
unsettled among experts. At The University of Texas MD Anderson Cancer
Center, the preferred treatment sequence is neoadjuvant therapy for
both resectable and borderline resectable pancreatic adenocarcinomas.
However, this sequence differs from the standard treatment at many
A deadly disease
Pancreatic adenocarcinoma has a well-deserved reputation as a deadly
disease. The survival rates of patients with pancreatic adenocarcinoma
are not improving, and the incidence of this complex disease appears to
Because pancreatic adenocarcinomas rarely cause early symptoms that
would prompt investigation, most patients present with advanced
disease. “It is possible that these tumors have been present for
several years before diagnosis,” said Jason Fleming, M.D., a professor
in the Department of Surgical Oncology.
Pancreatic adenocarcinoma is generally considered to be a biologically
aggressive disease. The high rate of local or distant recurrence
(80%–90%) in patients whose disease appeared to be localized and was
surgically removed suggests that micrometastatic disease is often
present but unrecognized at diagnosis. This possibility has prompted
many experts to consider pancreatic adenocarcinoma a systemic disease
in most patients at presentation and is the strongest rationale for
using chemotherapy or chemoradiation before rather than after surgery.
Assessment and staging
Initial treatment decisions for patients with pancreatic
adenocarcinomas are based on clinical staging because some of the
information needed for pathological staging is available only after
surgically removed specimens have been analyzed. The initial
classification of pancreatic adenocarcinomas as resectable, borderline
resectable, locally advanced/ nonresectable, or metastatic/disseminated
is based on clinical information and imaging studies.
Because surgery for pancreatic adenocarcinomas is complex and has a
high potential for morbidity and because resection must be complete
(all surgical margins are negative for tumor cells; R0) to be
effective, accurate pretreatment staging is essential. Advanced
diagnostic imaging techniques have made clinical staging possible
without exploratory laparotomy. These techniques include computed
tomography with a special pancreatic protocol, which employs
multiphasic helical scans to capture images during the arterial and
venous filling phases after contrast agent injection. Also, endoscopic
ultrasonography and endoscopic retrograde cholangiopancreatography make
it possible to perform fine-needle biopsy, assess critical vessel
involvement, and place stents for biliary decompression without open
Pancreatic adenocarcinomas are classified as resectable if they are
separated from critical vessels—the superior mesenteric and portal
veins, superior mesenteric artery, celiac axis, and hepatic artery—by a
clearly defined tissue plane. Borderline resectable tumors abut,
distort, or encase one or more of these vessels; this decreases the
likelihood that an R0 resection can be achieved. Tumors that encase
more than half the circumference of the celiac axis or the superior
mesenteric artery are considered locally advanced and unresectable.
According to Gauri Varadhachary, M.D., a professor in the Department of
Gastrointestinal Medical Oncology, multidisciplinary cooperation prior
to the initiation of any therapy for localized pancreatic
adenocarcinoma is critical. If neo adjuvant therapy will be the initial
treatment, certain interventions must precede it: biopsy confirmation
of disease must be obtained, and for patients who have biliary
obstruction, stents must be placed.
“Before any treatment begins, it’s necessary to determine whether
surgery is a possibility,” Dr. Fleming said. “This is very important in
terms of patient and family expectations.” He stressed that in addition
to tumor resectability, patient factors such as performance status,
which may be compromised by comorbidities, frailty, or the disease
itself, also influence surgical potential. “Many patients who present
with this cancer are quite weak, and some are malnourished, but these
conditions can improve after the obstructed biliary tree is drained and
the tumor treated preoperatively.” Dr. Fleming said.
At many institutions, the standard approach for patients whose
pancreatic adenocarcinoma is considered resectable is to perform
surgery first—a laparotomy in which the diagnosis is confirmed, staging
is completed, and the tumor is resected unless found to be
unresectable. Studies have shown that postoperative adjuvant therapy
offers a modest survival benefit; however, a substantial number of
patients do not receive postoperative therapy owing to a number of
factors, including disease progression, comorbid illnesses,
surgery-related morbidity, and delayed recovery from surgery.
When surgery is employed first, a recovery period of at least 8 weeks
is required before adjuvant chemotherapy can begin. During this time,
the potential for metastasis is heightened, as the surgery itself can
impair immune function and possibly even accelerate the growth of small
The MD Anderson approach
Noting the high percentage of patients whose disease recurred after
surgery, many physicians began to view pancreatic adenocarcinoma as a
disease with a high potential for clinically undetectable metastases at
presentation. These observations led MD Anderson physicians to begin
treating patients whose disease was considered resectable or borderline
resectable with neoadjuvant therapy rather than upfront surgery.
The goal of neoadjuvant therapy is to increase the probability of a
successful (R0) surgery and reduce the probability of local or distant
recurrence. At MD Anderson, neoadjuvant therapy consists of
chemotherapy, chemoradiation, or—for select patients considered to be
at high risk of developing metastatic disease on the basis of imaging
studies and serum markers—induction chemotherapy followed by
chemoradiation. Dr. Varadhachary said she encourages patients to
receive neoadjuvant therapy as part of a clinical study when available.
When given concurrently with radiation, some chemotherapy drugs act as
radiosensitizers. According to Dr. Varadhachary, the currently used
radiosensitizing chemotherapy regimens may include 5-fluorouracil,
capecitabine, or gemcitabine. Induction chemotherapy regimens often are
gemcitabine “doublets” (gemcitabine plus another drug). In addition,
the FOLFIRINOX regimen (oxaliplatin, irinotecan, 5-fluorouracil, and
leucovorin), which is used to treat advanced pancreatic adenocarcinoma,
is being evaluated as an induction chemotherapy (followed by
chemoradiation and surgery) in a clinical trial that began enrolling
patients with borderline resectable pancreatic adenocarcinoma earlier
Dr. Fleming noted that the neoadjuvant use of radiation in pancreatic
adenocarcinoma patients has not been validated in large trials and is
thus another area lacking widespread consensus. However, Dr. Fleming
said, “Our experience suggests that neoadjuvant radiation improves our
ability to achieve margin-negative surgery.” Dr. Fleming and his
colleagues postulate that radiation kills the outermost layer of tumor
cells to create a nonviable rim around the tumor, and this rim is very
often the margin needed to achieve a complete resection.
Christopher Crane, M.D., a professor in the Department of Radiation
Oncology, concurred. “We found that in borderline resectable tumors
where there was arterial invasion, the use of chemoradiation led to
margin-negative resection in 95% of patients, and these were cases
where we would have expected all of them to have positive margins.” Dr.
Crane added that radiation therapy delivered preoperatively also
prevents exocrine output at the pancreaticojejunal anastomoses, thereby
helping to prevent anastomotic leaking, one of the major complications
According to Dr. Crane, the standard neoadjuvant radiation therapy for
pancreatic adenocarcinoma patients at MD Anderson is three-dimensional
conformal radiation, usually delivered over 5 1⁄2 weeks. This technique
is effective and well tolerated; more advanced techniques would only
increase the cost to the patient.
Dr. Crane stressed the importance of using a well-tolerated
chemoradiation regimen and paying sufficient attention to supportive
care during treatment to maximize the patient’s potential to proceed to
“Under the old paradigm, surgery selected patients for adjuvant
therapy,” said Robert Wolff, M.D., a professor in the Department of
Gastrointestinal Medical Oncology. “It should be the other way around.”
Dr. Crane added that it is important that all members of the
multidisciplinary team, including the surgeon, have the opportunity to
observe the patient’s health during chemoradiation so that the
patient’s tolerance for surgery can be assessed. “Patients with this
disease tend to be quite ill, and often their performance status is
reduced,” he said, “so vigilance is required.”
The only potentially curative treatment for pancreatic adenocarcinoma
is surgery—complete resection of the tumor and surrounding tissue with
negative margins (R0), meaning that postsurgical pathological analysis
finds no gross or microscopic residual disease in an acceptable margin
of removed tissue. Studies have shown that anything less than an R0
resection diminishes the value of the surgery: The survival outcomes in
patients with even microscopic disease in the surgical margins (R1) are
similar to those of patients who received palliative treatment and no
Surgery for pancreatic adenocarcinoma typically involves exploratory
laparoscopy, during which staging is completed, immediately followed by
definitive resection unless the disease is found to be unresectable.
The definitive surgical treatment for adenocarcinoma of the pancreatic
head is pancreaticoduodenectomy (also known as a Whipple procedure).
This is a technically challenging surgery because the pancreas is
connected to numerous blood vessels and ducts that must be
reconstructed. Many anastomoses are required, and each represents a
potential site of leaks, which are among the many possible
complications of the surgery. The surgery is historically associated
with high perioperative mortality rates.
Patient outcomes from pancreaticoduodenectomy are greatly affected by
the experience of the surgical team. According to the American Cancer
Society, the surgical mortality rate of patients undergoing
pancreaticoduodenectomy is 15% at centers that perform few such
surgeries each year but less than 5% at centers that perform many. At
MD Anderson, the surgical mortality rate of patients who undergo the
procedure is less than 1%.
Toward wider adoption of neoadjuvant therapy
A number of studies have provided evidence of the effectiveness of the
MD Anderson approach to treating resectable or borderline resectable
pancreatic adenocarcinoma. For example, one retrospective analysis
showed that patients who underwent neoadjuvant therapy were more likely
to receive all planned therapy: Of those who had upfront surgery, fewer
than 60% were able to receive adjuvant therapy; in contrast, about 70%
of patients who received neoadjuvant therapy were able to undergo
subsequent surgery. The most common reason patients did not proceed to
surgery was that their disease progressed during neoadjuvant therapy.
The researchers believed these patients had aggressive or already
advanced disease and would have experienced recurrence shortly after
surgery if surgery had been performed first.
Even with these results, the neoadjuvant therapy approach has not been
widely used. However, Dr. Wolff believes that recent developments may
spur wider adoption of the approach. “First is the growing recognition
that surgery-first has not changed outcomes for 25 years,” he said.
“And second, with advances in imaging, a new clinical
subcategory—borderline resectable disease—has emerged.” He believes
that identifying this subset of patients has been pivotal because it
suggested the possibility that these patients might have better
surgical outcomes if they receive neoadjuvant therapy. In one MD
Anderson study, of 150 patients with borderline resectable disease who
were treated with neoadjuvant therapy, 60 (40%) ultimately went on to
have surgery. The median overall survival duration for the patients who
underwent surgery was more than 40 months, and fewer than 10% had
positive surgical margins.
Dr. Wolff said that practitioners are overcoming their reluctance to
move away from the standard surgery-first approach and use neoadjuvant
treatment for a subset of patients considered to be at higher risk of
developing metastatic disease. Dr. Wolff hopes that as more results
become available for patients with borderline resectable disease, the
neoadjuvant therapy paradigm will be easier to adopt for patients with
resectable disease. Additionally, Dr. Varadhachary is optimistic that
as better systemic approaches and novel agents are found to be
effective against advanced pancreatic cancer, they can be moved to the
neoadjuvant therapy setting with better results.
Dr. Fleming added that a key advantage of neoadjuvant therapy is that
it allows physicians to identify patients who have risk factors that
can be modified. He said, “We can use that time before surgery to
bolster nutritional factors, build up the person’s general strength and
condition, and even address other medical issues that might have
precluded surgery or placed the person at high risk for complications.”
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Evans DB, for the Multidisciplinary Pancreatic Cancer Study Group.
Resectable pancreatic cancer: the role for neoadjuvant/preoperative
therapy. HPB (Oxford). 2006;8:365–368.
Katz MH, Pisters PW, Evans DB, et al. Borderline resectable pancreatic
cancer: the importance of this emerging stage of disease. J Am Coll
Katz MH, Wang H, Fleming JB, et al. Long-term survival after multidisciplinary
management of resected pancreatic adenocarcinoma. Ann Surg Oncol.
National Comprehensive Cancer Network. Clinical Practice Guidelines in
Oncology: Pancreatic Adenocarcinoma, V1.2013 [subscription only].
Tempero MA, Arnoietti JP, Behrman S, et al. Pancreatic adenocarcinoma. J Natl Compr Canc Netw. 2010;8:972–1017.
The University of Texas MD Anderson Cancer Center
Christopher Crane, M.D.
Professor, Radiation Oncology
Jason B. Fleming, M.D.
Professor, Surgical Oncology
||Gauri R. Varadhachary, M.D.
Professor, Gastrointestinal Medical Oncology
||Robert A. Wolff, M.D.
Professor, Gastrointestinal Medical Oncology
information, talk to your physician, visit www.mdanderson.org, or call askMDAnderson at 877-632-6789.
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