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Update on Combined-Modality Treatment Options for Pancreatic Cancer

Update on Combined-Modality Treatment Options for Pancreatic Cancer

ABSTRACT: Cancer of the pancreas remains a formidable challenge in oncology. This malignancy ranks as the fourth leading cause of cancer death in the United States in 2003, with an estimated 30,700 new cases to be diagnosed and 30,000 deaths. Although gains have been achieved in the clinical management of these patients, this malignancy is rarely curable. Long-term survival is limited to patients undergoing resection. For patients with localized but unresectable malignancy, radiation therapy combined with fluorouracil, gemcitabine (Gemzar), or paclitaxel has shown modest improvements in survival and symptom palliation. However, there has been significant progress in the diagnostic evaluation of pancreatic cancer patients, which has aided clinicians in caring for these patients and in selecting therapies. The use of computed tomography, endoscopic ultrasonography, and laparoscopy techniques will be discussed. Newer techniques of radiation therapy, such as intraoperative electron-beam radiation therapy and threedimensional conformal radiation therapy, with the integration of new biologically targeted agents may provide new avenues of research and progress in this disease.

Cancer of the pancreas is the
fourth leading cause of cancer
death in the United States.[1]
In 2003, an estimated 30,700 new patients
and approximately 30,000
deaths are expected to occur from this
disease.[2] Because the etiology of
the disease is poorly understood and
clinical presentation is late in its natural
history, cure remains elusive. For
the 10% to 15% of patients undergoing
resection, the 5-year survival of
patients with "favorable" localized
disease (ie, no lymph node metastases
and disease confined to the pancreas
without capsular invasion) approaches
18% to 24%.[3] For patients with advanced
or metastatic disease, there are
only anecdotal reports of survivors beyond
5 years. For all stages combined,
the 5-year survival rate is 4%.[4] Because
of these poor survival results,
adjuvant and neoadjuvant treatment
strategies have been investigated. New
combinations of cytotoxic chemotherapy
and targeted agents, and improvements
in radiation therapy such as
three-dimensional (3D) conformal radiation,
may improve survival in patients
with locally advanced pancreatic
cancer. This review will highlight some
of these developments.

Palliation of symptoms is a major
goal of therapy for patients with locally
advanced or metastatic pancreatic
cancer. Gastric outlet or biliary
obstruction and pain are frequent and
significant clinical problems, and require
judicious selection of surgical,
medical, and endoscopic or radiologic
intervention. These procedures have
been helpful in palliation and improving
patient quality of life.[5,6]

When resection is feasible, longterm
survival may result.[3,7] For pa-
tients
with locally advanced unresectable
tumors, median survival is 8 to 13
months. The National Cancer Institute
recommends that patients with any stage
of pancreatic cancer be considered for
enrollment in a clinical trial.

Treatments for
Resectable Tumors
Adjuvant Therapy
At present, surgery offers the
only therapeutic means of cure for
pancreatic cancer. Only 5% to 25% of
patients present with tumors amenable
to resection. Patients who undergo
resection for localized pancreatic
carcinoma have a long-term survival
rate of approximately 20% and median
survival of 13 to 20 months.[8]
Favorable subsets include patients
with resected tumors measuring less
than 3 cm, no lymph node metastases,
and microscopically negative surgical
margins.

The Gastrointestinal Tumor Study
Group (GITSG) evaluated the potential
value of adjuvant therapy for patients
with pancreatic cancer (Table
1). In one of the GITSG's earlier trials,
patients with resected tumors
who received adjuvant combination
chemoradiation with fluorouracil
(5-FU) and split-course radiation of
40 Gy in 20 fractions had a significant
survival advantage, with a median
survival of 21 months compared
with 11 months for patients not receiving
radiation therapy and chemotherapy
after resection. These findings
were confirmed in a follow-up registry
trial which found that combined
adjuvant radiation/5-FU therapy yielded
a 2-year actuarial survival of 43%
(95% confidence interval [CI] = 25%-
63%) in those patients receiving the
adjuvant therapy, compared to 18%
(95% CI = 5%-36%) in those who
underwent surgical resection alone.[9]

The European Organization for
Research and Treatment of Cancer
(EORTC) was unable to reproduce
these positive results in a randomized
trial of 218 patients with pancreas or
periampullary cancers. A subset analysis
of patients with primary tumors
of the pancreas (114 patients) did,
however, show a trend toward improved
2-year (median) and 5-year
(overall) survival.[10] In this phase
III trial, resected patients received either
split-course irradiation (40 Gy)
with concurrent 5-FU or were observed.
Median survival was 19
months in observed patients compared
with 24.5 months in those who
received postoperative treatment
(P = .208), with an estimated 2-year
survival of 41% and 51%, respectively.
Subset analysis of pancreatic cancer
patients, however, showed an
estimated 2-year survival of 26% for
the observation patients compared to
34% for those receiving the adjuvant
treatment (P = .099). Patients with
periampullary tumors had a much
higher estimated 2-year survival of
63% to 67%. These investigators concluded
that for patients undergoing
surgical resection, the benefit of adjuvant
therapy was limited and did not
justify its routine use.

A second European trial has examined
various adjuvant treatment
approaches, including 40-Gy splitcourse
radiation therapy with concurrent
and maintenance chemotherapy
as well as chemotherapy alone.[11]
The European Study Group for Pancreatic
Cancer (ESPAC-1) phase III
trial showed no survival advantage
for postoperative irradiation and
5-FU chemotherapy vs no further
treatment after surgery. However, a
therapeutic benefit was seen for patients
receiving adjuvant chemotherapy
of 5-FU and leucovorin only. The
ESPAC-3 trial is defining the role of
adjuvant chemotherapy following curative
resection of pancreatic ductal
adenocarcinoma. In this study, 5-FU
plus folinic acid for 24 weeks will be
compared with gemcitabine (Gemzar)
for 24 weeks vs no chemotherapy following
surgery. The aim is to recruit
330 patients in each arm for a total of
990 patients. Enrollment is ongoing.

Given conflicting results from various
studies, the exact role of postoperative
radiation therapy is uncertain
at present. However, considering the
very poor outcomes with surgery
alone (15% 5-year survival) and the
encouraging results from well-designed
and controlled studies from single
institutions and cooperative groups
using contemporary techniques, there
is a rationale to support adjuvant therapy
with radiation therapy and 5-FU,
as for other gastrointestinal carcinomas.
The Radiation Therapy Oncology
Group, in conjunction with the GI
Intergroup, has recently completed a
phase III trial examining whether gemcitabine
improves survival over 5-FU
as maintenance therapy for patients
with resected pancreatic cancer receiving
radiation therapy and concurrent
5-FU.

Neoadjuvant Therapy
In addition to postoperative treatment
strategies, there has also been
interest in the use of preoperative radiation
therapy and chemotherapy for
patients with resectable pancreatic
cancer. In one institutional analysis
of 132 patients who had received pre-
operative chemoradiation (5-FU,
paclitaxel, or gemcitabine with either
45 to 50 Gy radiation at 1.8 Gy/fraction
or 30 Gy at 3.0 Gy/fraction) before
pancreaticoduodenectomy for
adenocarcinoma of the pancreas head,
a median survival of 21 months was
found for all chemoradiation combinations.[
12] In this study, superior
survival was observed for women
(P = .04) or those with no evidence of
lymph node metastasis (P = .03). Interestingly,
there was no difference in
median survival between standardfractionation
chemoradiotherapy
(50.4 Gy for 5.5 weeks) and rapidfractionation
radiation therapy (30 Gy
for 2 weeks).

In another analysis of neoadjuvant
chemoradiation therapy, patients who
received preoperative treatment of
5-FU (with or without mitomycin
[Mutamycin] or gemcitabine) plus radiation
therapy (50.4 Gy) demonstrated
a median overall survival of 34
months (range: 8-152 months) compared
with 8 months (range: 1-14
months) for those who could not undergo
surgery (P = .005).[13] The
results of these studies have suggested
specific advantages for preoperative
vs postoperative radiation therapy
and chemotherapy. Some of these potential
advantages include no delay in
initiation of radiation therapy (previous
studies showed that 25% of patients
required a 10-week delay for
postoperative recovery), reduced risk
of tumor cut-through, which is important
given the high rates of retroperitoneal
margin involvement of these
malignancies, and avoidance of a laparotomy
in patients who would not be
potentially curative given the frequent
development of detectable metastases
on restaging evaluation after radiation
therapy and chemotherapy.

Treatment of Unresectable
Tumors

In the past, 45% of patients with
newly diagnosed pancreatic cancer
presented with locally advanced disease.
More recent data confirming this
figure are lacking, and it is possible
that more advanced staging tools show
metastatic disease early in the course
of a patient's illness, thus decreasing
this percentage. In general, a tumor is
considered unresectable if it has one
of the following features: (1) extensive
peripancreatic lymph node involvement,
(2) encasement of the
superior mesenteric vein/portal vein
confluence, (3) direct involvement of
the superior mesenteric artery, inferior
vena cava, aorta, or celiac axis, or
(4) distant metastases. Through a series
of randomized studies published
in the 1980s, chemoradiotherapy has
become the accepted standard of care
for locally advanced and nonmetastatic
carcinoma.

Radiation Therapy
and Chemotherapy

A Mayo Clinic study and a series of
GITSG studies performed primarily in
the 1980s demonstrated that externalbeam
radiation therapy (EBRT) combined
with 5-FU was superior to either
radiation or chemotherapy treatment
alone (Table 2).[14-17] In the Mayo
Clinic study, 64 patients with unresectable
adenocarcinoma of the pancreas
were randomized to 40 Gy radiation
with either concurrent 5-FU or concurrent
placebo. The median survival for
the chemotherapy patients was 10.4
months, compared with only 6.3 months
for those receiving placebo.

In a similar GITSG trial that evaluated
194 patients with surgically confirmed
unresectable and nonmetastatic
disease, survival was improved when
a combined treatment of either 40 Gy
for 6 weeks or 60 Gy for 10 weeks
plus 5-FU (2 to 3 cycles with maintenance
5-FU after radiation) was used
as compared with radiation therapy
alone using 60 Gy.[15] Combinedmodality
therapy using 60 Gy showed
the greatest benefit compared with
combined chemotherapy with a
40-Gy dose or therapy with 60 Gy
radiation alone; the 1-year survival
was 10% for radiation alone, 35% for
40 Gy combined therapy, and 46%
for 60 Gy combined therapy.

Follow-up GITSG studies were
conducted to further clarify the benefit
of different chemotherapeutic regimens
with radiation therapy in these
patients. One trial was designed to
compare radiation plus either 5-FU or
doxorubicin. In this trial, 157 patients
were randomized to either 60 Gy splitcourse
EBRT with concurrent and
maintenance 5-FU, or 40 Gy continuous-
course radiation with concurrent
doxorubicin and maintenance doxorubicin
plus 5-FU. No survival advantage
was seen with either treatment
arm; however, those patients receiving
doxorubicin experienced significantly
higher rates of treatment-related
toxicity (P < .05).[16]

Another study compared the combined
treatment of streptozocin
(Zanosar)/mitomycin/5-FU (SMF)
chemotherapy alone to 5-FU chemotherapy
plus radiation followed by
adjuvant SMF chemotherapy. This
trial enrolled 48 patients random-
ized to chemotherapy alone or
chemoradiation. The 1-year survival
for patients receiving chemoradiation
was 41% compared with 19% of patients
receiving chemotherapy
alone.[17]

In these trials, it was shown that
the combination of radiation therapy
and chemotherapy was superior to radiation
(1-year survival, 40% vs 10%)
or chemotherapy alone (1-year survival,
41% vs 19%). However, when
the Eastern Cooperative Oncology
Group (ECOG) performed a similar
evaluation in 91 patients with locally
unresectable adenocarcinoma of the
pancreas, no survival benefit was
shown with the use of concurrent bolus
5-FU during week 1 with 40 Gy
radiation compared to 5-FU chemotherapy
alone.[18] The median survival
was 8.3 months with the
combined treatment vs 8.2 months
following treatment with 5-FU alone.
The 1-year survival was 26% for patients
receiving combination therapy
and 32% for those receiving 5-FU. In
this study, no patients received maintenance
chemotherapy.

With the exception of the ECOG
study, conventional external-beam radiation
combined with 5-FU appears
to provide some survival benefit over
monotherapy with radiation therapy
or chemotherapy for patients
with locally advanced unresectable
pancreatic tumors. As a result, combined-
modality therapy with 5-FU
and external-beam radiation has
become a frequently used treatment.

While multimodality treatment
with 5-FU has shown modest benefit,
recent investigative efforts have
moved to evaluation of gemcitabine
combinations with radiation therapy.
These studies have been prompted as
a result of phase III trials showing
efficacy of gemcitabine in the treatment
of patients with metastatic
pancreatic cancer.[19] In a large multicenter
randomized trial of patients
with locally advanced or metastatic
disease, clinical benefit and median
survival were significantly improved
with the use of gemcitabine as compared
to treatment with 5-FU (5.65
months vs 4.41 months). One-year
survival was 18% with gemcitabine
and 2% with 5-FU (P = .003); how
ever, survival was not extended beyond
19 months.

In an attempt to further improve
these results, ECOG performed a
phase III trial (E2297) of gemcitabine
in combination with 5-FU vs gemcitabine
alone, no significant survival
benefit was observed between the single-
agent or combination therapies.[
20] On the other hand, a small
institutional phase II study evaluating
weekly gemcitabine (1,000 mg/m2)
with 5-FU (2,000 mg/m2) in 23 patients
for 3 consecutive weeks followed
by 1 week without treatment
until tumor progression occurred suggests
that the gemcitabine/5-FU combination
may improve 1-year survival
and median survival.[21] As compared
with prior results with gemcitabine
alone,[20] the combination
therapy demonstrated a 1-year survival
rate of 30% (vs 18%) and a
median survival time of 8.3 months
(vs 5.65 months). Clearly, these phase
II results in the metastatic setting need
to be evaluated in a phase III trial to
know whether there is true benefit of
the combination.

The Cancer and Leukemia Group B
(CALGB) has released early phase II
results of its chemoradiation trial in
which gemcitabine was used as a radiation
sensitizing agent at 40 mg/m2
twice weekly in combination with
50.4 Gy radiation to the upper abdomen.
With 38 evaluable patients, the
study has concluded that toxicity is
manageable and median survival is encouraging
with chemoradiation, especially
for patients with a performance
status of 0, where median survival was
13.7 months as compared with 7.8
months for those with a performance
status of 1 or 2.[22] The follow-up
study in CALGB is evaluating weekly
gemcitabine combined with infusional
5-FU during radiation therapy.

Paclitaxel has also been investigated
in this setting due to its enhanced
radiosensitizing effects in
preclinical studies. A phase I study at
Brown University found the maximum
tolerated dose of weekly paclitaxel
to be 50 mg/m2 when given with
50 Gy of EBRT. This combination
yielded a 31% response rate among
13 evaluable patients. In a follow-up
phase II study, also at Brown University,
this same dosing combination
yielded a 26% response rate, and a
1-year survival rate of 30%.[23]

Potential Surgical Resection
After Chemoradiation of Locally
Advanced Pancreatic Cancer

Despite improvements in survival
with chemoradiation, surgery remains
the only potentially curative treatment
for pancreatic cancer. Chemoradiation
has been employed in an effort to
promote tumor regression and facilitate
resection for patients with locally
advanced tumors. Investigators from
New England Deaconess Hospital
treated 16 patients with unresectable
tumors with preoperative 5-FU chemotherapy
followed by 45 Gy of
EBRT and infusional 5-FU. Two of
the patients (13%) were able to undergo
resection following treatment.[
24] Similar results were found
in a Duke University study in which
two patients (8%) were able to be
resected after first being treated with
45 Gy of EBRT and 5-FU with or
without cisplatin or mitomycin.[25]

A phase I dose-ranging study of
twice-weekly gemcitabine (10 mg/m2
to maximum tolerated dose of approximately
50 mg/m2) in combination with
EBRT administered to 21 patients with
advanced adenocarcinoma of the pancreas
found that treatment enabled surgical
resection in three patients who
had previously unresectable tumors.[
26] In a phase II study, weekly
gemcitabine (1,000 mg/m2) was given
during an induction phase of 7 weeks,
followed by a combination of weekly
gemcitabine (400 mg/m2) with 50.4 Gy
radiation in 28 fractions in those who
had evidence of benefit from initial
chemotherapy. Three patients underwent
surgical resection. Results show
an overall median survival of 8 months
(all groups combined). Interestingly, at
the time of publication, the median survival
for the chemoradiation group had
not yet been reached.[27]

A retrospective analysis of patients
with locally advanced unresectable
pancreatic cancer treated concurrently
with weekly gemcitabine (250 to
500 mg/m2) and radiation therapy (30
to 33 Gy in 10 to 11 fractions over 2
weeks) showed a median survival of
11 months with 37 of 51 patients even-
tually progressing.[28] While six patients
were later able to undergo
pancreaticoduodenectomy, the combination
treatment was difficult to administer
safely.

Clearly, EBRT with chemotherapy
offers survival benefit as well as palliation
of pain associated with the tumor.
In the United States, combined-modality
therapy has been adopted as the
standard treatment for patients with locally
advanced pancreatic cancer. While
these combined treatments increase median
survival for patients with locally
advanced carcinoma, treatment resulting
in long-term survival is rare. As a
result, there have been renewed efforts
to enhance patient outcomes and longterm
survival by improving patient selection
through better staging of the
disease, and to offer treatments with
palliative benefits.

Palliative Benefits From
Chemoradiation

Despite improvements in shortterm
survival with therapy, patients
with locally advanced pancreatic cancer
will ultimately die of their disease.
It is for this reason that treatments
with palliative benefits that can improve
quality of life remain an important
priority in the management
of this disease. Unfortunately, improvements
in pain, anorexia, or fatigue
are not well documented in
many of the studies. Pain relief has
been documented in some of the larger
studies, including one using intraoperative
electron-beam radiation
therapy where relief was obtained in
50% to 80% of patients.[29] External-
beam radiation therapy with or
without chemotherapy has also been
associated with pain relief in 35% to
65% of patients.[15,29,30] A few other
studies have reported more subtle
improvements in performance status
and anorexic symptoms.[29-31]

Diagnostic Tools and
Patient Selection

Currently available tools for the
diagnosis and staging of pancreatic
cancer patients include helical
computed tomography (CT) scans,
endoscopic ultrasonography, MRIs,
PET scans, and laparoscopy and washings.
These imaging techniques have
aided physicians in characterizing the
tumor site, determining the feasibility
of resection, and identifying the absence
or presence of metastasis. After
appropriate staging and definition of
extent of disease, patients can then be
counseled regarding available therapies
and ongoing clinical trials.

Computed Tomography
Computed tomography scanning of
the abdomen is the most commonly
used tool for diagnosis and staging.
Newer-generation and higher-speed
machines now provide contrast enhancement
and thin-section imaging.[
32] As such, motion-free
high-resolution images, including 3D
reconstruction of the pancreas, are
available to define resectability of the
lesion. A tumor may be resected if
there is no extrapancreatic involvement
(eg, no extensive parapancreatic
lymph or distant involvement), no
encasement or occlusion of the superior
mesenteric vein (SMV) or SMV-
portal vein confluence, and no direct
involvement of the superior mesenteric
artery, inferior vena cava, aorta,
or celiac axis.

A recent study assessing the resectability
of pancreatic tumors preoper
atively using CT scanning verified the
accuracy of CT scanning by finding
that, with the above criteria, most tumors
(> 90%) considered unresectable
by CT scanning were also
considered unresectable at laparotomy.[
33] Similarly, a second analysis
concluded that the determination of
resectability of a pancreatic carcinoma
was best done with dual-phase
helical CT. The analysis further suggested
that for improved accuracy of
diagnosing lymph node involvement
by pancreatic cancer, endosonography
with fine-needle aspiration should
be used; this is especially true in patients
with suspected carcinoma, even
those with negative biopsy results.[34]

Combined CT/PET scan imaging
is further enhancing the ability to define
extent of disease. MRI scans are
also being employed to aid in evaluation
of the extent of pancreatic cancer.
Newer imaging contrast agents
may be helpful in detecting the presence
of metastases, even in small
lymph nodes. Ongoing improvements
in all of these technologies should
continue to refine the ability to stage
this malignancy.

Endoscopic Ultrasound
Endoscopic ultrasonography has
proven to be useful in further char-
acterizing the extent of the local
disease.[35] This procedure allows
fine-needle biopsy of the pancreatic
neoplasm and regional nodes, allowing
for diagnosis and staging without
exploratory surgery while decreasing
the potential for tumor seeding.[36]
The procedure is often performed at
the time of an endoscopic retrograde
cholangiopancreatography for the assessment
of pancreatic neoplasms.[37]

Staging Laparoscopy
Staging laparoscopy allows direct
visualization of the liver, peritoneum,
and omentum, and can identify 1- to
2-mm metastatic nodules in patients
with potentially resectable or locally
advanced disease. If metastatic disease
is encountered, laparotomy can
be avoided. In one study of 114 patients
with no evidence of metastasis
by CT, laparoscopy was able to identify
metastatic disease in 27 patients
(~24%).[38] Interestingly, a small
study of 64 patients designed to compare
endoscopic sonography with helical
CT for the identification and
staging of pancreatic ductal adenocarcinoma
found that endoscopic
sonography was more accurate than
helical CT (95.3% vs 89.1%). For
those who underwent laparotomy
(n = 43), however, helical CT more
accurately predicted resectability than
did endosonography (86% vs 81.4%).

With the advent of new laparoscopic
hand-access devices, a surgeon
is now able to place a hand in the
abdomen and perform functions previously
possible only during open surgery.[
40] Peritoneal washings may be
combined with laparoscopy to assess
the presence or absence of malignant
cells in peritoneal fluid. For patients
without visible metastases at laparoscopy
but cytologic involvement in
peritoneal washings, survival rates are
similar to patients with macroscopic
metastatic disease.[39]

Laparoscopic ultrasound may be
helpful in the diagnosis and staging of
local pancreatic lesions.[41] With this
technique, the head and body of the
pancreas are visualized by retroduodenal
or infragastric approaches, respectively.
When combined with
laparoscopic manipulations, laparoscopic
ultrasonography is able to assess
the size and extent of local disease.

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