Treatment for Pancreatic Cancer: Current Therapy and Continued Progress

GASTROENTEROLOGY 2005;128:1642–1654
Treatment for Pancreatic Cancer: Current Therapy and
Continued Progress
A. CRAIG LOCKHART, MACE L. ROTHENBERG, and JORDAN D. BERLIN
Department of Medicine, Division of Hematology/Oncology, Vanderbilt University, Medical Center, Nashville, Tennessee
In the last decade, continued efforts in pancreas cancer
research have led to the development of new, more
effective therapies. Additionally, progress in understanding the molecular processes underlying the development and progression of this disease provides hope for
the development of more effective treatment strategies.
Recent clinical trials have provided reason for hope that
novel chemotherapy combinations and molecularly targeted agents will lead to improved clinical outcomes for
patients with this disease. This article will summarize
the data that has led to the current standards of therapy
for patients with resectable and advanced pancreatic
cancer and review new treatment strategies for this
disease.
ancreas cancer is the fourth leading cause of cancer
death in the United States. The lethality of this
malignancy is demonstrated by the fact that the annual incidence (32,000) is approximately equal to the
annual deaths (31,000).1 Unfortunately, carcinoma of
the pancreas is increasing in incidence, and its exact
risk factors remain poorly understood; only 5%–10%
of all pancreatic adenocarcinomas have a clear hereditary association, and cigarette smoking is the only
consistently identified modifiable risk factor.2– 4 Over
95% of pancreatic malignancies originate in the pancreatic ducts and are adenocarcinoma by histology.
This paper will address the use of systemic therapy in
pancreatic adenocarcinoma, hereafter referred to as
pancreas cancer.
There are several factors that contribute to the high
mortality rate associated with pancreatic cancer. First
of all, with the exception of painless jaundice, there
are few signs or symptoms associated with early stage
pancreatic cancer. As a result, up to 90% of patients
will present with locally advanced or metastatic disease. Second, there is no effective screening test to
detect disease in asymptomatic patients. Third, pancreatic cancer is one of the most intrinsically drugresistant tumors. Finally, there is a high rate of relapse, even in patients with early stage disease who
receive adjuvant therapy. Thus, although surgical re-
P
section remains the only chance at cure, ⬍10% of
patients diagnosed with pancreas cancer can actually
have a curative resection.5 Despite surgery with curative intent, actuarial 5-year survival rates for these
patients remains at approximately 20%, indicating
that even patients with localized small cancers (⬍2
cm) with no lymph node metastases are likely to die of
metastatic disease.5 Therefore, improvements in therapy that serve as adjuncts to surgery and systemic
treatments for the more common scenario of advanced
disease provide the greatest hope of improving the
clinical outcomes in this disease.
As is the case with most tumors, the TNM staging
of pancreatic cancer is helpful in determining prognosis. However, for treatment purposes, a simplified
classification is used in which tumors are divided into
resectable, locally advanced, unresectable, and metastatic. It is important to note that there is some
variation in the definition of “resectability” that is
primarily because of the experience and skill of the
surgeon and the extent to which the surgeon will go
with regard to lymph node resection and venous reconstruction.
Adjuvant Therapy of Pancreas
Cancer
Patients with resectable disease comprise the
smallest subgroup of pancreas cancer patients
(⬃10%). Although all visible disease may be removed
by surgery, the cure rate for patients managed with
surgery alone is low.5 Therefore, researchers have focused on adjuvant therapy in an effort to increase the
rate of long-term survival. Adjuvant therapy is postoperative treatment administered to patients with no
detectable evidence of residual disease but who are
Abbreviations used in this paper: 5-FU, 5-fluorouracil; R0, resectionsurgery with negative margins; KPS, Karnofsky performance status;
TKI, tyrosine kinase inhibitor.
© 2005 by the American Gastroenterological Association
0016-5085/05/$30.00
doi:10.1053/j.gastro.2005.03.039
May 2005
SYSTEMIC THERAPY OF PANCREATIC CANCER
1643
Table 1. Results of Randomized Trials in Adjuvant Therapy of Pancreas Cancer
Study
GITSG
Norwegian trial
EORTC overall
EORTC pancreas cancer subset
EORTC periampullary cancer subset
ESPAC-1 chemo versus no chemo
ESPAC-1 chemoXRT versus no chemoXRT
Arms
No. patients
Surgery
Surgery ⫹ chemoXRT
Surgery
Surgery ⫹
chemotherapy
Surgery
Surgery ⫹ chemoXRT
Surgery
Surgery ⫹ chemoXRT
Surgery
Surgery ⫹ chemoXRT
No chemotherapy
Chemotherapy
No chemoXRT
ChemoXRT
22
21
31
30
103
104
54
60
48
44
142
147
144
145
11
20
11
23
Median survival
5-Year survival
months
months (P ⫽ .035)
months
months (P ⫽ .02)
N/A
19 months
24.5 months
12.6 months
17.1 months
40.1 months
39.0 months
15.5 months
20.1 months
17.9 months
15.9 months
(P ⫽ NS)
8%
4%
22%
28%
N/A
(P ⫽ .099)
N/A
(P ⫽ .0009)
(P ⫽ NS)
8%
21%
20%
10% (P ⫽ NS)
NOTE. EORTC data are presented with the total population and the 2 subsets. ESPAC-1 data are presented from the final report rather than the
early report. Only patients in the 2 ⫻ 2 randomized portion are included in that analysis.
ChemoXRT, chemoradiation.
likely to harbor microscopic tumor deposits that, left
untreated, will lead to tumor recurrence and death.
Four randomized trials have been reported that evaluate the impact of postoperative adjuvant therapy in
patients with resected pancreatic cancer.
Randomized Trials
The Gastrointestinal Tumor Study Group
(GITSG) trial from 1985 is the only American trial
conducted comparing surgery alone to surgery and
adjuvant therapy.6 The GITSG study randomized 43
patients to either surgery alone or surgery followed by
combined chemotherapy and radiation (“chemoradiation”) for 4 weeks followed by 24 months of chemotherapy. The chemotherapy administered throughout
was 5-fluorouracil (5-FU), an antimetabolite pyrimidine analog. In this study, radiation was administered
in a pair of 2-week courses separated by a 2-week
break. In addition, 5-FU was given as a bolus (quick
injection) on each of the first 3 days of each 2-week
course. The median survival for patients treated with
adjuvant therapy, 20 months, was significantly longer
than for those patients who did not receive any postoperative therapy, 11 months (P ⫽ .03) (Table 1).
However, several criticisms have long plagued the
GITSG trial, including the long duration of accrual (8
years), the small size of the study, and the measurement of survival from the date of surgery as opposed to
date of randomization. Subsequent to the GITSG trial,
knowledge about the principles of radiation therapy
changed the standard to a more continuous radiation
schedule (ie, no 2-week break). Additionally, technology now allows for continuous administration (24
hours a day, 7 days a week) of 5-FU, which, when
combined with radiotherapy in adjuvant treatment of
rectal cancer, has proved superior in terms of survival
and local control when compared with bolus 5-FU.7
A second early trial conducted in Norway randomly
assigned patients to chemotherapy with 5-FU, doxorubicin (an anthracycline), and mitomycin-C (an antitumor antibiotic) after surgery vs surgery alone.8 No
radiation was used in this study. With only 50 patients, it too was a small trial, but it also had a
statistically significant median survival improvement
for the adjuvant therapy arm (Table 1). However, by 3
years, there was no difference in the number of survivors in each arm, and further investigation of the
chemotherapy arm was abandoned because of the low
cure rates in both arms of the study. In addition, these
results may have been confounded by the fact that this
study included patients with tumors of the Ampulla of
Vater, which may have a different treatment sensitivity profile and prognosis.
After these 2 trials, the European Organization for
the Research and Treatment of Cancer (EORTC) conducted a clinical trial comparing continuous infusion
5-FU and radiation after surgery vs surgery alone.9
Chemotherapy was not continued beyond the course of
radiation therapy. As shown in Table 1, this larger
trial of 207 patients did not demonstrate an improvement in survival for those treated with adjuvant therapy. However, in addition to the short exposure to
systemic therapy, this trial included 2 disease sites:
pancreas and periampullary cancers. The median survivals for these 2 disease sites differed dramatically. It
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LOCKHART ET AL
is possible that combining the 2 disease sites with
different prognoses and variable responses to the regimen may have blunted any effect that may have
occurred in the pancreas cancer subset. In fact, subset
analyses demonstrated that the periampullary cancer
patients had identical survivals with or without adjuvant therapy. Although subset analysis suggested a
trend toward improved survival in pancreas cancer
patients given adjuvant therapy, it did not reach statistical significance (17.1 vs 12.6 months, respectively, P ⫽ .099) (Table 1).
The most recent randomized trial, European Study
Group for Pancreatic Cancer (ESPAC-1), was designed
to address 2 questions using a 2 ⫻ 2 randomization
design.10,11 One randomization was between postoperative chemoradiation or no chemoradiation. Chemoradiation consisted of two, 2-week courses of radiation
therapy combined with bolus 5-FU and separated by a
2-week break: the exact same technique used in the
original GITSG study reported 16 years earlier. The
other randomization was between chemotherapy or no
chemotherapy, consisting of a 6-month course of bolus
5-FU. If a patient was randomized to both chemoradiation and chemotherapy, the chemoradiation was
administered before the 6 months of chemotherapy. In
the initial report of the results of this trial, survival
benefit was observed in those patients who received
adjuvant chemotherapy vs those who did not (median
survival, 19.7 vs 14.0 months, respectively, P ⫽
.0005). On the other hand, there did not appear to be
any benefit to adjuvant chemoradiotherapy. An updated analysis of the 289 patients randomized in a 2 ⫻
2 fashion on this study confirmed the survival advantage with adjuvant chemotherapy and revealed an
apparent detrimental effect for adjuvant chemoradiotherapy (median survival, 15.9 vs 17.9 months, respectively, P ⫽ .05 compared with patients who did not
receive postoperative chemoradiotherapy) (Table 1).11
Both papers were accompanied by editorials that
raised some concerns.12,13 The first concern centered
on the use of 2 short courses of radiation separated by
a break; a technique that may permit tumor regrowth
during the break. A second concern related to the use
of bolus injections of 5-FU on some days of radiation
rather than infusional 5-FU administered throughout
the course of radiation. A third concern regarding this
study is that there was no central review or quality
control with regard to the planning and administration of radiation. A recent trial of adjuvant therapy in
gastric cancer found and corrected major or minor
deviations in the radiation ports of approximately
35% of patients.14 Because of these many concerns,
GASTROENTEROLOGY Vol. 128, No. 6
there has not been universal abandonment of adjuvant
chemoradiotherapy. As a result, reasonable options for
adjuvant treatment of patients with resected pancreatic cancer include chemoradiotherapy followed by
chemotherapy or chemotherapy alone. However, given
that the majority of patients treated with either strategy will eventually relapse and succumb to their disease, it could be argued that the best option for this
group of patients is participation in a clinical trial. An
American intergroup trial (R9704) comparing chemotherapy with gemcitabine or 5-FU has completed accrual, and results are anticipated soon. In that trial,
patients were given chemotherapy for 2 months before
and 2 months after an identical chemoradiation regimen utilizing continuous infusion 5-FU during radiation. The next intergroup trial, currently under development, will evaluate the safety of incorporating
novel agents targeting angiogenesis (bevacizumab) or
the epidermal growth factor receptor (EGFR; cetuximab) as well as the safety of switching to an oral
prodrug of 5-FU, capecitabine, during the radiation
therapy. In Europe, ESPAC-3 was originally designed
to evaluate surgery alone vs surgery followed by adjuvant therapy with either gemcitabine or 5-FU. After
the updated data from ESPAC-1 became available, the
surgery-alone arm was dropped, leaving the randomization to either gemcitabine or 5-FU. Radiation therapy is not included as a component of this trial.
Other Approaches to Adjuvant Therapy
Another approach to adjuvant therapy that has
been evaluated is a more aggressive regimen of chemoimmunotherapy with radiation. A single-institutional
trial combining cisplatin, 5-FU, and interferon with
radiation resulted in 1-, 2-, and 5-year estimated survival
rates of 95%, 64%, and 55%, respectively.15 Despite a
hospitalization rate of 42%, there were no deaths from
therapy. This regimen is currently being evaluated in a
multi-institutional phase II trial by the American College of Surgeons Oncology Group (ACOSOG) to determine whether similar results can be obtained in a multiinstitutional setting.
Another approach has been the neoadjuvant—preoperative—administration of therapy. Surgery devascularizes the tumor bed, resulting in reduced blood flow and
hypoxia to the tissues, which, theoretically, could reduce
the efficacy of radiation therapy. Additionally, despite
significant improvements in morbidity and mortality
from pancreatic cancer surgery, up to 25% of patients do
not recover quickly enough to receive postoperative adjuvant therapy. Therefore, some have postulated that
administering the chemoradiation before surgery may
May 2005
enhance its efficacy. In addition to the benefits listed
above, neoadjuvant therapy might theoretically shrink
the tumor and make complete resection more feasible.
Although promising results from several trials have been
reported, no randomized trials have been conducted.16 –19
It is unclear whether the neoadjuvant approaches have
increased resectability rates or the rates of resection with
negative margins (R0) resections (ie, complete resection
of the tumor with negative pathologic margins), but
these would be very important end points for randomized
trials.
Conclusions About Adjuvant Therapy
Postoperative adjuvant therapy improves survival
in patients with resected adenocarcinoma of the pancreas.
Unfortunately, median survival is less than 2 years, and
long-term survival is under 20% in most phase III trials.
The roles of chemotherapy, radiation, and newer therapies targeted against growth factor receptors and intracellular signaling pathways need to be clarified through
randomized trials.
Locally Advanced Disease
Locally advanced disease refers to extension of the
tumor to adjacent organs such that complete surgical
excision with negative pathologic margins is impossible.
Local extension includes nearby organs, such as the liver
or duodenum, regional lymph nodes, or, most commonly, vascular structures such as the superior mesenteric artery or celiac trunk that cannot be resected.
Treatment of locally advanced disease in the United
States has been defined by 2 early GITSG trials and an
Eastern Cooperative Oncology Group (ECOG) trial. In a
GITSG study published in 1981, 227 patients were
randomized to 1 of 3 arms: high-dose radiation (6000
cGy) alone, standard-dose radiation (4000 cGy) with
5-FU, or high-dose radiation with 5-FU.20 The 2 chemoradiation arms produced a significantly longer median
survival (9.3 and 9.7 months, respectively) compared
with the radiation alone arm (5.3 months, P ⬍ .05). The
other 2 trials had conflicting results. The GITSG trial
published in 1988 demonstrated in 43 patients a statistically significant improvement in survival in favor of
chemoradiation (9.7 months) over chemotherapy alone
(7.4 months, P ⬍ .02).21 The ECOG trial demonstrated
no difference in survival between chemoradiation (9.0
months) and chemotherapy (9.0 months) in 50 patients.22 However, both trials were small, and neither can
be considered conclusive. At the present time, common
practice in the United States is for patients with locally
advanced pancreatic cancer to receive continuous infusion
5-FU in combination with radiation therapy.23
SYSTEMIC THERAPY OF PANCREATIC CANCER
1645
Newer approaches to chemoradiation for locally advanced disease have largely focused on gemcitabine
(2=,2=-difluorodeoxycytidine), a deoxycytidine nucleoside
analog incorporated into DNA resulting in chain termination. Gemcitabine is a very potent radiation sensitizer,
and it has been difficult to identify an “optimal” dose and
schedule for gemcitabine in combination with radiotherapy. Several trials have incorporated gemcitabine into a
standard regimen of radiation (currently over 5000 cGy
administered over slightly longer than 5 weeks). The first
approach to be tested was a once-a-week administration
of gemcitabine, which is the way that it is given when
used without radiation.24 Response rates in these studies
have been low (⬃20%). A second approach has been to
use a twice weekly administration schedule based on
preclinical data suggesting that gemcitabine radiosensitization lasts for ⬃3 days.25,26 A third approach uses
full-dose gemcitabine and low-dose radiation.27 This
method also includes the use of very narrow beams of
radiation, focusing on the tumor itself rather than the
surrounding tissues. A phase II trial of full-dose gemcitabine and low-dose radiation including patients with
local and locally advanced disease had 2 responders and
25 stable disease patients of the 41 patients enrolled.28
Of the 12 patients deemed resectable prior to treatment,
8 were able to undergo an R0 resection (pathologically
negative margins of resection) and 2 patients initially
thought to be unresectable were able to have complete
resections.
Other agents that have demonstrated radiosensitization properties such as paclitaxel, rubitecan, and cisplatin
have all been tested in combination with radiation with
or without other chemotherapy agents.16 –18,29,30 Newer
studies are being designed to incorporate cetuximab,
bevacizumab, and other growth-factor and cell-signal
inhibitors that may have radiation sensitization properties.
Conclusions About Therapy for Locally
Advanced Disease
Due to the conflicting results obtained in 3 randomized trials, it is still not clear whether radiation is an
essential element of treatment for patients with locally
advanced pancreatic cancer. Because of that uncertainty,
the current Intergroup study E4201, a phase III trial
comparing gemcitabine alone to gemcitabine and radiation therapy for locally advanced disease patients, is a
critical study. It will define the current role of radiation
therapy for patients with inoperable disease that is not
metastatic.
In any discussion of locally advanced pancreatic cancer, it is important to recognize that the determination of
1646
LOCKHART ET AL
operable vs inoperable disease may be surgeon dependent. There are, in fact, probably different levels of
unresectability. Patients with tumors completely encasing the vasculature may differ from those who have
tumors that abut the major vessels. ECOG 1200 is a
randomized phase II trial that seeks to identify patients
with “borderline” unresectable tumors. These patients
are randomized to 1 of 2 chemoradiation regimens and
reevaluated for surgery. The primary end point of this
study is to determine which, if either, of the regimens is
capable of converting patients with surgically unresectable disease to fully resectable disease.
Chemotherapy for Advanced
Disease
Metastatic pancreatic cancer tends to be a rapidly
progressing disease, often accompanied by a constellation
of debilitating symptoms. More than half of all patients
with advanced pancreatic cancer suffer from weight loss,
visceral abdominal pain, anorexia, nausea, and/or depression. Although no curative treatment exists for this
group of patients, newer systemic therapies have
emerged over the past decade that provide meaningful
alleviation of tumor-related symptoms and prolong survival.
Gemcitabine
Gemcitabine is a nucleoside analogue that is sequentially phosphorylated to gemcitabine triphosphate
and incorporated into replicating DNA, resulting in
premature chain termination and apoptosis.31,32 Although significant tumor shrinkage (ie, ⱖ50% tumor
shrinkage) was achieved in only 5% of patients, a substantial subset of patients had significant and sustained
alleviation of tumor-related symptoms. As a result of
these observations, a pivotal phase III trial was designed
to capture prospectively and quantify this effect in a
cohort of patients with metastatic, symptomatic pancreatic cancer.33–35 One hundred twenty-six patients who
had not received prior chemotherapy for metastatic disease were randomized to weekly gemcitabine (n ⫽ 63) or
weekly bolus 5-FU (n ⫽ 63).36 Overall survival in patients treated with gemcitabine was significantly improved compared with patients treated with 5-FU (median survival, 5.7 vs 4.4 months respectively; P ⫽
.0025). The 1-year survival rates were 18% for patients
treated with gemcitabine vs 2% in patients treated with
5-FU. The primary efficacy measure in this study was
clinical benefit response, a composite of patient-oriented
parameters including pain, Karnofsky performance status
(KPS), daily analgesic usage, and weight. Clinical benefit
GASTROENTEROLOGY Vol. 128, No. 6
response, defined as a significant reduction in 1 or more
of these measures lasting for at least 4 weeks without
deterioration in another parameter, was experienced by
24% of the patients treated with gemcitabine compared
with only 5% of the patients treated with 5-FU (P ⫽
.0022). Clinical benefit response was seen in some patients who did not achieve a radiologic response, demonstrating that patients could have an improvement in
symptoms while on chemotherapy for a highly symptomatic disease without tumor shrinkage. Additional
randomized studies have since confirmed the efficacy of
single-agent gemcitabine.37–39
More recent clinical trials with single-agent gemcitabine have focused on the optimal administration of this
prodrug. As noted previously, one of the main mechanisms of action of gemcitabine is impairment of DNA
synthesis. The rate-limiting enzyme in this process, deoxycytidine kinase, appears to be saturable. The ability of
deoxycytidine kinase to activate gemcitabine may be
overwhelmed by the standard dosing administration of
1000 mg/m2 over 30 minutes. Based on preclinical models, an alternative method for administration of gemcitabine, termed “fixed-dose rate infusion,” administers the
drug at a rate of 10 mg/m2/min (using current dosing,
this works out to be 1500 mg/m2 over 150 minutes).40 A
randomized phase II trial in advanced pancreatic cancer
demonstrated that those patients administered gemcitabine by fixed dose rate had 3-fold higher levels of
gemcitabine triphosphate incorporated into peripheral
blood mononuclear cell DNA compared with those given
the standard 30-minute infusion and an encouraging
8-month median survival.41 Fixed-dose rate gemcitabine
is now being evaluated in phase III trials against standard
single-agent gemcitabine and gemcitabine-based combinations in patients with advanced pancreatic cancer.
5-FU
Prior to the FDA approval of gemcitabine, the
antimetabolite 5-FU was considered standard therapy for
advanced pancreas cancer. Although response rates up to
26% have been reported for treatment with 5-FU, most
of these reports predated the era of CT-imaging and were
based primarly on clinical tumor evaluation. More modern phase II trials have reported response rates ⱕ7% for
5-FU alone or with leucovorin.42– 46
Clinical trials comparing 5-FU combination regimens
against best supportive care (BSC) demonstrated that the
5-FU regimens conveyed a survival and quality-of-life
(QOL) advantage over BSC.45,46 Unfortunately, efforts to
build on this through the addition of other drugs to
5-FU were unsuccessful. In several phase III trials, combination regimens offered no survival benefit despite
May 2005
SYSTEMIC THERAPY OF PANCREATIC CANCER
1647
Table 2. Recently Reported Results of Phase III Randomized Trials for the Treatment of Advanced Pancreatic Cancer
Author or study group
ECOG (E2297)
C. M. Rocha Lima
D. A. Richards
P. Cheverton
E. M. O’Reilly
A. D. Jacobs
G. Colucci
C. Louvet
Regimens
Gemcitabine
Gemcitabine
Gemcitabine
Gemcitabine
Gemcitabine
Gemcitabine
Gemcitabine
Exatecan
Gemcitabine
Gemcitabine
“Best Care”
Rubitecan
Gemcitabine
Gemcitabine
Gemcitabine
Gemcitabine
⫹ 5-FU
⫹ irinotecan
⫹ pemetrexed
⫹ exatecan
⫹ cisplatin
⫹ oxaliplatin
increased toxicity when compared with 5-FU as a single
agent.47,48
Recent Phase II and III Clinical
Trials in Metastatic Pancreatic
Cancer
The FDA approval of gemcitabine for the treatment of patients with advanced pancreatic cancer in
1996 was a major step forward in the treatment of this
disease. However, the 1-year survival rate was only 18%,
indicating that metastatic pancreatic cancer remains a
devastating illness. Several recent clinical trials in patients with metastatic pancreatic cancer have tried to
improve on the clinical outcomes of these patients (Table
2). The design of these trials falls into 2 broad categories:
comparison of the new agent directly against gemcitabine or combination of the new agent with gemcitabine.
Gemcitabine Combined With
Chemotherapy
Antimetabolites. Results from the randomized
studies comparing 5-FU to gemcitabine as single agents
have been described in prior sections. As far as studies
combining gemcitabine with 5-FU, 3 phase II trials
evaluated a combination of gemcitabine with bolus
5-FU, with or without the biochemical modifier leucovorin.49 –51 Median survival times in these studies varied
from 4.3 to 11 months and prompted a phase III ECOG
sponsored study comparing gemcitabine alone to gemcitabine and 5-FU. Although the combination regimen
demonstrated a trend toward improved survival (Table 2)
for the combination arm (median survival: gemcitabine,
5.4 months vs gemcitabine ⫹ 5-FU, 6.7 months), that
trend did not reach statistical significance (P ⫽ .09).38
Although these results were not sufficient to establish the
No. patients
Median survival (mo)
1-Year survival
162
160
169
173
282
283
170
169
174
175
211
198
54
53
156
157
5.4
6.7
6.6
6.3
6.3
6.2
6.5
5.0
6.2
6.7
3.1
3.6
5
6
7.1
9.0
⬍20%
⬍20%
N/A
N/A
20.1%
21.4%
22.1%
17.9%
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
combination of gemcitabine ⫹ 5-FU as the new standard
for front-line chemotherapy, additional phase III trials
were undertaken using different and, possibly superior,
5-FU dosing strategies to determine whether survival
could be meaningfully increased over single-agent gemcitabine. The results of those trials are pending.
Another antimetabolite tested in pancreas cancer is the
multitargeted antifolate, pemetrexed (Alimta). In addition to thymidylate synthase, pemetrexed also inhibits
dihydrofolate reductase and glycinamide ribonucleotide
formyltransferase, thereby inhibiting purine as well as
pyrimidine nucleoside synthesis. Pemetrexed demonstrated provocative antitumor activity in single-agent
studies and in phase II trials in combination with gemcitabine.52,53 As single agents, there have been no reported randomized studies comparing pemetrexed with
gemcitabine, but a phase III study comparing the combination of gemcitabine and pemetrexed with gemcitabine alone enrolled over 450 patients in a randomized
design (Table 2).54 Patients in the pemetrexed plus gemcitabine arm had a significantly higher response rate
(18.3% vs 9.1%, respectively, P ⫽ .006) and a longer
time to tumor progression (5.2 months vs 3.6 months,
respectively, P ⫽ .042). However, the overall survival
was unchanged between the 2 treatment arms (6.2
months vs 6.3 months, respectively), and, unfortunately,
neutropenia was significantly higher in the gemcitabine
plus pemetrexed arm (45.1% vs 12.8%, respectively, P
⬍ .001). Therefore, this treatment approach has not been
adopted as a standard therapy.
Topoisomerase I Inhibitors. The camptothecinderived topoisomerase I inhibitors exatecan, irinotecan,
and rubitecan have all demonstrated response rates and
survival times of approximately 10% and 5– 6 months,
respectively, in phase II clinical trials in patients with
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LOCKHART ET AL
advanced pancreatic cancer.55–57 There have been no reported randomized studies comparing irinotecan with
gemcitabine as single agents. In a combination study, a
phase III clinical trial randomly assigned patients to
either a combination of irinotecan and gemcitabine (n ⫽
173) or gemcitabine (n ⫽ 169) alone. Tumor response
rates were 16.1% for the combination therapy vs 4.4%
for gemcitabine alone (P ⬍ .001). Unfortunately, there
was no significant difference between the 2 treatments in
the parameters of median time to tumor progression (3.5
months vs 3.0 months, respectively) or median survival
(6.3 months vs 6.6 months, respectively).58
A recently reported phase III study compared singleagent exatecan head-to-head against gemcitabine (Table
2). In this comparison, exatecan was inferior to gemcitabine as far as time to tumor progression, 12 month
survival, overall survival, and in quality-of-life measures.59 Another recently reported randomized phase III
study involving exatecan compared the combination of
exatecan and gemcitabine with gemcitabine alone. The
study evaluating the combination regimen showed similar response rates between the 2 regimens, with the
exatecan plus gemcitabine arm having a slightly higher
response rate (8.2% vs 6.3%, respectively). However, the
time to tumor progression, as well as the overall survival,
was essentially unchanged. Patients in the gemcitabine
plus exatecan treatment arm had greater frequency of
grade 3 and 4 toxicities, including neutropenia, thrombocytopenia, and nausea/vomiting, than those who received single-agent gemcitabine.60
Platinums. In vitro models suggest that platinum agents have significant, nonschedule-dependent
synergy when combined with gemcitabine. Cisplatin
has been shown to have some antitumor activity in
pancreas cancer, both as single agent and in combination with gemcitabine, but a randomized study comparing single-agent cisplatin vs gemcitabine has not
been reported.61– 64 A phase III trial comparing gemcitabine alone with gemcitabine with cisplatin (Table
2) demonstrated a longer time to tumor progression
for the gemcitabine and cisplatin arm compared with
gemcitabine alone (20 weeks vs 8 weeks, respectively,
P ⫽ .048).65 Similarly, the response rate was improved
for gemcitabine and cisplatin when compared with
gemcitabine alone (26.4% vs 9.2%, respectively, P ⫽
.02). However, median survival times were not significantly different in the 2 arms.
Another platinum agent, oxaliplatin, has not been
compared with gemcitabine as a single agent but has
demonstrated encouraging response rates (30.6%) and
median (9.2 months) and 1-year survival times (36%) in
a phase II trial when administered along with gemcit-
GASTROENTEROLOGY Vol. 128, No. 6
abine and prompted a phase III study of this combination
regimen.66 The subsequent European GERCOR phase
III study compared gemcitabine and oxaliplatin with
gemcitabine alone67 (Table 2). The combination arm
demonstrated a significantly improved response rate of
28.7% vs 16.7% (P ⫽ .02) for treatment with gemcitabine alone. Progression-free survival was also improved,
with the gemcitabine plus oxaliplatin treatment group
having a 5.5-month progression-free survival vs 3.7
months for gemcitabine alone (P ⫽ .04). The overall
survival for gemcitabine plus oxaliplatin was 9 months vs
7 months for gemcitabine alone, a difference that did not
reach statistical significance (P ⫽ .13). This regimen has
not replaced single-agent gemcitabine as standard therapy, but the results have been encouraging enough to
warrant continuing investigation in cooperative group
studies combining oxaliplatin with fixed-dose rate infusion gemcitabine and comparing it with standard gemcitabine alone or in a fixed-dose rate infusion (E6201).
Taxanes. The available taxanes, paclitaxel (Taxol)
and docetaxel (Taxotere), have been tested in phase II as
first-line therapy for pancreas cancer as single agents or in
combination with gemcitabine with varying success. As
single agents, the taxanes have very limited or no significant clinical activity.68 –70 The objective response
rates in 2 studies combining gemcitabine and docetaxel
were 12% and 18%, respectively, and the median survivals were 4.7 and 8.9 months, respectively. Unfortunately, hematologic toxicities have been prohibitive in
most of these trials, and investigations of these regimens
have been limited, with no phase III studies reported
with either of the taxanes as single agents or in combination with gemcitabine.71–73
Gemcitabine Combined With Molecularly
Targeted Agents
Over the past several years, agents have been
developed to exploit specific molecular targets in the
tumor cell or in the tumor microenvironment. Incorporating these targeted therapies into standard treatment
regimens have yielded clinical benefits in other malignancies, including breast, lung, and colorectal cancer,
and have therefore generated interest in the evaluation of
these agents against pancreatic cancer. Enthusiasm about
targeted therapy in pancreatic cancer is somewhat tempered by the previous failure of matrix metalloproteinases (proteins that regulate tumor invasion, metastasis,
and angiogenesis) and farnesyl transferase (inhibitors that
prevent K-ras activation and K-ras-mediated cellular
proliferation) to improve clinical outcomes in phase III
clinical trials.39,74 –76
May 2005
SYSTEMIC THERAPY OF PANCREATIC CANCER
1649
Figure 1. Simplified illustration of
an endothelial cell depicting the
VEGF receptor and signaling pathway with ligand interaction and receptor dimerization resulting in tyrosine kinase phosphorylation and
activation of intracellular signaling
pathways. The sites of action of anti-VEGF monoclonal antibodies and
VEGF receptor, tyrosine kinase inhibitors are shown. *These agents
are not discussed in the text.
Antiangiogenic Agents
Tumor angiogenesis is a complex and dynamic
process involving factors essential for the development
of new tumor blood vessels, tumor growth, and metastasis.77 Angiogenesis has been shown to be predictive for prognosis or clinical stage in most solid tumors that have been assessed, and the rationale for
antiangiogenic approaches as an anticancer strategy
has been extensively reviewed.78,79
Bevacizumab (Avastin) is a recombinant humanized
monoclonal antibody to vascular endothelial growth
factor subtype A (VEGF-A) (Figure 1) that has undergone extensive clinical evaluation. Bevacizumab was
approved by the FDA in 2004 for the treatment of
advanced colorectal cancer and has shown promise in
the treatment of renal cell cancer.80,81 A phase II study
of gemcitabine and bevacizumab recently reported
provocative and encouraging results, including a median survival of 8.7 months and a 1-year survival of
29%, which would be modestly greater than the generally accepted median survival and 1-year survival for
gemcitabine alone. Nineteen percent of the patients
on this treatment demonstrated a response to therapy.82 A larger phase III study (CALGB 80303) comparing gemcitabine alone vs gemcitabine ⫹ bevacizumab is accruing patients to try to confirm these
results.
EGF Tyrosine Kinase Receptors
Epidermal growth factor receptor (EGFR;
HER-1) is a member of the HER family of tyrosine
kinase growth factor receptors and is a potent stimulator of cell growth (Figure 2). The importance of
EGFR in tumor progression has been extensively reviewed.83,84 The binding of molecules (ligands) to the
receptor leads to receptor homodimerization or heterodimerization with another HER family receptor,
receptor activation through phosphorylation, and a
cascade of intracellular signals, eventually resulting in
the promotion of cancer cell growth and proliferation
(Figure 2). Two main targeting strategies have been
developed to block activation of the EGFR axis: antibodies to EGFR to block ligand binding and receptor
activation or small molecule tyrosine kinase inhibitors
(TKIs) that inhibit phosphorylation of the intracellular tyrosine kinase domain and block downstream
signaling.84 Pancreatic cancer is one of many tumors
that over-expresses EGFR, thereby making it a rational target for antitumor therapy in this disease. Recently, EGFR-targeted agents, specifically gefitinib
(Iressa), erlotinib (Tarceva), and cetuximab (Erbitux),
have been FDA approved for the treatment of advanced lung cancers (gefitinib and erlotinib) and advanced colorectal cancers (cetuximab).85,86
A phase II trial was performed of gemcitabine and
cetuximab as first-line chemotherapy in patients with
1650
LOCKHART ET AL
GASTROENTEROLOGY Vol. 128, No. 6
Figure 2. Simplified illustration of
a tumor cell depicting the EGFR
axis and showing ligand interaction
and receptor dimerization leading
to tyrosine kinase phosphorylation
and activation of intracellular signaling pathways that are important
for tumor progression. The sites of
action for anti-EGFR monoclonal antibodies and tyrosine kinase inhibitors are depicted.
advanced stage pancreatic cancer.87 Most of the patients screened for this study (89%) had tumors that
over-expressed EGFR. The results of this trial were
encouraging, with an objective response rate of 12%,
a median time to progression of 16 weeks, and a 1-year
survival rate of 32%. The Southwest Oncology Group
(SWOG) has taken this regimen into phase III trial
(S0205) against single-agent gemcitabine in patients
with advanced pancreatic cancer.
The small molecule TKI anti-EGFR agents gefitinib
(Iressa) and erlotinib (Tarceva) are being evaluated in
current clinical trials. In preliminary data available from
a study of 569 patients randomized to receive gemcitabine and erlotinib vs gemcitabine and placebo, a small
but statistically significant increase in survival was observed in those patients treated with the gemcitabine and
erlotinib combination. The death hazard ratio, adjusted
for performance status and extent of disease, for the
gemcitabine and erlotinib group relative to gemcitabine
and placebo group was 0.79 (95% CI: 0.66 – 0.95, P ⫽
.011). The median survival was 6.37 months in the
gemcitabine and erlotinib arm and 5.91 months in the
gemcitabine and placebo arm. The 1-year Kaplan–Meier
estimates for survival were 23.8% for the erlotinib arm
and 16.8% for the placebo arm. Although the death
hazard ratio was reduced by 21% in erlotinib-treated
patients, median survival in both arms was modest, and
patients treated with erlotinib experienced higher rates
of moderate diarrhea and rash than the placebo-treated
patients. As a result, the clinical implications of this trial
are unclear.
Conclusion
Although significant advances have occurred in
our knowledge of the factors that lead to the development and progression of pancreatic cancer, this knowledge has not yet translated into clinical breakthroughs in
this disease. However, the emergence of molecularly
targeted agents has led to a dramatic increase in research
activity and the number of new clinical trials in patients
with all stages of pancreatic cancer. In addition to trying
to improve survival, in patients with advanced stage
disease, many other clinically important questions remain to be answered, including the role of radiation
therapy in the adjuvant and locally advanced stage settings and the optimal drug(s) for use in all stages of
disease.
The chemotherapy agent gemcitabine remains a cornerstone of treatment for pancreas cancer. The role of
5-FU and the other cytotoxic therapies need to be defined, and several ongoing randomized trials should provide further insight into the best way to utilize gemcitabine as well as the true efficacy of the other cytotoxic
agents as single agents or in combination regimens. The
newer treatment paradigms of angiogenesis inhibition
and signal transduction inhibition through targeting of
the EGFR axis has resulted in clinical benefits for patients with other malignancies, and, as such, they provide optimism about future treatments for pancreatic
cancer. The clinical trials of some of the targeted agents
have shown results that indicate that these agents may
provide an incremental improvement in patient out-
May 2005
comes. Rationally designed and well-executed clinical
trials will be instrumental in improving the outcomes for
patients with this devastating disease.
SYSTEMIC THERAPY OF PANCREATIC CANCER
15.
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GASTROENTEROLOGY Vol. 128, No. 6
Received February 17, 2005. Accepted March 2, 2005.
Address requests for reprints to: Jordan D. Berlin, MD, Associate
Professor of Medicine, Vanderbilt University Medical Center, Division of
Hematology/Oncology, 777 Preston Research Building, Nashville, Tennessee 37232-6307. e-mail: [email protected]; fax: (615)
343-7602.