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Treatment of Pancreatic Cancer: Current Limitations, Future Possibilities

Treatment of Pancreatic Cancer: Current Limitations, Future Possibilities

ABSTRACT: In an attempt to improve the grave prognosis associated with the diagnosis of pancreatic cancer, researchers have explored a number of novel therapies. These include hormonal therapy, immunotherapy, radiopharmaceuticals, and novel chemotherapeutic agents. Unfortunately, most of these efforts have led at best to modest improvements in median survival, and have provided little opportunity for cure. Recent advances at the molecular level may provide an alternative approach to the management of pancreatic cancer. The majority of pancreatic cancers possess K-ras mutations. K-ras proteins are small (21- kd) proteins that normally serve as guanosine triphosphate(GTP)-regulated switches to control a diverse array of cellular signals that modulate highly regulated programs of proliferation, differentiation, and death. Newer therapies aimed at modifying the ras signal transduction pathways may provide avenues for future clinical investigation. [ONCOLOGY 10(3):301-323, 1996]

Introduction

Few malignancies have frustrated the persistent efforts of the
oncologist as has pancreatic cancer. In a review of 61 published
studies that included over 37,000 patients with pancreatic cancer,
Gudjonsson observed an overall survival rate of 3.5% for the 4,100
patients who had undergone resection [1]. More recent data indicate
continued poor results, with survival rates ranging from 2% to
5% [2]. The annual incidence and overall number of deaths from
pancreatic cancer in developing countries are virtually identical;
in 1994, an estimated 81,000 new cases were diagnosed, resulting
in 78,000 deaths [3]. The incidence of pancreatic cancer rose
1% per year from 1937 until 1973, and has remained unchanged since
then [2].

The dismal reports in the literature result, in part, from the
stage of disease at diagnosis [4]. Computed tomography (CT) and
magnetic resonance imaging (MRI) have made it easier to define
disease stage and determine the diagnosis. Needle biopsies and
laparoscopy guided by CT have resulted in fewer unnecessary laparotomies,
while biliary stenting, either endoscopically or, when necessary,
transhepatically, can lessen the need for a surgical procedure
in patients with advanced tumors. Unfortunately, these imaging
and diagnostic advances have not yielded detection of earlier-stage
disease.

Approximately half of all patients with pancreatic cancer have
metastatic disease at the time of diagnosis [4,5], while most
of the rest have locally advanced, unresectable disease [6,7].
In general, the overall curative resection rate is 10% to 15%,
with most authors reporting an overall 5-year survival rate of
10% [4,8]. The national cancer data base reported a 10% overall
survival rate for patients with pancreatic cancer diagnosed since
1990 [9].

It is clear from more recent surgical data that the survival rate
following a Whipple procedure has improved. Several major centers
are reporting perioperative mortality of less than 1% for a procedure
that some authors previously suggested abandoning due its high
complication and death rates [10-12]. This improvement is due,
in part, to increased surgical experience, advanced postoperative
intensive care techniques, and better preoperative selection with
the preopera tive use of abdominal CT, MRI, and laparoscopy to
assess local disease extent and resectability.

At Johns Hopkins, perioperative survival for resected patients
has shown a steady improvement. In-hospital mortality for patients
treated with resection in the 1970s was 30%, vs 0.9% for patients
similarly treated in the 1990s. As reported by Yeo et al, this
decrease in operative mortality has led, in part, to increased
median survival: 7.5 months for patients treated during the 1970s
vs 17.5 months for patient treated since 1990 [10].

This improvement in median survival also results from the increased
use of adjuvant postoperative radiation and chemotherapy. Radiation
therapy alone, chemotherapy alone, or the two in combination provides
palliative therapy for patients with locally advanced, unresectable
disease. Radiation alone has been shown to increase median survival
from 3 to 6 months [13], while concurrent radiation and 5-fluorouracil
(5-FU) may further increase median survival to 10 months (Table
1) [14]. Yet, reports of 5-year survival among patients managed
with nonsurgical therapies remain anecdotal.

At present, the most active single-agent chemotherapy agents are
5-FU and mitomycin (Mutamycin), with each demonstrating response
rates in the range of 10% to 30% [15,16]. Data from a number of
groups have shown little survival benefit with various single-agent
and combination chemotherapies for locally advanced or metastatic
pancreatic cancer [17,18]. Palmer et al, however, using 5-FU,
Adriamycin, and mitomycin (FAM), reported a median survival of
33 weeks, vs 15 weeks for no treatment, and they suggested that
previous studies were negative because they lacked a no-chemotherapy
treatment arm [19].

Our current arsenal of chemotherapeutic agents modestly prolongs
life while providing little possibility for cure. Of the reported
150 ten-year survivors of pancreatic cancer in the world literature,
only 12 have been cured with nonsurgical therapies [1]. Despite
these poor results, many experts consider radiation delivered
concurrently with 5-FU to be standard therapy for patients with
locally advanced pancreatic cancer.

There have been limited advances toward improving the overall
survival rate after resection with adjuvant therapies. Tepper
et al observed a local tumor recurrence rate of 50% in curatively
resected patients, suggesting a possible survival advantage to
improving local control with radiation therapy [20]. In randomized
data from the Gastrointestinal Tumor Study Group (GITSG), postoperative
radiation given concurrently with 5-FU not only resulted in a
local control advantage over surgery alone but also produced a
median survival advantage (Table 2) [21]. Data from this trial
at 5 and 10 years continue to show a survival advantage for patients
receiving adjuvant therapy; 5- and 10-year survival rates for
the surgery-alone arm were 5% and 0%, respectively, vs 19% at
both 5 and 10 years for patients receiving adjuvant chemoradiation
[22]. These data showing benefit with adjuvant therapy are supported
by nonrandomized studies from the University of Pennsylvania and
Johns Hopkins [10,23].

Numerous clinical trials have been performed with other innovative
radiation treatment techniques aimed at improving local control,
including neutron therapy [24], iodine-125 implantation [25],
and intraoperative radiation therapy [26,27]. Often, an improvement
in local control over conventional external-beam therapy has been
observed, but this has not translated into an overall survival
advantage.

Although the gains with surgery plus adjuvant therapy have been
modest, most consider standard therapy for patients with operable
pancreatic cancer to be resection followed by postoperative radiation
therapy with concurrent 5-FU. Because of the marginal advances
made thus far with standard oncologic therapies, a number of researchers
have focused on developing other strategies for the treatment
of pancreatic cancer. In this article, we will discuss some of
the more innovative of these approaches and their potential limitations
in the management of pancreatic cancer.

Hormonal Therapy

Somatostatin and its Analogs

Somatostatin is a cyclic peptide hormone widely distributed throughout
the gastrointestinal system [28], and can act as a potent inhibitor
of tumor cell growth [29]. It has been postulated that somatostatin
and its analogs inhibit cell growth by triggering signal transduction
pathways that negatively control cell growth or by downregulating
the stimuli responsible for tumor growth [29]. Szende et al recently
demonstrated that somatostatin may induce tumor regression through
a mechanism associated with programmed cell death [30]. Unfortunately,
clinical experience has demonstrated no significant benefit of
somatostatin monotherapy in the treatment of pancreatic cancer
[31,32].

More compelling clinical results were reported by Ebert et al
with high-dose octreotide (Sandostatin), an analog of somatostatin
with an increased duration of action. In a cohort of patients
with advanced pancreatic cancer, a low-dose octreotide regimen
resulted in a median survival of only 3 months, whereas the high-dose
produced a median survival of 6 months [33].

Antiestrogens

The presence of estrogen receptors in neoplastic mammary tissue
and the subsequent tumor responses observed following antiestrogen
treatment have been well documented in the literature [34]. Pancreatic
carcinomas also possess estrogen receptors; therefore, it is plausible
that a similar approach would result in an effective therapy for
pancreatic cancer [35]. Unfortunately, most of the clinical data,
including a randomized trial reported by Taylor et al, have not
demonstrated an improved median survival with tamoxifen alone
over placebo [36].

One of the few positive results comes from a case-control study
of 80 patients with metastatic pancreatic cancer reported by Wong
et al, which demonstrated a modest improvement in median survival
for patients receiving tamoxifen therapy (7 vs 3 months) [37].
Rosenberg et al reported a median survival advantage for patients
receiving a combined octreotide-tamoxifen regimen (12 months,
vs 3 months) for an untreated matched cohort) [38]. Although these
data are somewhat encouraging, tamoxifen and octreotide do not
appear to have great overall effectiveness in pancreatic cancer.

Luteinizing Hormone-Releasing Hormone Agonist

The use of leuprolide (Lupron), a luteinizing hormone-releasing
hormone agonist, alone or in combination with somatostatin, has
demonstrated in vitro and in vivo activity in pancreatic cancers
in hamsters [39]. In light of these and other supporting data
[40], Zaniboni et al conducted a phase II trial to test the combination
of leuprolide and tamoxifen in 15 patients with pancreatic cancer.
No objective responses were observed, and median survival was
a disappointing 5 months [41].

In conclusion, the clinical impact of hormonal therapy in pancreatic
cancer, either alone or in combination with other agents, appears
limited.

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