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New Developments in Chemotherapy for Patients With Advanced Pancreatic Cancer

New Developments in Chemotherapy for Patients With Advanced Pancreatic Cancer

ABSTRACT: Alleviation of tumor-related symptoms may be a more appropriate basis for judging drug efficacy in pancreatic cancer than is tumor shrinkage. Clinical benefit response (CBR), a new way to assess clinical efficacy based on marked, sustained improvement in pain intensity, analgesic consumption, and performance status, was used to evaluate a new chemotherapeutic agent, gemcitabine (2',2'-difluorodeoxycytidine [Gemzar]). A phase III study of newly diagnosed pancreatic cancer patients treated with either gemcitabine or fluorouracil (5-FU) and a phase II trial of gemcitabine in patients whose disease had progressed despite prior treatment with 5-FU both demonstrated that a significant number of patients achieved a CBR with gemcitabine. Prolonged survival was a secondary benefit demonstrated in the phase III trial. In both studies, gemcitabine was well tolerated, with a relatively mild toxicity profile. These results suggest that gemcita-bine may serve as a prototype for the development of more effective therapies for pancreatic cancer patients. [ONCOLOGY 10(Suppl):18-22, 1996]

Introduction

Because pancreatic cancer has no early signs or symptoms, it tends
to be diagnosed at an advanced stage; 80% to 90% of patients present
with disease that is not curable by surgery alone due to spread
of the cancer to adjacent tissues or beyond [1]. Metastatic pancreatic
cancer has proven to be one of the most chemotherapy-resistant
tumors, and, until recently, it has been difficult to demonstrate
any beneficial impact of systemic therapy on this disease. Sobering
testimony to this is the fact that pancreatic cancer has the lowest
5-year survival rate (3%) of any cancer listed in the Surveillance,
Epidemiology, and End Results (SEER) data base of the National
Cancer Institute (NCI) [2]. A brief review of clinical trial results
prior to 1995 will serve to place more recent results in proper
perspective.

Historical Perspective

Phase II Trials

A wide range of response rates can be found in single-agent phase
II trials in patients with advanced pancreatic cancer (as reviewed
by Rothenberg et al) [3]. In evaluating these data, it is important
to keep in mind that clinical trial methodology and criteria for
objective response have evolved over time. Phase II trials conducted
in the 1970s routinely included patients with different tumor
types in a single trial. As a result,response rates reported in
these studies were often based on a small number of patients with
that particular cancer and were therefore subject to a high degree
of statistical uncertainty. Trials performed prior to 1985 relied
heavily on estimation of tumor size by physical examination, with
responses defined as shrinkage of a palpable abdominal mass by
50% or more or a reduction in palpable liver span by 30% or more
[3].

The inherent inaccuracy of these techniques, intraobserver and
interobserver variability, and the influence of confounding factors
on the size of the measured lesions all contributed to the initial
reports of high response rates for drugs such as fluorouracil
(5-FU), chlorambucil (Leukeran), and mitomycin (Mutamycin), as
well as the failure to confirm these promising response rates
in subsequent trials, especially when CT scans were used to determine
tumor response. It is instructive to review how these factors
have led to a substantial decrease in response rates reported
for 5-FU during the past 35 years.

The earliest reports on the activity of 5-FU in pancreatic cancer
showed response rates as high as 56% [4]. Subsequent trials, involving
larger numbers of patients and relying on CT imaging to determine
response, reported response rates of 0% to 19%, even when biochemical
modulation or infusional schedules of drug administration were
utilized [5-9]. In effect, no drug has met the criteria for significant
antitumor activity (ie, an objective response rate of 20% or more)
using radiographic definitions of response in the post-CT era.

Phase III Trials

Two kinds of comparative studies have been conducted in patients
with advanced pancreatic cancer: those that compared active treatment
to best supportive care (to determine whether chemotherapy made
any difference in the outcome of these patients) and those that
compared multiagent regimens to single-agent chemotherapy (to
determine whether combinations of drugs with distinct mechanisms
of action could improve outcome over that achieved with single
agents). Of the three trials that compared active treatment to
best supportive care, two demonstrated no significant difference
[10,11], while one generated very provocative results suggesting
a substantial survival advantage in favor of a five-drug regimen
(Mallinson regimen) [12]. A confirmatory trial was never done,
and subsequent trials of the regimen failed to replicate the impressive
results of this trial [13].

In fact, phase III trials comparing this or other promising multiagent
regimens (such as streptozotocin, mitomycin, and 5-FU [SMF] or
5-FU, Adriamycin, and mitomycin [FAM]) to single-agent 5-FU failed
to demonstrate any advantage of multiagent chemotherapy over 5-FU
alone [13,14]. Despite a number of promising preclinical leads
and provocative phase II study results, virtually no progress
has been made in chemotherapy for metastatic pancreatic cancer
during the past 30 years.

Leads From a "Negative Trial"

Between 1991 and 1994, 25 investigational new drugs were evaluated
in phase II trials for the treatment of pancreatic cancer. The
median response rate in these trials was 0% (range, 0% to 14%)
and the median survival was 3 months [3]. One trial conducted
during this period focused on gemcitabine (2',2'-difluorodeoxycytidine
[Gemzar]). Although the objective response rate to this drug was
only 11% and median survival was 5.6 months, several important
observations were made in this trial [15]. The 1-year survival
rate was surprisingly high (23%), as the responses observed were
durable (more than 4 to more than 20 months). The most striking
aspect of this study, however, was the impact of gemcitabine on
tumor-related symptoms. Of the five patients who had an objective
response to gemcitabine, four were able to resume normal daily
activities. Three of the five patients were also able to reduce
their daily consumption of analgesics. An additional 14 patients
who did not meet radiographic criteria for response experienced
disease stabilization for 4 months or more, and, of these, 9 had
an improvement in performance status.

These results raised the question, how could a cytotoxic agent
produce any beneficial effect without substantial tumor shrinkage?
Several possible explanations have been proposed. First, gemcitabine
could have been acting merely as an analgesic. This explanation
was not felt to be likely since analgesic requirements tend to
increase as the patient develops tolerance, the tumor grows, and
the pain becomes more severe. Patients in this trial experienced
significant alleviation of tumor-related symptoms on a stable
dose of gemcitabine, and that effect was not lost during the 1
week out of every 4 in which the patient did not receive chemotherapy.

Another possible explanation was that gemcitabine may have interfered
with neurotrophic growth factors that are essential for the spread
and invasion of the tumor into the celiac plexus, which lies directly
behind the pancreas. Evidence to support this theory is currently
lacking.

Alternatively, minimal tumor shrinkage (ie, less than the 50%
shrinkage required to qualify as an objective response) may have
been sufficient to relieve the compression or invasion of the
celiac plexus by the tumor. In other words, the standard paradigm
for the determination of antitumor activity may not be well suited
for pancreatic cancer.

Further examination suggests that tumor shrinkage may be an especially
inappropriate way of determining the antitumor effect of cytotoxic
therapy in pancreatic cancer. It is important to recognize our
current limitations in the noninvasive imaging of pancreatic cancer.
Standard CT scanning does not reliably distinguish a pancreatic
tumor from normal pancreatic tissue, tumor desmoplasia, or pancreatitis.
Incomplete opacification of the small intestine makes it difficult
to distinguish tumor from gut, as well. As a result, inclusion
of noncancerous tissue may significantly overestimate tumor shrinkage
(as in the case of inflammatory tissue being included in the tumor
measurement) or underestimate tumor shrinkage (if fibrotic tissue
was included in the tumor measurement).

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