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Chemotherapy for Resectable and Advanced Pancreatic Cancer

Chemotherapy for Resectable and Advanced Pancreatic Cancer

ABSTRACT: This article will review the pertinent data on the use of chemotherapy for all stages of pancreatic cancer. For patients with metastatic disease, fluorouracil (5-FU) was the standard of care for several decades until a single randomized trial established that gemcitabine (Gemzar) produced a greater clinical benefit response, median survival, and 1-year survival. Among the currently available chemotherapy agents, the taxanes, fluoropyrimidines, and camptothecins are being evaluated in clinical trials alone or in combination with gemcitabine. Newer agents that are not classically cytotoxic are also under investigation and hold promise for the future. In patients with locally advanced unresectable disease, chemotherapy is commonly used to sensitize the cancer to radiation. Current investigations focus on trying to improve chemotherapy as a radiation sensitizer, using, for example, infusional 5-FU and gemcitabine. Early-stage, surgically resectable patients may benefit from the combination of chemotherapy and radiation, although more recent trials conducted in Europe raise some doubt. However, flaws in trial design do not allow firm conclusions to be drawn about the benefits of adjuvant therapy. Both chemotherapy and chemoradiation are under further investigation. Significant improvements in the survival of patients with pancreatic cancer will be achieved as more effective systemic therapies are developed, including agents with novel cellular targets. [ONCOLOGY 15:1241-1264, 2001]

Pancreatic carcinoma is the fourth leading cause of cancer death in the
United States. Among the approximately 28,000 cases diagnosed each year, fewer
than 5% live 5 years or longer. The American Joint Commission on Cancer (AJCC)
has divided the progression of pancreatic cancer into four stages, but clinical
decision-making is based on three levels of disease: local and resectable,
locally advanced and unresectable, and metastatic disease. This article will
discuss the role of chemotherapy at each stage of pancreatic cancer.

Metastatic Disease

Although a number of agents have been evaluated as treatment for pancreatic
cancer, efficacy has been limited.[1] Agents such as mitomycin (Mutamycin),
doxorubicin, and epirubicin (Ellence) have produced some of the highest response
rates, ranging from 13% to 27%.[1] A comparison of phase II trials is limited in
that most have been small, with varying proportions of patients with locally
advanced (stages II and III) and metastatic (stage IV) disease. In addition, the
use of various approaches to radiologic assessment and response criteria have
resulted in widely disparate response rates, often for the same therapies.

Fluorouracil

The antimetabolite fluorouracil (5-FU) was among the earliest chemotherapy
agents studied for the treatment of this disease. Until recently, it represented
the standard against which other agents or combination chemotherapy regimens
were tested. Early trials reported response rates > 20% for single-agent
5-FU.[1] However, trials in the early 1990s reported response rates < 15%. In
fact, a recent randomized trial showed no response in 57 patients with
measurable disease treated with single-agent 5-FU.[2] This decline in the
response rate may have been caused by a number of factors. Changes in
radiographic technology, which, in turn, led to an improvement in the ability to
accurately measure disease, may be the largest contributing factor to this
change.

Coadministration of other agents appears to modulate the intracellular
effects or metabolism of 5-FU. Modulation of 5-FU with agents such as
interferon-alpha, N-phosphonacetyl-l-aspartate (PALA), and leucovorin does not
appear to have improved the efficacy of 5-FU.[1,3,4] Altering the mode of 5-FU
administration from bolus to infusion clearly changes the side-effect profile of
5-FU but does not affect efficacy. Phase II trials of infusional 5-FU have
produced results similar to those obtained in trials of bolus 5-FU. Infusional
5-FU given to 24 patients in conjunction with interferon-alpha resulted in an 8%
response rate and a median survival of only 4.6 months.[4] Among 35
patients treated with infusional 5-FU in conjunction with PALA, the response
rate was 14%, and the median survival was 5.1 months.[3]

More recently, oral formulations of 5-FU have been developed that mimic
infusional 5-FU pharmacokinetically without the inconvenience of an infusion
port. One such agent is capecitabine (Xeloda), a prodrug converted
intracellularly to 5-FU. Another agent (UFT) combines a prodrug, tegafur, with
uracil; this compound competes with 5-FU for catabolism by dihydropyrimidine
dehydrogenase and thereby reduces 5-FU breakdown. UFT and capecitabine have both
been investigated for the treatment of pancreatic cancer and have produced
response rates of 0% and 7.3%, respectively, and median survivals of 3.5 and 6
months.[5,6]

Investigators have tried to improve the efficacy of single-agent 5-FU through
the use of combination regimens. Table 1 lists a sampling of randomized
chemotherapy trials in pancreatic cancer.[2,7-11] Although combinations of 5-FU
with doxorubicin (Adriamycin) and mitomycin (FAM), and 5-FU with a platinum,
have demonstrated promising results in phase II trials, neither has proved
superior to single-agent 5-FU.[7,8]

Other regimens have met similar fates. The 10.2-month median survival
reported in a small, early trial of an intensive multiagent schedule entitled
the Mallinson regimen could not be duplicated in a larger randomized trial,
which showed the strategy to be no more effective than 5-FU.[9]

Finally, although combination regimens have not improved upon the efficacy of
single-agent 5-FU, multiagent regimens such as FAM and ELF (etoposide,
leucovorin, 5-FU) have produced longer survivals than best supportive care in
small randomized trials (Table 1).[2,7-11] Nevertheless, single-agent 5-FU
remained the standard of care for patients with advanced pancreatic carcinoma
until recently.

Gemcitabine

Gemcitabine (Gemzar) has become the drug of choice for first-line treatment
of pancreatic cancer. A pyrimidine nucleoside analog, the agent is activated to
its triphosphate form by a series of enzymatic steps, starting with the actions
of a rate-limiting enzyme, deoxycytidine kinase. The antitumor activity of
gemcitabine correlates with DNA incorporation of gemcitabine triphosphate, and
may be caused partially by its inhibition of ribonucleotide reductase (a key
enzyme in the production of deoxynucleotides), leading to the depletion of
normal deoxynucleotide pools.

Phase II Trials—Phase II trials of gemcitabine in pancreatic cancer have
resulted in only 11% and 6.3% response rates.[12,13] Despite these low response
rates, gemcitabine produced median survivals of 5.6 and 6.3 months, and
investigators noted that some patients who did not achieve objective tumor
responses did experience relief of tumor-related symptoms. To better study this
observation, subsequent trials were designed to assess the effects of
gemcitabine on specific disease-related symptoms, using a new measure—"clinical
benefit response." Clinical benefit response encompasses an evaluation of
pain, Karnofsky performance status (KPS), and weight loss and was first reported
in a phase II trial in patients with pancreatic cancer refractory to 5-FU.[14]
Although only 10.5% of patients with measurable disease had objective partial
responses, 27% demonstrated clinical benefit responses.

Phase III Trial—A phase III trial comparing single-agent gemcitabine to
5-FU as first-line therapy was also conducted with a primary end point of
clinical benefit response.[2] Survival was the secondary end point. Of 160
patients enrolled, 34 were not randomized, mostly due to rapid clinical
deterioration. For the remaining 126 patients, clinical benefit response in the
gemcitabine arm was significantly better than in the 5-FU arm (23.8% vs 4.8%,
respectively, P = .0022). Survival analysis also favored the gemcitabine arm
with a median and 1-year survival of 5.65 months and 18%, respectively, compared
to 4.41 months and 2%, respectively, for the 5-FU arm.

The treatment IND (investigational new drug application) supported the
randomized trial data with a similar median survival of 5.1 months for
chemonaive patients treated with gemcitabine.[15] Food and Drug Administration
approval of gemcitabine was based on the randomized data. Gemcitabine was
replaced by 5-FU as the control arm and current standard in more recent
randomized trials.

Significant effort has been focused on improving results with gemcitabine.
First, laboratory data suggested that an alternative gemcitabine administration
schedule might be advantageous.[16] The rate-limiting step in activating
gemcitabine to its triphosphate form is deoxycytidine kinase. At an infusion
rate higher than 10 mg/m²/min, deoxycytidine kinase is saturated. Thus, the
standard schedule of 1,000 mg/m² over 30 minutes may not allow full
conversion and activation of gemcitabine to gemcitabine triphosphate.

After a phase I study established 1,500 mg/m² administered at a fixed-rate
infusion over 150 minutes as the recommended phase II dose, that dose was
evaluated against 2,200 mg/m² over 30 minutes in a randomized phase II
trial in patients with advanced pancreatic cancer.[16,17] As postulated, the 10
mg/m² infusion rate produced significantly higher intracellular levels of
gemcitabine triphosphate in peripheral blood mononuclear cells. Patients treated
with the longer infusion schedule also showed a trend toward improved survival,
but patient numbers were small. These results justify further testing of the
fixed-rate infusion in phase III trials.

Gemcitabine-Based Combinations—Another important development was the
evaluation of gemcitabine-based combinations. One logical partner was 5-FU.
Laboratory studies demonstrated additive effects against HT-29 cells when
gemcitabine was administered either prior to or following 5-FU.[18,19] Examples
of combination schedules that have been investigated are listed in Table
2
.[20-24] As noted earlier, phase II trials have enrolled varying
percentages of patients with locally advanced disease and other characteristics
that may have had an effect on survival.

Three trials using identical regimens of gemcitabine, 1,000 mg/m² IV over 30
minutes, followed by a weekly bolus of 5-FU at 600 mg/m² for 3 of 4 weeks,
illustrated the potential effects on survival in locally advanced
patients.[20-22] The Eastern Cooperative Oncology Group (ECOG) trial only
enrolled patients with metastatic disease and found a median survival of
4.4 months.[20] A larger study from the Italian Group for the Study of
Digestive Tract Cancer (GISCAD) enrolled 54 patients, 46% of whom had locally
advanced disease, and reported a median survival of 7 months.[21] The Gruppo
de Tumores Gastrointestinales (GETG) study, with 61% of patients having locally
advanced disease, showed an 11-month median survival.[22] However, patients in
the latter two studies also received leucovorin, 25 mg/m².[21,22] Because
leucovorin and other factors may have contributed to the variability in survival
rates, interpretation of these comparisons is limited.

Other institutions have approached the combination strategy using infusional
5-FU schedules.[23,24] One of these trials, in which 34% of patients had locally
advanced disease, reported a promising median survival > 10 months.[24] The
ECOG has completed accrual of over 320 patients with locally advanced and
metastatic pancreatic cancer to a phase III trial comparing gemcitabine plus
bolus 5-FU with gemcitabine alone. Survival was the primary end point. Results
were presented at the 2001 annual meeting of the American Society of Clinical
Oncology (ASCO). Although the gemcitabine plus 5-FU arm had a survival of 6.7
months compared to 5.4 months for gemcitabine alone, this did not achieve
significance (P = .09). Both arms of the trial had low response rates and
similar toxicity profiles.[24a]

Gemcitabine Plus Cisplatin—Another agent demonstrating evidence of
synergy in the laboratory when administered with gemcitabine is cisplatin (Platinol).
Limited trials of cisplatin have been conducted in pancreatic cancer. While
these have yielded mixed responses, early results from combination trials of
cisplatin with gemcitabine have reported response rates ranging from 11.5% to
36.4%.[25,26] The preliminary results of a randomized trial of cisplatin plus
gemcitabine vs single-agent gemcitabine in 63 evaluable patients reported a
higher response rate in the combination arm vs the gemcitabine arm (31% vs 10%,
respectively).[27] However, this trial also measured clinical benefit response,
which was fairly similar for the combination and gemcitabine arms (38% and 45%,
respectively). Other platinum agents, such as carboplatin (Paraplatin) and
oxaliplatin, are currently under investigation.

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