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 . 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) . A brief review of clinical trial results
prior to 1995 will serve to place more recent results in proper
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) . 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
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% . 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) . A confirmatory trial was never done,
and subsequent trials of the regimen failed to replicate the impressive
results of this trial .
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.
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 . 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 . 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
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).
1. Kelly DM, Benjamin IS: Pancreatic carcinoma. Ann Oncol 6:19-28,
2. Ries LAG, Miller BA, Hankey BF, et al (eds): SEER Cancer Statistics
Review, 1973-1991: Tables and Graphs, pp 356-368. National Cancer
Institute, NIH pub. no. 94-2789. Bethesda, MD, 1994.
3. Rothenberg ML, Abbruzzese JL, Moore M, et al: Commentary: A
rationale for expanding the endpoints for clinical trials in advanced
pancreas cancer (suppl). Cancer, 1996 (in press).
4. Hurley JD, Ellison EH: Chemotherapy of solid cancers arising
from the gastrointestinal tract. Ann Surg 152:568-582, 1960.
5. Hansen R, Quebbeman E, Ritch P, et al: Continuous 5-fluorouracil
(5FU) infusion in carcinoma of the pancreas: A phase II study.
Am J Med Sci 295:91-93, 1988.
6. Tajiri H, Yoshimori M, Okazaki N, et al: Phase II study of
continuous venous infusion of 5-fluorouracil in advanced pancreatic
cancer. Oncology 48:18-21, 1991.
7. Crown J, Casper ES, Botet J, et al: Lack of efficacy of high-dose
leucovorin and fluorouracil in patients with advanced pancreatic
adenocarcinoma. J Clin Oncol 9:1682-1686, 1991.
8. DeCaprio JA, Mayer RJ, Gonin R, et al: Fluorouracil and high-dose
leucovorin in previously untreated patients with advanced adenocarcinoma
of the pancreas: Results of a phase II trial. J Clin Oncol 9:2128-2133,
9. Pazdur R, Ajani JJ, Abbruzzese JL, et al: Phase II evaluation
of fluorouracil and recombinant a-2a-interferon in previously
untreated patients with pancreatic adenocarcinoma. Cancer 70:2073-2076,
10. Andersen JR, Friis-Mollek A, Hancke S, et al: A controlled
trial of combination chemotherapy with 5-FU and BCNU in pancreatic
cancer. Scand J Gastroenterol 16:973, 1981.
11. Frey C, Twomey P, Keehn R, et al: Randomized study of 5-FU
and CCNU in pancreatic cancer: Report of the Veterans Administration
Surgical Adjuvant Cancer Chemotherapy Study Group. Cancer 47:27-31,
12. Mallinson CN, Rake MO, Cocking JB, et al: Chemotherapy in
pancreatic cancer: Results of a controlled, prospective, randomised,
multicentre trial. Br Med J 281:1589-1591, 1980.
13. Cullinan S, Moertel CG, Wieand HS, et al: A phase III trial
on the therapy of advanced pancreatic cancer: Evaluations of the
Mallinson regimen and combined 5-fluorouracil, doxorubicin, and
cisplatin. Cancer 65:2207-2212, 1990.
14. Cullinan SA, Moertel CG, Fleming TR, et al for the North Central
Cancer Treatment Group: A comparison of three chemotherapeutic
regimens in the treatment of advanced pancreatic and gastric carcinoma:
Fluorouracil vs fluorouracil and doxorubicin vs fluorouracil,
doxorubicin, and mitomycin. JAMA 253:2061-2067, 1985.
15. Casper ES, Green MR, Kelsen DP, et al: Phase II trial of gemcitabine
(2',2'-difluorodeoxycytidine) in patients with adenocarcinoma
of the pancreas. Invest New Drugs 12:29-34, 1994.
16. O'Shaughnessy JA, Wittes RE, Burke G, et al: Commentary concerning
demonstration of safety and efficacy of investigational anticancer
agents in clinical trials. J Clin Oncol 9:2225-2232, 1991.
17. Moossa AR, Dawson PJ, Franklin WA, et al: Tumors of the pancreas,
in Moosa AR, Robson MC, Schimpff SC (eds): Comprehensive Textbook
of Oncology, p 1105. Baltimore, Williams & Wilkins, 1986.
18. Schipper H, Clinch J, McMurray A, et al: Measuring the quality
of life of cancer patients: The Functional Living Index--Cancer:
Development and validation. J Clin Oncol 2:472-483, 1984.
19. Cella DF, Tulsky DS, Gray G, et al: The Functional Assessment
of Cancer Therapy Scale: Development and validation of the general
measure. J Clin Oncol 11:570-579, 1993.
20. Ganz PA, Schag CAC, Lee JJ, et al: The CARES: A generic measure
of health-related quality of life for patients with cancer. Qual
Life Res 1:19-29, 1992.
21. Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organization
for Research and Treatment of Cancer QLQ-C30: A quality-of-life
instrument for use in international clinical trials in oncology.
J Natl Cancer Inst 85:365-376, 1993.
22. Andersen JS, Burris HA, Casper E, et al: Development of a
new system for assessing clinical benefit for patients with advanced
pancreatic cancer (abstract). Proc Am Soc Clin Oncol 13:A1600,
23. Moore M, Andersen J, Burris H, et al: A randomized trial of
gemcitabine vs 5-FU as first-line therapy in advanced pancreatic
cancer (abstract). Proc Am Soc Clin Oncol 14:A473, 1995.
24. Rothenberg ML, Moore MJ, Cripps MC, et al: A phase II trial
of gemcitabine in patients with 5-FU-refractory pancreas cancer.
Ann Oncol 7:347-353, 1996.
25. Taylor I: Should further studies of chemotherapy be carried
out in pancreatic cancer? Eur J Cancer 29A:1078-1081, 1993.