In 2002, an estimated 30,300 new cases of pancreatic
cancer will be diagnosed, and 29,700 people will die from the disease. The
overall 5-year survival rate for patients with pancreatic cancer ranges from
less than 1% to less than 5% with little improvement in survival observed in the
past 20 years. Approximately two-thirds of all pancreatic cancer patients
have metastatic disease at the time of diagnosis,[2,3] while the majority of the
remaining patients have locally advanced unresectable disease.[4,5]
Several chemotherapeutic agents have been evaluated either alone or in
combination in patients with metastatic pancreatic cancer, but the results
continue to be disappointing: reproducible objective response rates range from
0% to 20% and median survival times are less than 6 months.[6-9] Results for
patients presenting with locally advanced (nonmetastatic) unresectable disease
have also been disappointing. The combination of concurrent fluorouracil (5-FU)
and ionizing radiation therapy for patients with unresectable disease has
resulted in a twofold increase in median survival: approximately 10 months vs 5
months.[10-12] Despite these limited benefits, many consider external beam
radiation and concurrent 5-FU as the standard therapy for locally advanced
In an attempt to improve systemic disease control, which could possibly
impact overall survival, investigators at several centers are testing
neoadjuvant chemotherapy strategies. Such strategies have potential advantages
for patients with pancreatic cancer. The morbidity of definitive chemoradiation
is not insignificant, and can thwart the possibility of using systemic
chemotherapy. In addition, preoperative chemotherapy allows the oncologist to
identify those patients with aggressive disease who are destined to progress
quicklyspecifically, patients with micrometastatic disease who are less
likely to benefit from a course of locoregional chemoradiotherapy. While
induction chemotherapy has several potential advantages, a challenge for
investigators is to discover a regimen with consistent activity in pancreatic
Results of phase I and II clinical trials have demonstrated that single-agent
[CPT-11, Camptosar]), a camptothecin analog, has activity in pancreatic cancer.
In previously untreated patients with advanced pancreatic cancer, Sakata et al
reported an 11% partial response rate (4 out of 35 patients) using irinotecan at
100 mg/m²/wk or 150 mg/m² every other week. Wagener et al observed three
partial responses among 32 patients (9%) with pancreatic cancer who received
irinotecan at 350 mg/m² by 30-minute intravenous infusion every 3 weeks.
Response durations were 7.2, 7.5, and 7.8 months.
In contrast, O’Reilly et al evaluated topotecan (Hycamtin), another
topoisomerase I inhibitor, in 27 previously untreated advanced pancreatic cancer
patients, and noted no responses. Scher et al, however, reported three (10%)
partial responders in a similar patient cohort receiving a comparable topotecan
dosing schedule. Additional information on this combination has been discussed
by Rocha Lima et al elsewhere in this supplement.
Use of a gemcitabine/irinotecan combination regimen seems attractive, based
on the complementary toxicity profiles, different mechanisms of cytotoxicity,
and overlapping antitumor activity spectra of the two compounds.
Early results of limited phase I/II trials that combined radiation and
gemcitabine have been reported.[17-20] Data from a phase I study from Wake
Forest University/University of North Carolina Chapel Hill determined that the
maximum tolerated dose of concurrent twice-weekly gemcitabine with upper
abdominal radiation was 40 mg/m² given each Monday and Thursday of the
radiation. The preliminary Cancer and Leukemia Group B report of this
regimen in the phase II setting indicated that it was safe and feasible. While
only four local (in-field) failures were observed, systemic disease progression
limited median survival to 13.7 months and 7.8 months in patients with Eastern
Cooperative Oncology Group (ECOG) performance status of 0 and 1 to 2,
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pancreatic cancer: Report of the Veterans Administration Surgical Adjuvant
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doxorubicin, and mitomycin. JAMA 253:2061-2067, 1985.
9. Oster MW, Gray R, Panasci L, et al: Chemotherapy for advanced pancreatic
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10. Radiation therapy combined with Adriamycin or 5-fluorouracil for the
treatment of locally unresectable pancreatic carcinoma. Gastrointestinal Tumor
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pancreatic carcinoma: A randomized comparison of high dose (6000 rads) radiation
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radiation + 5-fluorouracil: The Gastrointestinal Tumor Study Group. Cancer
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of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy
alone. Gastrointestinal Tumor Study Group. J Natl Cancer Inst 80:751-755, 1988.
13. Sakata Y, Shimada Y, Yoshino M, et al: A late phase II study of CPT-11,
irinotecan hydrochloride, in patients with advanced pancreatic cancer. CPT-11
Study Group on Gastrointestinal Cancer. Gan To Kagaku Ryoho 21:1039-1046, 1994.
14. Wagener DJ, Verdonk HE, Dirix LY, et al: Phase II trial of CPT-11 in
patients with advanced pancreatic cancer, an EORTC early clinical trials group
study [see comments]. Ann Oncol 6:129-132, 1995.
15. O’Reilly S, Donehower RC, Rowinsky EK, et al: A phase II trial of
topotecan in patients with previously untreated pancreatic cancer. Anticancer
Drugs 7:410-414, 1996.
16. Rocha Lima CS, Savarese D, Bruckner H, et al: Multicenter phase II trial
of first-line irinotecan and gemcitabine in patients with locally advanced or
metastatic pancreatic cancer (abstract 1023). Proc Am Soc Clin Oncol 19:263a,
17. Talamonti MS, Catalano PJ, Vaughn DJ, et al: Eastern Cooperative Oncology
Group phase I trial of protracted venous infusion fluorouracil plus weekly
gemcitabine with concurrent radiation therapy in patients with locally advanced
pancreas cancer: A regimen with unexpected early toxicity. J Clin Oncol
18. Wolff RA, Evans DB, Gravel DM, et al: Phase I trial of gemcitabine
combined with radiation for the treatment of locally advanced pancreatic
adenocarcinoma. Clin Cancer Res 7:2246-2253, 2001.
19. Pingpank JF, Hoffman JP, Ross EA, et al: Effect of preoperative
chemoradiotherapy on surgical margin status of resected adenocarcinoma of the
head of the pancreas. J Gastrointest Surg 5:121-130, 2001.
20. McGinn CJ, Zalupski MM, Shureiqi I, et al: A phase I trial of radiation
dose escalation with concurrent weekly full dose gemcitabine in patients with
advanced pancreatic cancer. J Clin Oncol 19: 4202-4208, 2001.
21. Blackstock AW, Bernard SA, Richards F, et al: Phase I trial of
twice-weekly gemcitabine and concurrent radiation in patients with advanced
pancreatic cancer. J Clin Oncol 17:2208, 1999.