CN Mobile Logo

Search form


Irinotecan/Gemcitabine Followed by Twice-Weekly Gemcitabine/Radiation in Locally Advanced Pancreatic Cancer

Irinotecan/Gemcitabine Followed by Twice-Weekly Gemcitabine/Radiation in Locally Advanced Pancreatic Cancer

ABSTRACT: Early clinical studies combining irinotecan (CPT-11, Camptosar) and gemcitabine (Gemzar) have yielded encouraging results. Gemcitabine administered via a twice-weekly schedule results in an enhanced radiation-sensitizing effect. This multi-institution phase II trial of induction irinotecan/gemcitabine followed by twice-weekly gemcitabine and upper abdominal radiation has been initiated to determine the activity of this regimen in patients with unresectable pancreatic cancer. Patients received two cycles of induction irinotecan (100 mg/m² IV) and gemcitabine (1,000 mg/m² IV) on days 1 and 8 of each 3-week cycle. Following the induction therapy, patients without disease progression received twice-weekly gemcitabine at 40 mg/m² and radiation. Nine patients have been enrolled in the study to date. Median patient age was 71 years (range: 65-85 years). The major toxicity observed thus far was grade 3/4 neutropenia. Grade 3/4 nonhematologic toxicity was rarely observed and included dehydration (12%) and diarrhea (12%), which were likely related to the irinotecan. No treatment-related deaths have occurred. These preliminary data suggest that this regimen is well tolerated. Although the data are limited, tumor progression during the induction chemotherapy has not been observed thus far (radiographically or biochemically [CA-19-9]). [ONCOLOGY 16(Suppl 5):25-28, 2002]

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.[1] 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
pancreatic cancer.

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
quickly—specifically, 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

Irinotecan/Gemcitabine for Advanced Pancreatic Cancer

Results of phase I and II clinical trials have demonstrated that single-agent
irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin
[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.[13] 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.[14]
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.[15] 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.[16]

Concurrent Radiation and Gemcitabine

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.[21] 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,


Loading comments...

By clicking Accept, you agree to become a member of the UBM Medica Community.