Pancreatic cancer is the fourth leading cause of cancer death in males
and females in the United States. Worldwide, 170,000 new cases and 168,000
deaths were projected for the year 2000. The anatomy of the pancreas, with
its close proximity to other vital tissues, as well as the propensity of
pancreatic cancer for early spread, make the treatment of this disease
difficult. Median survival is 6 to 10 months for patients with locally advanced
disease and 3 to 6 months for metastatic disease, depending on performance
status and extent of disease at diagnosis. Overall, only 1% to 4% of all
patients with pancreatic cancer will be alive 5 years after diagnosis.
Despite recent progress, the treatment of patients with locally
advanced and metastatic disease continues to be palliative. Use of chemotherapy
and/or radiation should not jeopardize quality of life in patients with advanced
and metastatic pancreatic cancer who are candidates for treatment. Many single
agents and chemotherapy combinations have been evaluated in this disease and,
with few exceptions, there had been little evidence of a meaningful impact on
survival or quality of life until the advent of gemcitabine (Gemzar).
The antimetabolite gemcitabine has been approved by the US Food
and Drug Administration (FDA) as a single agent for the treatment of advanced
pancreas cancer. To better evaluate the impact of gemcitabine in this disease,
an alternative methodology to measure clinical benefitone that focuses on
patient symptomswas developed.[4,5] Applying the clinical benefit criteria, a
phase III trial in previously untreated pancreatic cancer patients was performed
comparing gemcitabine with fluorouracil (5-FU). This trial demonstrated an
improved rate of clinical benefit and an overall survival advantage for
gemcitabine. At 12 months of follow-up, 18% of the gemcitabine-treated
patients remained alive compared with only 2% of the 5-FU-treated patients. In
that pivotal phase III trial, the statistically significant advantages for
gemcitabine were seen despite an objective partial response rate of only
5.4%. This level of activity of gemcitabine was also observed in phase II
trials (Table 1).[7-9]
Improvements in the management of locally advanced and
metastatic pancreatic cancer are clearly needed. Developing gemcitabine
combinations is one strategy to achieve this goal. The experience with
gemcitabine combinations in non-small-cell lung cancer suggests that the
gemcitabine doublets are feasible and active. Translating the lung cancer
experience to pancreatic cancer patients might not be a simple task. Choosing
the right gemcitabine partner is very important for the success of the
combination. The agents active against non-small-cell lung cancer are not
necessarily active against pancreatic cancer.
The topoisomerase I inhibitor irinotecan (CPT-11, Camptosar) is
approved by the FDA for the management of relapsed and metastatic colon cancer
and is active in other gastrointestinal malignancies. In pancreas cancer,
irinotecan was tested in two phase II trials.[10,11] The level of activity of
irinotecan is apparently similar to that of gemcitabine, with equivalent median
survival, as suggested by results of the European Organization for Research and
Treatment of Cancer (EORTC) trial (Table 1).
Preclinical data for the combination of gemcitabine and
irinotecan suggest antagonism at low concentrations but synergism at
concentrations of gemcitabine above 0.1 µM and irinotecan above 3.2 µM in the
SCOG small-cell lung cancer cell line. Synergism at concentrations of 0.1 to 2
µM for gemcitabine and 0.2 to 10 µM for irinotecan, but antagonism at high
concentrations (ie, concentrations > 2 µM for gemcitabine and 20 µM for
irinotecan), was seen in MCF-7 breast cancer cells.
These preclinical observations were translated into a phase I
trial in which both agents were administered on a day 1, day 8 every-3-week
schedule (IrinoGem). The gemcitabine dose was fixed at 1,000 mg/m2 and the
irinotecan dose was escalated from an initial dose of 50 mg/m2. The maximum
tolerated dose of irinotecan was 100 mg/m2 given intravenously over 90 minutes
on days 1 and 8 every 3 weeks immediately following gemcitabine at 1,000 mg/m2
on days 1 and 8 given intravenously over 30 minutes (Figure
dose-limiting toxicity was grade 3 diarrhea in two of seven patients at an
irinotecan dose of 115 mg/m2.
A total of 18 patients were accrued to the trial. Two of three
previously untreated pancreas cancer patients and one patient with metastatic
carcinoma of unknown primary (possible pancreatic cancer primary) had documented
partial responses. The third previously untreated pancreas cancer patient had
tumor reduction short of a partial response based on radiologic assessment, and
clinical benefit for eight cycles of treatment (Table
O’Reilly et al from Memorial Sloan-Kettering Cancer Center
(MSKCC) reported their phase I experience with a different schedule of
gemcitabine and irinotecan. Both drugs were given on days 1, 8, and 15 on an
every-4-week cycle. As in the IrinoGem study, the gemcitabine dose was fixed at
1,000 mg/m2 over 30 minutes and the irinotecan dose was escalated. Thirty-five
patients were accrued and both sequences of drug administration were tested.
Preliminary results of pharmacokinetic studies assessing levels
of gemcitabine, the uridine metabolite of gemcitabine, irinotecan, SN-38, and
SN-38G did not show pharmacokinetic differences between the two administration
sequences. When gemcitabine was given first immediately followed by
irinotecan, diarrhea, nausea/vomiting, neutropenia, and fatigue were
dose-limiting. When irinotecan was given first, immediately followed by
gemcitabine, the dose-limiting toxicities were neutropenic fever and diarrhea.
The maximum tolerated doses in both sequences were 1,000 mg/m2 of gemcitabine
and 60 mg/m2 of irinotecan (Figure
A durable partial response was observed in one patient with
gastric cancer, and five other patients had stable disease for ³ 6 months
(Table 2). There was no clear evidence of a superior drug sequence, although
patients who achieved long-term stable disease and response had received
gemcitabine first followed by irinotecan.
Maintaining single-agent doses of chemotherapy drugs when used
in combination regimens may be more challenging in pancreatic cancer patients,
as they are generally more frail and less tolerant of toxic side effects. A
strategy one might consider to improve the dose intensity of gemcitabine and
irinotecan combinations is related to the schedule of administration.
Gemcitabine regimens using the day 1 and 8 every-21-day cycle
instead of the day 1, 8, and 15 every-28-day cycle have been associated with
increased dose intensity. By avoiding the day-15 dose, when marrow suppression
frequently prevented delivery of the gemcitabine combinations, the every-3-week
schedule has been better tolerated, requiring fewer doses to be withheld. With
single-agent irinotecan, a schedule of four weekly doses for an every-6-week
cycle is generally associated with more diarrhea during weeks 3 and 4.
By developing the day 1 and 8 every-3-week cycle in IrinoGem,
the irinotecan-induced diarrhea and the myelosuppression of gemcitabine and
irinotecan have been minimized, allowing almost single-agent doses of these two
drugs in combination. In addition, the activity in previously untreated pancreas
cancer patients observed in the phase I trial with IrinoGem led us to perform a
phase II study of this combination in previously untreated patients with locally
advanced or metastatic pancreatic cancer (Figure
The phase II trial accrued 45 chemotherapy-naive (7% had been
treated pre-viously with radiation therapy), locally advanced (unresectable), or
metastatic pancreatic cancer patients at eight US centers from July 1998 through
June 30, 1999. Measurable disease, adequate organ function, and performance
status of 0 to 2 were required. No previous chemotherapy except for 5-FU given
as a radiation sensitizer was allowed. The primary efficacy parameter was tumor
response; secondary efficacy parameters were CA 19-9 response, response
duration, and overall survival. Median age was 60 years (range: 31 to 89 years),
and the male/female ratio was 60%/40%. A performance status of 0/1/2 was
recorded in 24%, 60%, and 16%, respectively. Seventy-three percent of patients
had metastatic and 27% had locally advanced disease.
Preliminary results were reported at the American Society of
Clinical Oncology (ASCO) 2000 meeting, and suggest that the combination is
active and well tolerated in patients with locally advanced and metastatic
pancreatic cancer. Of 351 total doses delivered (day 1 or 8), full doses of
irinotecan and gemcitabine were given for 91% and 88%, respectively. Toxicity
has been modest, with no reports of toxic deaths or neutropenic fever thus far (Table
3). Preliminary radiologic response rate is 20% (9 out of 45), and the
rate of CA 19-9 decrease of more than 50% from baseline value is 32.5% (13 out
of 40). Median survival is 6 months (range: 0.9 to 12.2+ months) and median time
to treatment failure is 2.9 months (range: 0.1 to 11.3+ months) (Table
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