During the past few years, tremendous progress has occurred in
chemotherapy for colorectal cancer, as reflected in the numerous
chemotherapy trials that are ongoing or planned. Several new drugs
have shown activity in advanced disease, adding treatment
alternatives to fluorouracil (5-FU), which has been the sole agent
for advanced colorectal cancer for almost 40 years. These drugs
include irinotecan (CPT-11 [Camptosar]), raltitrexed (Tomudex),
oxaliplatin, and capecitabine (Xeloda).
This article will focus on irinotecan, which has demonstrated
activity as a single agent in several phase II studies in Europe,
Japan, and the United States. Two large, randomized, multicenter
studies established its superiority over best supportive care and
other second-line chemotherapy regimens.[1,2] These data indicate
that irinotecan should be integrated rapidly into combined protocols
for advanced colorectal cancer.
In this article, we will present the results of ongoing or recently
published European trials of irinotecan-based combinations, mainly
irinotecan combined with 5-FU alone; 5-FU plus folinic acid
(leucovorin); or mitomycin (Mutamycin). Other articles in this
monograph will review the results achieved with irinotecan alone or
combined with other drugs (ie, oxaliplatin or raltitrexed).
Two protocols combining irinotecan with 5-FU alone have been tested
in Europe; the Mayo Clinic schedule and the Lokich schedule.
Mayo Clinic Schedule
A study performed at the Salpêtrière Hospital in
Paris was aimed at evaluating the feasibility and safety profile
of irinotecan combined with 5-FU administered as a daily intravenous
(IV) bolus injection for 5 consecutive days. A secondary aim was to
study the pharmacokinetic interaction between the two drugs.
This open-label, single-center, phase I study with dose escalation
included 41 patients with advanced solid tumors (29 with colorectal
cancer, 5 with other gastrointestinal tumors, and 7 with other solid
tumors). Patients were treated with at least two 4-week cycles, one
in which irinotecan was administered before the 5 days of 5-FU and
the other in which irinotecan was given on day 6 (Figure
Neutropenia was the dose-limiting toxicity. Grade 3 or 4 neutropenia
occurred in 5 of 6 patients treated at the 5-FU/irinotecan dose level
of 375/350 mg/m2. The other maximum tolerated dose (MTD)
was achieved at a 5-FU/irinotecan dose level of 450/300 mg/m2;
this dose level resulted in grade 3 or 4 neutropenia in four of four
patients. Other toxicities included mild diarrhea, fever, anemia, and
thrombocytopenia. Based on this study, the recommended doses were 300 mg/m2
of irinotecan and 375 mg/m2 of 5-FU.
The pharmacokinetic analysis showed no statistically significant
differences in clearance of either irinotecan or its active
metabolite, SN-38, regardless of whether irinotecan was given before
or after 5-FU. However, when irinotecan was given before 5-FU, a
minor pharmacokinetic interaction between irinotecan and 5-FU was
observed, resulting in statistically lower 5-FU catabolism (Table
1). This finding indicated that irinotecan should be given
In a phase I study conducted in Spain by Paz-Ares et al,
irinotecan was given over 90 minutes on day 1, followed by a 14-day
infusion of 5-FU (250 mg/m2/d), with cycles repeated every
3 weeks. The study involved 11 patients with advanced solid tumors (4
of whom had colorectal cancer; 2, esophageal cancer; 2, head and neck
cancer; and 3, other solid tumors). To date, four doses of irinotecan
have been tested: 150, 175, 200, and 250 mg/m2.
No dose-limiting toxicity has been reported yet, but the main
toxicity is diarrhea. Mild nausea, vomiting, malaise, and alopecia
also have been reported. Minor responses and disease stabilization
have been observed, but no partial or complete responses have been noted.
The high activity of the combination of 5-FU and folinic acid (FUFOL)
in advanced colorectal cancer is now unquestionable. These results
make the two drugs attractive candidates for irinotecan-based
combinations. Four such combinations have been tested in Europe.
Alternating Irinotecan and FUFOL
Preliminary results of a multicenter study of irinotecan alternated
with FUFOL, performed in Italy, were recently presented by Barone et
al.[5,6] As shown schematically in Figure
2, 5-FU 425 mg/m2/d was administered as an IV bolus
injection that was repeated for 5 consecutive days, according to the
Mayo Clinic schedule. Low-dose folinic acid (20 mg/m2/d)
was also injected as a daily bolus for 5 consecutive days. Irinotecan
350 mg/m2 was administered as a 90-minute infusion on day
1. One 21-day cycle of irinotecan was alternated with one 21-day
cycle of FUFOL. The study included 33 colorectal cancer patients
receiving first-line chemotherapy for metastatic disease.
Neutropenia (20%) and diarrhea (20%) were the main toxicities
encountered. However, the combination was relatively well tolerated.
Of the 133 cycles evaluated for toxicity, only 14 cycles had to be
delayed and 11 required a dose reduction due to toxicity. Of the 29
patients evaluable for response, 9 showed a partial remission (31%)
and 4 exhibited a minor response.
Weekly Irinotecan and FUFOL
A phase I study of weekly irinotecan and FUFOL was conducted in
Germany. As reported by Vanhoefer et al in Amsterdam in October
1997, this study included 26 patients receiving first-line therapy
for advanced colorectal cancer. Seven dose levels, administered over
4 or 6 weeks (Figure 3), were
evaluated. Irinotecan was given over 90 minutes on day 1 of a weekly
cycle at doses ranging from 80 to 100 mg/m2. Folinic acid
500 mg/m2 was administered over 2 hours, followed by a
24-hour infusion of 5-FU given at doses ranging from 2 g/m2/wk
for 4 weeks to 2.6 g/m2/wk for 6 weeks. Based on their
findings, these authors recommended irinotecan 80 mg/m2,
folinic acid 500 mg/m2, and 5-FU 2.6 g/m2,
given for 6 consecutive weeks, followed by 1 week of rest.
The main toxicities were gastrointestinal. Eleven patients had World
Health Organization (WHO) grade 2 or higher vomiting and 2 patients
had WHO grade 2 or higher diarrhea. However, out of 17 patients
evaluable for response, 11 (61%) had a partial response.
Irinotecan Combined With LV/5-FU2
Another FUFOL regimen combines irinotecan with folinic acid
(leucovorin) and a double dose (bolus and infusion) of 5-FU
(LV/5-FU2). This regimen, also called the "de Gramont
schedule," was compared to irinotecan alone in a large French
phase I/II study reported by Rougier et al.[8,9] The study involved
46 patients with advanced colorectal cancer who had received one or
more prior chemotherapy regimens.
As shown in Figure 4, these
patients were treated with a 90-minute infusion of irinotecan given
at increasing doses starting at 100 mg/m2. After 1 hour,
folinic acid (200 mg/m2/d) was infused over 2 hours on
days 1 and 2; on both days, folinic acid was followed by 5-FU given
as a bolus injection (400 mg/m2/d) and as a 22-hour
continuous infusion (600 mg/m2/d). To date, seven doses of
irinotecan have been evaluated: 100, 120, 150, 180, 200, 220, and 300 mg/m2.
No dose-limiting toxicity has been reported as yet; the 300-mg/m2
dose level is still being tested. However, some delayed diarrhea,
nausea, vomiting, and severe asthenia have been observed. Among 50
evaluable patients, 2 complete response and 8 partial responses have
been achieved (overall response rate, 22%).
Irinotecan Plus Simplified LV/5-FU2 Regimen
An ongoing phase II study being performed by de Gramont et al under
the auspices of the GERCOD-MARMIHC French collaborative group is
testing the combination of irinotecan plus a simplified LV/5-FU2
regimen. The treatment plan is very similar to the LV/5-FU2
protocol described above, except the daily bolus of 5-FU is omitted.
This study is being conducted in colorectal cancer patients who have
been heavily pretreated (more than two previous chemotherapy
regimens). Although it is too early for results to be evaluated,
responses and disease stabilization apparently have been observed.
Among 34 evaluable patients, there have been 2 partial responses (6%).
Mitomycin is another active compound in the treatment of
gastrointestinal tract tumors, including advanced colorectal cancer.
A study evaluating the combination of mitomycin and irinotecan was
recently completed at the Salpêtrière Hospital in
Paris[11,12] in collaboration with Professor H. Bismuth and
colleagues at the Center for Hepatobiliary Disease, Paul Brousse
Hospital. This phase I/II study involved 26 patients with advanced
gastrointestinal tumors (22 with colorectal cancer, 2 with pancreatic
cancer, and 2 with cholangiocarcinoma). Four dose levels of
irinotecan/mitomycin were evaluated: 300/8, 325/8, 350/8, and 325/10 mg/m2.
Mitomycin was injected as an IV bolus, and irinotecan was
administered as a 90-minute infusion; cycles were repeated every 21 days.
The dose-limiting toxicity was hematologic; five cases of grade 3-4
neutropenia and two of grade 3-4 thrombocytopenia were observed among
six patients treated at the highest dose level. The recommended
doses, therefore, were 325 mg/m2 of irinotecan and 8 mg/m2
of mitomycin. Other toxicities included diarrhea, infection,
immunoallergic pneumopathy, and one case of delayed hemolytic-uremic syndrome.
Responses were observed at each dose level, although all but one
patient had been pretreated. There were a total of three complete
responses (at 6, 6, and 9 months, respectively) and three partial responses.
Several combination regimens tested in Europe during the past 2 years
have attempted to incorporate irinotecan into more classic cytotoxic
regimens for advanced colorectal cancer. These regimens have included
the combination of irinotecan with: (1) 5-FU alone, given as a bolus
or protracted infusion; (2) 5-FU modulated by folinic acid, using
different combinations of the two drugs; or (3) mitomycin.
In each of these studies, clinical activity has been observed in
patients with advanced disease, including those who had been heavily
pretreated. Response rates ranging from 29% to 61% have been
reported, with a few cases of complete remission. The toxicity of
these combinations seems to be relatively acceptable. Neutropenia and
gastrointestinal toxicities are the most frequently encountered side effects.
The superiority of these irinotecan-based combination regimens over
the same 5-FU or 5-FU/folinic acid regimens without irinotecan has
yet to be demonstrated, however. Several large, multicenter, phase
III studies have recently been initiated in Europe and other parts of
the world in order to confirm the potential benefit of these
combination regimens. The preliminary results of these studies should
be available within a year.
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randomized study of CPT-11 supportive care (SC) alone in patients
with 5-FU-resistant metastatic colorectal cancer (abstract). Proc Am
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2. Schweigert M, Mergenthaler HG, Possinger K: Randomized comparison
of irinotecan vs best-estimated 5-FU-containing chemotherapy for
second-line treatment of advanced colorectal cancer: Preliminary
report of a single center experience in a multicenter trial (ENG) and
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3. Benhammouda A, Bastian G, Rixe O, et al: A phase I and
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8. Ducreux M, Rougier P, Ychou M, et al: Phase I/II study of
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9. Rougier P, Ychou M, Seitz JF, et al: Phase I/II study of CPT-11 in
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10. Phase II GERCOD-MARMIHC CRC > 2 line chemotherapy (A. De
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Proc Am Assoc Cancer Res 38(3):304, 1997.
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