Irinotecan (CPT-11 [Camptosar]) is a novel semisynthetic analog of
camptothecin that has recently become commercially available and
continues to undergo extensive clinical evaluations. The unique
mechanism of action of this agent, topoisomerase I inhibition,
combined with preclinical studies assessing its efficacy and
toxicologic profile, suggested the possibility of schedule-dependent
antitumor and toxicologic effects.
In order to gain further insight into the potential
schedule-dependency of irinotecan, this article will review the
initial phase I studies that were conducted (Table
1). For simplicity, the studies have been grouped according to
country and then by administration schedule. Phase I schedules that
were explored initially can be grouped into single-dose,
intermittent, and prolonged-infusion regimens. Interestingly, the
irinotecan schedule favored for subsequent efficacy trials differed
among the regions: Whereas the single-dose infusion every 3 weeks was
used in France, both the United States and Japan selected a weekly regimen.
The principal toxicities noted for all of the administration
schedules were diarrhea and neutropenia (Table
2, Table 3, Table
4, and Table 5). In the
single-dose study in France, the institution of an intensive
loperamide regimen resulted in fewer episodes of serious diarrhea
requiring hospitalization, and this regimen has since become part of
standard supportive care.
Although the pharmacologic behavior of irinotecan will not be
reviewed in detail in this article, pharmacodynamic relationships
varied among the different studies and schedules (Table
6). Preliminary antitumor activity was noted in colon cancer
refractory to fluorouracil (5-FU) and advanced non-small-cell lung
cancer, as well as other tumors. An interesting phase I/II trial
conducted in Japan in patients with refractory or relapsed leukemia
or lymphoma revealed evidence of a schedule-dependent antitumor effect.
The results of the phase I trials of irinotecan reflect the unique
properties of this agent and should be used in choosing the optimal
schedule for future efficacy and combination studies.
One of the earliest schedules of irinotecan explored was a single
intravenous (IV) dose administered every 3 to 4 weeks. In a small
phase I study conducted in 17 patients in Japan, doses ranged from 25
to 350 mg/m² administered by a 30-minute IV infusion.
The principal dose-limiting toxicity (DLT) was leukopenia, which
appeared at doses ³ 100 mg/m²
and became dose-limiting at 350 mg/m². The leukopenia occurred
at approximately 7 days, with a median time to recovery of 16 days
after the nadir. In addition, diarrhea was reported. The recommended
phase II dose of 200 mg/m² was based on concerns about the
combination of leukopenia and diarrhea at doses ³
A second phase I study of irinotecan, conducted in France,
extensively explored a single-dose administration schedule. The
initial dose-finding portion of this trial included 64 patients
(median age, 51 years), most of whom (60/64, 94%) had received prior
therapy. The doses studied ranged from 100 to 750 mg/m²
administered by a 30-minute IV infusion every 3 weeks.
An acute cholinergic syndrome was reported, consisting predominantly
of gastrointestinal cramps and diaphoresis at doses
³ 260 mg/m², as well as salivation, visual
disturbances, and lacrimation at doses of 300 to 750 mg/m². This
syndrome occurred during and for 1 hour after the drug infusion.
Atropine (0.25 to 0.50 mg) administered subcutaneously ameliorated
these symptoms in two patients.
Noncumulative diarrhea, which began approximately 6 days after the
administration of irinotecan, became dose-limiting at 260 mg/m²,
and a regimen of intensive loperamide was instituted to allow for
further dose escalation. The high-dose loperamide regimen, which is
now standard, consisted of 2 mg orally at the first diarrheal
episode, followed by 2 mg every 2 hours until the patient had been
free of diarrhea for a 12-hour period. With the advent of this
regimen, the incidence of grade 3 or 4 diarrhea, which had been 50%
at 260 mg/m², remained < 20% until the 750-mg/m² dose
level, at which point neutropenia became dose-limiting.
Severe (grade 3 or 4) nausea and vomiting were uncommon (9%) in this
study. The only other common nonhematologic toxicity was asthenia,
which was reported in > 50% of patients at doses
³ 600 mg/m².
Hematologic toxicity, consisting of neutropenia, was the DLT of this
schedule. Neutropenia developed between days 6 and 9 of therapy, and
white blood cell count recovered in approximately 5 days. The
neutropenia exhibited both interpatient and intrapatient variability,
was noncumulative and resulted in complications primarily in patients
who were heavily pretreated or had bone metastases. Thrombocytopenia
was rare, and only two patients experienced grade 4 events.
The dose recommended for subsequent phase II studies was 350
mg/m², although it was suggested that a dose of 500 mg/m²
be explored further in a feasibility study using high-dose loperamide.
A total of 34 patients were assessable for response in this study.
Two complete responses (cervical and head and neck cancers) and six
partial responses (5-FU-refractory colon cancer) occurred, all in
previously treated patients.
The pharmacologic profile of irinotecan and its active metabolite,
SN-38, showed linear pharmacokinetics, long terminal half-lives (~14
hours) for both compounds, and a statistically significant
correlation between the area under the curve (AUC) of irinotecan and
that of SN-38 (r = 0.60; P < .001). Interestingly, irinotecan was
detected in saliva, sweat, and pleural fluid. In addition, the
appearance of plasma rebound concentrations of both irinotecan and
SN-38 suggested enterohepatic recirculation.
Pharmacodynamic analysis revealed a relationship between the extent
of neutropenia for both irinotecan and SN-38, whereas only diarrhea
up to grade 2 correlated with the AUCs of irinotecan and SN-38. Of
note, in the extension of this trial, performed to gain experience at
the 500- and 600-mg/m² dose levels, it was determined that 600
mg/m2 was not tolerated, resulting in grade 3 or 4 diarrhea or
neutropenia in 64% and 78% of patients, respectively. The
500-mg/m² dose was considered acceptable in minimally pretreated
patients, resulting in grade 3 or 4 diarrhea or neutropenia in 24%
and 41% of patients, respectively.
In a third single-dose study performed in the United States, 32
patients (median age, 49 years) were treated with 100 to 345
mg/m² of irinotecan administered as a 90-minute infusion. Of
the 32 patients, 30 had received prior therapy, and 13 of these were
considered heavily pretreated.
In contrast to the French and Japanese studies, the DLT in the US
study consisted of a constellation of severe hematologic and
nonhematologic events at doses ³ 290
mg/m². Gastrointestinal toxicity, consisting of nausea,
vomiting, anorexia, abdominal cramps, or diarrhea, became
particularly prominent at doses ³ 240
mg/m². The nausea and vomiting occurred and resolved primarily
in the peritreatment period, whereas anorexia persisted for 2 to 3
weeks in some patients, resulting in significant weight loss and a
decline in performance status.
Both early and late diarrhea occurred. The early form was associated
with cholinergic symptoms of diaphoresis and flushing, whereas the
late form occurred 2 to 7 days following treatment and was not
associated with these symptoms. A premedication regimen was
instituted at the 240-mg/m² dose level, consisting of
diphenhydramine 50 mg IV and ondansetron (Zofran) 0.15 mg/kg IV, both
administered prior to treatment and then every 4 hours for 2 doses.
Despite this premedication, irinotecan doses above 240 mg/m²
resulted in unacceptable gastrointestinal toxicity. An intensive
loperamide regimen was not used.
Both neutropenia and thrombocytopenia were prominent hematologic
toxicities, although they were rarely dose-limiting. The recommended
dose for subsequent trials of this schedule was 240 mg/m².
Three objective responses (all partial responses) were noted in this
trial, occurring in previously treated patients with colon, renal,
and cervical cancer.
The pharmacologic profile of irinotecan revealed linear
pharmacokinetic behavior over the dose range studied. The AUCs for
the lactone forms of irinotecan and SN-38 comprised 44% and 51% of
their respective total AUCs, whereas the mean AUC values for the
total and lactone forms of irinotecan were 12- to 34-fold higher than
the AUC values for the total and lactone forms of SN-38.
No pharmacodynamic relationship was established between the
gastrointestinal symptoms and the AUC of either forms of irinotecan
or SN-38. In contrast, the decrement in neutrophils correlated with
the exposure to total SN-38, but not to total or lactone irinotecan.
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