Four factors must be taken into account in the development of new
methods of administration for a topoisomerase I inhibitor (Table
1), such as irinotecan hydrochloride (CPT-11 [Camptosar]).
First, the dosing schedule should optimize biological effects
resulting in topoisomerase inhibition. These include not only
exposure of the cells to the topoisomerase I inhibitor during the
S-phase of the cell cycle and prolonged stabilization of the
cleavable complex, but also periodic release of inhibition to avoid
the downregulation of cellular topoisomerase I levels as a mechanism
for drug resistance.
The second factor that should be considered is camptothecin pharmacology.
In the case of irinotecan, this would mean selection of a dosing
schedule that generates the highest (and potentially most effective)
plasma and intracellular levels of SN-38, the active metabolite of
irinotecan. The schedule would also take into account ways in which
the conversion of irinotecan to SN-38 could be maximized and the
balance between SN-38 and its inactive metabolite, SN-38 glucuronide
(SN-38G) could be optimized.
The third consideration in selecting a schedule of drug
administration is toxicity. Some schedules may be associated with
less severe (or different) toxicity profiles without a loss of efficacy.
Lastly, pragmatic factors should be taken into account, including the
regimens cost, convenience, and ease of compliance. An
additional pragmatic consideration is how well the schedule
accommodates other drugs and/or modalities, such as radiation, that
will be given with irinotecan.
Since the introduction of irinotecan into clinical trials more than a
decade ago, a number of clinical strategies have been pursued in an
attempt to identify the schedule with the optimal balance between
clinical activity, safety, and convenience. The two schedules that
have been used most often in phase II and III testing are: (1) the
weekly schedule (most popular in the United States and Japan), in
which the drug is administered once a week for 4 consecutive weeks,
followed by 2 weeks of rest; and (2) the once-every-3-week schedule
(the most commonly used schedule in Europe).
Irinotecan, like all of the camptothe- cins, is considered a
cell-cycle-specific drug. The lethal lesion is created when the DNA
replication fork collides with a single-strand DNA break that has
been created by topoisomerase I and has been stabilized (ie, not
allowed to reseal) by the camptothecin analog. When the replication
fork encounters the stabilized cleavable complex, the single-strand
break is converted into an irreversible--and lethal--double-strand
DNA break. This is referred to as the "fork-collision"
model. Given that cells must be in S-phase of the cell cycle for the
fork collision to occur and that, at any given time, only a small
percentage of cells are in S-phase, one could argue that more
frequent (ie, weekly) dosing would be most desirable.
On the other hand, many drugs, including irinotecan, have a clear
dose-response relationship in vitro. This suggests that irinotecan
should be given at the highest single dose possible in order to
achieve maximal antitumor effect. This approach has been taken in the
development of irinotecan in Europe, where the drug is most commonly
administered at a dose of 350 mg/m² once every 3 weeks. In
addition to exploiting the dose-response relationship, this approach
has the added advantage of greater patient convenience, as it entails
less frequent dosing than is required on a weekly schedule.
As our knowledge of and experience with topoisomerase I inhibitors
have increased, several new routes and schedules of drug
administration have been explored in phase I trials.
Protracted Intravenous Dosing Schedule
One strategy that has been tested recently is a protracted
intravenous (IV) dosing schedule. Since the DNA-topoisomerase I
cleavable complex is readily reversible, and the plasma half-life of
SN-38, the active metabolite of irinotecan, is 13 to 15 hours, daily
dosing may approximate the level of topoisomerase I inhibition
achievable with continuous infusion but without the requirement for a
central line or infusion pump. In addition, lower doses of
irinotecan, given more frequently, could allow more complete
glucuronidation to take place and result in decreased toxicity.
Lastly, in vitro and in vivo data suggest that camptothecin analogs
may have enhanced activity and reduced toxicity when lower doses are
administered more frequently.[7,8]
Saltz and colleagues from Memorial Sloan-Kettering Cancer Center
performed a phase I trial in which patients were given intravenous
irinotecan on a daily × 5 basis. When the starting dose of 10
mg/m²/d for 5 days every 3 weeks proved to be tolerable, the
duration of treatment was extended to 2 weeks, with treatment given
on a Monday-through-Friday schedule (ie, 5 days on, 2 days off) every
3 weeks. A total of 21 patients were treated at dose levels of 10 to
22 mg/m2/d. Late-onset, grade 3 diarrhea and neutropenic
fever were the dose-limiting toxicities (DLTs) at the 22-mg/m2/d
dose level. Two patients with colorectal cancer had objective
partial responses, and an additional six patients (five with
colorectal cancer and one with soft-tissue sarcoma) achieved stable
disease as their best response. The maximum tolerated dose
(MTD)/recommended phase II dose was determined to be 17 mg/m2
in heavily pretreated patients.
A follow-up study combining this daily IV dosing schedule with pelvic
radiation in patients with locally advanced rectal cancer has been initiated.
Two ongoing trials are examining the toxicity and tolerability of
low-dose, daily IV irinotecan in children. The Pediatric Oncology
Group is evaluating irinotecan given daily × 5 every 3 weeks,
while researchers at St. Jude Childrens Research Hospital are
testing a daily × 5 schedule given every week for 4 consecutive
weeks, followed by a 2-week rest. Both studies are performing
detailed pharmacokinetic assessment.
An alternative approach with a similar rationale is being explored in
an ongoing phase I trial at the National Cancer Institute. In this
trial, irinotecan is being given as a 96-hour continuous IV infusion
for 2 out of 3 weeks.
Every-Two-Week Dosing Schedule
The finding of similar antitumor activity, but slightly different
toxicity profiles, with the weekly and every-3-week schedules piqued
interest in administering irinotecan once every 2 weeks to determine
whether toxicity could be modified while antitumor activity was
retained. A total of 51 patients were treated with irinotecan at dose
levels ranging from 125 to 325 mg/m2 administered every 2
weeks. Of the 51 patients, 41 (80%) had received prior chemotherapy
and 20 (40%), prior radiation. The median number of prior
chemotherapy regimens was 3 (range, 1 to 10).
Dose-limiting toxicity, in the form of grade 4 neutropenia and fever,
occurred in two of two patients treated at the 300-mg/m2 dose
level. The study was amended to include granulocyte
colony-stimulating factor (G-CSF, filgrastim [Neupogen]), 5 mg/kg
subcutaneously on days 2 through 13. A second DLT of delayed, grade 3
diarrhea (one patient) and grade 3 vomiting despite optimal
antiemetics (one patient) was defined for irinotecan at 325 mg/m2
every 2 weeks (with G-CSF).
Non-dose-limiting grade 3 vomiting (acute and delayed) occurred at
the 275-mg/m2 dose level. A serotonin antagonist plus
dexamethasone given before and for 3 days after chemotherapy
effectively prevented this toxicity. Grade 3 diarrhea occurred in
only 1 of 10 patients treated at the MTD/recommended phase II dose of
irinotecan of 250 mg/m2 (without G-CSF) and in none of 6
patients treated at the MTD/recommended phase II dose of irinotecan
of 300 mg/m2 (with G-CSF).
Pharmacokinetic analysis revealed a linear relationship between
irinotecan dose and area under the concentration-time curves (AUCs)
for irinotecan and, to a lesser extent, SN-38, suggesting that the
peripheral conversion of irinotecan to SN-38 is not saturated at
these doses. The AUC for SN-38G appeared to increase with irinotecan
dose, suggesting that hepatic glucuronidation is not saturated at
doses up to 325 mg/m2.
Severe diarrhea was not a frequent toxicity with this schedule. No
pharmacodynamic relationship between diarrhea and the AUCs for
irinotecan, SN-38, or SN-38G was identified, and biliary index did
not predict the occurrence of grade 3 or 4 diarrhea. Two patients
with recurrent colorectal cancer achieved partial responses, lasting
6.8 and 13.4 months, and 26 patients had stable disease as their best response.
Although the spectrum of toxicity with the every-2-week schedule
appeared to be similar to that observed with other irinotecan
schedules, neutropenia and vomiting appeared to be more common in
this trial, while delayed diarrhea seemed to be less common. The
every-2-week schedule has now been tested in a phase II trial in
patients with fluorouracil-refractory colorectal cancer and has
demonstrated antitumor activity similar to that attained with a
weekly or every-3-week schedule.
Oral Dosing Schedule
As noted above, low-dose, daily administration of irinotecan has been
shown to be more effective and less toxic than higher-dose,
intermittent administration in vitro and in vivo.[7,8] However, the
oral route of administration has several additional advantages.
First, the oral route takes advantage of low gastric pH, which may
favor retention of the drug in the active lactone ring configuration.
Second, high concentrations of tissue carboxylesterases in the liver
and gut should promote presystemic conversion of irinotecan to SN-38.
This, coupled with the first-pass effect, should result in high
concentrations of SN-38 in the liver, the most common site of colon
cancer metastases. Lastly, the oral route should provide a
convenient, cost-effective option for protracted dosing of irinotecan.
A phase I trial of short-course, oral irinotecan has now been
completed. [Drengler RL et al, unpublished data, 1998] In this trial,
the intravenous preparation of irinotecan was administered orally
once daily for 5 consecutive days every 3 weeks. The safety,
pharmacokinetics, and antitumor activity of irinotecan were assessed
in 28 patients.
Late-onset, grade 4 diarrhea, with or without concomitant grade 4
neutropenia, was the DLT. Different MTDs were defined for patients
above and below the age of 65 years; the MTD (and recommended phase
II dose) was 66 mg/m2/d for patients < 65 years old and
50 mg/m2/d for those ³ 65
Several provocative observations were made regarding the
pharmacokinetic behavior of irinotecan given by the oral route. There
was an association between irinotecan dose and SN-38
pharmacokinetics, implying that there was no saturation of the
enzymes responsible for the conversion of irinotecan to SN-38 when
irinotecan was administered orally. There was a very high ratio of
SN-38 AUC (both the total and glucuronide forms) to irinotecan AUC,
suggesting that the oral route resulted in substantial presystemic
conversion of irinotecan to SN-38. Lastly, more than two thirds of
all the SN-38 present during the first 24 hours following drug
administration was detectable in the active lactone ring form.
In addition to these important pharmacokinetic observations, clinical
antitumor activity was also observed. One patient with previously
treated colorectal cancer and liver metastases achieved a confirmed
partial response, and an additional 17 patients experienced stable
disease lasting from 2.5 to 14.7 months.
Several follow-up phase I studies using an encapsulated oral form of
irinotecan have now been initiated.
The sound scientific rationale for exploring alternative dosing
routes and schedules of irinotecan is being borne out by the data
emerging from phase I trials. Although the spectrum of
toxicity seen with new routes and schedules of administration does
not appear to differ from that observed with the more traditional
administration schedules, the relative frequency and severity
of irinotecan-induced toxicities seem to vary with different
routes and schedules.
Antitumor activity has been observed in phase I trials using these
newer approaches. As we gain more experience with the newer routes
and schedules of drug administration, we can expect to see the
emergence of more convenient, more effective combination chemotherapy
and combined-modality treatment regimens using irinotecan.
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