NEW HAVEN, ConnecticutThe combination of irinotecan (Camptosar)
and a taxane is well tolerated in dose-finding studies and deserves
further evaluation in nonsmall-cell lung cancer, according to
Randy S. Rich, MD, of Yale University School of Medicine.
Continued evaluation of nonplatinum regimens is warranted,
Dr. Rich stated. They should be better tolerated than platinum
regimens, and possibly more effective.
Dr. Rich and colleagues have conducted two dose-finding studies to
identify optimal doses of irinotecan plus paclitaxel (Taxol) and
irinotecan plus docetaxel (Taxotere) in patients with histologically
confirmed malignancies. The irinotecan plus paclitaxel study was
followed by a phase II investigation.
The rationale for these investigations of nonplatinum regimens,
according to Dr. Rich, includes the known toxicities of platinum
regimens, the noted single-agent activity of new drugs such as
irinotecan, and the superior activity of the new agents when they are
included in platinum regimens.
Two Paclitaxel Studies
In one initial study, 21 patients with histologically confirmed solid
malignancies and no other available treatment options, were treated
at recommended doses of irinotecan 50 mg/m²/week (two of the
patients received irinotecan 65 mg/m²/week) plus paclitaxel 75
mg/m²/week. All patients had Eastern Cooperative Oncology Group
(ECOG) performance status of 0 or 1. The patients had a variety of
malignancies, including four nonsmall-cell lung cancers.
Irinotecan was infused over 90 minutes and then followed immediately
by a paclitaxel infusion over 1 hour. Chemotherapy was administered
weekly for 4 weeks with a 2- week resting period.
The sequence of drug administration was reversed on the second cycle.
This did not produce significant differences in the pharmacokinetics
of irinotecan or SN-38 among patients subject to pharmacokinetic
studies, suggesting a lack of drug interactions.
Of the 21 patients, 1 had a partial response and 5 had stable
disease. The dose-limiting toxicity of the irinotecan/paclitaxel
combination was neutropenia, which caused dose delays. Nonhematologic
toxicity was acceptable.
A subsequent phase II trial of irinotecan plus paclitaxel in
histologically confirmed stage IIIB or IV nonsmall-cell lung
cancer showed similar results. None of the nine patients enrolled in
the study had prior chemotherapy. All received paclitaxel 75 mg/m²
infused over 1 hour, followed immediately by irinotecan 50 mg/m²
infused over 30 minutes (escalation to 60 mg/m² was allowed if
well tolerated on the previous cycle).
At the time of analysis, 48 cycles had been delivered. Irinotecan was
escalated in four patients and reduced in one due to gastrointestinal toxicity.
Also evaluated was the combination of irinotecan plus docetaxel in a
variety of malignancies for which no treatment was available. Again,
chemotherapy was administered weekly for 4 weeks with a 2-week
In this phase-I study, 26 patients with histologically confirmed
solid malignancies were enrolled and treated with irinotecan 50
mg/m²/week and docetaxel at 25, 30, 35, or 40 mg/m²/week.
Dose-limiting toxicities were low-grade gastrointestinal toxicity and
asthenia. Neutropenia of grade 3 or higher was seen in less than 10%
of treatment cycles. Investigators determined that the maximum
tolerated dose of docetaxel on this schedule was 35 mg/m²/dose.
Dose intensification of docetaxel may be possible with further
modification of the schedule, Dr. Rich concluded.