This study is the first to report use of an all-oral regimen of temozolomide and irinotecan. This strategy capitalizes on the known antineuroblastoma effects of these agents, the potential for schedule-dependent synergy and nonoverlapping toxicities, the more efficient conversion of oral irinotecan to SN-38 through first-pass metabolism, and the convenience and reduced cost of oral administration.
Previous attempts to administer oral irinotecan have been limited by relatively poor bioavailability, necessitating higher doses that resulted in dose-limiting diarrhea. Furman et al23
reported this toxicity may be ameliorated with daily cefixime, which allowed for a 50% increase in the MTD of protracted oral irinotecan, corresponding to an 87% increase in median SN-38 exposure. It is theorized that cefixime eradicates enteric Gram-negative bacteria, which produce glucuronidases that prolong gut exposure to the toxic metabolites of irinotecan. As seen previously,23
cefixime allowed for the achievement of SN-38 exposures similar to those seen with protracted intravenous irinotecan at its single-agent MTD.46
Importantly, we did not observe any infectious problems related to prolonged antibiotic therapy. Such theoretical complications could be further minimized if prophylaxis could be targeted to those at risk. However, our results did not show any correlation between UGT1A1
genotype and toxicity, consistent with a recent pediatric study.43
Other trials of oral irinotecan using different schedules are summarized in . Irinotecan for those studies was supplied as either a powder-filled capsule,24,27,30
a semi-solid matrix,26,28,29
or, as done in this study, with the intravenous formulation diluted in cranberry-grape juice.23,25
There have been no direct comparisons of pharmacokinetic properties between these formulations. Comparison of drug exposures between studies is difficult because of interpatient variability and the use of different assays and sampling schedules. However, because SN-38 exposures with protracted administration generally increase with higher dosages,23,30
and because preclinical antitumor activity of oral irinotecan also increases in a dose-dependent fashion,47
it is intuitive that higher irinotecan doses may be optimal. Only our study and that of Furman et al23
used cephalosporin prophylaxis against irinotecan-associated diarrhea, and both regimens were able to achieve doses providing up to 140% more oral irinotecan per 21-day course. A caveat to this finding is that these two trials were performed in children, who may be able to tolerate higher doses of chemotherapy compared with adults, many of whom had colon cancer.
Previous Phase I Trials Using Oral Irinotecan in 3-Week Courses
Toxicity attributable to therapy on this trial was minimal. There was no grade 4 toxicity in six patients receiving 29 courses of therapy at the MTD. In addition, there were minimal infections or requirements for transfusions or filgrastim. The relative tolerance of this drug combination has also been reported in other studies.19,20,35
Considering the favorable pharmacokinetic exposures achieved and the likelihood of greater toxicity with higher irinotecan dosages,23
we recommend 60 mg/m2
/d of irinotecan for further study of this combination. It is possible the temozolomide dose of 75 mg/m2
/d, which compares to 200 mg/m2
/d in single-agent trials,16,45
could be increased in less heavily pretreated patients or by using filgrastim.48
However, preclinical synergy is seen even with relatively low temozolomide dosages,3
and higher dosages combined with irinotecan are of unknown additional benefit and may result in treatment delays and dose reductions.15,48
In this trial, six (43%) of 14 patients remained progression-free through at least six courses, including one patient with a complete response. The ongoing COG phase II trial of temozolomide and intravenous irinotecan for first relapse high-risk neuroblastoma should provide a more accurate estimate of the activity of this regimen, as well as a comparison to historical controls treated with cyclophosphamide and topotecan, which is standard first-line salvage therapy that had already been administered to 79% of patients in this study. Although both are camptothecin agents, topotecan and irinotecan may have different mechanisms of resistance.49
Because cyclophosphamide/topotecan is now used in front-line COG induction regimens, potentially non–cross-resistant agents like temozolomide and irinotecan are attractive for either maintenance or salvage therapy.
A recent randomized trial in patients with rhabdomyosarcoma suggested that a 5-day schedule of irinotecan combined with vincristine was as efficacious and tolerable as the more protracted schedule used in our study.50
On the basis of these data, the COG is now evaluating a 5-day course of oral irinotecan together with temozolomide and vincristine. If feasible, this schedule would be more convenient. Results from a recent study using temozolomide concurrent with 5 days of intravenous irinotecan support a shorter irinotecan schedule, because complete and partial responses were seen in patients with relapsed or refractory high-risk neuroblastoma.48
In conclusion, this all-oral regimen was safe and had activity in heavily pretreated patients with relapsed/refractory high-risk neuroblastoma. Oral antibiotic prophylaxis allowed for SN-38 systemic exposures similar to that observed after intravenous irinotecan administration. This combination could serve as a backbone for adding other synergistic drugs such as vincristine, bortezomib, or O6
and may be explored in other cancers as well. For patients with neuroblastoma, this all-oral regimen is attractive because of convenience and tolerability, particularly if activity is confirmed in the ongoing COG phase II trial.