Irinotecan is a topoisomerase I inhibitor previously shown to be active in the treatment of malignant glioma. We now report the results of a phase 1 trial of irinotecan plus BCNU, or ...1,3-bis(2-chloroethyl)-1-nitrosourea, for patients with recurrent or progressive MG. Irinotecan dose escalation occurred independently within 2 strata: patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) and patients not receiving EIAEDs. BCNU was administered at a dose of 100 mg/m
2
over 1 h every 6 weeks on the same day as the first irinotecan dose was administered. Irinotecan was administered intravenously over 90 min once weekly. Treatment cycles consisted of 4 weekly administrations of irinotecan followed by a 2-week rest with dose escalation in cohorts of 3 to 6 patients. Seventy-three patients were treated, including 49 patients who were on EIAEDs and 24 who were not on EIAEDs. The maximum tolerated dose for patients not on EIAEDs was 125 mg/m
2
. The maximum tolerated dose for patients on EIAEDs was 225 mg/m
2
. Dose-limiting toxicity was evenly distributed among the following organ systems: pulmonary, gastrointestinal, cardiovascular, neurologic, infectious, and hematologic, without a clear predominance of toxicity involving any one organ system. There was no evidence of increasing incidence of toxicity involving one organ system as irinotecan dose was escalated. On the basis of these results, we conclude that the recommended doses of irinotecan for a phase 2 clinical trial when given in combination with BCNU (100 mg/m
2
) are 225 mg/m
2
for patients on EIAEDs and 125 mg/m
2
for patients not on EIAEDs.
In preclinical studies, BCNU, or 1,3-bis(2-chloroethyl)-1-nitrosourea, plus CPT-11 (irinotecan) exhibits schedule-dependent, synergistic activity against malignant glioma (MG). We previously ...established the maximum tolerated dose of CPT-11 when administered for 4 consecutive weeks in combination with BCNU administered on the first day of each 6-week cycle. We now report a phase 2 trial of BCNU plus CPT-11 for patients with MG. In the current study, BCNU (100 mg/m
2
) was administered on day 1 of each 6-week cycle. CPT-11 was administered on days 1, 8, 15, and 22 at 225 mg/m
2
for patients receiving CYP3A1- or CYP3A4-inducing anticonvulsants and at 125 mg/m
2
for those not on these medications. Newly diagnosed patients received up to 3 cycles before radiotherapy, while recurrent patients received up to 8 cycles. The primary end point of this study was radiographic response, while time to progression and overall survival were also assessed. Seventy-six patients were treated, including 37 with newly diagnosed tumors and 39 with recurrent disease. Fifty-six had glioblastoma multiforme, 18 had anaplastic astrocytoma, and 2 had anaplastic oligodendroglioma. Toxicities (grade ⩾3) included infections (13%), thromboses (12%), diarrhea (10%), and neutropenia (7%). Interstitial pneumonitis developed in 4 patients. Five newly diagnosed patients (14%; 95% CI, 5%–29%) achieved a radiographic response (1 complete response and 4 partial responses). Five patients with recurrent MG also achieved a response (1 complete response and 4 partial responses; 13%; 95% CI, 4%–27%). More than 40% of both newly diagnosed and recurrent patients achieved stable disease. Median time to progression was 11.3 weeks for recurrent glioblastoma multiforme patients and 16.9 weeks for recurrent anaplastic astrocytoma/anaplastic oligodendroglioma patients. We conclude that the activity of BCNU plus CPT-11 for patients with MG appears comparable to that of CPT-11 alone and may be more toxic.
To evaluate the prognostic significance of presence, intensity, and extent of amino acid uptake in patients with suspected primary or recurrent brain tumors.
We retrospectively analyzed 181 ...consecutive studies of amino acid uptake using single-photon emission computed tomography and the amino acid l-3-(123)Iiodo-alpha-methyltyrosine (IMT). In a blinded analysis, all studies were evaluated for presence, maximal uptake (IMT(max)), and extent (IMT(ext)) of focal tracer uptake.
The most frequent tumors were 53 astrocytomas (World Health Organization Grade I-III), 41 glioblastomas, 16 metastases, 13 oligodendrogliomas (Grade II-III), and 10 medulloblastomas. The other patients exhibited various parenchymal tumors or nonneoplastic lesions. IMT uptake was present in 69% of the patients with IMT(max) ranging from 1.4 to 6.2. IMT(max) and IMT(ext) were significant predictors of survival in the whole group. When the group was divided according to primary versus recurrent tumor, only the primary tumors achieved a high level of significance (P < 0.01). When patients without any IMT uptake were excluded from the analysis, statistical significance for both IMT(max) and IMT(ext) was lost. Multiple regression analysis, including IMT(max), IMT(ext), age, and tumor grade, revealed only extent of IMT uptake as an independent predictor of prognosis.
Absence of IMT uptake is a significant predictor of long-term survival in patients with suspected primary or recurrent brain tumors. Only the extent of a given lesion provided minor supplementary prognostic information as compared with histopathology and age. These findings suggest caution in relating high amino acid uptake values to poor prognosis, despite the capability of amino acid imaging to help determine the presence and extent of gliomas.
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