Children and young adults with recurrent or treatment-induced malignant gliomas have limited responses to temozolomide or oral VP-16 when either is administered as a single agent. We postulated that a combination of these two drugs for patients with recurrent or treatment-induced malignant gliomas might result in better and more prolonged responses. A retrospective analysis was performed on patients treated with the combination of temozolomide and VP-16.
Eleven patients with recurrent or treatment-induced malignant gliomas were treated with varying combinations of temozolomide (150-210 mg/m2/d for 5 days) and oral VP-16 (50 mg/m2/d for 4-12 days). Responses were assessed by MRI scan, and data on clinical course and toxicity were retrospectively obtained from the medical record.
The median age of the 11 patients was 17 years (range 5-23 years). Diagnoses included recurrent brain stem glioma (2), recurrent anaplastic astrocytoma (2), and glioblastoma (7) (3 treatment-induced, 2 malignant transformations of lower grade tumors, 1 recurrence, and 1 second tumor arising 10 months after diagnosis of medulloblastoma). All 11 patients had received radiotherapy (including 4 who received craniospinal radiation), and 7 had prior chemotherapy. Nine patients were treated at first recurrence, two at second recurrence. One patient had a complete response (CR), six had partial responses (PR), and four had progressive disease (PD). The median progression-free survival for the seven responding patients was 6 months (range 4-15+ months). There was one grade 4 neutropenia, but no other grade 3 or 4 toxicities.
These data suggest there is activity of temozolomide in combination with oral VP-16 for children and young adults with recurrent malignant gliomas.
"TMZ has been also administered with the topoisomerase II inhibitor etoposide that, similarly to TMZ, penetrates the blood-brain barrier, is orally bioavailable and has activity against brain tumors. This drug combination has shown promising activity in pediatric and adult patients with recurrent or treatment-induced malignant gliomas  . "
[Show abstract][Hide abstract] ABSTRACT: Temozolomide (TMZ) is an oral anticancer agent approved for the treatment of newly diagnosed glioblastoma in combination with radiotherapy. Moreover, TMZ has shown comparable efficacy with respect to dacarbazine, the reference drug for metastatic melanoma. Due to its favorable toxicity and pharmacokinetic profile, TMZ is under clinical investigation for brain metastasis from solid tumors and refractory leukemias. TMZ interacts with DNA generating a wide spectrum of methyl adducts mainly represented by N-methylpurines. However, its antitumor activity has been mainly attributed to O(6)-methylguanine, since tumor cell sensitivity inversely correlates with the levels of O(6)-alkylguanine DNA alkyltransferase and requires an intact mismatch repair system. Therefore, an increasing number of studies have been performed in order to identify patients who will benefit from TMZ treatment on the basis of their molecular/genetic profile. Unfortunately, resistance to the methylating agent occurs relatively often and strongly affects the rate and durability of the clinical response in cancer patients. Thus, different approaches have been developed to abrogate resistance or to increase the efficacy of TMZ and for many of them investigation is still underway. Herein, we provide an overview on the recent findings of preclinical and clinical studies on TMZ in combination with inhibitors of DNA repair, chemotherapeutic drugs with different mechanisms of action or radiotherapy, anti-angiogenic agents and other biological modulators.
Current Medicinal Chemistry 02/2009; 16(2):245-57. DOI:10.2174/092986709787002718 · 3.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Reports of secondary high-grade glioma (HGG) in survivors of childhood cancer are scarce. The aim of this study was to review the pattern of diagnosis, the treatment, and outcome of secondary pediatric HGG.
We performed a multi-center retrospective study among the 17 paediatric institutions participating in the Canadian Pediatric Brain Tumour Consortium (CPBTC).
We report on 18 patients (14 males, 4 females) treated in childhood for a primary cancer, who subsequently developed a HGG as a second malignancy. All patients had previously received radiation therapy +/- chemotherapy for either acute lymphoblastic leukaemia (n=9) or solid tumour (n=9). All HGG occurred within the previous radiation fields. At the last follow-up, 17 patients have died and the median survival time is 9.75 months.
Although aggressive treatment seems to provide sustained remissions in some patients, the optimal management is still to be defined. Further documentation of such cases is necessary in order to better understand the pathogenesis, the natural history and the prevention of these tumours.
Radiotherapy and Oncology 11/2006; 81(1):33-8. DOI:10.1016/j.radonc.2006.08.005 · 4.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Malignant gliomas are the most fre- quent primary brain tumors in adults. Temozolo- mide is an oral alkylating cytotoxic agent of second generation, used in the treatment of high- grade gliomas. It is indicated in newly diagnosed glioblastoma multiform as well as in recurrent or progressive malignant gliomas, such as glioblas- toma multiform or anaplastic astrocytoma. Howe- ver, temozolomide is also used, off label, in other clinical situations and the main objective of this study was to establish recommendations and guide- lines for relevant prescriptions of temozolomide in primary brain tumors and brain metastasis in adults. The literature review was analysed by experts who determined the evidence level (A to E) according to the scale of recommendations adopted by the "Haute Autorité de santé - HAS - (French National Authority for Health)". For high-grade and low- grade gliomas, based on the level of evidence from the literature, the use of temozolomide can be justified, with a B2 score attributed to these indi- cations. In contrast, for the others indications, the use of temozolomide appeared to be more contro- versial or even not recommended (score C to E). Regarding the dosing schedule and administration scheme, as well as the co-administration with other anticancer drugs, a C score was attributed for the off label situations.▲
Note: This list is based on the publications in our database and might not be exhaustive.
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