Temozolomide after Radiotherapy for Newly Diagnosed High-grade Glioma and Unfavorable Low-grade Glioma in Children

Abstract

Chemotherapy is commonly used in the treatment of children with high-grade glioma, although its usefulness is uncertain. We conducted a multi-institutional study to evaluate the efficacy of temozolomide given after radiotherapy in children with newly diagnosed high-grade glioma and unfavorable low-grade glioma (gliomatosis cerebri or bithalamic involvement). Optional window therapy of intravenous irinotecan (10 doses of 20 mg/m2 per cycle x 2) was given over 6 weeks. The 5-day schedule of temozolomide (200 mg/m2 per day) started 4 weeks after the completion of radiotherapy and continued for a total of 6 cycles. Thirty-one eligible patients (median age: 12.3 years) participated. Tumors most commonly involved cerebral hemispheres (n = 13, 42%) and thalamus (n = 14, 45%). Whereas six patients underwent radical resection, the remainder had limited surgery, including biopsy (n = 14, 45%). The predominant histologic diagnoses were glioblastoma multiforme (n = 15, 48%) and anaplastic astrocytoma (n = 10, 32%). Two patients had bithalamic grade II astrocytoma. Twenty-seven patients received radiotherapy (median dose: 59.4 Gy), including craniospinal irradiation in 3 because of leptomeningeal spread. Four patients did not receive radiotherapy in this study because of consent withdrawn (n = 2), toxicity during window therapy (n = 1), or at the physician's discretion (n = 1). Twenty-three patients received 112 cycles of temozolomide therapy. The 2-year progression-free and overall survival estimates were 11 +/- 5% and 21 +/- 7%, respectively. Although the heterogeneity of prognostic factors in our patients made assessment of treatment outcome more difficult, the addition of 6 cycles of temozolomide after radiotherapy did not seem to alter the poor outcome of these patients.

Clinical Experience with Glioblastoma Multiforme in Pediatric Patients

“…They reported that the 3-year EFS (eventfree survival) rate for GBM was 7% ± 4% in the children's oncology group study ACNS0126 compared with 15% ± 5% in the Children's Oncology Group study CCG-945. These results that temozolomide had no superiority to conventional treatments were reported as well in another study (7).…”

Immediate Induction and Consolidation Therapy May Improve Outcomes for Patients with Anaplastic Astrocytoma: a Case Series

“…While initial trials by the CCG demonstrated improvements in PFS in patients treated with a combination of chemotherapy and radiation after resection, later trials were unable to replicate the initial findings [2,11,15]. Lack of new chemo-therapeutic combinations in the immediate postresection stage has kept the 5-year overall survival from high grade astrocytomas between 10-20% [1,3,16].…”

“…Initial trials by the Children's Cancer Group (CCG) in children with HGG treated with post-radiation chemotherapy (vincristine, lomustine and predinose) had an improved progression free survival (PFS) of 46% compared to 26% of those treated with radiation alone [15].Despite these initial findings, successive chemotherapeutic trials were unable to significantly improve outcomes [3,11]. Promising data has been published in adult patients with HGG treated with the methylating agent Temozolamide when administered with concurrent radiation therapy, suggesting a role for adjuvant chemotherapy in pediatric patients as well although subsequent trials have been slow to demonstrate similar improvement [1]. Recent trials in adults with recurrent glioblastoma multiforme have shown that the combination of Bevacixumab and Irinotecan have improved 6 month PFS was 46% and overall survival (OS) at 6 months of 77% [19].…”

Treatment of high-grade glioma in children

“…[17] Erişkin GBM'li hastalarda Temozolomide'nin (TMZ) etkinliği gösterildikten sonra, birçok pediatrik çalışma bu tedavi protokolünü denemiş ancak benzer yaşam sürelerini gösterememiştir. [18][19][20] St Jude Çocuk Hastanesi'nde (SJHG98 study) yapılan çalışmada RT sırasında ve sonrasında TMZ verilen 31 yeni tanılı YDG'lu çocukta (GBM=15; AA=10; diğer YDG=4), 2 yıllık OS ve yaşam sü-resi sırasıyla %11±%5 ve %21 ±%7 olarak sonuç-lanmıştır. [19] COG'nin yeni tanılı YDG'lu hastalarda yaptğı en kapsamlı çalışmada (ACNS0126 çalışması), 99 hastaya (55 GBM, 31 AA ve 4 diğer YDG), RT (54Gy+boost 5.4 Gy) sırasında TMZ (90 mg/m 2 /g 42 gün) ve 4 hf dinlenme sonrasında TMZ 200 mg/m 2 /g x 5 g 28 g bir x 10 kür uygulanmıştır.…”

“…[18][19][20] St Jude Çocuk Hastanesi'nde (SJHG98 study) yapılan çalışmada RT sırasında ve sonrasında TMZ verilen 31 yeni tanılı YDG'lu çocukta (GBM=15; AA=10; diğer YDG=4), 2 yıllık OS ve yaşam sü-resi sırasıyla %11±%5 ve %21 ±%7 olarak sonuç-lanmıştır. [19] COG'nin yeni tanılı YDG'lu hastalarda yaptğı en kapsamlı çalışmada (ACNS0126 çalışması), 99 hastaya (55 GBM, 31 AA ve 4 diğer YDG), RT (54Gy+boost 5.4 Gy) sırasında TMZ (90 mg/m 2 /g 42 gün) ve 4 hf dinlenme sonrasında TMZ 200 mg/m 2 /g x 5 g 28 g bir x 10 kür uygulanmıştır. [20] CCG-945 çalışmasıyla karşılaştırıldı-ğında üç yıllık OS ve yaşam süreleri bakımından aralarında hiçbir fark bulunamamıştır.…”