Temozolomide with Radiation Therapy in High Grade Brain Gliomas: Pharmaceuticals Considerations and Efficacy;A Review Article

Abstract

Malignant gliomas (glioblastoma multiforme and anaplastic astrocytoma) which have a combined incidence of 5–8/100,000 population, represent the most common primary central nervous system tumors. The treatment outcomes even with aggressive approach including surgery, radiaton therapy and chemotherapy are dismal with median reported survival is less than 1 year. Temozolomide is a new drug which has shown promise in treating malignant gliomas and other difficult-to-treat tumors. This drug is a per os (p.o) imidazotetrazine second-generation alkylating agent which represents the leading compound in a new class of chemotherapeutic agents that enter the cerebrospinal fluid and do not require hepatic metabolism for activation. The efficacy of temozolomide was tested in vitro studies and has demonstrated schedule-dependent antitumor activity against highly resistant malignancies, including high-grade glioma (HGG). In addition, in clinical studies, temozolomide consistently demonstrates reproducible linear pharmacokinetics with approximately 100% p.o. bioavailability, noncumulative minimal myelosuppression that is rapidly reversible, and activity against a variety of solid tumors in both children and adults. Moreover, preclinical studies have evaluated the combination of temozolomide with other alkylating agents and inhibitors of the DNA repair protein O6-alkylguanine alkyltransferase to overcome resistance to chemotherapy in malignant glioma and malignant metastatic melanoma. At the present time temozolomide is approved in the United States for the treatment of adult patients with refractory anaplastic astrocytoma and, in the European Union, for treatment of glioblastoma multiforme showing progression or recurrence after standard therapy. Temozolomide’s characteristics which make it a candidate for a wide range of clinical testing to evaluate the potential of combination treatments in different tumor types are its predictable bioavailability and minimal toxicity. An overview of the mechanism of action of temozolomide and a summary of results from more important randomized controlled clinical trials in high grade gliomas are presented here.

Temozolomide with or without Radiotherapy in Patients with Newly Diagnosed Glioblastoma Multiforme: A Meta-Analysis

“…Similarly, the TMZ-induced enhanced radiation response is shown to be due to an increased degree of radiation-induced double-strand DNA damage, which is more prominent in MGMT-negative glioblastomas [27]. Several reports indicate that methylation of the MGMT promoter is the strongest predictor of outcome and benefit in TMZ chemotherapy [6,12,18,28,29]. …”

“…The situation changed in the 1970s when temozolomide (TMZ) was discovered [11]. TMZ is an oral chemotherapeutic drug that induces DNA methylation and tumor cytotoxicity through cell cycle arrest [12,13]. Furthermore, it exhibits a linear pharmacokinetics with excellent bioavailability, readily enters the cerebrospinal fluid, and it does not require hepatic metabolism for activation [12].…”

“…TMZ is an oral chemotherapeutic drug that induces DNA methylation and tumor cytotoxicity through cell cycle arrest [12,13]. Furthermore, it exhibits a linear pharmacokinetics with excellent bioavailability, readily enters the cerebrospinal fluid, and it does not require hepatic metabolism for activation [12]. Stupp et al [14] demonstrated that a combination of TMZ with postoperative radiation prolonged the overall survival compared to radiation alone.…”

Subcutaneous malignant melanoma of the scalp surgical flap after brain irradiation for anaplastic astrocytoma

“…Radio-chemotherapy is a standard adjuvant treatment for malignant brain gliomas (BGs) [1][2][3][4][5][6][7], although arteritis, radionecrosis, leukoencephalopathy, and secondary malignant tumours (SMTs) originating from surrounding tissues, which inevitably absorb ionizing radiation (IR), are possible late effects [8][9][10][11][12][13][14].…”

Molecular biomarkers for prognosis and optimal treatment strategy of glioblastomas

“…Пðåïàðàò îäîбðåí â США äëя ëåчåíèя àíàïëàñ-òèчåñêîé àñòðîöèòîмы, â Яïîíèè -ãëèîбëàñòîмы, â ñòðàíàх Еâðîïåéñêîãî ñîюзà -ïðîäîëaeåííîãî ðîñòà ãëèîбëàñòîмы, ïðàêòèчåñêè ïîëíîñòüю âыòåñíèâ ïðåïàðàòы íèòðîзîмîчåâèíы [22]. Тàêèм îбðàзîм, мы ðàññмàòðèâàåм ñхåмó îïåðàöèя+ðàäèîòåðàïèя +òåмîзîëàмèä.…”