Abstract
Purpose: Radiotherapy with concurrent temozolomide (TMZ), followed by 6 cycles of adjuvant TMZ, is the standard of care for newly diagnosed Glioblastoma Mulltiforme (GBM). However tumor progression is the role with median survival of almost 14 months. With lack of effective second line chemotherapy, many physicians and some guidelines advocate prolonged use of adjuvant TMZ more than 6 months. We conduct this study to test the efficacy of protracted adjuvant conventional dose TMZ over the standard 6 doses of adjuvant TMZ. Material and Methods: This phase II trial enrolled patients newly diagnosed as GBM, older than age 18 years, with a Karnofsky performance score (KPS) of ≥60, Neurological Performance Scale (NPS) of ≤3. Patients were randomly assigned to the standard concurrent chemoradiotherapy (CCRT) followed by 6 cycles of adjuvant TMZ or the same treatment with more than 6 cycles of adjuvant chemotherapy extended as long as the patient in good performance, with no unacceptable toxicity, no signs of disease progression. The primary end point was OS. Results: A total of 59 patients were recruited in the study and were randomized in two arms. 29 patients joined arm 1 aiming at receiving CCRT followed by adjuvant 6 cycles TMZ (6 cycles arm) and 30 joined arm 2 aiming at receiving the same treatment with more than 6 cycles of TMZ (>6 cycles). 16 patients managed to complete the adjuvant 6 cycles in arm 1. 19 patients in arm 2, completed the 6 cycles with additive more doses with a median of 11 cycles (range: 8 - 23 cycles). Median PFS was 12.1 months for (6 cycles) arm, and 18.8 months for (>6 cycles) arm, HR 0.88 (95% CI: 1.185 - 4.901) (P 0.015); the overall survival for (6 cycles) arm was 18.1 months, versus 24.1 months, HR 0.70 (95% CI: 1.007 - 4.037) (P 0.048). No significant added toxicity was notice and the 4 weekly TMZ was well tolerated. Conclusion: This study concluded that protracted adjuvant TMZ after concurrent chemoradiotherapy could be a feasible strategy for GBM. This strategy warrants a large phase III randomized trial.
Highlights
Gliomas are the most common form of malignant primary brain tumors in adults, with an annual incidence of approximately four to five per 100,000 people [1]
Stupp and colleagues (2005) published the result of a phase III study conducted over 573 patients from 85 centers by the European Organization for Research and Treatment of Cancer and the National Cancer Institute of Canada (EORTC/NCIC) comparing between maximum safe resection or biopsy followed by radiotherapy versus adding concurrent temozolomide (TMZ) followed by six cycles of adjuvant TMZ
A small percentage of patients experienced grade III to IV toxicity, and concluded that these results suggested that long-term treatment with temozolomide was feasible and well tolerated [6]
Summary
Gliomas are the most common form of malignant primary brain tumors in adults, with an annual incidence of approximately four to five per 100,000 people [1]. The updated 5-years survival result was 9.8% in the RT with TMZ compared to 1.9% in RT alone group [4] These randomized prospective data were the first to demonstrate a significant and meaningful survival benefit when a chemotherapeutic agent was given in combination with RT in this disease it constituted the current standard of care for the adjuvant treatment of GBM. A prospective phase II randomized trial in which glioma patients were divided into two groups: group one received post surgery CCRT followed by 6 cycles of adjuvant TMZ (EORTC/NCIC protocol) and the second group received the same treatment with more than 6 cycles of chemotherapy or till disease progression. Secondary endpoint is PFS of the same groups, PFS and OS based on intension-to-treat (ITT) analysis to the two randomized groups
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