Mar 4, 2009 - Roberta Muni1, Giuseppe Minniti1,2, Gaetano Lanzetta2, Paola Caporello3,. Alessandro ... sion-free survival were estimated using the Kaplan-.
Tumori, 96: 60-64, 2010
Short-term radiotherapy followed by adjuvant chemotherapy in poor-prognosis patients with glioblastoma Roberta Muni1, Giuseppe Minniti1,2, Gaetano Lanzetta2, Paola Caporello3, Alessandro Frati2, Maurizio Maurizi Enrici1, Paolo Marchetti3, and Riccardo Maurizi Enrici1 1
Department of Radiotherapy S. Andrea Hospital, University “Sapienza”, Rome; 2Department of Neurological Sciences, Neuromed Institute, Pozzilli (IS); 3Department of Medical Oncology, S. Andrea Hospital, University “Sapienza”, Rome, Italy
ABSTRACT
Objectives. The optimal treatment for patients with glioblastoma with unfavorable prognostic factors, such as old age and low performance status, remains controversial. We conducted a prospective study to assess the effect of temozolomide and short-course radiation versus short-course radiation alone in the treatment of poorprognosis patients with newly diagnosed glioblastoma. Patients and methods. Forty-five patients with a newly diagnosed glioblastoma, older than 70 years or aged 50-70 years and with a Karnofsky performance score ≤70 were enrolled in this prospective study. Twenty-three patients were treated with an abbreviated course of radiotherapy (30 Gy in 6 fractions over 2 weeks) and 22 patients with the same radiotherapy schedule plus adjuvant temozolomide at the dose of 150-200 mg/m2 for 5 days every 28-day cycle. The primary end point was overall survival. Secondary end points included progression-free survival and toxicity. Results. Median overall survival was 7.3 months in the radiotherapy group and 9.4 months in the radiotherapy plus temozolomide group (P = 0.003), with respective 6month overall survivals of 78% and 95%, respectively. Median progression-free survival was 4.4 months in the radiotherapy group and 5.5 months in the radiotherapy plus temozolomide group (P = 0.01), and respective 6-month progression-free survival rates were 22% and 45%. In multivariate analysis, Karnofsky performance score was the only significant independent predictive factor of survival (P = 0.03). Adverse effects of radiotherapy were mainly represented by neurotoxicity (24%), which resolved in most cases with the use of steroids. Grade 3-4 hematologic toxicity occurred in 36% of patients treated with temozolomide. Conclusions. The addition of temozolomide to short-term radiotherapy resulted in a statistically significant survival benefit with minimal additional toxicity in poor-prognosis patients with newly diagnosed glioblastoma. Future studies need to define the best combined regimens of radiotherapy and temozolomide on survival and quality of life in this subgroup of patients. Free full text available at www.tumorionline.it
Introduction Current treatment of glioblastoma includes surgery followed by radiotherapy and concomitant and adjuvant temozolomide. The recent published randomized European and Canadian trial (EORTC/NCIC)1 clearly demonstrated that addition of temozolomide to standard radiotherapy in patients 60 years of age with glioblastoma, Roa et al.7 found a similar survival of approximately 6 months among patients receiving standard radiotherapy (60 Gy in 30 fractions over 6 weeks) or short-course radiotherapy (40 Gy in 15 fractions over 3 weeks). A recent French randomized trial8 showed an overall survival of 29.1 weeks in 39 elderly patients treated with radiotherapy (50 Gy in 20 fractions over 4 weeks) compared to 16.9 weeks in patients who received supportive care alone. Similar survival has been reported in patients treated with 30-40 Gy in 6-15 fractions2-6. Temozolomide has been recently advocated as an alternative treatment in newly diagnosed elderly patients with glioblastoma9-11. Glantz et al.9 reported a median survival of 6 months in 32 elderly patients treated with temozolomide alone, with a 1-year survival rate of 12%. Toxicity was minimal, with grade 3-4 thrombocytopenia and neutropenia reported in less than 15% of treated patients and no documented neurotoxicity. Similar results have been reported by others10,11, suggesting that temozolomide could be an alternative therapeutic option to irradiation, especially based on its ease of administration and low morbidity. The current study reports our results in a series of poor-prognosis patients with glioblastoma who received short-term radiotherapy or a combination of radiotherapy and temozolomide. The addition of temozolomide to radiotherapy resulted in significant survival advantages. The median overall survival and progression-free survival were respectively 9.4 and 5.5 months in the radiotherapy plus temozolomide group versus 7.3 and 4.4 months in the radiotherapy group. These findings are important in two respects. First, they confirm that less-intensive radiotherapy schedules are associated with potential survival benefit and might be appropriated for patients with unfavorable prognostic factors. The reported survival after radiotherapy in our study is similar to that previously reported by others with either an abbreviated course of radiotherapy2-8 or standard radiotherapy7,14,15. Certainly, future studies need to define the risk/benefit ratio of different schedules of short-term radiotherapy in this population. Second, in the present study we demonstrated that the combination of short-term radiotherapy plus adjuvant temozolomide is associated with a longer survival than short-term radiotherapy alone. Moreover, our results compare favorably with previous series on the use of standard radiotherapy7,14,15 or chemotherapy with temozolomide alone9-11, suggesting that abbreviated radiotherapy plus temozolomide may provide survival benefit in poor-prognosis patients with glioblastoma. Only recently, few series have explored the use of standard radiotherapy plus concomitant and/or adjuvant
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temozolomide in elderly patients with glioblastoma, reporting a median survival of 10-14 months16-19. Although this aggressive regimen is associated with longer survival, it is usually reserved only for patients with favorable prognostic factors, such as minimal residual disease, KPS score >70, and good neurological status. Sixty percent of patients progressed early during adjuvant temozolomide. More recently, epigenetic inactivation of the DNA repair enzyme methylguanine methyltransferase (MGMT) has emerged as an independent strong factor for outcome in patients treated with temozolomide 20. Patients whose tumors do not have MGMT promoter methylation may benefit less from the addition of temozolomide to radiotherapy. So far, analysis of MGMT should be considered in future protocols for better stratification of patients. Severe myelosuppression occurred in approximately one third of patients, leading to the early discontinuation of chemotherapy in 13%. In the other patients, temozolomide cycles were delayed or the dose reduced. Our findings confirm that temozolomide is well tolerated and relatively safe in elderly patients or in patients with a low performance status, with no more toxicity than in younger patients with good neurological status1,21. In conclusion, the addition of temozolomide to shortterm radiotherapy resulted in a statistically significant survival benefit with minimal additional toxicity in poor-prognosis patients with newly diagnosed glioblastoma. Randomized studies need to determine the impact of different combined regimens of radiotherapy and temozolomide on survival and quality of life in this subgroup of patients.
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