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Strahlentherapie und Onkologie

Original Article

Single-Arm Phase II Study of Conformal Radiation Therapy and Temozolomide plus Fractionated Stereotactic Conformal Boost in High-Grade Gliomas Final Report Mario Balducci1, Giuseppina Apicella1, 2, Stefania Manfrida1, Annunziato Mangiola3, Alba Fiorentino1, Luigi Azario4, Giuseppe Roberto D’Agostino1, Vincenzo Frascino1, Nicola Dinapoli1, Giovanna Mantini1, Alessio Albanese3, Pasquale de Bonis3, Silvia Chiesa1, Vincenzo Valentini1, Carmelo Anile3, Numa Cellini1

Purpose: To assess survival, local control and toxicity using fractionated stereotactic conformal radiotherapy (FSCRT) boost and temozolomide in high-grade gliomas (HGGs). Patients and Methods: Patients affected by HGG, with a CTV1 (clinical target volume, representing tumor bed ± residual tumor + a margin of 5 mm) ≤ 8 cm were enrolled into this phase II study. Radiotherapy (RT, total dose 6,940 cGy) was administered using a combination of two different techniques: three-dimensional conformal radiotherapy (3D-CRT, to achieve a dose of 5,040 or 5,940 cGy) and FSCRT boost (19 or 10 Gy) tailored by CTV1 diameter (≤ 6 cm and > 6 cm, respectively). Temozolomide (75 mg/m2) was administered during the first 2 or 4 weeks of RT. After the end of RT, temozolomide (150–200 mg/m2) was administered for at least six cycles. The sample size of 41 patients was assessed by the single proportion–powered analysis. Results: 41 patients (36 with glioblastoma multiforme [GBM] and five with anaplastic astrocytoma [AA]) were enrolled; RTOG neurological toxicities G1–2 and G3 were 12% and 3%, respectively. Two cases of radionecrosis were observed. At a median follow-up of 44 months (range 6–56 months), global and GBM median overall survival (OS) were 30 and 28 months. The 2-year survival rate was significantly better compared to the standard treatment (63% vs. 26.5%; p < 0.00001). Median progression-free survival (PFS) was 11 months, in GBM patients 10 months. Conclusion: FSCRT boost plus temozolomide is well tolerated and seems to increase survival compared to the standard treatment in patients with HGG. Key Words: Malignant glioma · Stereotactic radiotherapy · Temozolomide · Boost Strahlenther Onkol 2010;186:558–64

DOI 10.1007/s00066-010-2101-x Einarmige Phase-II-Studie zur konformalen Strahlentherapie mit Temozolomid plus fraktionierter stereotaktischer konformaler Boostbestrahlung bei höhergradigen Gliomen. Abschlussbericht Ziel: Untersuchung von Überleben, lokaler Tumorkontrolle und Toxizität einer fraktionierten stereotaktischen konformalen Strahlentherapie (FSCRT) mit Boostbestrahlung in Kombination mit Temozolomid bei hochmalignen Gliomen (HMG). Patienten und Methodik: Patienten mit HMG und einem CTV1 (klinisches Zielvolumen, d. h. Tumorbett ± Resttumor + einem Sicherheitsabstand von 5 mm) ≤ 8 cm wurden in diese Phase-II-Studie eingeschlossen. Die Strahlentherapie (Gesamtdosis 6 940 cGy) wurde als Kombination aus zwei unterschiedlichen Techniken appliziert: dreidimensionale konformale Strahlentherapie (3D-CRT, um eine Strahlendosis von 5 040 oder 5 940 cGy zu erreichen) und lokale Dosisaufsättigung mit FSCRT-Boost (19 oder 10 Gy), die auf den CTV1-Durchmesser (≤ 6 cm bzw. > 6 cm) zugeschnitten war. Temozolomid (75 mg/m2) wurde wahrend der ersten 2 oder 4 Wochen der Strahlentherapie verabreicht. Nach dem Ende der Strahlentherapie erhielten die Patienten Temozolomid (150–200 mg/m2) für wenigstens sechs Zyklen. Die Fallzahl wurde mit Hilfe eines einfach-proportionalen Testverfahrens („single proportion-powered analysis“) bei 41 Patienten bestimmt. 1

Department of Radiotherapy, Catholic University of the Sacred Heart, Rome, Italy, Department of Radiotherapy, University Hospital Maggiore della Carità, Novara, Italy, 3 Department of Neurosurgery, Catholic University of the Sacred Heart, Rome, Italy, 4 Department of Physics, Catholic University of the Sacred Heart, Rome, Italy. 2

Received: November 11, 2009; accepted: April 1, 2010 Published Online: September 30, 2010

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Strahlenther Onkol 2010 · No. 10 © Urban & Vogel

Balducci M, et al. Stereotactic Conformal Therapy Boost and Temozolomide in HGG

Ergebnisse: 41 Patienten (36 mit Glioblastoma multiforme [GBM] und fünf mit anaplastischem Astrozytom [AA]) wurden behandelt; Neurotoxizität gemäß RTOG-Skala G1–2 bzw. G3 wurde in 12% bzw. 3% der Patienten beobachtet. Zwei Fälle von Radionekrose traten auf. Bei einer mittleren Beobachtungszeit von 44 Monaten (Range 6–56 Monate) lagen die mittlere Gesamt- und die GBM-spezifische Überlebenszeit (OS) bei 30 und 28 Monaten. Die 2-Jahres-Überlebensrate war signifikant besser im Vergleich zur Standardbehandlung (63% vs. 26,5%; p < 0.00001). Die mittlere progressionsfreie Überlebenszeit (PFS) betrug 11 Monate, bei GBM-Patienten 10 Monate. Schlussfolgerung: FSCRT-Boostbestrahlung plus Temozolomid wird gut toleriert und scheint im Vergleich zur Standardbehandlung die Überlebenszeit von Patienten mit HMG zu verbessern. Schlüsselwörter: Maligne Gliome · Stereotaktische Radiotherapie · Temozolomid · Boost

Introduction High-grade gliomas (HGGs) have an high tendency to local recurrence, especially within 2 cm of the enhancing edge of the original tumor [11, 19]. Factors influencing outcome include histological type (glioblastoma multiforme [GBM] vs. anaplastic astrocytoma [AA]), patient’s age, Karnofsky performance status (KPS), surgical resectability, and radiation dose [15, 18, 31]. Primary treatment includes surgical resection followed by radiochemotherapy [35]. Surgery is limited by the lack of obvious anatomic distinction between tumor and adjacent normal brain tissue and the risk of permanent neurological damage [21]. Radiation therapy (RT) remains the most effective postoperative treatment and a radiation dose-survival relationship has been reported [37]. Dose increased by three-dimensional conformal radiation therapy (3D-CRT) is limited by the significant risks of normal brain injury and failed to demonstrate a survival benefit [5, 27]. Stereotactic RT has been used in the treatment of recurrent gliomas [12, 14, 33] or as a boost in the initial management with encouraging results in retrospective studies [3, 6, 32] with an acceptable toxicity profile in both settings. Two prospective trials, RTOG 93-05 and RTOG 0023, failed to demonstrate a survival improvement with stereotactic RT but did not conclude the debate about this therapeutic modality, especially since temozolomide, which, added to RT in concomitant and adjuvant regimen, led to a significant improvement in survival and represents the standard therapy for patients with GBM, was not included in these schedules [4, 34, 36]. Our study was performed in order to assess the impact on survival, local control and toxicity using a fractionated stereotactic boost combined with 3D-CRT (FSCRT) plus temozolomide in the initial management of selected patients with malignant gliomas. Patients and Methods Patients’ Eligibility Patients > 18 years of age with a histopathologic diagnosis of supratentorial malignant gliomas (AA, GBM) were considered eligible for this study. Other inclusion criteria were: no prior cranial RT or chemotherapy; KPS > 70; normal hematologic parameters. Patients with multifocal, brainstem-located, perichiasmatic

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tumors or CTV1 (clinical target volume) > 80 mm in diameter were excluded from this study. A written informed consent form was required from all patients enrolled. Study Design All patients were submitted to clinical examination, preoperative and postoperative gadolinium magnetic resonance imaging (MRI). Patient’s immobilization was obtained by using a thermoplastic mask (“Uni-Frame”) during the 3D-CRT phase, and by a noninvasive, stereotactic, relocatable immobilization system (a modified version of Leksell’s frame, by 3D-Line® s.r.l., Milan, Italy) during the stereotactic phase. Image fusion with MRI scans was performed for contouring; CTVs were defined by a radiation oncologist and a neuroradiologist. CTV1, defined on gadolinium-enhanced T1-weighted MRI scans, was the only volume receiving the stereotactic boost and included surgical cavity contrast enhancement plus residual tumor, if present, plus a 5-mm margin. CTV2 included CTV1 plus a 10-mm margin. CTV3 was defined with T2-weighted MRI and represented CTV1 plus edema zone. PTV1–2–3 (planning target volumes) were obtained by adding a 5-mm margin to CTV2–3 and 3 mm to CTV1. The organ at risk (OAR) constraints were those described by Emami et al. [10]; in all patients, however, the OARs were outside the PTVs. Treatment planning was carried out with the TPS Eclipse (Varian Medical System®, Palo Alto, CA, USA) for the 3D-CRT phase and with TPS Ergo (3D Line Medical Systems®, Milan, Italy) for the stereotactic treatment. The dose was pre-scribed to the isocenter with the 95% isodose encompassing CTVs. Three or four multiple noncoplanar static beams were used during the 3D-CRT and stereotactic phase. Stereotactic beams were shaped to PTV beem’s eye view by a dynamic micro multileaf collimator (3D Line Medical Systems®) mounted on linear accelerator (VARIAN® CLINAC 2100 CD) with a nominal energy of 6 MV. Radiochemotherapy was tailored to CTV1 diameter (Figure 1). All patients received a total dose of 6,940 cGy on CTV1 and a dose of 3,960 cGy to CTV3. Patient with CTV1 ≤ 6 cm (group A) received both concomitant (9 Gy, in ten fractions of 90 cGy, starting from the 3rd week of 3D-CRT on alternating days) and sequential stereotactic boost (10 Gy, in

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The primary endpoint was 2-year survival, while secondary endpoints 3D-CRT included feasibility, toxicity, and local TEMOZOLOMIDE control. TEMOZOLOMIDE FSCRT 150–200 mg/m2 75 mg/m2 Toxicity was graded using the a RTOG/EORTC Acute and the Late FSCRT Morbidity Scoring Scheme [8]. Patients 3D-CRT were classified according to RPA (recursive partitioning analysis) score [9]. TEMOZOLOMIDE TEMOZOLOMIDE The Kaplan-Meier method was used to 150–200 mg/m2 75 mg/m2 estimate overall survival (OS, measured b from the date of diagnosis to the date of death or last follow-up) and progresFigures 1a and 1b. Treatment schedules. a) Group A: concomitant + sequential Fractionated sion-free survival (PFS, measured from Stereotactic Conformal Radiotherapy (FSCRT). b) Group B: sequential (FSCRT). the date of study entry to the date progresAbbildungen 1a und 1b. Behandlungschemata. a) Gruppe A: gleichzeitige + sequentielle sion or last follow-up) [16]. fraktionierte stereotaktische konformale Radiotherapie (FSCRT). b) Gruppe B: sequentielle Extent of surgery, tumor type, and RPA FSCRT. class were analyzed as potential prognostic four fractions of 250 cGy each). In order to reduce acute toxicfactors for OS and PFS using the univariate log-rank test [22]. ity in patients with CTV1 > 6 cm (group B), stereotactic boost The Cox proportional hazards model was used for the stepwas delivered only sequentially, in four fractions of 250 cGy wise multivariate analysis [7]. each. Dose delivered to CTV2 was 5,940 or 5,040 cGy, according to stereotactic dose. To compare these two schedules with Results standard radiation dose (60 Gy), we computed the 2-Gy/fracPatients’ Characteristics tion biologically effective dose (BED) according to the linearFrom November 2003 to March 2008, 41 patients with histoquadratic model: BED = nd {1 + [d / (α/β)]} where α/β is 10 for logically confirmed HGG were enrolled. Patients’ charactertumor, n is the number of fractions, and d is the dose of fracistics are shown in Tables 1 and 2. Thirty-six patients (88%) tion. The BED was 85 Gy for both groups. All patients received were affected by GBM, five (12%) by AA. temozolomide (75 mg/m2 daily) during the first 2 or 4 weeks of Postsurgical MRI evaluation showed residual tumor in RT, when stereotactic boost was not administered. 2 weeks 28 patients (68%). after the end of RT, temozolomide (150–200 mg/m2) was administered for six cycles or until disease progression/relapse in Toxicity both groups (Figure 1). MRI scans were also acquired every During radiochemotherapy, 12% of patients experienced three cycles during adjuvant chemotherapy, every 2 months G1–2 neurological acute toxicity, such as headache, confufor the first 2 years of follow-up, and every 3 months thereafsion and seizures, while G3 toxicity was observed in only one ter. Clinical response was measured on MRI scans according patient. Hematologic acute toxicity G1–2 was observed in to the criteria by Macdonald et al. [20]. only 2%. During adjuvant chemotherapy, G2 hematologic toxicity was seen in 10% of patients and G3 toxicity in 7% Statistical Analysis of patients, one of which suspended chemotherapy after two This trial was designed to demonstrate an improvement cycles. > 20% in 2-year survival rate of the patients treated with the Late neurological toxicity included two cases (4.8%) of stereotactic tailored treatment plus temozolomide versus radionecrosis (at 14 and 24 months) in patients submitted to the 2-year survival rate of the patients treated with 3D-CRT surgery because of the suspicion of a disease recurrence, but plus temozolomide in the study by Stupp et al. [36]. The acwithout evidence of tumor cells in the histological specimens: crual was determined by the single proportion-powered of these patients, one died of ovarian cancer after 33 months analysis (Systat 11, SPSS Science®, Chicago, IL, USA) for from the diagnosis of GBM, the other is still alive without evitesting p0 = 0.265 (“bad” response probability, 2-year surdence of disease. vival of the study by Stupp et al.), p1 = 0.475 (“good” response probability of ongoing study), α = 0.05, power = 0.8: Response a total of 41 subjects were required. The analysis of response The 28 patients with subtotal resection were evaluable for rerate against the H0 (“bad” response probability, RTOG) sponse to RT. A clinical response (complete + partial) was was performed by a single proportion test (Systat 11, SPSS observed in 15 patients (53%), stable disease in 10 (36%), and Science®). early disease progression in three (11%). FSCRT

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Table 1. Patients’ characteristics. AA: anaplastic astrocytoma; GBM: glioblastoma multiforme; RPA: recursive partitioning analysis. Tabelle 1. Patientencharakteristika. AA: anaplastisches Astrozytom; GBM: Glioblastoma multiforme; RPA: rekursive Partitionsanalyse. Total n = 41 Age (years) • Median • Range Sex [n (%)] • Male • Female Histology [n (%)] • GBM • AA Type of surgery [n (%)] • Subtotal resection • Total resection RPA class [n (%)] • I • III • IV • V

52 25–72 26 (64) 15 (36) 36 (88) 5 (12) 28 (68) 13 (32) 5 (12) 9 (22) 26 (63) 1 (3)

Table 2. Patients’ characteristics according to clinical target volume (CTV1) diameter. AA: anaplastic astrocytoma; GBM: glioblastoma multiforme; RPA: recursive partitioning analysis. Tabelle 2. Patientencharakteristika gemäß Durchmesser des klinischen Zielvolumens (CTV1). AA: anaplastisches Astrozytom; GBM: Glioblastoma multiforme; RPA: rekursive Partitionsanalyse.

Age (years) • Median • Range Sex (n) • Male • Female Histology (n) • GBM • AA Type of surgery (n) • Subtotal resection • Total resection RPA class (n) • I • III • IV • V

Group A n = 23

Group B n = 18

51 34–72

53 25–65

14 9

12 6

20 3

16 2

18 5

10 8

3 5 15 0

2 4 11 1

Local Control Thirty disease progressions were observed during the followup period. Patterns of failure were prevalently in field or mar-


Table 3. Patterns of failure. Tabelle 3. Muster des Therapieversagens. Site of recurrence

Total n (%)

Group A n

Group B n

In field (95% isodose region) Marginal (< 80% isodose region) Out of field

21 (70) 3 (10) 6 (20)

9 1 5

12 2 1

ginal (80%, Table 3). 14 patients (47%) underwent surgery as salvage therapy: in two cases of MRI- suspected recurrence, histopathologic specimens documented only “radionecrosis”. Median PFS was 11 months; 1-and 2-year PFS rates were 49% and 33% respectively (Figure 2a). In GBM patients, median PFS was 10 months (41% and 25% at 1-and 2-years, respectively). PFS was 20 months for R0 and 10 months for R1 patients, without significant difference (p = 0.28). Patients submitted to radical surgery experienced a longer PFS than patients with macroscopic disease (20 months vs. 10 months) without statistical significance (p = 0.28). Similarly, a longer PFS was observed among group A patients (19 months vs. 10 months; Table 4). Survival At a median follow-up of 44 months (range 6–56 months), 19 patients (46%) are alive and 22 (54%) had died of disease except one for ovarian cancer. Median OS was 30 months, and 1-and 2-year survival rates were 87% and 63%, respectively (Figure 2b). This endpoint satisfied the null hypothesis expressed in the single proportion-powered analysis of an improvement > 20% in 2-year survival rate with respect to the 2-year survival rate of the patients treated with 3D-CRT plus temozolomide in the reference study (p < 0.00001). In the subset of patients affected by GBM, median OS was 28 months (1-year OS 85% and 2-year OS 57%). Neither the RPA class nor the schedule of stereotactic boost was significantly related to survival (Table 4). In particular, median survival was 29 months for RPA class III patients and 26 months for RPA class IV patients (p = 0.7). Only residual tumor after surgery affected survival (median not reached for patients without macroscopic residual tumor vs. 26 months for patients with macroscopic residual tumor; p = 0.04). The Cox logistic regression revealed that the absence of residual tumor and sequential FSCRT boost significantly improved survival with an hazard ratio (HR) of 3.41 (R0 vs. R1, 95% confidence interval [CI] 1.05–11.05; p = 0.041) and 0.39 (concomitant and sequential FSCRT vs. sequential FSCRT, 95% CI 0.15–0.98; p = 0.047), respectively (Table 5). Analysis According to CTV1 Diameter Four patients in group A and one patient in group B experienced G1–2 neurological acute toxicity, one case of G3 toxicity was observed in group B. Late neurological toxicity was similar in both groups. Global response was seen in eleven group

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Discussion Despite multimodality therapy for patients with malignant glioma, local 0.8 0.8 control remains the Achilles’ heel, because nearly all patients die of local PFS OS 0.6 0.6 disease relapse/progression [1, 29]. Radiation doses up to 60 Gy with “old” techniques produced consider0.4 0.4 able incidence of late toxicity (radionecrosis rate about 18%) [23]. 3D-CRT 0.2 0.2 obtained a reduction of late toxicity but failed to demonstrate a survival benefit, 0.0 0.0 0 10 20 30 40 50 60 0 10 20 30 40 50 60 also when using a dose up to 90 Gy [25]. a Months b Months Stereotactic RT was used with encouraging results in retrospective studies [28, 30]. Figures 2a and 2b. Actuarial progression-free survival (PFS, a) and overall survival (OS, b). In the phase III study RTOG 93Abbildungen 2a und 2b. Progressionsfreies Überleben (PFS, a) und Gesamtüberleben (OS, b) 05, patients were randomly assigned either to postoperative external-beam Table 4. Univariate analysis of overall survival (OS) and progresradiotherapy (EBRT) plus BCNU with or without up-front sion-free survival (PFS). FSCRT: fractionated stereotactic conformal rastereotactic radiosurgery (SRS); this is the only study using a diotherapy; NE: not evaluated; RPA: recursive partitioning analysis. stereotactic boost before EBRT; it did not demonstrate a surTabelle 4. Univariate Analyse des Gesamtüberlebens (OS) und des provival and local control advantage in up-front FSRT modality gressionsfreien Überlebens (PFS). FSCRT: fraktionierte stereotaktische (p = 0.57) [34]. In 2006, Cardinale et al. did not obtain any adkonformale Strahlentherapie; NE: not bestimmt; RPA: rekursive Partivantage with respect to a historical group after a stereotactic tionsanalyse. boost up to 70–78 Gy [4]. It is important to notice that RTOG Variable p-value 0023 trial omits temozolomide, which represents the actual OS PFS standard chemotherapy. RPA classes (RPA III vs. RPA IV) 0.7 NE Our study is the first prospective, monoinstitutional trial Schedule (concomitant + sequential FSCRT vs. 0.15 0.18 of dose-intense RT using a tailored conformal stereotactic sequential FSCRT) boost plus temozolomide for patients affected by HGGs. Type of surgery (R0 vs. R1) 0.04 0.28 However, some limits in our study should be underlined. First, we did not compare our results to the previous studies Table 5. Multivariate analysis of overall survival. AA: anaplastic astrocyperformed with FSCRT or radiosurgery, even if our results toma; CI: confidence interval; FSCRT: fractionated stereotactic conforare better, since none of them included temozolomide in their mal radiotherapy; GMB: glioblastoma multiforme; HR: hazard ratio. schedule. Even if it is hazardous to compare two studies outTabelle 5. Multivariate Analyse des Gesamtüberlebens. AA: anaplasside a randomized trial, we compared our series with the corretisches Astrozytom; CI: Konfidenzintervall; FSCRT: fraktionierte stereotaktische konformale Strahlentherapie; GMB: Glioblastoma multispondent subgroup of patients who received a standard radiaforme; HR: Hazard-Ratio. tion dose of 60 Gy plus temozolomide in the EORTC-NCIC trial that, at the moment, represents the standard therapy Variable HR (95% CI) [36]. Differently by EORTC schedule, we chose to underdose Type of surgery (R0 vs. R1) 3.41 (1.05–11.05) temozolomide in both groups (chemotherapy only in the steSchedule (concomitant + sequential FSCRT vs. 0.39 (0.15–0.98) reotactic boost-off windows) to avoid a cumulative neurologisequential FSCRT) cal toxicity. Moreover, in another study comparing an altered Histology (GBM vs AA) 0.27 (0.03–2.14) temozolomide schedule with that by Stupp et al. [36], we observed comparable results [2]. It was not possible to perform A and four group B patients; two patients in group A and one a matched-pair analysis with EORTC trial for the absence patient in group B experienced early disease progression. of analytic data. The risk of a favorable selection bias in our 15 disease progressions were observed in each group. series, especially concerning the RPA classification (that was Eight patients in group A and six in group B underwent surconfirmed to be the principal prognostic score in HGG) [24], gery as salvage therapy. No significant differences in PFS or probably does exist, even if the highest percentage of poorerOS were found between the two groups. At the Cox logistic prognosis RPA V class in the series by Stupp et al. (32% vs. 3% regression, sequential FSCRT boost resulted in a better surin our study) should probably be balanced by the highest pervival (HR = 0.39, 95% CI 0.15–0.98; p = 0.047). centage of incompletely resected patients in our series (68%

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1.0

Alive (%)

Alive (%)

1.0



vs. 51%). Surprisingly, no impact on survival by RPA class was observed in our study: it probably depends on the small size; therefore, in this context, it has not any clinical relevance. Another limit of this study, frequently observed in the literature regarding HGGs, could be the presence of a little percentage of AA (12%), having a more favorable prognosis. However, when we analyzed survival by histology, the 2-year survival was 57% in GBM patients; this finding satisfies the primary endpoint. Recently, some experiences of conventional RT with dose-dense chemotherapy and/or new drugs, such as bevacizumab, have been published. Glas et al. [13] obtained a median overall survival of 23.1 months adding an intensified dose of CCNU and temozolomide to a standard RT schedule of 60 Gy. Two other groups [17, 26] reported a safe toxicity profile, when bevacizumb was added to standard schedule with 1-year PFS and OS rates of 59.3% and 86.7%, respectively. In our series, even with the limit of small size, the median survival of 28 months in GBM patients compares favorably with the results reported in the recent studies, suggesting a strong role of radiation dose intensification on outcomes. Conclusion The role of fractionated stereotactic RT for newly diagnosed malignant glioma is still unclear. RTOG 93-05 and 0023 trials failed to increase outcome when FSCRT was used in up-front modality or without temozolomide but they did not definitively solve the role of FSCRT boost. In our study, a better outcome is obtained when higher doses (> 60 Gy) by FSCRT are used in combination with temozolomide without worsening the neurological toxicity (radionecrosis < 5%). Even within the limits of a single-arm phase II study, the promising results should encourage the start-up of a new prospective trial in GBM patients. References 1.

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Address for Correspondence Giuseppina Apicella Department of Radiotherapy, University Hospital Maggiore della Carità Corso Mazzini 18 28100 Novara Italy Phone (+49/0321) 373-3424, Fax -3698 e-mail: [email protected]
