A Phase I Clinical Trial Of Dose Escalation With Intensity Modulated Radiation Therapy For Resected High Grade Gliomas

Purpose/Objective(s)This paper was to determine the biologic target volume (BTV) and morphologic target volume (MTV) for resected high-grade gliomas (HGG) using 11C-methionine (MET)-PET/CT and MRI, respectively. A phase I dose escalation trial for BTV was performed using intensity modulated radiation therapy (IMRT). We aimed to evaluate the safety and effectiveness of escalating BTV dose in the treatment of resected HGG.Materials/MethodsFrom Feb 2004 to Jan 2007, 18 consecutive patients (14 male, 4 female) with resected supratentorial HGG (9 glioblastoma multiforme, 9 anaplastic astrocytoma) were entered into this study. Age ranged from 19 to 70 years (median 52). Karnofsky scores ranged from 50 to 100 (median 90). There were 7 patients for gross total resection, 8 for subtotal resection, and 3 for partial resection. Before the treatment of IMRT, all patients underwent MRI and MET-PET/CT scan in the same treatment position, respectively. The BTV was defined as the local high uptake areas displayed on MET-PET/CT images and the MTV as the operative bed with T1-enhancing lesions seen on MRI. The first clinical target volume (CTV1) was defined as the BTV and MTV plus 1.0 cm margin, and the second CTV (CTV2) as the CTV1 plus 1.0–1.5 cm margin (included T2 abnormalities). The planning target volume (PTV) was defined as the above target volumes plus 0.5 cm margin for setup uncertainties. The dose escalation of BTV was scheduled to stratify into 4 prescription dose levels: level 1: 67.2 Gy in 28 fractions; level 2:70 Gy in 28 fractions; level 3:72.8 Gy in 28 fractions; and level 4:72 Gy in 24 fractions. The prescription dose in both MTV and CTV1 was the same, being 58.8 Gy in 28 fractions for level 1–3, and 60 Gy in 24 fractions for level 4. The CTV2 dose was 50.4 Gy in 28 fractions for level 1–3 and 50.4 Gy in 24 fractions for level 4. The size of BTV ranged from 3.1 to 163.6 cc (median 17.1 cc), with 3 patients in level 1, 4 in level 2, 6 in level 3, and 5 in level 4. Treatment planning was performed using the NOMOS Peacock/Corvus system and treatment delivered using a mini-multileaf collimator (MIMiC). The radiation was given 1 fraction per day and 5 days per week. The primary endpoint of the study was acute toxicity. If toxicity was acceptable, dose escalation was planned to go along. Patients were followed every 3 months by clinical examination and MRI or MET-PET/CT after completing IMRT. Median survival time was calculated as a secondary endpoint.ResultsAll patients successfully completed the treatment without interruption. Seventeen (94%) patients had acceptable toxicity (grade 0 in 2, grade 1 in 1, grade 2 in 14). Only one (6%) patient in the dose level 3 developed reversible grade 3 toxicity. The median overall survival time for all patients was 13.0 months (95% CI: 8.1 to 17.8). The median progress-free survival time was 6.8 months (95% CI: 4.6 to 9.0). The 1- and 2-year actuarial survival rates were 59.5% and 21.4%, respectively. The 1- and 2-year progress-free survival rates were 18.1% and 9.0%, respectively.ConclusionsEscalating dose to BTV with 72 Gy in 24 fractions using IMRT for the patients with resected supratentorial high grade gliomas is safe and feasible. Further dose escalation may be investigated. Purpose/Objective(s)This paper was to determine the biologic target volume (BTV) and morphologic target volume (MTV) for resected high-grade gliomas (HGG) using 11C-methionine (MET)-PET/CT and MRI, respectively. A phase I dose escalation trial for BTV was performed using intensity modulated radiation therapy (IMRT). We aimed to evaluate the safety and effectiveness of escalating BTV dose in the treatment of resected HGG. This paper was to determine the biologic target volume (BTV) and morphologic target volume (MTV) for resected high-grade gliomas (HGG) using 11C-methionine (MET)-PET/CT and MRI, respectively. A phase I dose escalation trial for BTV was performed using intensity modulated radiation therapy (IMRT). We aimed to evaluate the safety and effectiveness of escalating BTV dose in the treatment of resected HGG. Materials/MethodsFrom Feb 2004 to Jan 2007, 18 consecutive patients (14 male, 4 female) with resected supratentorial HGG (9 glioblastoma multiforme, 9 anaplastic astrocytoma) were entered into this study. Age ranged from 19 to 70 years (median 52). Karnofsky scores ranged from 50 to 100 (median 90). There were 7 patients for gross total resection, 8 for subtotal resection, and 3 for partial resection. Before the treatment of IMRT, all patients underwent MRI and MET-PET/CT scan in the same treatment position, respectively. The BTV was defined as the local high uptake areas displayed on MET-PET/CT images and the MTV as the operative bed with T1-enhancing lesions seen on MRI. The first clinical target volume (CTV1) was defined as the BTV and MTV plus 1.0 cm margin, and the second CTV (CTV2) as the CTV1 plus 1.0–1.5 cm margin (included T2 abnormalities). The planning target volume (PTV) was defined as the above target volumes plus 0.5 cm margin for setup uncertainties. The dose escalation of BTV was scheduled to stratify into 4 prescription dose levels: level 1: 67.2 Gy in 28 fractions; level 2:70 Gy in 28 fractions; level 3:72.8 Gy in 28 fractions; and level 4:72 Gy in 24 fractions. The prescription dose in both MTV and CTV1 was the same, being 58.8 Gy in 28 fractions for level 1–3, and 60 Gy in 24 fractions for level 4. The CTV2 dose was 50.4 Gy in 28 fractions for level 1–3 and 50.4 Gy in 24 fractions for level 4. The size of BTV ranged from 3.1 to 163.6 cc (median 17.1 cc), with 3 patients in level 1, 4 in level 2, 6 in level 3, and 5 in level 4. Treatment planning was performed using the NOMOS Peacock/Corvus system and treatment delivered using a mini-multileaf collimator (MIMiC). The radiation was given 1 fraction per day and 5 days per week. The primary endpoint of the study was acute toxicity. If toxicity was acceptable, dose escalation was planned to go along. Patients were followed every 3 months by clinical examination and MRI or MET-PET/CT after completing IMRT. Median survival time was calculated as a secondary endpoint. From Feb 2004 to Jan 2007, 18 consecutive patients (14 male, 4 female) with resected supratentorial HGG (9 glioblastoma multiforme, 9 anaplastic astrocytoma) were entered into this study. Age ranged from 19 to 70 years (median 52). Karnofsky scores ranged from 50 to 100 (median 90). There were 7 patients for gross total resection, 8 for subtotal resection, and 3 for partial resection. Before the treatment of IMRT, all patients underwent MRI and MET-PET/CT scan in the same treatment position, respectively. The BTV was defined as the local high uptake areas displayed on MET-PET/CT images and the MTV as the operative bed with T1-enhancing lesions seen on MRI. The first clinical target volume (CTV1) was defined as the BTV and MTV plus 1.0 cm margin, and the second CTV (CTV2) as the CTV1 plus 1.0–1.5 cm margin (included T2 abnormalities). The planning target volume (PTV) was defined as the above target volumes plus 0.5 cm margin for setup uncertainties. The dose escalation of BTV was scheduled to stratify into 4 prescription dose levels: level 1: 67.2 Gy in 28 fractions; level 2:70 Gy in 28 fractions; level 3:72.8 Gy in 28 fractions; and level 4:72 Gy in 24 fractions. The prescription dose in both MTV and CTV1 was the same, being 58.8 Gy in 28 fractions for level 1–3, and 60 Gy in 24 fractions for level 4. The CTV2 dose was 50.4 Gy in 28 fractions for level 1–3 and 50.4 Gy in 24 fractions for level 4. The size of BTV ranged from 3.1 to 163.6 cc (median 17.1 cc), with 3 patients in level 1, 4 in level 2, 6 in level 3, and 5 in level 4. Treatment planning was performed using the NOMOS Peacock/Corvus system and treatment delivered using a mini-multileaf collimator (MIMiC). The radiation was given 1 fraction per day and 5 days per week. The primary endpoint of the study was acute toxicity. If toxicity was acceptable, dose escalation was planned to go along. Patients were followed every 3 months by clinical examination and MRI or MET-PET/CT after completing IMRT. Median survival time was calculated as a secondary endpoint. ResultsAll patients successfully completed the treatment without interruption. Seventeen (94%) patients had acceptable toxicity (grade 0 in 2, grade 1 in 1, grade 2 in 14). Only one (6%) patient in the dose level 3 developed reversible grade 3 toxicity. The median overall survival time for all patients was 13.0 months (95% CI: 8.1 to 17.8). The median progress-free survival time was 6.8 months (95% CI: 4.6 to 9.0). The 1- and 2-year actuarial survival rates were 59.5% and 21.4%, respectively. The 1- and 2-year progress-free survival rates were 18.1% and 9.0%, respectively. All patients successfully completed the treatment without interruption. Seventeen (94%) patients had acceptable toxicity (grade 0 in 2, grade 1 in 1, grade 2 in 14). Only one (6%) patient in the dose level 3 developed reversible grade 3 toxicity. The median overall survival time for all patients was 13.0 months (95% CI: 8.1 to 17.8). The median progress-free survival time was 6.8 months (95% CI: 4.6 to 9.0). The 1- and 2-year actuarial survival rates were 59.5% and 21.4%, respectively. The 1- and 2-year progress-free survival rates were 18.1% and 9.0%, respectively. ConclusionsEscalating dose to BTV with 72 Gy in 24 fractions using IMRT for the patients with resected supratentorial high grade gliomas is safe and feasible. Further dose escalation may be investigated. Escalating dose to BTV with 72 Gy in 24 fractions using IMRT for the patients with resected supratentorial high grade gliomas is safe and feasible. Further dose escalation may be investigated.