A phase I dose-escalation study (ISIDE-BT-1) of accelerated IMRT with temozolomide in patients with glioblastoma.
OBJECTIVE
To determine the maximum tolerated dose (MTD) of fractionated intensity-modulated radiotherapy (IMRT) with temozolomide (TMZ) in patients with glioblastoma.


METHODS
A Phase I clinical trial was performed. Eligible patients had surgically resected or biopsy-proven glioblastoma. Patients started TMZ (75 mg/day) during IMRT and continued for 1 year (150-200 mg/day, Days 1-5 every 28 days) or until disease progression. Clinical target volume 1 (CTV1) was the tumor bed +/- enhancing lesion with a 10-mm margin; CTV2 was the area of perifocal edema with a 20-mm margin. Planning target volume 1 (PTV1) and PTV2 were defined as the corresponding CTV plus a 5-mm margin. IMRT was delivered in 25 fractions over 5 weeks. Only the dose for PTV1 was escalated (planned dose escalation: 60 Gy, 62.5 Gy, 65 Gy) while maintaining the dose for PTV2 (45 Gy, 1.8 Gy/fraction). Dose limiting toxicities (DLT) were defined as any treatment-related nonhematological adverse effects rated as Grade >or=3 or any hematological toxicity rated as >or=4 by Radiation Therapy Oncology Group (RTOG) criteria.


RESULTS
Nineteen consecutive glioblastoma were treated with step-and-shoot IMRT, planned with the inverse approach (dose to the PTV1: 7 patients, 60 Gy; 6 patients, 62.5 Gy; 6 patients, 65 Gy). Five coplanar beams were used to cover at least 95% of the target volume with the 95% isodose line. Median follow-up time was 23 months (range, 8-40 months). No patient experienced DLT. Grade 1-2 treatment-related neurologic and skin toxicity were common (11 and 19 patients, respectively). No Grade >2 late neurologic toxicities were noted.


CONCLUSIONS
Accelerated IMRT to a dose of 65 Gy in 25 fractions is well tolerated with TMZ at a daily dose of 75 mg.
Morganti
Alessio G
AG
Department of Radiotherapy, John Paul II Center for High Technology Research and Education in Biomedical Sciences, Catholic University, Campobasso, Italy.
Balducci
Mario
M
Salvati
Maurizio
M
Esposito
Vincenzo
V
Romanelli
Pantaleo
P
Ferro
Marica
M
Calista
Franco
F
Digesù
Cinzia
C
Macchia
Gabriella
G
Ianiri
Massimo
M
Deodato
Francesco
F
Cilla
Savino
S
Piermattei
Angelo
A
Valentini
Vincenzo
V
Cellini
Numa
N
Cantore
Gian Paolo
GP
D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000009:adverse effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D019583:Dose Fractionation, Radiation; D004334:Drug Administration Schedule; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011446:Prospective Studies; D050397:Radiotherapy, Intensity-Modulated / Q000379:methods*; D000077204:Temozolomide; D047368:Tumor Burden
D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D000077204:Temozolomide